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Zhang Z, Wang X, Zhao C, Zhu H, Liao X, Tsai HI. STING and metabolism-related diseases: Roles, mechanisms, and applications. Cell Signal 2025; 132:111833. [PMID: 40294833 DOI: 10.1016/j.cellsig.2025.111833] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2025] [Revised: 04/08/2025] [Accepted: 04/22/2025] [Indexed: 04/30/2025]
Abstract
The stimulator of interferon genes (STING) pathway plays a critical role in innate immunity, acting as a central mediator that links cytosolic DNA sensing to inflammatory signaling. STING not only responds to cellular metabolic states but also actively regulates key metabolic processes, including glycolysis, lipid metabolism, and redox balance. This bidirectional interaction underscores the existence of a dynamic feedback mechanism between STING signaling and metabolic pathways, which is essential for maintaining cellular homeostasis. This review provides a comprehensive analysis, beginning with an in-depth overview of the classical STING signaling pathway, followed by a detailed examination of its reciprocal regulation of various metabolic pathways. Additionally, it explores the role and mechanisms of STING signaling in metabolic disorders, including obesity, diabetes, and atherosclerosis. By integrating these insights into the mutual regulation between STING and its metabolism, novel therapeutic strategies targeting this pathway in metabolic diseases have been proposed.
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Affiliation(s)
- Zhengyang Zhang
- Institute of Medical Imaging and Artificial Intelligence, Jiangsu University, Zhenjiang 212001, China; School of Medicine, Jiangsu University, Zhenjiang 212013, China
| | - Xirui Wang
- Department of Biomedical Engineering, School of Medical Imaging, Xuzhou Medical University, Xuzhou 221000, China
| | - Chuangchuang Zhao
- Institute of Medical Imaging and Artificial Intelligence, Jiangsu University, Zhenjiang 212001, China; School of Medicine, Jiangsu University, Zhenjiang 212013, China
| | - Haitao Zhu
- Institute of Medical Imaging and Artificial Intelligence, Jiangsu University, Zhenjiang 212001, China; Department of Medical Imaging, The Affiliated Hospital of Jiangsu University, Zhenjiang 212001, China
| | - Xiang Liao
- Institute of Medical Imaging and Artificial Intelligence, Jiangsu University, Zhenjiang 212001, China.
| | - Hsiang-I Tsai
- Institute of Medical Imaging and Artificial Intelligence, Jiangsu University, Zhenjiang 212001, China; Department of Medical Imaging, The Affiliated Hospital of Jiangsu University, Zhenjiang 212001, China.
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Yang C, Chai X, Wang Y, Li D, Zhu D, Liang K, Wang J, Yang Z, Gong Q, Zhang J, Shao R. Atherogenic lipid parameters in people with normal glucose tolerance: implications from elevated 1-hour post-load plasma glucose. Cardiovasc Diabetol 2025; 24:207. [PMID: 40369580 PMCID: PMC12079842 DOI: 10.1186/s12933-025-02722-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2025] [Accepted: 04/02/2025] [Indexed: 05/16/2025] Open
Abstract
BACKGROUND Existing evidence suggests that elevated 1-hour post-load plasma glucose (1-h PG ≥ 8.6 mmol/L) during an oral glucose tolerance test (OGTT) is associated with atherogenic lipid parameters which are linked to an increased risk of cardiovascular disease (CVD). However, it remains unclear whether normal glucose tolerance (NGT) individuals with elevated 1-h PG (NGT-1hPG-high) should still be considered low-risk. Therefore, this study aims to demonstrate comprehensive lipid characteristics in individuals with different glycemic status stratified by 1-h PG, with a particular focus on those with NGT-1hPG-high. METHODS This cross-sectional study included individuals aged 25-55 years with high-risk of diabetes from the Daqing Diabetes Prevention Study II (Daqing DPS-II). Individuals were categorized into different glycemic status based on the World Health Organization's 1999 criteria and the International Diabetes Federation's 2024 position statement on 1-h PG. Traditional (TC, TG, HDL-C, LDL-C) and non-traditional lipid parameters [ApoA-1, ApoB, sdLDL-C, Lp(a), non-HDL-C, remnant cholesterol (RC), ApoB/ApoA-1, LDL-C/ApoB] were measured. Dyslipidemia was defined according to the 2023 Chinese Guidelines for Lipid Management. The China-PAR equation was used to estimate 10-year CVD risk. Spearman's correlation coefficients were calculated to evaluate the correlation between lipid parameters and 10-year CVD risk. Logistic and multiple linear regression models were performed to assess the association between 1-h PG and dyslipidemia as well as lipid parameters adjusting for covariates. RESULTS Among 2 469 individuals, 22.7% had NGT with normal 1-h PG (NGT-1hPG-normal), 19.9% had NGT-1hPG-high, 2.6% had prediabetes with normal 1-h PG (PDM-1hPG-normal), 34.2% had prediabetes with elevated 1-h PG (PDM-1hPG-high), and 20.6% had newly diagnosed diabetes. The prevalence of dyslipidemia did not significantly differ between NGT-1hPG-high and PDM-1hPG-high (OR = 1.13, 95%CI: 0.88-1.44, P > 0.05). Higher 1-h PG levels were consistently associated with an atherogenic lipid profile, characterized by increased TC, TG, LDL-C, ApoB, sdLDL-C, non-HDL-C, RC and ApoB/ApoA-1, along with decreased ApoA-1, HDL-C and LDL-C/ApoB (all P < 0.05). Among lipid parameters, TG, sdLDL-C, RC, ApoB/ApoA-1, LDL-C/ApoB and HDL-C showed the strongest correlation with 10-year CVD risk, with Spearman's correlation coefficients of 0.41, 0.38, 0.35, 0.31, - 0.37 and - 0.36, respectively. In the NGT-1hPG-high, TG, sdLDL-C, and ApoB/ApoA-1 levels were significantly higher, while HDL-C and LDL-C/ApoB levels were significantly lower compared to counterparts with NGT-1hPG-normal (all P < 0.05). Moreover, except for TG and RC (both P < 0.01), the majority of lipid parameter levels in NGT-1hPG-high did not significantly differ from those in PDM (all P > 0.05). CONCLUSIONS NGT-1hPG-high exhibited a similar atherogenic lipid profile to that observed in PDM. 1-h PG could serve as a potential indicator for the early identification of at-risk individuals who may otherwise go undetected among NGT population.
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Affiliation(s)
- Chunyu Yang
- School of Population Medicine and Public Health, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730, China
| | - Xin Chai
- School of Population Medicine and Public Health, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730, China
| | - Yachen Wang
- School of Population Medicine and Public Health, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730, China
| | - Di Li
- Daqing Oilfield General Hospital (Daqing First Hospital), Daqing, 163000, China
| | - Dongli Zhu
- Daqing Oilfield General Hospital (Daqing First Hospital), Daqing, 163000, China
| | - Kaipeng Liang
- School of Population Medicine and Public Health, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730, China
| | - Jinping Wang
- Daqing Oilfield General Hospital (Daqing First Hospital), Daqing, 163000, China
| | - Zhiwei Yang
- Daqing Oilfield General Hospital (Daqing First Hospital), Daqing, 163000, China
| | - Qiuhong Gong
- Center of Endocrinology, National Center of Cardiology & Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, China
| | - Juan Zhang
- School of Population Medicine and Public Health, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730, China.
| | - Ruitai Shao
- School of Population Medicine and Public Health, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730, China
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Armato J, DeFronzo RA, Abdul-Ghani M, Ruby R. Pre-Prediabetes: Insulin Resistance Is Associated With Cardiometabolic Risk in Nonobese Patients (STOP DIABETES). J Clin Endocrinol Metab 2025; 110:e1481-e1487. [PMID: 39109850 DOI: 10.1210/clinem/dgae540] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2024] [Indexed: 04/24/2025]
Abstract
CONTEXT Prior studies have demonstrated glycemic and cardiometabolic risk in the prediabetic state. OBJECTIVE This work aims to examine if insulin resistance (IR) is associated with markers of glycemic, cardiometabolic, and atherosclerotic risk in nonobese, nonprediabetic individuals compared to insulin-sensitive (IS) individuals matched for body mass index (BMI), sex, and age. METHODS Of 1860 patients from the STOP DIABETES study, 624 had normal fasting plasma glucose, BMI less than 30, and glycated hemoglobin A1c (HbA1c) less than 5.7%. All received an oral glucose tolerance test. Insulin sensitivity was quantitated using the Matsuda index: less than the 25th percentile equals IR (n = 151) and 25th percentile or greater equals IS (n = 473). Measures of dysglycemia and cardiometabolic risk were compared between IR individuals (n = 151) and a subset of IS individuals who were matched for BMI, sex, and age (n = 151). Carotid intima media thickness and carotid plaque were measured in 65 IR and 76 IS individuals. RESULTS Compared to matched IS patients, IR nonobese individuals demonstrated increased indicators of glycemic and cardiometabolic risk, including increased 60-minute plasma glucose and percentage of patients with 60-minute plasma glucose greater than 155 mg/dL; increased 120-minute plasma glucose; unrecognized impaired glucose tolerance and type 2 diabetes, decreased disposition index; increased systolic and diastolic blood pressure; elevated plasma triglycerides (TGs); reduced high-density lipoprotein (HDL) cholesterol; increased TGs/HDL ratio, and high-sensitivity C-reactive protein. The presence, size, and number of carotid plaques was greater in the IR group. CONCLUSION Approximately 1 in 4 nonobese patients in this population with normal fasting glucose and HbA1c were IR. In these nonobese participants, IR was associated with multiple indicators of dysglycemia and cardiometabolic risk.
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Affiliation(s)
- John Armato
- Providence Little Company of Mary Cardiometabolic Center, Providence Medical Associates, Torrance, CA 90503, USA
| | - Ralph A DeFronzo
- Diabetes Division, University of Texas Health Science Center and Texas Diabetes Institute, San Antonio, TX 78207, USA
| | - Muhammad Abdul-Ghani
- Diabetes Division, University of Texas Health Science Center and Texas Diabetes Institute, San Antonio, TX 78207, USA
| | - Ron Ruby
- Providence Little Company of Mary Cardiometabolic Center, Providence Medical Associates, Torrance, CA 90503, USA
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Ježek P. Physiological Fatty Acid-Stimulated Insulin Secretion and Redox Signaling Versus Lipotoxicity. Antioxid Redox Signal 2025; 42:566-622. [PMID: 39834189 DOI: 10.1089/ars.2024.0799] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/22/2025]
Abstract
Significance: Type 2 diabetes as a world-wide epidemic is characterized by the insulin resistance concomitant to a gradual impairment of β-cell mass and function (prominently declining insulin secretion) with dysregulated fatty acids (FAs) and lipids, all involved in multiple pathological development. Recent Advances: Recently, redox signaling was recognized to be essential for insulin secretion stimulated with glucose (GSIS), branched-chain keto-acids, and FAs. FA-stimulated insulin secretion (FASIS) is a normal physiological event upon postprandial incoming chylomicrons. This contrasts with the frequent lipotoxicity observed in rodents. Critical Issues: Overfeeding causes FASIS to overlap with GSIS providing repeating hyperinsulinemia, initiates prediabetic states by lipotoxic effects and low-grade inflammation. In contrast the protective effects of lipid droplets in human β-cells counteract excessive lipids. Insulin by FASIS allows FATP1 recruitment into adipocyte plasma membranes when postprandial chylomicrons come late at already low glycemia. Future Directions: Impaired states of pancreatic β-cells and peripheral organs at prediabetes and type 2 diabetes should be revealed, including the inter-organ crosstalk by extracellular vesicles. Details of FA/lipid molecular physiology are yet to be uncovered, such as complex phenomena of FA uptake into cells, postabsorptive inactivity of G-protein-coupled receptor 40, carnitine carrier substrate specificity, the role of carnitine-O-acetyltransferase in β-cells, and lipid droplet interactions with mitochondria. Antioxid. Redox Signal. 42, 566-622.
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Affiliation(s)
- Petr Ježek
- Department of Mitochondrial Physiology, No.75, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic
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Lin Y, McCrimmon RJ, Pearson ER. Exploring the potential role of C-peptide in type 2 diabetes management. Diabet Med 2025; 42:e15469. [PMID: 39797595 PMCID: PMC11823364 DOI: 10.1111/dme.15469] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2024] [Revised: 09/26/2024] [Accepted: 09/29/2024] [Indexed: 01/13/2025]
Abstract
Type 2 diabetes (T2D) is a complex condition characterised by the interaction between insulin resistance and beta cell dysfunction. C-peptide, a key biomarker of endogenous insulin secretion, has a role in diagnosing type 1 diabetes (T1D). However, its utility in T2D has not been extensively studied. This review provides an overview of the progression of C-peptide levels over time in T2D and discuss its interpretation in clinical settings. We reviewed current evidence on the relationship between C-peptide levels and response to antidiabetic drugs, as well as the utility of C-peptide testing in T2D treatment strategies. We also reviewed available evidence for C-peptide in predicting future outcomes in T2D. In this review, we hoped to clarify the value of C-peptide testing in understanding and managing T2D and to highlight areas where further research is needed.
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Affiliation(s)
- YeunYi Lin
- School of MedicineUniversity of Dundee, Ninewells Hospital & Medical SchoolDundeeScotland
| | - Rory J. McCrimmon
- School of MedicineUniversity of Dundee, Ninewells Hospital & Medical SchoolDundeeScotland
| | - Ewan R. Pearson
- School of MedicineUniversity of Dundee, Ninewells Hospital & Medical SchoolDundeeScotland
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Gong T, Wang D, Wang J, Huang Q, Zhang H, Liu C, Liu X, Ye H. Study on the mechanism of plant metabolites to intervene oxidative stress in diabetic retinopathy. Front Pharmacol 2025; 16:1517964. [PMID: 39974734 PMCID: PMC11835683 DOI: 10.3389/fphar.2025.1517964] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2024] [Accepted: 01/14/2025] [Indexed: 02/21/2025] Open
Abstract
Diabetic retinopathy is the main microvascular complication of diabetes and the first blinding eye disease in the working-age population. Oxidative stress is an important pathogenesis of diabetic retinopathy. Plant metabolites can be divided into two types: primary metabolites and secondary metabolites, secondary metabolites are the main active components and important sources for developing new drugs. It has unique effect in the treatment of diabetic retinopathy. However, the research on the intervention mechanism of plant metabolites in diabetic retinopathy are still relatively shallow, which limit the application of plant metabolites. With the deepening of research, more and more plant metabolites have been reported to play a role in treating diabetic retinopathy through anti-oxidative stress, including polyphenols, polysaccharides, saponins, alkaloids, etc. Therefore, this article reviewed the potential of plant metabolites in the treatment of diabetic retinopathy in the last 10 years and elucidated their mechanism of action. We hope to provide some references for the application of plant metabolites and provide valuable resources for the research and development of new drugs for diabetic retinopathy.
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Affiliation(s)
- Tianyao Gong
- Eye School of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Dongmei Wang
- Eye School of Chengdu University of Traditional Chinese Medicine, Chengdu, China
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Jinyan Wang
- Eye School of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Qun Huang
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Haiyan Zhang
- Eye School of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Chunmeng Liu
- Eye School of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xinglin Liu
- School of Management, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Hejiang Ye
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
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Correa-da-Silva F, Yi CX. Neuroglia in eating disorders (obesity, Prader-Willi syndrome and anorexia nervosa). HANDBOOK OF CLINICAL NEUROLOGY 2025; 210:313-324. [PMID: 40148052 DOI: 10.1016/b978-0-443-19102-2.00019-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/29/2025]
Abstract
The hypothalamus is widely recognized as one of the most extensively studied brain regions involved in the central regulation of energy homeostasis. Within the hypothalamus, peptidergic neurons play a crucial role in monitoring peripheral concentrations of metabolites and hormones, and they finely adjust the sensing of these factors, leading to the activation of either anorexigenic (appetite-suppressing) or orexigenic (appetite-stimulating) pathways. While cortical innervation of the hypothalamus does influence these processes, it is generally considered of secondary importance. Eating-related disorders, such as obesity and anorexia nervosa, are strongly associated with imbalances in energy intake and expenditure. The phenotypes of these disorders can be attributed to dysfunctions in the hypothalamus. Traditionally, it has been believed that hypothalamic dysfunction in these disorders primarily stems from defects in neural pathways. However, recent evidence challenges this perception, highlighting the active participation of neuroglial cells in shaping both physiologic and behavioral characteristics. This review aims to provide an overview of the latest insights into glial biology in three specific eating disorders: obesity, Prader-Willi syndrome, and anorexia. In these disorders, neural dysfunction coincides with glial malfunction, suggesting that neuroglia actively contribute to the development and progression of various neurologic disorders. These findings underscore the importance of glial cells and open up potential new avenues for therapeutic interventions.
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Affiliation(s)
- Felipe Correa-da-Silva
- Department of Endocrinology and Metabolism, Amsterdam Gastroenterology Endocrinology and Metabolism, Amsterdam University Medical Center (UMC), University of Amsterdam, Amsterdam, The Netherlands; Laboratory of Endocrinology, Amsterdam University Medical Center (UMC), University of Amsterdam, Amsterdam, The Netherlands; Netherlands Institute for Neuroscience, Amsterdam, The Netherlands
| | - Chun-Xia Yi
- Department of Endocrinology and Metabolism, Amsterdam Gastroenterology Endocrinology and Metabolism, Amsterdam University Medical Center (UMC), University of Amsterdam, Amsterdam, The Netherlands; Laboratory of Endocrinology, Amsterdam University Medical Center (UMC), University of Amsterdam, Amsterdam, The Netherlands; Netherlands Institute for Neuroscience, Amsterdam, The Netherlands.
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Masrouri S, Tamehri Zadeh SS, Tohidi M, Azizi F, Hadaegh F. Linking extent of return to fasting state after oral glucose tolerance test to future risk of prediabetes and type 2 diabetes: Insights from the TLGS. J Diabetes Investig 2024; 15:1743-1752. [PMID: 39344286 PMCID: PMC11615687 DOI: 10.1111/jdi.14308] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Revised: 08/16/2024] [Accepted: 08/26/2024] [Indexed: 10/01/2024] Open
Abstract
AIMS To assess the risk of difference between 2 h post-load plasma glucose (2 h-PG) and fasting plasma glucose (FPG) on incident prediabetes/type 2 diabetes (T2DM) among normoglycemic individuals. METHODS Among 4,971 individuals aged ≥20 years, the associations of the difference between 2 h-PG and FPG with outcomes were examined using multivariable-adjusted Cox regression analysis. Participants were categorized into three groups: a low post-load group (2 h-PG ≤ FPG, as the reference group); a high post-load group (2 h-PG > FPG and ≥75th percentile of the difference); and a medium post-load group (2 h-PG > FPG and <75th percentile of the difference), which was further categorized into three groups by equal ranges. RESULTS Over a median of 11.5 years of follow-up, 2,331 new cases of prediabetes/type 2 diabetes and 360 cases of type 2 diabetes occurred. Greater risks of incident prediabetes/type 2 diabetes in second (9-16 mg/dL) and third (17-24 mg/dL) medium post-load, as well as high post-load (≥25 mg/dL) categories, were found, with hazard ratios (95% confidence intervals) of 1.26 (1.11-1.44), 1.32 (1.15-1.51), and 1.69 (1.51-1.90), respectively; the issue was more prominent among women (P for interaction = 0.005). The risk of incident type 2 diabetes was also higher for these categories. After further adjustment for the homeostasis model assessment of insulin resistance, result remained essentially unchanged. Even among individuals with low normal FPG (i.e., <90 mg/dL), ≥9 mg/dL difference between 2 h-PG and FPG increased the risk of composite prediabetes/ type 2 diabetes. CONCLUSIONS Greater levels of 2 h-PG as low as 9 mg/dL than FPG among normoglycemic individuals is a harbinger of prediabetes/type 2 diabetes development.
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Affiliation(s)
- Soroush Masrouri
- Prevention of Metabolic Disorders Research Center, Research Institute for Endocrine SciencesShahid Beheshti University of Medical SciencesTehranIran
| | - Seyed Saeed Tamehri Zadeh
- Prevention of Metabolic Disorders Research Center, Research Institute for Endocrine SciencesShahid Beheshti University of Medical SciencesTehranIran
| | - Maryam Tohidi
- Prevention of Metabolic Disorders Research Center, Research Institute for Endocrine SciencesShahid Beheshti University of Medical SciencesTehranIran
| | - Fereidoun Azizi
- Endocrine Research Center, Research Institute for Endocrine SciencesShahid Beheshti University of Medical SciencesTehranIran
| | - Farzad Hadaegh
- Prevention of Metabolic Disorders Research Center, Research Institute for Endocrine SciencesShahid Beheshti University of Medical SciencesTehranIran
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Mather KJ, Mari A, Heise T, DeVries JH, Hua M, Urva S, Coskun T, Haupt A, Heine RJ, Pratt E, Thomas MK, Milicevic Z. Effects of Tirzepatide vs Semaglutide on β-Cell Function, Insulin Sensitivity, and Glucose Control During a Meal Test. J Clin Endocrinol Metab 2024; 109:3046-3054. [PMID: 38795393 DOI: 10.1210/clinem/dgae319] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2024] [Revised: 04/16/2024] [Accepted: 05/06/2024] [Indexed: 05/27/2024]
Abstract
CONTEXT In a clinical study, tirzepatide, a glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 receptor agonist (GIP/GLP-1RA), provided superior glycemic control vs the GLP-1RA semaglutide. The physiologic mechanisms are incompletely understood. OBJECTIVE This work aimed to evaluate treatment effects by model-based analyses of mixed-meal tolerance test (MMTT) data. METHODS A 28-week double-blind, randomized, placebo-controlled trial of patients with type 2 diabetes treated with metformin was conducted at 2 clinical research centers in Germany. Interventions included tirzepatide 15 mg, semaglutide 1 mg, and placebo. Main outcome measures included glycemic control, model-derived β-cell function indices including insulin secretion rate (ISR) at 7.2-mmol/L glucose (ISR7.2), β-cell glucose sensitivity (β-CGS), insulin sensitivity, and estimated hepatic insulin-to-glucagon ratio. RESULTS Tirzepatide significantly reduced fasting glucose and MMTT total glucose area under the curve (AUC) vs semaglutide (P < .01). Incremental glucose AUC did not differ significantly between treatments; therefore, greater total glucose AUC reduction with tirzepatide was mainly attributable to greater suppression of fasting glucose. A greater reduction in total ISR AUC was achieved with tirzepatide vs semaglutide (P < .01), in the context of greater improvement in insulin sensitivity with tirzepatide (P < .01). ISR7.2 was significantly increased with tirzepatide vs semaglutide (P < .05), showing improved β-CGS. MMTT-derived β-CGS was increased but not significantly different between treatments. Both treatments reduced fasting glucagon and total glucagon AUC, with glucagon AUC significantly reduced with tirzepatide vs semaglutide (P < .01). The estimated hepatic insulin-to-glucagon ratio did not change substantially with either treatment. CONCLUSION These results suggest that the greater glycemic control observed for tirzepatide manifests as improved fasting glucose and glucose excursion control, due to improvements in ISR, insulin sensitivity, and glucagon suppression.
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Affiliation(s)
- Kieren J Mather
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA
| | - Andrea Mari
- Institute of Neuroscience, National Research Council, 2-35122 Padua, Italy
| | - Tim Heise
- Profil Institute for Metabolic Research, 41460 Neuss, Germany
| | - J Hans DeVries
- Profil Institute for Metabolic Research, 41460 Neuss, Germany
| | - Ming Hua
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA
| | - Shweta Urva
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA
| | - Tamer Coskun
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA
| | - Axel Haupt
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA
| | - Robert J Heine
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA
| | - Edward Pratt
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA
| | - Melissa K Thomas
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA
| | - Zvonko Milicevic
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA
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10
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Tura A, Göbl C, El-Tanani M, Rizzo M. In-silico modelling of insulin secretion and pancreatic beta-cell function for clinical applications: is it worth the effort? FRONTIERS IN CLINICAL DIABETES AND HEALTHCARE 2024; 5:1452400. [PMID: 39559404 PMCID: PMC11570995 DOI: 10.3389/fcdhc.2024.1452400] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Accepted: 08/29/2024] [Indexed: 11/20/2024]
Affiliation(s)
- Andrea Tura
- CNR Institute of Neuroscience, Padova, Italy
| | - Christian Göbl
- Department of Obstetrics and Gynecology, Medical University of Vienna, Vienna, Austria
- Department of Obstetrics and Gynecology, Medical University of Graz, Graz, Austria
| | - Mohamed El-Tanani
- College of Pharmacy, Ras Al Khaimah Medical and Health Sciences University, Ras Al Khaimah, United Arab Emirates
| | - Manfredi Rizzo
- School of Medicine, Mohammed Bin Rashid University, Dubai, United Arab Emirates
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, School of Medicine, University of Palermo, Palermo, Italy
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Lu X, Xie Q, Pan X, Zhang R, Zhang X, Peng G, Zhang Y, Shen S, Tong N. Type 2 diabetes mellitus in adults: pathogenesis, prevention and therapy. Signal Transduct Target Ther 2024; 9:262. [PMID: 39353925 PMCID: PMC11445387 DOI: 10.1038/s41392-024-01951-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Revised: 07/21/2024] [Accepted: 08/06/2024] [Indexed: 10/03/2024] Open
Abstract
Type 2 diabetes (T2D) is a disease characterized by heterogeneously progressive loss of islet β cell insulin secretion usually occurring after the presence of insulin resistance (IR) and it is one component of metabolic syndrome (MS), and we named it metabolic dysfunction syndrome (MDS). The pathogenesis of T2D is not fully understood, with IR and β cell dysfunction playing central roles in its pathophysiology. Dyslipidemia, hyperglycemia, along with other metabolic disorders, results in IR and/or islet β cell dysfunction via some shared pathways, such as inflammation, endoplasmic reticulum stress (ERS), oxidative stress, and ectopic lipid deposition. There is currently no cure for T2D, but it can be prevented or in remission by lifestyle intervention and/or some medication. If prevention fails, holistic and personalized management should be taken as soon as possible through timely detection and diagnosis, considering target organ protection, comorbidities, treatment goals, and other factors in reality. T2D is often accompanied by other components of MDS, such as preobesity/obesity, metabolic dysfunction associated steatotic liver disease, dyslipidemia, which usually occurs before it, and they are considered as the upstream diseases of T2D. It is more appropriate to call "diabetic complications" as "MDS-related target organ damage (TOD)", since their development involves not only hyperglycemia but also other metabolic disorders of MDS, promoting an up-to-date management philosophy. In this review, we aim to summarize the underlying mechanism, screening, diagnosis, prevention, and treatment of T2D, especially regarding the personalized selection of hypoglycemic agents and holistic management based on the concept of "MDS-related TOD".
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Affiliation(s)
- Xi Lu
- Department of Endocrinology and Metabolism, Research Centre for Diabetes and Metabolism, West China Hospital, Sichuan University, Chengdu, China
| | - Qingxing Xie
- Department of Endocrinology and Metabolism, Research Centre for Diabetes and Metabolism, West China Hospital, Sichuan University, Chengdu, China
| | - Xiaohui Pan
- Department of Endocrinology and Metabolism, Research Centre for Diabetes and Metabolism, West China Hospital, Sichuan University, Chengdu, China
| | - Ruining Zhang
- Department of Endocrinology and Metabolism, Research Centre for Diabetes and Metabolism, West China Hospital, Sichuan University, Chengdu, China
| | - Xinyi Zhang
- Department of Endocrinology and Metabolism, Research Centre for Diabetes and Metabolism, West China Hospital, Sichuan University, Chengdu, China
| | - Ge Peng
- Department of Endocrinology and Metabolism, Research Centre for Diabetes and Metabolism, West China Hospital, Sichuan University, Chengdu, China
| | - Yuwei Zhang
- Department of Endocrinology and Metabolism, Research Centre for Diabetes and Metabolism, West China Hospital, Sichuan University, Chengdu, China
| | - Sumin Shen
- Department of Endocrinology and Metabolism, Research Centre for Diabetes and Metabolism, West China Hospital, Sichuan University, Chengdu, China
| | - Nanwei Tong
- Department of Endocrinology and Metabolism, Research Centre for Diabetes and Metabolism, West China Hospital, Sichuan University, Chengdu, China.
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12
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Mohammadi S, Khorasani M. Implications of the cGAS-STING pathway in diabetes: Risk factors and therapeutic strategies. Int J Biol Macromol 2024; 278:134210. [PMID: 39069057 DOI: 10.1016/j.ijbiomac.2024.134210] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2024] [Revised: 07/20/2024] [Accepted: 07/25/2024] [Indexed: 07/30/2024]
Abstract
Diabetes mellitus is an increasingly prevalent metabolic disorder characterized by chronic hyperglycemia and impaired insulin action. Although the pathogenesis of diabetes is multifactorial, emerging evidence suggests that chronic low-grade inflammation plays a significant role in the development and progression of the disease. The cyclic GMP-AMP synthase (cGAS) and its downstream signaling pathway, the stimulator of interferon genes (STING), have recently gained attention in the field of diabetes research. This article aims to provide an overview of the role of cGAS-STING in diabetes, focusing on its involvement in the regulation of immune responses, inflammation, insulin resistance, and β-cell dysfunction. Understanding the contribution of cGAS-STING signaling in diabetes may lead to the development of targeted therapeutic strategies for this prevalent metabolic disorder. The results section presents key findings from multiple studies on the impact of STING in diabetes. It discusses the influence of STING on inflammation levels within a diabetic environment, its effect on insulin resistance, and its implications for the development and progression of diabetes. The cGAS-STING signaling pathway plays a crucial role in the development and progression of diabetes.
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Affiliation(s)
- Saeed Mohammadi
- Natural and Medical Sciences Research Center, University of Nizwa, 611, Oman
| | - Milad Khorasani
- Healthy Ageing Research Centre, Neyshabur University of Medical Sciences, Neyshabur, Iran; Department of Biochemistry and Nutrition, Neyshabur University of Medical Sciences, Neyshabur, Iran.
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13
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Abdul-Ghani M, Maffei P, DeFronzo RA. Managing insulin resistance: the forgotten pathophysiological component of type 2 diabetes. Lancet Diabetes Endocrinol 2024; 12:674-680. [PMID: 39098317 DOI: 10.1016/s2213-8587(24)00127-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2023] [Revised: 03/15/2024] [Accepted: 04/29/2024] [Indexed: 08/06/2024]
Abstract
Glucagon-like peptide-1 (GLP-1) receptor agonists have gained widespread use in the treatment of individuals with type 2 diabetes because of their potent weight loss promoting effect, ability to augment β-cell function, and cardiovascular protective effects. However, despite causing impressive weight loss, GLP-1 receptor agonists do not normalise insulin sensitivity in people with type 2 diabetes and obesity, and the long-term effects of this class of antidiabetic medication on muscle mass, frailty, and bone density have been poorly studied. Although GLP-1 receptor agonists improve insulin sensitivity secondary to weight loss, the only true direct insulin-sensitising drugs are thiazolidinediones. Because of side-effects associated with type 2 diabetes therapy, these drugs have not gained widespread use. In lieu of the important role of insulin resistance in the cause of type 2 diabetes and in the pathogenesis of atherosclerotic cardiovascular disease in type 2 diabetes, development of potent insulin-sensitising drugs that can be used in combination with GLP-1 receptor agonists remains a large unmet need in the management of individuals with type 2 diabetes.
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14
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Kanbay M, Copur S, Topçu AU, Guldan M, Ozbek L, Gaipov A, Ferro C, Cozzolino M, Cherney DZI, Tuttle KR. An update review of post-transplant diabetes mellitus: Concept, risk factors, clinical implications and management. Diabetes Obes Metab 2024; 26:2531-2545. [PMID: 38558257 DOI: 10.1111/dom.15575] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Revised: 03/09/2024] [Accepted: 03/09/2024] [Indexed: 04/04/2024]
Abstract
OBJECTIVE Kidney transplantation is the gold standard therapeutic alternative for patients with end-stage renal disease; nevertheless, it is not without potential complications leading to considerable morbidity and mortality such as post-transplant diabetes mellitus (PTDM). This narrative review aims to comprehensively evaluate PTDM in terms of its diagnostic approach, underlying pathophysiological pathways, epidemiological data, and management strategies. METHODS Articles were retrieved from electronic databases using predefined search terms. Inclusion criteria encompassed studies investigating PTDM diagnosis, pathophysiology, epidemiology, and management strategies. RESULTS PTDM emerges as a significant complication following kidney transplantation, influenced by various pathophysiological factors including peripheral insulin resistance, immunosuppressive medications, infections, and proinflammatory pathways. Despite discrepancies in prevalence estimates, PTDM poses substantial challenges to transplant. Diagnostic approaches, including traditional criteria such as fasting plasma glucose (FPG) and HbA1c, are limited in their ability to capture early PTDM manifestations. Oral glucose tolerance test (OGTT) emerges as a valuable tool, particularly in the early post-transplant period. Management strategies for PTDM remain unclear, within sufficient evidence from large-scale randomized clinical trials to guide optimal interventions. Nevertheless, glucose-lowering agents and life style modifications constitute primary modalities for managing hyperglycemia in transplant recipients. DISCUSSION The complex interplay between PTDM and the transplant process necessitates individualized diagnostic and management approaches. While early recognition and intervention are paramount, modifications to maintenance immunosuppressive regimens based solely on PTDM risk are not warranted, given the potential adverse consequences such as increased rejection risk. Further research is essential to refine management strategies and enhance outcomes for transplant recipients.
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Affiliation(s)
- Mehmet Kanbay
- Division of Nephrology, Department of Medicine, Koc University School of Medicine, Istanbul, Turkey
| | - Sidar Copur
- Department of Medicine, Koc University School of Medicine, Istanbul, Turkey
| | - A Umur Topçu
- Department of Medicine, Koc University School of Medicine, Istanbul, Turkey
| | - Mustafa Guldan
- Department of Medicine, Koc University School of Medicine, Istanbul, Turkey
| | - Lasin Ozbek
- Department of Medicine, Koc University School of Medicine, Istanbul, Turkey
| | - Abduzhappar Gaipov
- Department of Medicine, School of Medicine, Nazarbayev University, Astana, Kazakhstan
| | - Charles Ferro
- Department of Nephrology, University Hospitals Birmingham and Institute of Cardiovascular Sciences, University of Birmingham, Birmingham, UK
| | - Mario Cozzolino
- Department of Health Sciences, Renal Division, University of Milan, Milan, Italy
| | - David Z I Cherney
- Department of Medicine, Division of Nephrology, University Health Network, Toronto, Ontario, Canada
| | - Katherine R Tuttle
- Department of Medicine, Division of Nephrology, University of Washington, Seattle, Washington, USA
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15
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Moon JH, Choe HJ, Lim S. Pancreatic beta-cell mass and function and therapeutic implications of using antidiabetic medications in type 2 diabetes. J Diabetes Investig 2024; 15:669-683. [PMID: 38676410 PMCID: PMC11143426 DOI: 10.1111/jdi.14221] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2024] [Revised: 03/23/2024] [Accepted: 04/09/2024] [Indexed: 04/28/2024] Open
Abstract
Nowadays, the focus of diabetes treatment has switched from lowering the glucose level to preserving glycemic homeostasis and slowing the disease progression. The main pathophysiology of both type 1 diabetes and long-standing type 2 diabetes is pancreatic β-cell mass loss and dysfunction. According to recent research, human pancreatic β-cells possess the ability to proliferate in response to elevated insulin demands. It has been demonstrated that in insulin-resistant conditions in humans, such as obesity or pregnancy, the β-cell mass increases. This ability could be helpful in developing novel treatment approaches to restore a functional β-cell mass. Treatment strategies aimed at boosting β-cell function and mass may be a useful tool for managing diabetes mellitus and stopping its progression. This review outlines the processes of β-cell failure and detail the many β-cell abnormalities that manifest in people with diabetes mellitus. We also go over standard techniques for determining the mass and function of β-cells. Lastly, we provide the therapeutic implications of utilizing antidiabetic drugs in controlling the mass and function of pancreatic β-cells.
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Affiliation(s)
- Joon Ho Moon
- Department of Internal MedicineSeoul National University College of MedicineSeongnamSouth Korea
- Department of Internal MedicineSeoul National University Bundang HospitalSeongnamSouth Korea
| | - Hun Jee Choe
- Department of Internal MedicineHallym University Dongtan Sacred Heart HospitalHwaseongSouth Korea
| | - Soo Lim
- Department of Internal MedicineSeoul National University College of MedicineSeongnamSouth Korea
- Department of Internal MedicineSeoul National University Bundang HospitalSeongnamSouth Korea
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16
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Ho JPY, Lau ESH, Kwan O C, Fan B, Ko GTC, Kong APS, Ma RCW, Chow EYK, Chan JCN, Luk AOY. One-hour post-load plasma glucose level predicts future type 2 diabetes in a community-based study of Hong Kong Chinese workforce. Diabetes Res Clin Pract 2024; 212:111718. [PMID: 38796080 DOI: 10.1016/j.diabres.2024.111718] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Revised: 05/08/2024] [Accepted: 05/19/2024] [Indexed: 05/28/2024]
Abstract
BACKGROUND We compared performance of high 1-hour PG level, impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) in predicting type 2 diabetes in a longitudinal community-based cohort of Hong Kong Chinese. METHODS Between 2001 and 2003, 472 adults aged 18-55 years without diabetes underwent 75-gram oral glucose tolerance test (OGTT). Between 2012 and 2014, progression to diabetes was ascertained by reviewing medical records or repeating OGTT and HbA1c. We defined high 1-hour PG as PG ≥ 8.6 mmol/L at 1-hour. RESULTS In this cohort, 23.5% had normal glucose tolerance and high 1-hour PG, 10.0% had isolated IGT, 4.2% had isolated IFG. Over 12-year follow-up, 9.3% developed type 2 diabetes. In logistic regression, high 1-hour PG was associated with progression to type 2 diabetes with adjusted odds ratio (95% CI) of 4.20 (1.60, 12.40), independent of IFG, IGT and other clinical variables. Areas under ROC (95% CI) for type 2 diabetes were similar between 1-hour (0.84 [0.78, 0.89], 2-hour (0.79 [0.72, 0.86]) and fasting PG (0.79 [0.71, 0.86]). CONCLUSION High 1-hour PG identified young Chinese with 5-fold increased risk of type 2 diabetes independent of other intermediate hyperglycaemia status and clinical factors. 1-hour PG is similar to fasting and 2-hour PG in predicting type 2 diabetes.
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Affiliation(s)
- Jane Pui-Ying Ho
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong Special Administrative Region
| | - Eric Siu-Him Lau
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong Special Administrative Region
| | - Chun Kwan O
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong Special Administrative Region
| | - Baoqi Fan
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong Special Administrative Region
| | - Gary Tin-Choi Ko
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong Special Administrative Region
| | - Alice Pik-Shan Kong
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong Special Administrative Region; Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong Special Administrative Region; Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Hong Kong Special Administrative Region
| | - Ronald Ching-Wan Ma
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong Special Administrative Region; Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong Special Administrative Region; Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Hong Kong Special Administrative Region
| | - Elaine Yee-Kwan Chow
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong Special Administrative Region; Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong Special Administrative Region; Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Hong Kong Special Administrative Region
| | - Juliana Chung-Ngor Chan
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong Special Administrative Region; Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong Special Administrative Region; Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Hong Kong Special Administrative Region
| | - Andrea On-Yan Luk
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong Special Administrative Region; Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong Special Administrative Region; Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Hong Kong Special Administrative Region.
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17
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Bergman M, Manco M, Satman I, Chan J, Schmidt MI, Sesti G, Vanessa Fiorentino T, Abdul-Ghani M, Jagannathan R, Kumar Thyparambil Aravindakshan P, Gabriel R, Mohan V, Buysschaert M, Bennakhi A, Pascal Kengne A, Dorcely B, Nilsson PM, Tuomi T, Battelino T, Hussain A, Ceriello A, Tuomilehto J. International Diabetes Federation Position Statement on the 1-hour post-load plasma glucose for the diagnosis of intermediate hyperglycaemia and type 2 diabetes. Diabetes Res Clin Pract 2024; 209:111589. [PMID: 38458916 DOI: 10.1016/j.diabres.2024.111589] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/10/2024]
Abstract
Many individuals with intermediate hyperglycaemia (IH), including impaired fasting glycaemia (IFG) and impaired glucose tolerance (IGT), as presently defined, will progress to type 2 diabetes (T2D). There is confirmatory evidence that T2D can be prevented by lifestyle modification and/or medications, in people with IGT diagnosed by 2-h plasma glucose (PG) during a 75-gram oral glucose tolerance test (OGTT). Over the last 40 years, a wealth of epidemiological data has confirmed the superior value of 1-h plasma glucose (PG) over fasting PG (FPG), glycated haemoglobin (HbA1c) and 2-h PG in populations of different ethnicity, sex and age in predicting diabetes and associated complications including death. Given the relentlessly rising prevalence of diabetes, a more sensitive, practical method is needed to detect people with IH and T2D for early prevention or treatment in the often lengthy trajectory to T2D and its complications. The International Diabetes Federation (IDF) Position Statement reviews findings that the 1-h post-load PG ≥ 155 mg/dL (8.6 mmol/L) in people with normal glucose tolerance (NGT) during an OGTT is highly predictive for detecting progression to T2D, micro- and macrovascular complications, obstructive sleep apnoea, cystic fibrosis-related diabetes mellitus, metabolic dysfunction-associated steatotic liver disease, and mortality in individuals with risk factors. The 1-h PG of 209 mg/dL (11.6 mmol/L) is also diagnostic of T2D. Importantly, the 1-h PG cut points for diagnosing IH and T2D can be detected earlier than the recommended 2-h PG thresholds. Taken together, the 1-h PG provides an opportunity to avoid misclassification of glycaemic status if FPG or HbA1c alone are used. The 1-h PG also allows early detection of high-risk people for intervention to prevent progression to T2D which will benefit the sizeable and growing population of individuals at increased risk of T2D. Using a 1-h OGTT, subsequent to screening with a non-laboratory diabetes risk tool, and intervening early will favourably impact the global diabetes epidemic. Health services should consider developing a policy for screening for IH based on local human and technical resources. People with a 1-h PG ≥ 155 mg/dL (8.6 mmol/L) are considered to have IH and should be prescribed lifestyle intervention and referred to a diabetes prevention program. People with a 1-h PG ≥ 209 mg/dL (11.6 mmol/L) are considered to have T2D and should have a repeat test to confirm the diagnosis of T2D and then referred for further evaluation and treatment. The substantive data presented in the Position Statement provides strong evidence for redefining current diagnostic criteria for IH and T2D by adding the 1-h PG.
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Affiliation(s)
- Michael Bergman
- NYU Grossman School of Medicine, Departments of Medicine and of Population Health, Division of Endocrinology, Diabetes and Metabolism, VA New York Harbor Healthcare System, New York, NY, USA.
| | - Melania Manco
- Predictive and Preventive Medicine Research Unit, Bambino Gesù Children's Hospital IRCCS, Rome, Italy
| | - Ilhan Satman
- Istanbul University Faculty of Medicine, Department of Internal Medicine, Division of Endocrinology and Metabolism, Istanbul, Turkey
| | - Juliana Chan
- The Chinese University of Hong Kong, Faculty of Medicine, Department of Medicine and Therapeutics, Hong Kong Institute of Diabetes and Obesity, Hong Kong, China
| | - Maria Inês Schmidt
- Postgraduate Program in Epidemiology, School of Medicine and Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
| | - Giorgio Sesti
- Department of Clinical and Molecular Medicine, University of Rome-Sapienza, 00189 Rome, Italy
| | - Teresa Vanessa Fiorentino
- Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy
| | - Muhammad Abdul-Ghani
- Division of Diabetes, University of Texas Health Science Center at San Antonio, San Antonio Texas, USA
| | - Ram Jagannathan
- Hubert Department of Global Health Rollins, School of Public Health, Emory University, Atlanta, GA, USA
| | | | - Rafael Gabriel
- Department of International Health, National School of Public Health, Instituto de Salud Carlos III, Madrid, Spain
| | - Viswanathan Mohan
- Dr. Mohan's Diabetes Specialities Centre and Madras Diabetes Research Foundation, Chennai, India
| | - Martin Buysschaert
- Department of Endocrinology and Diabetology, Université Catholique de Louvain, University, Clinic Saint-Luc, Brussels, Belgium
| | - Abdullah Bennakhi
- Dasman Diabetes Institute Office of Regulatory Affairs, Ethics Review Committee, Kuwait
| | - Andre Pascal Kengne
- South African Medical Research Council, Francie Van Zijl Dr, Parow Valley, Cape Town, 7501, South Africa
| | - Brenda Dorcely
- NYU Grossman School of Medicine, Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, New York, NY, USA
| | - Peter M Nilsson
- Department of Clinical Sciences and Lund University Diabetes Centre, Lund University, Skåne University Hospital, Malmö, Sweden
| | - Tiinamaija Tuomi
- Folkhälsan Research Center, Helsinki, Finland; Abdominal Center, Endocrinology, Helsinki University Central Hospital, Research Program for Diabetes and Obesity, Center of Helsinki, Helsinki, Finland
| | | | - Akhtar Hussain
- Faculty of Health Sciences, Nord University, Bodø, Norway; Faculty of Medicine, Federal University of Ceará (FAMED-UFC), Brazil; International Diabetes Federation (IDF), Brussels, Belgium; Diabetes in Asia Study Group, Post Box: 752, Doha-Qatar; Centre for Global Health Research, Diabetic Association of Bangladesh, Dhaka, Bangladesh
| | | | - Jaakko Tuomilehto
- Department of International Health, National School of Public Health, Instituto de Salud Carlos III, Madrid, Spain; Public Health Promotion Unit, Finnish Institute for Health and Welfare, Helsinki, Finland; Department of Public Health, University of Helsinki, Helsinki, Finland; Saudi Diabetes Research Group, King Abdulaziz University, Jeddah, Saudi Arabia
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18
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Mathew GM, Nahmod NG, Master L, Reichenberger DA, Rosinger AY, Chang AM. Effects of a 1-hour per night week-long sleep extension in college students on cardiometabolic parameters, hydration status, and physical activity: A pilot study. Sleep Health 2024; 10:S130-S139. [PMID: 37996285 DOI: 10.1016/j.sleh.2023.10.006] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Revised: 10/10/2023] [Accepted: 10/12/2023] [Indexed: 11/25/2023]
Abstract
OBJECTIVES Short sleep duration is associated with poor physical health in college students. Few studies examine the effects of sleep extension on physical health in this population, who are susceptible to sleep loss. We examined health effects of a 1-week, 1-hour nightly sleep extension in college students. METHODS Twelve healthy undergraduate college students (83% female; age 20.2 ± 1.5years) completed a study consisting of sleeping typically for 1week ("Habitual"), then extending sleep by ≥1 hour/night during the second week ("Extension"). Sleep and physical activity actigraphy were collected throughout. Following each week, participants completed cardiometabolic assessments including a meal response and provided a urine sample for markers of hydration. RESULTS In Extension compared to Habitual, average sleep duration increased (mean change±SEM, +42.6 ± 15.1 minutes; p = .005), while subjective sleepiness (-1.8 ± 0.8 units; p = .040), systolic blood pressure (-6.6 ± 2.8 mmHg; p = .037), postprandial glucose area under the curve (-26.5 ± 10.2 mg/dL × h; p = .025) and time to baseline (-83.0 ± 46.4 minutes; p = .031) after the meal response, sedentary time (-44.3 ± 15.7 minutes; p = .018), and percentage of wake in moderate-to-vigorous activity (-0.89% ± 0.35%; p = .030) decreased. Participants who increased average sleep duration by ≥20 minutes (n = 9) were better hydrated according to urine osmolality (-187.0 ± 68.4 mOsm/kg; p = .026) and specific gravity (-0.01 ± 0.002 g/mL; p = .012) and had reduced odds of dehydration according to urine osmolality (≥800 mOsm/kg; -67%; OR=0.03; p = .035). CONCLUSIONS This pilot study's findings suggest that sleep extension may improve cardiometabolic functioning and hydration, and alter sedentary behavior and physical activity, in college students. Sleep extension may be employed to improve multiple aspects of health in this sleep-deprived population.
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Affiliation(s)
- Gina Marie Mathew
- Department of Biobehavioral Health, College of Health and Human Development, Pennsylvania State University, University Park, Pennsylvania, USA.
| | - Nicole G Nahmod
- Department of Biobehavioral Health, College of Health and Human Development, Pennsylvania State University, University Park, Pennsylvania, USA
| | - Lindsay Master
- Department of Biobehavioral Health, College of Health and Human Development, Pennsylvania State University, University Park, Pennsylvania, USA
| | - David A Reichenberger
- Department of Biobehavioral Health, College of Health and Human Development, Pennsylvania State University, University Park, Pennsylvania, USA
| | - Asher Y Rosinger
- Department of Biobehavioral Health, College of Health and Human Development, Pennsylvania State University, University Park, Pennsylvania, USA; Department of Anthropology, College of Liberal Arts, Pennsylvania State University, University Park, Pennsylvania, USA
| | - Anne-Marie Chang
- Department of Biobehavioral Health, College of Health and Human Development, Pennsylvania State University, University Park, Pennsylvania, USA
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Galderisi A, Carr ALJ, Martino M, Taylor P, Senior P, Dayan C. Quantifying beta cell function in the preclinical stages of type 1 diabetes. Diabetologia 2023; 66:2189-2199. [PMID: 37712956 PMCID: PMC10627950 DOI: 10.1007/s00125-023-06011-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2023] [Accepted: 08/08/2023] [Indexed: 09/16/2023]
Abstract
Clinically symptomatic type 1 diabetes (stage 3 type 1 diabetes) is preceded by a pre-symptomatic phase, characterised by progressive loss of functional beta cell mass after the onset of islet autoimmunity, with (stage 2) or without (stage 1) measurable changes in glucose profile during an OGTT. Identifying metabolic tests that can longitudinally track changes in beta cell function is of pivotal importance to track disease progression and measure the effect of disease-modifying interventions. In this review we describe the metabolic changes that occur in the early pre-symptomatic stages of type 1 diabetes with respect to both insulin secretion and insulin sensitivity, as well as the measurable outcomes that can be derived from the available tests. We also discuss the use of metabolic modelling to identify insulin secretion and sensitivity, and the measurable changes during dynamic tests such as the OGTT. Finally, we review the role of risk indices and minimally invasive measures such as those derived from the use of continuous glucose monitoring.
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Affiliation(s)
| | - Alice L J Carr
- Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada
| | - Mariangela Martino
- Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, UK
| | - Peter Taylor
- Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, UK
| | - Peter Senior
- Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada
| | - Colin Dayan
- Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, UK.
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20
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Ansari MA, Chauhan W, Shoaib S, Alyahya SA, Ali M, Ashraf H, Alomary MN, Al-Suhaimi EA. Emerging therapeutic options in the management of diabetes: recent trends, challenges and future directions. Int J Obes (Lond) 2023; 47:1179-1199. [PMID: 37696926 DOI: 10.1038/s41366-023-01369-3] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2023] [Revised: 07/04/2023] [Accepted: 08/17/2023] [Indexed: 09/13/2023]
Abstract
Diabetes is a serious health issue that causes a progressive dysregulation of carbohydrate metabolism due to insufficient insulin hormone, leading to consistently high blood glucose levels. According to the epidemiological data, the prevalence of diabetes has been increasing globally, affecting millions of individuals. It is a long-term condition that increases the risk of various diseases caused by damage to small and large blood vessels. There are two main subtypes of diabetes: type 1 and type 2, with type 2 being the most prevalent. Genetic and molecular studies have identified several genetic variants and metabolic pathways that contribute to the development and progression of diabetes. Current treatments include gene therapy, stem cell therapy, statin therapy, and other drugs. Moreover, recent advancements in therapeutics have also focused on developing novel drugs targeting these pathways, including incretin mimetics, SGLT2 inhibitors, and GLP-1 receptor agonists, which have shown promising results in improving glycemic control and reducing the risk of complications. However, these treatments are often expensive, inaccessible to patients in underdeveloped countries, and can have severe side effects. Peptides, such as glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), are being explored as a potential therapy for diabetes. These peptides are postprandial glucose-dependent pancreatic beta-cell insulin secretagogues and have received much attention as a possible treatment option. Despite these advances, diabetes remains a major health challenge, and further research is needed to develop effective treatments and prevent its complications. This review covers various aspects of diabetes, including epidemiology, genetic and molecular basis, and recent advancements in therapeutics including herbal and synthetic peptides.
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Affiliation(s)
- Mohammad Azam Ansari
- Department of Epidemic Disease Research, Institute for Research and Medical Consultations (IRMC), Imam Abdulrahman Bin Faisal University, P.O. Box 1982, Dammam, 31441, Saudi Arabia.
| | - Waseem Chauhan
- Department of Hematology, Duke University, Durham, NC, 27710, USA
| | - Shoaib Shoaib
- Department of Biochemistry, Faculty of Medicine, Aligarh Muslim University, Aligarh, Uttar Pradesh, India
| | - Sami A Alyahya
- Wellness and Preventive Medicine Institute, King Abdulaziz City for Science and Technology (KACST), Riyadh, 11442, Saudi Arabia
| | - Mubashshir Ali
- USF Health Byrd Alzheimer's Center and Neuroscience Institute, Department of Molecular Medicine, Tampa, FL, USA
| | - Hamid Ashraf
- Rajiv Gandhi Center for Diabetes and Endocrinology, Faculty of Medicine, Aligarh Muslim University, Aligarh, Uttar Pradesh, India
| | - Mohammad N Alomary
- Advanced Diagnostic and Therapeutic Institute, King Abdulaziz City for Science and Technology (KACST), Riyadh, 11442, Saudi Arabia.
| | - Ebtesam A Al-Suhaimi
- King Abdulaziz & his Companions Foundation for Giftedness & Creativity, Riyadh, Saudi Arabia.
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21
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Rahman MM, Pathak A, Schueler KL, Alsharif H, Michl A, Alexander J, Kim JA, Bhatnagar S. Genetic ablation of synaptotagmin-9 alters tomosyn-1 function to increase insulin secretion from pancreatic β-cells improving glucose clearance. FASEB J 2023; 37:e23075. [PMID: 37432648 PMCID: PMC10348599 DOI: 10.1096/fj.202300291rr] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2023] [Revised: 06/19/2023] [Accepted: 06/22/2023] [Indexed: 07/12/2023]
Abstract
Stimulus-coupled insulin secretion from the pancreatic islet β-cells involves the fusion of insulin granules to the plasma membrane (PM) via SNARE complex formation-a cellular process key for maintaining whole-body glucose homeostasis. Less is known about the role of endogenous inhibitors of SNARE complexes in insulin secretion. We show that an insulin granule protein synaptotagmin-9 (Syt9) deletion in mice increased glucose clearance and plasma insulin levels without affecting insulin action compared to the control mice. Upon glucose stimulation, increased biphasic and static insulin secretion were observed from ex vivo islets due to Syt9 loss. Syt9 colocalizes and binds with tomosyn-1 and the PM syntaxin-1A (Stx1A); Stx1A is required for forming SNARE complexes. Syt9 knockdown reduced tomosyn-1 protein abundance via proteasomal degradation and binding of tomosyn-1 to Stx1A. Furthermore, Stx1A-SNARE complex formation was increased, implicating Syt9-tomosyn-1-Stx1A complex is inhibitory in insulin secretion. Rescuing tomosyn-1 blocked the Syt9-knockdown-mediated increases in insulin secretion. This shows that the inhibitory effects of Syt9 on insulin secretion are mediated by tomosyn-1. We report a molecular mechanism by which β-cells modulate their secretory capacity rendering insulin granules nonfusogenic by forming the Syt9-tomosyn-1-Stx1A complex. Altogether, Syt9 loss in β-cells decreases tomosyn-1 protein abundance, increasing the formation of Stx1A-SNARE complexes, insulin secretion, and glucose clearance. These outcomes differ from the previously published work that identified Syt9 has either a positive or no effect of Syt9 on insulin secretion. Future work using β-cell-specific deletion of Syt9 mice is key for establishing the role of Syt9 in insulin secretion.
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Affiliation(s)
- Md Mostafizur Rahman
- Heersink School of Medicine, Division of Endocrinology, Diabetes, & Metabolism, Comprehensive Diabetes Center, University of Alabama, Birmingham, AL, 35294
| | - Asmita Pathak
- Heersink School of Medicine, Division of Endocrinology, Diabetes, & Metabolism, Comprehensive Diabetes Center, University of Alabama, Birmingham, AL, 35294
| | | | - Haifa Alsharif
- Heersink School of Medicine, Division of Endocrinology, Diabetes, & Metabolism, Comprehensive Diabetes Center, University of Alabama, Birmingham, AL, 35294
| | - Ava Michl
- Heersink School of Medicine, Division of Endocrinology, Diabetes, & Metabolism, Comprehensive Diabetes Center, University of Alabama, Birmingham, AL, 35294
| | - Justin Alexander
- Heersink School of Medicine, Division of Endocrinology, Diabetes, & Metabolism, Comprehensive Diabetes Center, University of Alabama, Birmingham, AL, 35294
| | - Jeong-A Kim
- Heersink School of Medicine, Division of Endocrinology, Diabetes, & Metabolism, Comprehensive Diabetes Center, University of Alabama, Birmingham, AL, 35294
| | - Sushant Bhatnagar
- Heersink School of Medicine, Division of Endocrinology, Diabetes, & Metabolism, Comprehensive Diabetes Center, University of Alabama, Birmingham, AL, 35294
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22
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Ramanadham S, Turk J, Bhatnagar S. Noncanonical Regulation of cAMP-Dependent Insulin Secretion and Its Implications in Type 2 Diabetes. Compr Physiol 2023; 13:5023-5049. [PMID: 37358504 PMCID: PMC10809800 DOI: 10.1002/cphy.c220031] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/27/2023]
Abstract
Impaired glucose tolerance (IGT) and β-cell dysfunction in insulin resistance associated with obesity lead to type 2 diabetes (T2D). Glucose-stimulated insulin secretion (GSIS) from β-cells occurs via a canonical pathway that involves glucose metabolism, ATP generation, inactivation of K ATP channels, plasma membrane depolarization, and increases in cytosolic concentrations of [Ca 2+ ] c . However, optimal insulin secretion requires amplification of GSIS by increases in cyclic adenosine monophosphate (cAMP) signaling. The cAMP effectors protein kinase A (PKA) and exchange factor activated by cyclic-AMP (Epac) regulate membrane depolarization, gene expression, and trafficking and fusion of insulin granules to the plasma membrane for amplifying GSIS. The widely recognized lipid signaling generated within β-cells by the β-isoform of Ca 2+ -independent phospholipase A 2 enzyme (iPLA 2 β) participates in cAMP-stimulated insulin secretion (cSIS). Recent work has identified the role of a G-protein coupled receptor (GPCR) activated signaling by the complement 1q like-3 (C1ql3) secreted protein in inhibiting cSIS. In the IGT state, cSIS is attenuated, and the β-cell function is reduced. Interestingly, while β-cell-specific deletion of iPLA 2 β reduces cAMP-mediated amplification of GSIS, the loss of iPLA 2 β in macrophages (MØ) confers protection against the development of glucose intolerance associated with diet-induced obesity (DIO). In this article, we discuss canonical (glucose and cAMP) and novel noncanonical (iPLA 2 β and C1ql3) pathways and how they may affect β-cell (dys)function in the context of impaired glucose intolerance associated with obesity and T2D. In conclusion, we provide a perspective that in IGT states, targeting noncanonical pathways along with canonical pathways could be a more comprehensive approach for restoring β-cell function in T2D. © 2023 American Physiological Society. Compr Physiol 13:5023-5049, 2023.
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Affiliation(s)
- Sasanka Ramanadham
- Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, Alabama, USA
- Comprehensive Diabetes Center, University of Alabama at Birmingham, Alabama, USA
| | - John Turk
- Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Sushant Bhatnagar
- Comprehensive Diabetes Center, University of Alabama at Birmingham, Alabama, USA
- Department of Medicine, University of Alabama at Birmingham, Alabama, USA
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23
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Vidmar AP, Durazo-Arvizu R, Weigensberg MJ, Alderete TL, Goran MI. Rapid Decline in β-Cell Function and Increasing Adiposity Are Associated With Conversion to Type 2 Diabetes in At-Risk Latino Youth. Diabetes 2023; 72:735-745. [PMID: 36972018 PMCID: PMC10202769 DOI: 10.2337/db22-1034] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Accepted: 03/22/2023] [Indexed: 04/16/2023]
Abstract
Youth-onset type 2 diabetes (T2D) is becoming increasingly prevalent, especially among Latino youth, and there is limited information on its pathophysiology and causative factors. Here, we describe findings from a longitudinal cohort study in 262 Latino children with overweight/obesity at risk of developing T2D with annual measures of oral and intravenous glucose tolerance (IVGTT), body composition, and fat distribution. Logistic binomial regression was used to identify significant predictors in those who developed T2D compared with matched control participants, and mixed-effects growth models were used to compare rates of change in metabolic versus adiposity measures between groups. Overall conversion rate to T2D at year 5 was 2% (n = 6). Rate of decline in disposition index (DI), measured with an IVGTT, over 5 years was three times higher in case patients (-341.7 units per year) compared with the extended cohort (-106.7 units per year) and 20 times higher compared with control participants (-15.2 units per year). Case patients had significantly higher annual increases in fasting glucose, hemoglobin A1c (HbA1c), waist circumference, and trunk fat, and there was an inverse correlation between rate of decline in DI and rates of increase in adiposity measures. T2D development in at-risk Latino youth is associated with a substantial and rapid decrease in DI that is directly correlated with increases in fasting glucose, HbA1c, and adiposity. ARTICLE HIGHLIGHTS Youth-onset type 2 diabetes is becoming increasingly prevalent, especially among Latino youth, and there is limited information on its pathophysiology and causative factors. Overall conversion rate to type 2 diabetes over 5 years was 2%. In youth who converted to type 2 diabetes, disposition index decreased rapidly by 85% compared with that in patients who did not convert during the study period. There was an inverse correlation between rate of decline in disposition index and rates of increase in various adiposity measures.
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Affiliation(s)
- Alaina P. Vidmar
- Division of Endocrinology, Department of Pediatrics, Saban Research Institute, Children’s Hospital Los Angeles, Los Angeles, CA
- Department of Pediatrics, Keck School of Medicine, Los Angeles, CA
| | - Ramon Durazo-Arvizu
- Southern California Clinical and Translational Science Institute Biostatistics Core, The Saban Research Institute, Children’s Hospital Los Angeles, Los Angeles, CA
| | - Marc J. Weigensberg
- Department of Pediatrics, University of Southern California, Los Angeles, CA
| | - Tanya L. Alderete
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO
| | - Michael I. Goran
- Division of Endocrinology, Department of Pediatrics, Saban Research Institute, Children’s Hospital Los Angeles, Los Angeles, CA
- Department of Pediatrics, Keck School of Medicine, Los Angeles, CA
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24
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Qureshi FM, Panzer JK, Põder J, Malek TR, Caicedo A. Immunotherapy With Low-Dose IL-2/CD25 Prevents β-Cell Dysfunction and Dysglycemia in Prediabetic NOD Mice. Diabetes 2023; 72:769-780. [PMID: 36939730 PMCID: PMC10202767 DOI: 10.2337/db22-0482] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Accepted: 03/15/2023] [Indexed: 03/21/2023]
Abstract
Low-dose IL-2 is a promising immunotherapy in clinical trials for treating type 1 diabetes. A new IL-2 analog, IL-2/CD25 fusion protein, has been shown to more efficiently delay or prevent diabetes in NOD mice by expanding the population of activated regulatory T cells. This therapy is intended for use before clinical diagnosis, in the early stages of type 1 diabetes progression. During this prediabetic period, there is a chronic decline in β-cell function that has long-term implications for disease pathogenesis. Yet, to date, the effects of IL-2/CD25 on β-cell function have not been evaluated. In this study, we treated prediabetic NOD mice with low-dose mouse IL-2/CD25 over 5 weeks and determined its impact on β-cell function. This treatment limited the progressive impairment of glucose tolerance and insulin secretion typical of the later stages of prediabetes. Intracellular Ca2+ responses to glucose in β-cells became more robust and synchronous, indicating that changing the local immune cell infiltrate with IL-2/CD25 preserved β-cell function even after treatment cessation. Our study thus provides mechanistic insight and serves as a steppingstone for future research using low-dose IL-2/CD25 immunotherapy in patients. ARTICLE HIGHLIGHTS Immunotherapies such as IL-2/CD25 are known to prevent or delay diabetes. However, their impact on individual β-cell function is not yet understood. Female NOD mice progress from stage 1 to 2 pre-type 1 diabetes between 12 and 17 weeks. Treatment with mouse IL-2 (mIL-2)/CD25 prevents this progression even after treatment cessation. Individual β-cell function (measured via intracellular Ca2+ responses to glucose) declines during the pathogenesis of type 1 diabetes. Treatment with mIL-2/CD25 therapy limits β-cell dysfunction, and function continues to improve after treatment cessation. Insulin secretion is improved with mIL-2/CD25 therapy.
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Affiliation(s)
- Farhan M. Qureshi
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL
- Department of Molecular, Cell and Developmental Biology, University of Miami Miller School of Medicine, Miami, FL
- Medical Scientist Training Program, University of Miami Miller School of Medicine, Miami, FL
| | - Julia K. Panzer
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL
| | - Janika Põder
- Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL
| | - Thomas R. Malek
- Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL
| | - Alejandro Caicedo
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL
- Department of Molecular, Cell and Developmental Biology, University of Miami Miller School of Medicine, Miami, FL
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25
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Linkens AMA, Eussen SJMP, Houben AJHM, Mari A, Dagnelie PC, Stehouwer CDA, Schalkwijk CG. Habitual intake of advanced glycation endproducts is not associated with worse insulin sensitivity, worse beta cell function, or presence of prediabetes or type 2 diabetes: The Maastricht Study. Clin Nutr 2023:S0261-5614(23)00163-2. [PMID: 37302878 DOI: 10.1016/j.clnu.2023.05.021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2022] [Revised: 05/15/2023] [Accepted: 05/26/2023] [Indexed: 06/13/2023]
Abstract
BACKGROUND & AIMS A diet high in advanced glycation endproducts (AGEs) is a potential risk factor for insulin resistance, beta cell dysfunction, and ultimately type 2 diabetes. We investigated associations between habitual intake of dietary AGEs and glucose metabolism in a population-based setting. METHODS In 6275 participants of The Maastricht Study (mean ± SD age: 60 ± 9, 15.1% prediabetes and 23.2% type 2 diabetes), we estimated habitual intake of dietary AGEs Nε-(carboxymethyl)lysine (CML), Nε-(1-carboxyethyl)lysine (CEL), and Nδ-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (MG-H1) by combining a validated food frequency questionnaire (FFQ) with our mass-spectrometry dietary AGE database. We determined insulin sensitivity (Matsuda- and HOMA-IR index), beta cell function (C-peptidogenic index, glucose sensitivity, potentiation factor, and rate sensitivity), glucose metabolism status, fasting glucose, HbA1c, post-OGTT glucose, and OGTT glucose incremental area under the curve. Cross-sectional associations between habitual AGE intake and these outcomes were investigated using a combination of multiple linear regression and multinomial logistic regression adjusting for several potential confounders (demographic, cardiovascular, and lifestyle factors). RESULTS Generally, higher habitual intake of AGEs was not associated with worse indices of glucose metabolism, nor with increased presence of prediabetes or type 2 diabetes. Higher dietary MG-H1 was associated with better beta cell glucose sensitivity. CONCLUSIONS The present study does not support an association of dietary AGEs with impaired glucose metabolism. Whether higher intake of dietary AGEs translates to increased incidence of prediabetes or type 2 diabetes on the long term should be investigated in large prospective cohort studies.
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Affiliation(s)
- Armand M A Linkens
- Department of Internal Medicine, Maastricht University Medical Center, 6229ER, Maastricht, the Netherlands; CARIM School for Cardiovascular Diseases, Maastricht University, 6229ER, Maastricht, the Netherlands
| | - Simone J M P Eussen
- CARIM School for Cardiovascular Diseases, Maastricht University, 6229ER, Maastricht, the Netherlands; Department of Epidemiology, Maastricht University, 6229HA, Maastricht, the Netherlands; CAPHRI School for Care and Public Health Research Unit, Maastricht University, 6229ER, Maastricht the Netherlands
| | - Alfons J H M Houben
- Department of Internal Medicine, Maastricht University Medical Center, 6229ER, Maastricht, the Netherlands; CARIM School for Cardiovascular Diseases, Maastricht University, 6229ER, Maastricht, the Netherlands
| | - Andrea Mari
- Institute of Neuroscience, National Research Council, 35131, Padova, PD, Padua, Italy
| | - Pieter C Dagnelie
- Department of Epidemiology, Maastricht University, 6229HA, Maastricht, the Netherlands
| | - Coen D A Stehouwer
- Department of Internal Medicine, Maastricht University Medical Center, 6229ER, Maastricht, the Netherlands; CARIM School for Cardiovascular Diseases, Maastricht University, 6229ER, Maastricht, the Netherlands
| | - Casper G Schalkwijk
- Department of Internal Medicine, Maastricht University Medical Center, 6229ER, Maastricht, the Netherlands; CARIM School for Cardiovascular Diseases, Maastricht University, 6229ER, Maastricht, the Netherlands.
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26
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Abstract
Insulin action is impaired in type 2 diabetes. The functions of the hormone are an integrated product of insulin secretion from pancreatic β-cells and insulin clearance by receptor-mediated endocytosis and degradation, mostly in liver (hepatocytes) and, to a lower extent, in extrahepatic peripheral tissues. Substantial evidence indicates that genetic or acquired abnormalities of insulin secretion or action predispose to type 2 diabetes. In recent years, along with the discovery of the molecular foundation of receptor-mediated insulin clearance, such as through the membrane glycoprotein CEACAM1, a consensus has begun to emerge that reduction of insulin clearance contributes to the disease process. In this review, we consider the evidence suggesting a pathogenic role for reduced insulin clearance in insulin resistance, obesity, hepatic steatosis, and type 2 diabetes.
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Affiliation(s)
- Sonia M Najjar
- Department of Biomedical Sciences and the Diabetes Institute, Heritage College of Osteopathic Medicine, Ohio University, Athens, Ohio, USA;
| | - Sonia Caprio
- Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Amalia Gastaldelli
- Cardiometabolic Risk Unit, Institute of Clinical Physiology-National Research Council, Pisa, Italy
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27
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Sinatra VJ, Lin B, Parikh M, Berger JS, Fisher EA, Heffron SP. Bariatric surgery normalizes diabetes risk index by one month post-operation. Acta Diabetol 2023; 60:265-271. [PMID: 36350383 PMCID: PMC10868715 DOI: 10.1007/s00592-022-02002-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Accepted: 10/30/2022] [Indexed: 11/11/2022]
Abstract
AIM The Diabetes risk index (DRI) is a composite of NMR-measured lipoproteins and branched chain amino acids predictive of diabetes mellitus development. Bariatric surgery is indicated in patients with severe obesity, many of whom are at high-risk for developing diabetes. Substantial weight loss occurs following bariatric surgery and sustained weight loss likely contributes to reductions in the development of diabetes and cardiovascular disease. However, some evidence suggests that bariatric surgical procedures themselves may contribute to reducing risk of these conditions independent of weight loss. We aimed to investigate DRI and its association with reductions in body weight and adiposity over one year following bariatric surgery. METHODS We examined 51 severely obese premenopausal women without diabetes. DRI, BMI, body weight and waist measurements were made before and at 1, 6 and 12 months after Roux-en-Y Gastric Bypass (RYGB) or Sleeve Gastrectomy. Values were compared to healthy women with normal BMI (18.5-24.9 kg/m2; n = 15). RESULTS Non-diabetic women with severe obesity (BMI 44.7 ± 6.2 kg/m2) exhibited significantly elevated DRI scores prior to surgery versus controls (35 [26, 39] vs 12 [1, 20]; p < 0.0001). At 1 month after surgery, BMI decreased 5.1 ± 1.1 kg/m2, but DRI decreased so that it no longer differed from that of normal BMI controls (1.9 [1, 17] vs control 12 [1, 20]; p = 0.35). Subjects continued to lose weight, whereas DRI remained similar, throughout follow-up with DRI 1.0 [1, 7] at 12 months. Changes in DRI did not correlate with changes in BMI, body weight or waist circumference at any time during follow-up. There was no difference in change in DRI between surgical procedures or pre-operative metabolic syndrome status. CONCLUSIONS Our analysis of DRI scores supports the capacity of bariatric surgery to reduce risk of developing diabetes in severely obese individuals. Our findings suggest that bariatric surgical techniques may have inherent effects that improve cardiometabolic risk independent of reductions in body weight or adiposity.
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Affiliation(s)
- Vincent J Sinatra
- Leon H Charney Division of Cardiology, Department of Medicine, NYU Grossman School of Medicine, 435 East 30Th St. #515, New York, NY, 10016, USA
| | - BingXue Lin
- Leon H Charney Division of Cardiology, Department of Medicine, NYU Grossman School of Medicine, 435 East 30Th St. #515, New York, NY, 10016, USA
| | - Manish Parikh
- Department of Surgery, NYU Grossman School of Medicine, New York, NY, USA
| | - Jeffrey S Berger
- Leon H Charney Division of Cardiology, Department of Medicine, NYU Grossman School of Medicine, 435 East 30Th St. #515, New York, NY, 10016, USA
- NYU Center for the Prevention of Cardiovascular Disease, NYU Grossman School of Medicine, New York, NY, USA
- Division of Vascular Surgery, Department of Surgery, NYU Grossman School of Medicine, New York, NY, USA
| | - Edward A Fisher
- Leon H Charney Division of Cardiology, Department of Medicine, NYU Grossman School of Medicine, 435 East 30Th St. #515, New York, NY, 10016, USA
- NYU Center for the Prevention of Cardiovascular Disease, NYU Grossman School of Medicine, New York, NY, USA
| | - Sean P Heffron
- Leon H Charney Division of Cardiology, Department of Medicine, NYU Grossman School of Medicine, 435 East 30Th St. #515, New York, NY, 10016, USA.
- NYU Center for the Prevention of Cardiovascular Disease, NYU Grossman School of Medicine, New York, NY, USA.
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28
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Mendham AE, Micklesfield LK, Karpe F, Kengne AP, Chikowore T, Kufe CN, Masemola M, Crowther NJ, Norris SA, Olsson T, Elmståhl S, Fall T, Lind L, Goedecke JH. Targeted proteomics identifies potential biomarkers of dysglycaemia, beta cell function and insulin sensitivity in Black African men and women. Diabetologia 2023; 66:174-189. [PMID: 36114877 DOI: 10.1007/s00125-022-05788-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Accepted: 06/09/2022] [Indexed: 12/13/2022]
Abstract
AIMS/HYPOTHESIS Using a targeted proteomics approach, we aimed to identify and validate circulating proteins associated with impaired glucose metabolism (IGM) and type 2 diabetes in a Black South African cohort. In addition, we assessed sex-specific associations between the validated proteins and pathophysiological pathways of type 2 diabetes. METHODS This cross-sectional study included Black South African men (n=380) and women (n=375) who were part of the Middle-Aged Soweto Cohort (MASC). Dual-energy x-ray absorptiometry was used to determine fat mass and visceral adipose tissue, and fasting venous blood samples were collected for analysis of glucose, insulin and C-peptide and for targeted proteomics, measuring a total of 184 pre-selected protein biomarkers. An OGTT was performed on participants without diabetes, and peripheral insulin sensitivity (Matsuda index), HOMA-IR, basal insulin clearance, insulin secretion (C-peptide index) and beta cell function (disposition index) were estimated. Participants were classified as having normal glucose tolerance (NGT; n=546), IGM (n=116) or type 2 diabetes (n=93). Proteins associated with dysglycaemia (IGM or type 2 diabetes) in the MASC were validated in the Swedish EpiHealth cohort (NGT, n=1706; impaired fasting glucose, n=550; type 2 diabetes, n=210). RESULTS We identified 73 proteins associated with dysglycaemia in the MASC, of which 34 were validated in the EpiHealth cohort. Among these validated proteins, 11 were associated with various measures of insulin dynamics, with the largest number of proteins being associated with HOMA-IR. In sex-specific analyses, IGF-binding protein 2 (IGFBP2) was associated with lower HOMA-IR in women (coefficient -0.35; 95% CI -0.44, -0.25) and men (coefficient -0.09; 95% CI -0.15, -0.03). Metalloproteinase inhibitor 4 (TIMP4) was associated with higher insulin secretion (coefficient 0.05; 95% CI 0.001, 0.11; p for interaction=0.025) and beta cell function (coefficient 0.06; 95% CI 0.02, 0.09; p for interaction=0.013) in women only. In contrast, a stronger positive association between IGFBP2 and insulin sensitivity determined using an OGTT (coefficient 0.38; 95% CI 0.27, 0.49) was observed in men (p for interaction=0.004). A posteriori analysis showed that the associations between TIMP4 and insulin dynamics were not mediated by adiposity. In contrast, most of the associations between IGFBP2 and insulin dynamics, except for insulin secretion, were mediated by either fat mass index or visceral adipose tissue in men and women. Fat mass index was the strongest mediator between IGFBP2 and insulin sensitivity (total effect mediated 40.7%; 95% CI 37.0, 43.6) and IGFBP2 and HOMA-IR (total effect mediated 39.1%; 95% CI 31.1, 43.5) in men. CONCLUSIONS/INTERPRETATION We validated 34 proteins that were associated with type 2 diabetes, of which 11 were associated with measures of type 2 diabetes pathophysiology such as peripheral insulin sensitivity and beta cell function. This study highlights biomarkers that are similar between cohorts of different ancestry, with different lifestyles and sociodemographic profiles. The African-specific biomarkers identified require validation in African cohorts to identify risk markers and increase our understanding of the pathophysiology of type 2 diabetes in African populations.
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Affiliation(s)
- Amy E Mendham
- South African Medical Research Council/WITS Developmental Pathways for Health Research Unit, Department of Paediatrics, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
- Health through Physical Activity, Lifestyle and Sport Research Centre, International Federation of Sports Medicine (FIMS), International Collaborating Centre of Sports Medicine, Division of Physiological Sciences, Department of Human Biology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
| | - Lisa K Micklesfield
- South African Medical Research Council/WITS Developmental Pathways for Health Research Unit, Department of Paediatrics, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
| | - Fredrik Karpe
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK
- National Institute for Health and Care Research, Oxford Biomedical Research Centre, Oxford University Hospitals Foundation Trust, Oxford, UK
| | - Andre Pascal Kengne
- Biomedical Research and Innovation Platform and Non-Communicable Diseases Research Unit, South African Medical Research Council, Cape Town, South Africa
| | - Tinashe Chikowore
- South African Medical Research Council/WITS Developmental Pathways for Health Research Unit, Department of Paediatrics, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
| | - Clement N Kufe
- South African Medical Research Council/WITS Developmental Pathways for Health Research Unit, Department of Paediatrics, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
- Epidemiology and Surveillance Section, National Institute for Occupational Health, National Health Laboratory Service, Johannesburg, South Africa
| | - Maphoko Masemola
- South African Medical Research Council/WITS Developmental Pathways for Health Research Unit, Department of Paediatrics, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
| | - Nigel J Crowther
- Department of Chemical Pathology, National Health Laboratory Service and University of the Witwatersrand Faculty of Health Sciences, Johannesburg, South Africa
| | - Shane A Norris
- South African Medical Research Council/WITS Developmental Pathways for Health Research Unit, Department of Paediatrics, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
- School of Human Development and Health, University of Southampton, Southampton, UK
| | - Tommy Olsson
- Department of Public Health and Clinical Medicine, Medicine, Umeå University, Umeå, Sweden
| | - Sölve Elmståhl
- Department of Clinical Sciences in Malmö, Division of Geriatric Medicine, Lund University, Lund, Sweden
- Clinical Research Centre, Skåne University Hospital, Malmö, Sweden
| | - Tove Fall
- Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden
| | - Lars Lind
- Department of Medical Sciences, Uppsala University Hospital, Uppsala University, Uppsala, Sweden
| | - Julia H Goedecke
- South African Medical Research Council/WITS Developmental Pathways for Health Research Unit, Department of Paediatrics, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
- Health through Physical Activity, Lifestyle and Sport Research Centre, International Federation of Sports Medicine (FIMS), International Collaborating Centre of Sports Medicine, Division of Physiological Sciences, Department of Human Biology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
- Biomedical Research and Innovation Platform and Non-Communicable Diseases Research Unit, South African Medical Research Council, Cape Town, South Africa
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Díaz-Balzac CA, Pillinger D, Wittlin SD. Continuous subcutaneous insulin infusions: Closing the loop. J Clin Endocrinol Metab 2022; 108:1019-1033. [PMID: 36573281 DOI: 10.1210/clinem/dgac746] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Indexed: 12/29/2022]
Abstract
CONTEXT Continuous subcutaneous insulin infusions (CSIIs) and continuous glucose monitors (CGMs) have revolutionized the management of diabetes mellitus (DM). Over the last two decades the development of advanced, small, and user-friendly technology has progressed substantially, essentially closing the loop in the fasting and post-absorptive state, nearing the promise of an artificial pancreas. The momentum was mostly driven by the diabetes community itself, to improve its health and quality of life. EVIDENCE ACQUISITION Literature regarding CSII and CGM was reviewed. EVIDENCE SYNTHESIS Management of DM aims to regulate blood glucose to prevent long term micro and macrovascular complications. CSIIs combined with CGMs provide an integrated system to maintain tight glycemic control in a safe and uninterrupted fashion, while minimizing hypoglycemic events. Recent advances have allowed to 'close the loop' by better mimicking endogenous insulin secretion and glucose level regulation. Evidence supports sustained improvement in glycemic control with reduced episodes of hypoglycemia using these systems, while improving quality of life. Ongoing work in delivery algorithms with or without counterregulatory hormones will allow for further layers of regulation of the artificial pancreas. CONCLUSION Ongoing efforts to develop an artificial pancreas have created effective tools to improve the management of DM. CSIIs and CGMs are useful in diverse populations ranging from children to the elderly, as well as in various clinical contexts. Individually and more so together, these have had a tremendous impact in the management of DM, while avoiding treatment fatigue. However, cost and accessibility are still a hindrance to its wider application.
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Affiliation(s)
- Carlos A Díaz-Balzac
- Division of Endocrinology, Diabetes and Metabolism, University of Rochester Medical Center, 601 Elmwood Avenue, Box 693, Rochester, NY 14642, USA
| | - David Pillinger
- Division of Endocrinology, Diabetes and Metabolism, University of Rochester Medical Center, 601 Elmwood Avenue, Box 693, Rochester, NY 14642, USA
| | - Steven D Wittlin
- Division of Endocrinology, Diabetes and Metabolism, University of Rochester Medical Center, 601 Elmwood Avenue, Box 693, Rochester, NY 14642, USA
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Peters A, Sprengell M, Kubera B. The principle of 'brain energy on demand' and its predictive power for stress, sleep, stroke, obesity and diabetes. Neurosci Biobehav Rev 2022; 141:104847. [PMID: 36067964 DOI: 10.1016/j.neubiorev.2022.104847] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2022] [Revised: 08/10/2022] [Accepted: 08/26/2022] [Indexed: 12/01/2022]
Abstract
Does the brain actively draw energy from the body when needed? There are different schools of thought regarding energy metabolism. In this study, the various theoretical models are classified into one of two categories: (1) conceptualizations of the brain as being purely passively supplied, which we call 'P-models,' and (2) models understanding the brain as not only passively receiving energy but also actively procuring energy for itself on demand, which we call 'A-models.' One prominent example of such theories making use of an A-model is the selfish-brain theory. The ability to make predictions was compared between the A- and P-models. A-models were able to predict and coherently explain all data examined, which included stress, sleep, caloric restriction, stroke, type-1-diabetes mellitus, obesity, and type-2-diabetes, whereas the predictions of P-models failed in most cases. The strength of the evidence supporting A-models is based on the coherence of accurate predictions across a spectrum of metabolic states. The theory test conducted here speaks to a brain that pulls its energy from the body on-demand.
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Affiliation(s)
- Achim Peters
- Medical Clinic 1, Center of Brain, Behavior and Metabolism, University of Lübeck, Ratzeburger Allee 160, D-23538 Lübeck, Germany.
| | - Marie Sprengell
- Medical Clinic 1, Center of Brain, Behavior and Metabolism, University of Lübeck, Ratzeburger Allee 160, D-23538 Lübeck, Germany
| | - Britta Kubera
- Medical Clinic 1, Center of Brain, Behavior and Metabolism, University of Lübeck, Ratzeburger Allee 160, D-23538 Lübeck, Germany
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Subramanian V, Bagger JI, Holst JJ, Knop FK, Vilsbøll T. A glucose-insulin-glucagon coupled model of the isoglycemic intravenous glucose infusion experiment. Front Physiol 2022; 13:911616. [PMID: 36148302 PMCID: PMC9485803 DOI: 10.3389/fphys.2022.911616] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2022] [Accepted: 07/19/2022] [Indexed: 11/13/2022] Open
Abstract
Type 2 diabetes (T2D) is a pathophysiology that is characterized by insulin resistance, beta- and alpha-cell dysfunction. Mathematical models of various glucose challenge experiments have been developed to quantify the contribution of insulin and beta-cell dysfunction to the pathophysiology of T2D. There is a need for effective extended models that also capture the impact of alpha-cell dysregulation on T2D. In this paper a delay differential equation-based model is developed to describe the coupled glucose-insulin-glucagon dynamics in the isoglycemic intravenous glucose infusion (IIGI) experiment. As the glucose profile in IIGI is tailored to match that of a corresponding oral glucose tolerance test (OGTT), it provides a perfect method for studying hormone responses that are in the normal physiological domain and without the confounding effect of incretins and other gut mediated factors. The model was fit to IIGI data from individuals with and without T2D. Parameters related to glucagon action, suppression, and secretion as well as measures of insulin sensitivity, and glucose stimulated response were determined simultaneously. Significant impairment in glucose dependent glucagon suppression was observed in patients with T2D (duration of T2D: 8 (6-36) months) relative to weight matched control subjects (CS) without diabetes (k1 (mM)-1: 0.16 ± 0.015 (T2D, n = 7); 0.26 ± 0.047 (CS, n = 7)). Insulin action was significantly lower in patients with T2D (a1 (10 pM min)-1: 0.000084 ± 0.0000075 (T2D); 0.00052 ± 0.00015 (CS)) and the Hill coefficient in the equation for glucose dependent insulin response was found to be significantly different in T2D patients relative to CS (h: 1.4 ± 0.15; 1.9 ± 0.14). Trends in parameters with respect to fasting plasma glucose, HbA1c and 2-h glucose values are also presented. Significantly, a negative linear relationship is observed between the glucagon suppression parameter, k1, and the three markers for diabetes and is thus indicative of the role of glucagon in exacerbating the pathophysiology of diabetes (Spearman Rank Correlation: (n = 12; (-0.79, 0.002), (-0.73,.007), (-0.86,.0003)) respectively).
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Affiliation(s)
- Vijaya Subramanian
- Institute for Computational Medicine, Johns Hopkins University, Baltimore, MD, United States
| | - Jonatan I. Bagger
- Center for Clinical Metabolic Research, Herlev and Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Clinical Research, Steno Diabetes Center Copenhagen, Herlev, Denmark
| | - Jens J. Holst
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Filip K. Knop
- Center for Clinical Metabolic Research, Herlev and Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Clinical Research, Steno Diabetes Center Copenhagen, Herlev, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Tina Vilsbøll
- Center for Clinical Metabolic Research, Herlev and Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
- Clinical Research, Steno Diabetes Center Copenhagen, Herlev, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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Åkerström T, Stolpe MN, Widmer R, Dejgaard TF, Højberg JM, Møller K, Hansen JS, Trinh B, Holst JJ, Thomsen C, Pedersen BK, Ellingsgaard H. Endurance Training Improves GLP-1 Sensitivity and Glucose Tolerance in Overweight Women. J Endocr Soc 2022; 6:bvac111. [PMID: 35935071 PMCID: PMC9351379 DOI: 10.1210/jendso/bvac111] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Indexed: 11/19/2022] Open
Abstract
Context and objective Obesity and inactivity are risk factors for developing impaired glucose tolerance characterized by insulin resistance and reduced beta-cell function. The stimulatory effect of glucagon-like peptide 1 (GLP-1) on insulin secretion is also impaired in obese, inactive individuals. The aim of this study was to investigate whether endurance training influences beta-cell sensitivity to GLP-1. Participants and intervention Twenty-four female participants, age 46 ± 2 years, body mass index 32.4 ± 0.9 kg/m2, and maximal oxygen consumption 24.7 ± 0.8 mL/kg/min participated in a 10-week exercise training study. Methods Beta-cell sensitivity to GLP-1 was assessed in a subset of participants (n = 6) during a 120-minute hyperglycemic glucose clamp (8.5 mM) including a 1-hour GLP-1 (7-36 amide) infusion (0.4 pmol/kg/min). Changes in glucose tolerance, body composition, and cardiorespiratory fitness were assessed by oral glucose tolerance tests (OGTTs), dual-energy X-ray absorptiometry scans, magnetic resonance scans, and maximal oxygen consumption (VO2max) tests, respectively. Results The c-peptide response to infusion of GLP-1 increased 28 ± 3% (P < 0.05) toward the end of the hyperglycemic clamp. The insulin response remained unchanged. Training improved glucose tolerance and reduced GLP-1, insulin, and glucagon levels during the OGTTs. Training increased VO2max (from 24.7 ± 0.8 to 27.0 ± 0.7 mL/kg/min; P < 0.05) and reduced visceral fat volume (from 4176 ± 265 to 3888 ± 266 cm3; P < 0.01). Conclusion Along with improved glycemic control, endurance training improved beta-cell sensitivity to GLP-1 in overweight women. The study was deemed not to constitute a clinical trial and was not registered as such.
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Affiliation(s)
- Thorbjörn Åkerström
- Centre of Inflammation and Metabolism and Centre for Physical Activity Research, Rigshospitalet, Copenhagen University Hospital – Rigshospitalet , DK 2100 Copenhagen , Denmark
- Diabetes Pharmacology 1, Novo Nordisk A/S , Maaløv , Denmark
| | - Malene N Stolpe
- Centre of Inflammation and Metabolism and Centre for Physical Activity Research, Rigshospitalet, Copenhagen University Hospital – Rigshospitalet , DK 2100 Copenhagen , Denmark
- Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen , DK 2200 Copenhagen , Denmark
| | - Renate Widmer
- Centre of Inflammation and Metabolism and Centre for Physical Activity Research, Rigshospitalet, Copenhagen University Hospital – Rigshospitalet , DK 2100 Copenhagen , Denmark
| | - Thomas F Dejgaard
- Centre of Inflammation and Metabolism and Centre for Physical Activity Research, Rigshospitalet, Copenhagen University Hospital – Rigshospitalet , DK 2100 Copenhagen , Denmark
| | - Jens M Højberg
- Department of Cardiothoracic Anesthesiology and Intensive Care, Rigshospitalet , DK 2100 Copenhagen , Denmark
| | - Kirsten Møller
- Centre of Inflammation and Metabolism and Centre for Physical Activity Research, Rigshospitalet, Copenhagen University Hospital – Rigshospitalet , DK 2100 Copenhagen , Denmark
- Intensive Care Unit 4131, Rigshospitalet , DK 2100 Copenhagen , Denmark
| | - Jakob S Hansen
- Centre of Inflammation and Metabolism and Centre for Physical Activity Research, Rigshospitalet, Copenhagen University Hospital – Rigshospitalet , DK 2100 Copenhagen , Denmark
- Novo Nordisk A/S , Søborg , Denmark
| | - Beckey Trinh
- Centre of Inflammation and Metabolism and Centre for Physical Activity Research, Rigshospitalet, Copenhagen University Hospital – Rigshospitalet , DK 2100 Copenhagen , Denmark
| | - Jens J Holst
- Department of Biomedical Sciences and the NNF Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen , DK 2200 Copenhagen , Denmark
| | - Carsten Thomsen
- Department of Radiology, Rigshospitalet, University of Copenhagen , DK 2100 Copenhagen , Denmark
| | - Bente K Pedersen
- Centre of Inflammation and Metabolism and Centre for Physical Activity Research, Rigshospitalet, Copenhagen University Hospital – Rigshospitalet , DK 2100 Copenhagen , Denmark
| | - Helga Ellingsgaard
- Centre of Inflammation and Metabolism and Centre for Physical Activity Research, Rigshospitalet, Copenhagen University Hospital – Rigshospitalet , DK 2100 Copenhagen , Denmark
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Beaudry KM, Surdi JC, Mari A, Devries MC. Exercise mode influences post-exercise glucose sensitivity and insulin clearance in young, healthy males and females in a sex-dependent manner: A randomized control trial. Physiol Rep 2022; 10:e15354. [PMID: 35785485 PMCID: PMC9251832 DOI: 10.14814/phy2.15354] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Revised: 05/11/2022] [Accepted: 05/21/2022] [Indexed: 06/15/2023] Open
Abstract
Type 2 diabetes (T2D) risk is lower in females than males. It has been reported that females have greater pancreatic 𝛽-cell function than males, which may at least in part contribute to the T2D risk in females. 𝛽-cell function is influenced by exercise training; however, previous trials comparing 𝛽-cell function between the sexes have not included participants matched for training status. Furthermore, the acute effects of different modes of exercise on 𝛽-cell function, and whether sex inherently influences these effects, are largely unexamined. Males and females (12/sex) completed a 120-min oral glucose tolerance test (OGTT) at rest (CON) and following acute bouts of high-intensity interval exercise (HIIE), moderate intensity continuous (MIC) exercise, and low-load high-repetition (LLHR) resistance exercise to assess whether sex inherently influences baseline and/or post-exercise pancreatic function in the absence of pathology. We found no sex differences in basal pancreatic 𝛽-cell function. Females had greater basal insulin clearance following MIC exercise compared to males (p = 0.01) and males tended to have a higher potentiation ratio following HIIE (p = 0.07). Females also had lower glucose sensitivity following MIC exercise compared to HIIE (p = 0.007) and LLHR (p = 0.003). Insulin clearance during the OGTT was greater following HIIE as compared with CON and MIC exercise (p = 0.02). 2-H oral glucose insulin sensitivity was greater following LLHR compared to CON (p = 0.01). Acute bouts of different modes of exercise do not differentially influence 𝛽-cell function but do influence insulin clearance and insulin sensitivity. Therefore, sex and exercise mode interact to differentially influence insulin clearance and glucose sensitivity.
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Affiliation(s)
| | - Julian C. Surdi
- Department of KinesiologyUniversity of WaterlooWaterlooCanada
| | - Andrea Mari
- Institute of Neuroscience, National Research CouncilPadovaItaly
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Moon JS, Riopel M, Seo JB, Herrero-Aguayo V, Isaac R, Lee YS. HIF-2α Preserves Mitochondrial Activity and Glucose Sensing in Compensating β-Cells in Obesity. Diabetes 2022; 71:1508-1524. [PMID: 35472707 PMCID: PMC9233300 DOI: 10.2337/db21-0736] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Accepted: 04/08/2022] [Indexed: 11/13/2022]
Abstract
In obesity, increased mitochondrial metabolism with the accumulation of oxidative stress leads to mitochondrial damage and β-cell dysfunction. In particular, β-cells express antioxidant enzymes at relatively low levels and are highly vulnerable to oxidative stress. Early in the development of obesity, β-cells exhibit increased glucose-stimulated insulin secretion in order to compensate for insulin resistance. This increase in β-cell function under the condition of enhanced metabolic stress suggests that β-cells possess a defense mechanism against increased oxidative damage, which may become insufficient or decline at the onset of type 2 diabetes. Here, we show that metabolic stress induces β-cell hypoxia inducible factor 2α (HIF-2α), which stimulates antioxidant gene expression (e.g., Sod2 and Cat) and protects against mitochondrial reactive oxygen species (ROS) and subsequent mitochondrial damage. Knockdown of HIF-2α in Min6 cells exaggerated chronic high glucose-induced mitochondrial damage and β-cell dysfunction by increasing mitochondrial ROS levels. Moreover, inducible β-cell HIF-2α knockout mice developed more severe β-cell dysfunction and glucose intolerance on a high-fat diet, along with increased ROS levels and decreased islet mitochondrial mass. Our results provide a previously unknown mechanism through which β-cells defend against increased metabolic stress to promote β-cell compensation in obesity.
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Affiliation(s)
- Jae-Su Moon
- Division of Endocrinology and Metabolism, Department of Medicine, University of California San Diego, La Jolla, CA
| | - Matthew Riopel
- Division of Endocrinology and Metabolism, Department of Medicine, University of California San Diego, La Jolla, CA
| | - Jong Bae Seo
- Division of Endocrinology and Metabolism, Department of Medicine, University of California San Diego, La Jolla, CA
| | - Vicente Herrero-Aguayo
- Division of Endocrinology and Metabolism, Department of Medicine, University of California San Diego, La Jolla, CA
- Maimonides Institute of Biomedical Research of Cordoba, Cordoba, Spain
| | - Roi Isaac
- Division of Endocrinology and Metabolism, Department of Medicine, University of California San Diego, La Jolla, CA
| | - Yun Sok Lee
- Division of Endocrinology and Metabolism, Department of Medicine, University of California San Diego, La Jolla, CA
- Corresponding author: Yun Sok Lee,
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35
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Moore BF, Sauder KA, Shapiro ALB, Crume T, Kinney GL, Dabelea D. Fetal Exposure to Cannabis and Childhood Metabolic Outcomes: The Healthy Start Study. J Clin Endocrinol Metab 2022; 107:e2862-e2869. [PMID: 35357471 PMCID: PMC9202691 DOI: 10.1210/clinem/dgac101] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Indexed: 02/07/2023]
Abstract
OBJECTIVE To assess the impact of fetal exposure to cannabis on adiposity and glucose-insulin traits in early life. RESEARCH DESIGN AND METHODS We leveraged a subsample of 103 mother-child pairs from Healthy Start, an ethnically diverse Colorado-based cohort. Twelve cannabinoids/metabolites of cannabis (including Δ9-tetrahydrocannabinol and cannabidiol) were measured in maternal urine collected at ~27 weeks' gestation. Fetal exposure to cannabis was dichotomized as exposed (any cannabinoid > limit of detection [LOD]) and not exposed (all cannabinoids < LOD). Fat mass and fat-free mass were measured via air displacement plethysmography at follow-up (mean age: 4.7 years). Glucose and insulin were obtained after an overnight fast. Generalized linear models estimated the associations between fetal exposure to cannabis with adiposity measures (fat mass [kg], fat-free mass [kg], adiposity [fat mass percentage], body mass index [BMI], and BMI z-scores) and metabolic measures (glucose [mg/dL], insulin [uIU/mL], and homeostatic model assessment of insulin resistance [HOMA-IR]). RESULTS Approximately 15% of the women had detectable levels of any cannabinoid, indicating fetal exposure to cannabis. Exposed offspring had higher fat mass (1.0 kg; 95% CI, 0.3-1.7), fat-free mass (1.2 kg; 95% CI, 0.4-2.0), adiposity (2.6%; 95% CI, 0.1-5.2), and fasting glucose (5.6 mg/dL; 95% CI, 0.8-10.3) compared with nonexposed offspring. No associations were found with fasting insulin (in the fully adjusted model), HOMA-IR, BMI, or BMI z-scores. CONCLUSIONS We provide novel evidence to suggest an association between fetal exposure to cannabis with increased adiposity and fasting glucose in childhood, a finding that should be validated in other cohorts.
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Affiliation(s)
- Brianna F Moore
- Correspondence: Brianna F. Moore, PhD, Lifecourse Epidemiology of Adiposity and Diabetes (LEAD) Center, Colorado School of Public Health, 12474 East 19th Avenue, Campus Box F426, Aurora, CO 80045, USA. E-mail:
| | - Katherine A Sauder
- Lifecourse Epidemiology of Adiposity and Diabetes (LEAD) Center, Colorado School of Public Health, Aurora, CO 80045, USA
- Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO 80045, USA
- Department of Epidemiology, Colorado School of Public Health, Aurora, CO 80045, USA
| | - Allison L B Shapiro
- Department of Psychiatry, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Tessa Crume
- Department of Epidemiology, Colorado School of Public Health, Aurora, CO 80045, USA
| | - Gregory L Kinney
- Department of Epidemiology, Colorado School of Public Health, Aurora, CO 80045, USA
| | - Dana Dabelea
- Lifecourse Epidemiology of Adiposity and Diabetes (LEAD) Center, Colorado School of Public Health, Aurora, CO 80045, USA
- Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO 80045, USA
- Department of Epidemiology, Colorado School of Public Health, Aurora, CO 80045, USA
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Luseogliflozin preserves the pancreatic beta-cell mass and function in db/db mice by improving mitochondrial function. Sci Rep 2022; 12:9740. [PMID: 35697838 PMCID: PMC9192642 DOI: 10.1038/s41598-022-13888-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Accepted: 05/30/2022] [Indexed: 11/20/2022] Open
Abstract
We aimed to determine the mechanism by which the sodium glucose co-transporter 2 inhibitor, luseogliflozin, preserves pancreatic beta-cell mass and function in db/db mice. Six-week-old db/db mice were fed to standard chow or standard chow containing 0.01% luseogliflozin. After 4 weeks, DNA microarray analysis, real-time PCR analysis, and measurement of mitochondrial respiratory capacity and reactive oxygen species (ROS) generation were performed using isolated islets. Immunohistochemistry and electron microscopic analysis were performed using pancreatic tissues. Metabolites extracted from the islets were measured by capillary electrophoresis mass spectrometry. The expression of genes involved in the tricarboxylic acid (TCA) cycle and electron transport chain was upregulated by luseogliflozin. Luseogliflozin improved the mitochondrial complex II-linked oxidative phosphorylation capacity and reduced ROS generation. Mitochondrial morphology was normally maintained by luseogliflozin. Luseogliflozin increased NK6 homeobox 1 (NKX6.1) expression and TCA cycle metabolites. Relief of glucotoxicity by luseogliflozin may involve lower mitochondrial ROS generation and an improvement in complex II-linked mitochondrial respiration. Reducing ROS generation through preventing complex II damage likely increases NKX6.1 expression and ameliorate glucose metabolism in the TCA cycle, contributing to the protection of pancreatic beta-cells. Protection of complex II in pancreatic beta-cells represents a novel therapeutic target for type 2 diabetes.
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Lavynenko O, Abdul-Ghani M, Alatrach M, Puckett C, Adams J, Abdelgani S, Alkhouri N, Triplitt C, Clarke GD, Vasquez JA, Li J, Cersosimo E, Gastaldelli A, DeFronzo RA. Combination therapy with pioglitazone/exenatide/metformin reduces the prevalence of hepatic fibrosis and steatosis: The efficacy and durability of initial combination therapy for type 2 diabetes (EDICT). Diabetes Obes Metab 2022; 24:899-907. [PMID: 35014145 DOI: 10.1111/dom.14650] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Revised: 01/05/2022] [Accepted: 01/06/2022] [Indexed: 12/11/2022]
Abstract
AIM To compare the efficacy of triple therapy (metformin/exenatide/pioglitazone) versus stepwise conventional therapy (metformin → glipizide → glargine insulin) on liver fat content and hepatic fibrosis in newly diagnosed, drug-naïve patients with type 2 diabetes. METHODS Sixty-eight patients completed the 6-year follow-up and had an end-of-study (EOS) FibroScan to provide measures of steatosis (controlled attenuation parameter [CAP] in dB/m) and fibrosis (liver stiffness measurement [LSM] in kPa); 59 had magnetic resonance imaging-proton density fat fraction (MRI-PDFF) to measure liver fat. RESULTS At EOS, HbA1c was 6.8% and 6.0% in triple and conventional therapy groups, respectively (P = .0006). Twenty-seven of 39 subjects (69%) receiving conventional therapy had grade 2/3 steatosis (CAP, FibroScan) versus nine of 29 (31%) in triple therapy (P = .0003). Ten of 39 (26%) subjects receiving conventional therapy had stage 3/4 fibrosis (LSM) versus two of 29 (7%) in triple therapy (P = .04). Conventional therapy subjects had more liver fat (MRI-PDFF) than triple therapy (12.9% vs. 8.8%, P = .03). The severity of steatosis (CAP) (r = 0.42, P < .001) and fibrosis (LSM) (r = -0.48, P < .001) correlated inversely with the Matsuda Index of insulin sensitivity, but not with percentage body fat. Aspartate aminotransferase (AST) to Platelet Ratio Index (APRI), non-alcoholic fatty liver disease fibrosis score (NFS), plasma AST, and alanine aminotransferase (ALT) all decreased significantly with triple therapy, but only the decrease in plasma AST and ALT correlated with the severity of steatosis and fibrosis at EOS. CONCLUSIONS At EOS, subjects with type 2 diabetes treated with triple therapy had less hepatic steatosis and fibrosis versus conventional therapy; the severity of hepatic steatosis and fibrosis were both strongly and inversely correlated with insulin resistance; and changes in liver fibrosis scores (APRI, NFS, Fibrosis-4, and AST/ALT ratio) have limited value in predicting response to therapy.
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Affiliation(s)
- Olga Lavynenko
- University of Texas Health Science Center and Texas Diabetes Institute, San Antonio, Texas
| | - Muhammad Abdul-Ghani
- University of Texas Health Science Center and Texas Diabetes Institute, San Antonio, Texas
| | - Mariam Alatrach
- University of Texas Health Science Center and Texas Diabetes Institute, San Antonio, Texas
| | - Curtiss Puckett
- University of Texas Health Science Center and Texas Diabetes Institute, San Antonio, Texas
| | - John Adams
- University of Texas Health Science Center and Texas Diabetes Institute, San Antonio, Texas
| | - Siham Abdelgani
- University of Texas Health Science Center and Texas Diabetes Institute, San Antonio, Texas
| | - Naim Alkhouri
- University of Texas Health Science Center and Texas Diabetes Institute, San Antonio, Texas
| | - Curtis Triplitt
- University of Texas Health Science Center and Texas Diabetes Institute, San Antonio, Texas
| | - Geoffrey D Clarke
- University of Texas Health Science Center and Texas Diabetes Institute, San Antonio, Texas
| | - Juan A Vasquez
- University of Texas Health Science Center and Texas Diabetes Institute, San Antonio, Texas
| | - Jinqi Li
- University of Texas Health Science Center and Texas Diabetes Institute, San Antonio, Texas
| | - Eugenio Cersosimo
- University of Texas Health Science Center and Texas Diabetes Institute, San Antonio, Texas
| | - Amalia Gastaldelli
- University of Texas Health Science Center and Texas Diabetes Institute, San Antonio, Texas
| | - Ralph A DeFronzo
- University of Texas Health Science Center and Texas Diabetes Institute, San Antonio, Texas
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Wang H, Zhou Y, Wang Y, Cai T, Hu Y, Jing T, Ding B, Su X, Li H, Ma J. Basal Insulin Reduces Glucose Variability and Hypoglycaemia Compared to Premixed Insulin in Type 2 Diabetes Patients: A Study Based on Continuous Glucose Monitoring Systems. Front Endocrinol (Lausanne) 2022; 13:791439. [PMID: 35574003 PMCID: PMC9092280 DOI: 10.3389/fendo.2022.791439] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Accepted: 03/29/2022] [Indexed: 11/16/2022] Open
Abstract
AIMS To examine the glycaemic variability and safety of basal and premixed insulin by using continuous glucose monitoring (CGM) systems. METHODS 393 patients with type 2 diabetes mellitus (T2DM) treated with basal or premixed insulin for more than 3 months were enrolled. Patients were classified into a basal insulin group or premixed insulin group according to their insulin regimens. CGMs were used for 72 h with their previous hypoglycaemic regimen unchanged. The following glycaemic parameters were calculated for each 24 h using CGM data. RESULTS Despite similar HbA1c and fasting C-peptide concentrations, glycaemic variability (GV), including the mean amplitude of glycaemic excursion (MAGE), standard deviation (SD) and coefficient of variation (CV), and the time below range (TBR) were significantly lower in the basal insulin group than these in the premixed insulin group. Night-time hypoglycaemia was lower in the basal insulin group than that in the premixed insulin group (p<0.01). Among participants with haemoglobin A1c (HbA1c) < 7%, the GV and TBR were higher in the premixed insulin group than that in the basal insulin group. CONCLUSION Compared with basal insulin, the patients who use premixed insulin had higher GV, smaller TIR and an increased incidence of hypoglycaemia. For patients who use premixed insulin and with HbA1c < 7%, more attention needs to be given to hypoglycaemic events and asymptomatic hypoglycaemia. CLINICAL TRIAL REGISTRATION ClinicalTrials.gov, identifier NCT03566472.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Huiqin Li
- Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Jianhua Ma
- Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
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Kobayashi H, Zha X, Nagase K, Inamura S, Taga M, Aoki Y, Ito H, Yokoyama O. Phosphodiesterase 5 inhibitor suppresses prostate weight increase in type 2 diabetic rats. Life Sci 2022; 298:120504. [PMID: 35367242 DOI: 10.1016/j.lfs.2022.120504] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2022] [Revised: 03/22/2022] [Accepted: 03/24/2022] [Indexed: 10/18/2022]
Abstract
AIMS Hyperinsulinemia is an important causative factor of prostate enlargement in type 2 diabetes (T2D), however, clinically prostate weight increases during hypoinsulinemic condition. To investigate the pathogenesis of prostate enlargement and effects of phosphodiesterase 5 inhibitor (PDE5i), male Otsuka Long-Evans Tokushima Fatty (OLETF) and Long-Evans Tokushima Otsuka (LETO) rats were used as T2D and control, respectively. MATERIALS AND METHODS OLETF and LETO rats were treated with oral tadalafil (100 μg/kg/day) or vehicle for 12 wks from at the age of 36 wks. KEY FINDINGS Prostate weight of OLETF rats was significantly higher than that of LETO at 36 wks, and increased at 48 wks. In OLETF rats, prostate blood flow was significantly lower at 48 wks versus 36 wks. Twelve-week-tadalafil treatment increased prostate blood flow and suppressed prostate weight increase in both strains. This change was inversely correlated with changes in prostate expressions of hypoxia-inducible factor-1 alpha (HIF-1α) and 8-hydroxy-2'-deoxyguanosine (8-OHdG). Increases with age were observed in mRNA and/or protein levels of cytokines interleukin (IL)-6, IL-8, and tumor necrosis factor-alpha (TNF-α) and cell growth factors insulin-like growth factor-1 (IGF-1), basic fibroblast growth factor (bFGF), and transforming growth factor-beta (TGF-β); especially IL-6, TNF-α, IGF-1, bFGF and TGF-β increased with T2D. Tadalafil suppressed these cytokines and growth factors. SIGNIFICANCE These data suggest chronic ischemia caused by T2D leads to oxidative stress, resulting in prostate enlargement through upregulation of several cytokines and growth factors. Treatment with PDE5i improves prostate ischemia and might prevent enlargement via suppression of cytokines and growth factors in T2D.
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Affiliation(s)
- Hisato Kobayashi
- Department of Urology, Faculty of Medical Science, University of Fukui, Fukui, Japan.
| | - Xinmin Zha
- Department of Urology, Faculty of Medical Science, University of Fukui, Fukui, Japan
| | - Keiko Nagase
- Department of Urology, Faculty of Medical Science, University of Fukui, Fukui, Japan
| | - So Inamura
- Department of Urology, Faculty of Medical Science, University of Fukui, Fukui, Japan
| | - Minekatsu Taga
- Department of Urology, Faculty of Medical Science, University of Fukui, Fukui, Japan
| | - Yoshitaka Aoki
- Department of Urology, Faculty of Medical Science, University of Fukui, Fukui, Japan
| | - Hideaki Ito
- Department of Urology, Faculty of Medical Science, University of Fukui, Fukui, Japan
| | - Osamu Yokoyama
- Department of Urology, Faculty of Medical Science, University of Fukui, Fukui, Japan
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Ilegems E, Bryzgalova G, Correia J, Yesildag B, Berra E, Ruas JL, Pereira TS, Berggren PO. HIF-1α inhibitor PX-478 preserves pancreatic β cell function in diabetes. Sci Transl Med 2022; 14:eaba9112. [PMID: 35353540 DOI: 10.1126/scitranslmed.aba9112] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
During progression of type 2 diabetes, pancreatic β cells are subjected to sustained metabolic overload. We postulated that this state mediates a hypoxic phenotype driven by hypoxia-inducible factor-1α (HIF-1α) and that treatment with the HIF-1α inhibitor PX-478 would improve β cell function. Our studies showed that the HIF-1α protein was present in pancreatic β cells of diabetic mouse models. In mouse islets with high glucose metabolism, the emergence of intracellular Ca2+ oscillations at low glucose concentration and the abnormally high basal release of insulin were suppressed by treatment with the HIF-1α inhibitor PX-478, indicating improvement of β cell function. Treatment of db/db mice with PX-478 prevented the rise of glycemia and diabetes progression by maintenance of elevated plasma insulin concentration. In streptozotocin-induced diabetic mice, PX-478 improved the recovery of glucose homeostasis. Islets isolated from these mice showed hallmarks of improved β cell function including elevation of insulin content, increased expression of genes involved in β cell function and maturity, inhibition of dedifferentiation markers, and formation of mature insulin granules. In response to PX-478 treatment, human islet organoids chronically exposed to high glucose presented improved stimulation index of glucose-induced insulin secretion. These results suggest that the HIF-1α inhibitor PX-478 has the potential to act as an antidiabetic therapeutic agent that preserves β cell function under metabolic overload.
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Affiliation(s)
- Erwin Ilegems
- The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, SE-171 76 Stockholm, Sweden
| | - Galyna Bryzgalova
- The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, SE-171 76 Stockholm, Sweden
| | - Jorge Correia
- Department of Physiology and Pharmacology, Molecular and Cellular Exercise Physiology, Karolinska Institutet, SE-171 77 Stockholm, Sweden
| | | | - Edurne Berra
- Centro de Investigación Cooperativa en Biociencias CIC bioGUNE, 48160 Derio, Spain
| | - Jorge L Ruas
- Department of Physiology and Pharmacology, Molecular and Cellular Exercise Physiology, Karolinska Institutet, SE-171 77 Stockholm, Sweden
| | - Teresa S Pereira
- The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, SE-171 76 Stockholm, Sweden.,Department of Physiology and Pharmacology, Molecular and Cellular Exercise Physiology, Karolinska Institutet, SE-171 77 Stockholm, Sweden
| | - Per-Olof Berggren
- The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, SE-171 76 Stockholm, Sweden.,Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.,Lee Kong Chian School of Medicine, Nanyang Technological University, Novena Campus, 308232 Singapore, Singapore.,School of Biomedical Sciences, Ulster University, BT52 1SA Coleraine, Northern Ireland, UK
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Tong X, Liu S, Stein R, Imai Y. Lipid Droplets' Role in the Regulation of β-Cell Function and β-Cell Demise in Type 2 Diabetes. Endocrinology 2022; 163:6516108. [PMID: 35086144 PMCID: PMC8826878 DOI: 10.1210/endocr/bqac007] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Indexed: 01/29/2023]
Abstract
During development of type 2 diabetes (T2D), excessive nutritional load is thought to expose pancreatic islets to toxic effects of lipids and reduce β-cell function and mass. However, lipids also play a positive role in cellular metabolism and function. Thus, proper trafficking of lipids is critical for β cells to maximize the beneficial effects of these molecules while preventing their toxic effects. Lipid droplets (LDs) are organelles that play an important role in the storage and trafficking of lipids. In this review, we summarize the discovery of LDs in pancreatic β cells, LD lifecycle, and the effect of LD catabolism on β-cell insulin secretion. We discuss factors affecting LD formation such as age, cell type, species, and nutrient availability. We then outline published studies targeting critical LD regulators, primarily in rat and human β-cell models, to understand the molecular effect of LD formation and degradation on β-cell function and health. Furthermore, based on the abnormal LD accumulation observed in human T2D islets, we discuss the possible role of LDs during the development of β-cell failure in T2D. Current knowledge indicates that proper formation and clearance of LDs are critical to normal insulin secretion, endoplasmic reticulum homeostasis, and mitochondrial integrity in β cells. However, it remains unclear whether LDs positively or negatively affect human β-cell demise in T2D. Thus, we discuss possible research directions to address the knowledge gap regarding the role of LDs in β-cell failure.
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Affiliation(s)
- Xin Tong
- Department of Molecular Physiology & Biophysics, Vanderbilt University, Nashville, Tennessee 37232, USA
| | - Siming Liu
- Department of Internal Medicine Carver College of Medicine, Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, Iowa 52242, USA
| | - Roland Stein
- Department of Molecular Physiology & Biophysics, Vanderbilt University, Nashville, Tennessee 37232, USA
| | - Yumi Imai
- Department of Internal Medicine Carver College of Medicine, Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, Iowa 52242, USA
- Iowa City Veterans Affairs Medical Center, Iowa City, Iowa 52246, USA
- Correspondence: Yumi Imai, MD, Department of Internal Medicine Carver College of Medicine, Fraternal Order of Eagles Diabetes Research Center, University of Iowa, 200 Hawkins Dr, PBDB Rm 3318, Iowa City, IA 52242, USA.
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Magkos F, Lee MH, Lim M, Cook AR, Chhay V, Loh TP, Chia KS, Baig S, Ang IYH, Tay JYY, Khoo CM, Halter JB, Toh SA. Dynamic assessment of insulin secretion and insulin resistance in Asians with prediabetes. Metabolism 2022; 128:154957. [PMID: 34942192 DOI: 10.1016/j.metabol.2021.154957] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2021] [Revised: 12/03/2021] [Accepted: 12/13/2021] [Indexed: 11/18/2022]
Abstract
AIMS/HYPOTHESIS Prediabetes and type 2 diabetes are highly prevalent in Asia. Understanding the pathophysiology of abnormal glucose homeostasis in Asians will have important implications for reducing disease burden, but there have been conflicting reports on the relative contributions of insulin secretion and action in disease progression. In this study, we aimed to assess the contribution of β-cell dysfunction and insulin resistance in the Asian prediabetes phenotype. METHODS We recruited 1679 Asians with prediabetes (n = 659) or normoglycemia (n = 1020) from a multi-ethnic population in Singapore. Participants underwent an oral glucose tolerance test, an intravenous glucose challenge, and a hyperinsulinemic-euglycemic clamp procedure to determine glucose tolerance, β-cell responsivity, insulin secretion, insulin clearance and insulin sensitivity. RESULTS Participants with prediabetes had significantly higher glucose concentrations in the fasting state and after glucose ingestion than did normoglycemic participants. Insulin sensitivity (M/I ratio) was ~15% lower, acute insulin response (AIR) to intravenous glucose and β-cell responsivity to oral glucose were ~35% lower, but total insulin secretion rate in the fasting state and after glucose ingestion was ~10% greater in prediabetic than in normoglycemic participants. The decrease in β-cell function with worsening glucose homeostasis in Asians with prediabetes was associated with progressively greater defects in AIR rather than M/I. However, analysis using static surrogate measures (HOMA indices) of insulin resistance and β-cell function revealed a different pattern. CONCLUSIONS Lower AIR to intravenous glucose and β-cell responsivity to oral glucose, on a background of mild insulin resistance, are the major contributors to the dysregulation of glucose homeostasis in Asians with prediabetes.
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Affiliation(s)
- Faidon Magkos
- Department of Nutrition, Exercise and Sports, University of Copenhagen, Denmark
| | - Michelle H Lee
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Maybritte Lim
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Alex R Cook
- Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore
| | - Vanna Chhay
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Tze Ping Loh
- Department of Laboratory Medicine, National University Hospital, Singapore
| | - Kee Seng Chia
- Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore
| | - Sonia Baig
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Ian Yi Han Ang
- Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore
| | | | - Chin Meng Khoo
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Department of Medicine, National University Hospital, Singapore
| | - Jeffrey B Halter
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Division of Geriatric and Palliative Medicine, University of Michigan, USA
| | - Sue-Anne Toh
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; NOVI Health, Singapore; Department of Medicine, National University Hospital, Singapore; Regional Health System Office, National University Health System, Singapore; Singapore Population HEalth ImpRovement Centre (SPHERiC), National University Health System, Singapore.
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Eguchi N, Toribio AJ, Alexander M, Xu I, Whaley DL, Hernandez LF, Dafoe D, Ichii H. Dysregulation of β-Cell Proliferation in Diabetes: Possibilities of Combination Therapy in the Development of a Comprehensive Treatment. Biomedicines 2022; 10:biomedicines10020472. [PMID: 35203680 PMCID: PMC8962301 DOI: 10.3390/biomedicines10020472] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Revised: 02/12/2022] [Accepted: 02/15/2022] [Indexed: 02/01/2023] Open
Abstract
Diabetes mellitus (DM) is a metabolic disorder characterized by chronic hyperglycemia as a result of insufficient insulin levels and/or impaired function as a result of autoimmune destruction or insulin resistance. While Type 1 DM (T1DM) and Type 2 DM (T2DM) occur through different pathological processes, both result in β-cell destruction and/or dysfunction, which ultimately lead to insufficient β-cell mass to maintain normoglycemia. Therefore, therapeutic agents capable of inducing β-cell proliferation is crucial in treating and reversing diabetes; unfortunately, adult human β-cell proliferation has been shown to be very limited (~0.2% of β-cells/24 h) and poorly responsive to many mitogens. Furthermore, diabetogenic insults result in damage to β cells, making it ever more difficult to induce proliferation. In this review, we discuss β-cell mass/proliferation pathways dysregulated in diabetes and current therapeutic agents studied to induce β-cell proliferation. Furthermore, we discuss possible combination therapies of proliferation agents with immunosuppressants and antioxidative therapy to improve overall long-term outcomes of diabetes.
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Physiologic Insulin Resensitization as a Treatment Modality for Insulin Resistance Pathophysiology. Int J Mol Sci 2022; 23:ijms23031884. [PMID: 35163806 PMCID: PMC8836751 DOI: 10.3390/ijms23031884] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 01/28/2022] [Accepted: 02/03/2022] [Indexed: 12/10/2022] Open
Abstract
Prevalence of type 2 diabetes increased from 2.5% of the US population in 1990 to 10.5% in 2018. This creates a major public health problem, due to increases in long-term complications of diabetes, including neuropathy, retinopathy, nephropathy, skin ulcers, amputations, and atherosclerotic cardiovascular disease. In this review, we evaluated the scientific basis that supports the use of physiologic insulin resensitization. Insulin resistance is the primary cause of type 2 diabetes. Insulin resistance leads to increasing insulin secretion, leading to beta-cell exhaustion or burnout. This triggers a cascade leading to islet cell destruction and the long-term complications of type 2 diabetes. Concurrent with insulin resistance, the regular bursts of insulin from the pancreas become irregular. This has been treated by the precise administration of insulin more physiologically. There is consistent evidence that this treatment modality can reverse the diabetes-associated complications of neuropathy, diabetic ulcers, nephropathy, and retinopathy, and that it lowers HbA1c. In conclusion, physiologic insulin resensitization has a persuasive scientific basis, significant treatment potential, and likely cost benefits.
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Dunseath GJ, Luzio SD, Peter R, Owens DR. The pathophysiology of glucose intolerance in newly diagnosed, untreated T2DM. Acta Diabetol 2022; 59:207-215. [PMID: 34561756 PMCID: PMC8841334 DOI: 10.1007/s00592-021-01785-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Accepted: 08/09/2021] [Indexed: 02/07/2023]
Abstract
AIMS The two predominant pathophysiological defects resulting in glucose intolerance are beta-cell dysfunction and insulin insensitivity. This study aimed to re-examine beta-cell function and insulin sensitivity across a continuum from normal glucose tolerance (NGT) to early type 2 diabetes (T2DM) employing highly specific insulin, C-peptide and intact proinsulin assays. MATERIALS AND METHODS A total of 104 persons with NGT, 85 with impaired glucose tolerance (IGT) and 554 with newly diagnosed T2DM were investigated. Following an overnight fast, all underwent a 4-h standardised mixed meal tolerance test (MTT), and on a second day, a sub-group underwent a frequently sampled insulin-modified intravenous glucose tolerance test (FSIVGTT) over a 3-h period. The participants were stratified according to fasting glucose and BMI for analysis. RESULTS The MTT revealed that increasing FPG was accompanied by progressively elevated and delayed postprandial glucose peaks. In parallel, following an initial compensatory increase in fasting and postprandial insulin responses there followed a progressive demise in overall beta-cell secretory capacity. FSIVGTT demonstrated a major reduction in the early insulin response to IV glucose in persons with IGT accompanied by a dramatic fall in insulin sensitivity. Beyond pre-diabetes, ever-increasing fasting and postprandial hyperglycaemia resulted predominantly from a progressively decreasing beta-cell secretory function. CONCLUSION This study utilising improved assay technology re-affirms that beta-cell dysfunction is evident throughout the spectrum of glucose intolerance, whereas the predominant fall in insulin sensitivity occurs early in its evolution.
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Affiliation(s)
- Gareth J Dunseath
- Diabetes Research Group, Grove Building, Singleton Park, Swansea, SA2 8PP, UK.
| | - Stephen D Luzio
- Diabetes Research Group, Grove Building, Singleton Park, Swansea, SA2 8PP, UK
| | - Rajesh Peter
- Diabetes Research Group, Grove Building, Singleton Park, Swansea, SA2 8PP, UK
| | - David R Owens
- Diabetes Research Group, Grove Building, Singleton Park, Swansea, SA2 8PP, UK
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Ali D, Mohammedsalih R, Salih R. Glycemic response of honey and dates consumption. BAGHDAD JOURNAL OF BIOCHEMISTRY AND APPLIED BIOLOGICAL SCIENCES 2022. [DOI: 10.47419/bjbabs.v3i01.83] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Background and objective: The current study aims to evaluate the glycemic index of local honey and date intake in healthy adults.
Methods: The study was conducted on 24 healthy volunteers. They were given 50 g of carbohydrates from Haji Omeran local honey, Khudri (or Khadrawi) local date and reference food (white bread). The average body mass index and age of volunteers are almost similar. The blood samples were collected from finger capillaries to assess the glucose levels by using glucometer at selected time points (0, 15, 30, 60, 90, and 120 minutes). The data was recorded and statistically analyzed by one-way ANOVA and Duncan comparison.
Results: The study results showed that the glycemic index of the honey and date is classified as a medium glycemic index, referring to their high carbohydrates content. The results also indicated that honey and dates have significantly different effects (P<0.05) on the blood glucose responses compared to reference food (white bread) in healthy subjects. The mean blood glucose levels after honey ingestion were higher than that when the date was ingested and lower than that of the reference food. In addition, the blood glucose responses for different foods in the study for females and males are not significantly different (P>0.05).
Conclusions: In conclusion, eating behavior regarding honey and date consumption, particularly portion size and ingestion timing, is essential to manage blood glucose levels. Thus, glycemic index values should be considered in promoting a healthy lifestyle from chronic related metabolic disorders especially, diabetes mellitus, cardiovascular disease, and obesity.
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Mittendorfer B, Patterson BW, Smith GI, Yoshino M, Klein S. Beta-cell function and plasma insulin clearance in people with obesity and different glycemic status. J Clin Invest 2021; 132:154068. [PMID: 34905513 PMCID: PMC8803344 DOI: 10.1172/jci154068] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Accepted: 12/08/2021] [Indexed: 12/02/2022] Open
Abstract
Background It is unclear how excess adiposity and insulin resistance affect β cell function, insulin secretion, and insulin clearance in people with obesity. Methods We used a hyperinsulinemic-euglycemic clamp procedure and a modified oral glucose tolerance test to evaluate the interrelationships among obesity, insulin sensitivity, insulin kinetics, and glycemic status in 5 groups of individuals: normoglycemic lean and obese individuals with (a) normal fasting glucose and normal glucose tolerance (Ob-NFG-NGT), (b) NFG and impaired glucose tolerance (Ob-NFG-IGT), (c) impaired fasting glucose and IGT (Ob-IFG-IGT), or (d) type 2 diabetes (Ob-T2D). Results Glucose-stimulated insulin secretion (GSIS), an assessment of β cell function, was greater in the Ob-NFG-NGT and Ob-NFG-IGT groups than in the lean group, even when insulin sensitivity was matched in the obese and lean groups. Insulin sensitivity, not GSIS, was decreased in the Ob-NFG-IGT group compared with the Ob-NFG-NGT group, whereas GSIS, not insulin sensitivity, was decreased in the Ob-IFG-IGT and Ob-T2D groups compared with the Ob-NFG-NGT and Ob-NFG-IGT groups. Insulin clearance was directly related to insulin sensitivity and inversely related to the postprandial increase in insulin secretion and plasma insulin concentration. Conclusion Increased adiposity per se, not insulin resistance, enhanced insulin secretion in people with obesity. The obesity-induced increase in insulin secretion, in conjunction with a decrease in insulin clearance, sufficiently raised the plasma insulin concentrations needed to maintain normoglycemia in individuals with moderate, but not severe, insulin resistance. A deterioration in β cell function, not a decrease in insulin sensitivity, was a determinant of IFG and ultimately leads to T2D. CLINICAL TRIALS REGISTRATION ClinicalTrials.gov NCT02706262, NCT04131166, and NCT01977560. FUNDING NIH (P30 DK056341, P30 DK020579, and UL1 TR000448); American Diabetes Association (1-18-ICTS-119); Longer Life Foundation; Pershing Square Foundation; and Washington University-Centene ARCH Personalized Medicine Initiative (P19-00559).
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Affiliation(s)
- Bettina Mittendorfer
- Center for Human Nutrition, Washington University School of Medicine, St. Louis, United States of America
| | - Bruce W Patterson
- Center for Human Nutrition, Washington University School of Medicine, St. Louis, United States of America
| | - Gordon I Smith
- Center for Human Nutrition, Washington University School of Medicine, St. Louis, United States of America
| | - Mihoko Yoshino
- Center for Human Nutrition, Washington University School of Medicine, St. Louis, United States of America
| | - Samuel Klein
- Center for Human Nutrition, Washington University School of Medicine, St. Louis, United States of America
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Vivek S, Carnethon MR, Prizment A, Carson AP, Bancks MP, Jacobs DR, Thyagarajan B. Association of the extent of return to fasting state 2-hours after a glucose challenge with incident prediabetes and type 2 diabetes: The CARDIA study. Diabetes Res Clin Pract 2021; 180:109004. [PMID: 34391830 PMCID: PMC8655852 DOI: 10.1016/j.diabres.2021.109004] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Revised: 06/24/2021] [Accepted: 08/09/2021] [Indexed: 11/25/2022]
Abstract
AIM To evaluate whether the extent of return to fasting state 2-hours after a glucose challenge among normoglycemic individuals is associated with lower risk of incident prediabetes/ type 2 diabetes in the Coronary Artery Risk Development in Young Adults (CARDIA) cohort study. METHODS We evaluated this association among 1879 normoglycemic adults who were categorized into three groups: 'Low post load' (2hPG < FPG); 'Medium post load' (2hPG ≥ FPG and < 75th percentile of the difference); and 'High post load' (2hPG > FPG and ≥ 75th percentile of the difference). We used Cox proportional hazards regression to evaluate the association of the difference in 2hPG and FPG with incident diabetes/prediabetes after adjustment for demographic and clinical covariates. RESULTS During 20 years of follow-up, 8% developed type 2 diabetes and 35% developed prediabetes. Compared to those with 'Low post load', the risk of type 2 diabetes was higher for participants with 'High post load' [HR: 1.56, 95% CI (1.03, 2.37)] and similar for participants with 'Medium post load' [HR: 0.99, 95% CI (0.64, 1.52)]. However, HRs for incident prediabetes among participants with 'High post load' [HR = 1.2, 95 %CI = (0.98, 1.46)] was not significantly different compared to participants with 'Low post load'. CONCLUSION Among normoglycemic individuals, a difference between 2hPG and FPG concentration > 0.9 mmol/L can be used to stratify individuals at higher risk for developing type 2 diabetes.
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Affiliation(s)
- Sithara Vivek
- University of Minnesota, School of Medicine, Department of Laboratory Medicine and Pathology, United States
| | - Mercedes R Carnethon
- Northwestern University, Chicago, Department of Preventive Medicine, United States
| | - Anna Prizment
- University of Minnesota, Division of Hematology, Oncology and Transplantation, United States
| | - April P Carson
- University of Alabama at Birmingham, School of Public Health, Department of Epidemiology, United States
| | - Michael P Bancks
- Wake Forest, School of Medicine, Department of Epidemiology and Prevention, United States
| | - David R Jacobs
- University of Minnesota, Division of Epidemiology and Community Health, United States
| | - Bharat Thyagarajan
- University of Minnesota, School of Medicine, Department of Laboratory Medicine and Pathology, United States.
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Kahn SE, Chen YC, Esser N, Taylor AJ, van Raalte DH, Zraika S, Verchere CB. The β Cell in Diabetes: Integrating Biomarkers With Functional Measures. Endocr Rev 2021; 42:528-583. [PMID: 34180979 PMCID: PMC9115372 DOI: 10.1210/endrev/bnab021] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Indexed: 02/08/2023]
Abstract
The pathogenesis of hyperglycemia observed in most forms of diabetes is intimately tied to the islet β cell. Impairments in propeptide processing and secretory function, along with the loss of these vital cells, is demonstrable not only in those in whom the diagnosis is established but typically also in individuals who are at increased risk of developing the disease. Biomarkers are used to inform on the state of a biological process, pathological condition, or response to an intervention and are increasingly being used for predicting, diagnosing, and prognosticating disease. They are also proving to be of use in the different forms of diabetes in both research and clinical settings. This review focuses on the β cell, addressing the potential utility of genetic markers, circulating molecules, immune cell phenotyping, and imaging approaches as biomarkers of cellular function and loss of this critical cell. Further, we consider how these biomarkers complement the more long-established, dynamic, and often complex measurements of β-cell secretory function that themselves could be considered biomarkers.
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Affiliation(s)
- Steven E Kahn
- Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, VA Puget Sound Health Care System and University of Washington, Seattle, 98108 WA, USA
| | - Yi-Chun Chen
- BC Children's Hospital Research Institute and Centre for Molecular Medicine and Therapeutics, Vancouver, BC, V5Z 4H4, Canada.,Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, V5Z 4H4, Canada.,Department of Surgery, University of British Columbia, Vancouver, BC, V5Z 4H4, Canada
| | - Nathalie Esser
- Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, VA Puget Sound Health Care System and University of Washington, Seattle, 98108 WA, USA
| | - Austin J Taylor
- BC Children's Hospital Research Institute and Centre for Molecular Medicine and Therapeutics, Vancouver, BC, V5Z 4H4, Canada.,Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, V5Z 4H4, Canada.,Department of Surgery, University of British Columbia, Vancouver, BC, V5Z 4H4, Canada
| | - Daniël H van Raalte
- Department of Internal Medicine, Amsterdam University Medical Center (UMC), Vrije Universiteit (VU) University Medical Center, 1007 MB Amsterdam, The Netherlands.,Department of Experimental Vascular Medicine, Amsterdam University Medical Center (UMC), Academic Medical Center, 1007 MB Amsterdam, The Netherlands
| | - Sakeneh Zraika
- Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, VA Puget Sound Health Care System and University of Washington, Seattle, 98108 WA, USA
| | - C Bruce Verchere
- BC Children's Hospital Research Institute and Centre for Molecular Medicine and Therapeutics, Vancouver, BC, V5Z 4H4, Canada.,Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, V5Z 4H4, Canada.,Department of Surgery, University of British Columbia, Vancouver, BC, V5Z 4H4, Canada
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Bizzotto R, Tricò D, Natali A, Gastaldelli A, Muscelli E, De Fronzo RA, Arslanian S, Ferrannini E, Mari A. New Insights on the Interactions Between Insulin Clearance and the Main Glucose Homeostasis Mechanisms. Diabetes Care 2021; 44:2115-2123. [PMID: 34362813 DOI: 10.2337/dc21-0545] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Accepted: 06/14/2021] [Indexed: 02/03/2023]
Abstract
OBJECTIVE Endogenous insulin clearance (EIC) is physiologically reduced at increasing insulin secretion rate (ISR). Computing EIC at the prevailing ISR does not distinguish the effects of hypersecretion from those of other mechanisms of glucose homeostasis. We aimed to measure EIC in standardized ISR conditions (i.e., at fixed ISR levels) and to analyze its associations with relevant physiologic factors. RESEARCH DESIGN AND METHODS We estimated standardized EIC (EICISR) by mathematical modeling in nine different studies with insulin and glucose infusions (N = 2,067). EICISR association with various traits was analyzed by stepwise multivariable regression in studies with both euglycemic clamp and oral glucose tolerance test (OGTT) (N = 1,410). We also tested whether oral glucose ingestion, as opposed to intravenous infusion, has an independent effect on EIC (N = 1,555). RESULTS Insulin sensitivity (as M/I from the euglycemic clamp) is the strongest determinant of EICISR, approximately four times more influential than insulin resistance-related hypersecretion. EICISR independently associates positively with M/I, fasting and mean OGTT glucose or type 2 diabetes, and β-cell glucose sensitivity and negatively with African American or Hispanic race, female sex, and female age. With oral glucose ingestion, an ISR-independent ∼10% EIC reduction is necessary to explain the observed insulin concentration profiles. CONCLUSIONS Based on EICISR, we posit the existence of two adaptive processes involving insulin clearance: the first reduces EICISR with insulin resistance (not with higher BMI per se) and is more relevant than the concomitant hypersecretion; the second reduces EICISR with β-cell dysfunction. These processes are dysregulated in type 2 diabetes. Finally, oral glucose ingestion per se reduces insulin clearance.
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Affiliation(s)
| | - Domenico Tricò
- Department of Surgical, Medical and Molecular Pathology and Critical Care Medicine, University of Pisa, Pisa, Italy
| | - Andrea Natali
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | | | - Elza Muscelli
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Ralph A De Fronzo
- Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX
| | - Silva Arslanian
- Center for Pediatric Research in Obesity and Metabolism, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA
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