|
1
|
Ohira M, Kawagoe N, Kameyama C, Kondou Y, Igarashi M, Ueshiba H. Association of serum cortisol with insulin secretion and plasma aldosterone with insulin resistance in untreated type 2 diabetes: a cross-sectional study. Diabetol Metab Syndr 2025; 17:144. [PMID: 40296149 PMCID: PMC12036189 DOI: 10.1186/s13098-025-01706-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2025] [Accepted: 04/18/2025] [Indexed: 04/30/2025] Open
Abstract
BACKGROUND Insulin secretion and resistance are key pathophysiological factors in type 2 diabetes. However, only 55% of patients achieve long-term blood glucose treatment goals, highlighting the need to clarify the pathophysiology of type 2 diabetes. While cortisol and aldosterone levels have been linked to insulin secretion and resistance in participants without type 2 diabetes, their role in patients with type 2 diabetes remains unclear. In this study, we aimed to investigate the relationships among insulin secretion, insulin resistance, and cortisol or aldosterone levels in patients with untreated type 2 diabetes. METHODS We retrospectively reviewed 121 patients with untreated type 2 diabetes mellitus. We analyzed the relationships between various clinical parameters, including adrenal hormones, and insulin secretion (homeostatic model assessment [HOMA2-%B]) or insulin resistance (HOMA2-IR). Multiple regression analysis was performed to identify parameters associated with HOMA2-%B or HOMA2-IR. RESULTS Spearman's rank correlation coefficient revealed that body weight (BW); body mass index (BMI); estimated glomerular filtration rate; and serum creatinine, uric acid, total cholesterol, high-density lipoprotein cholesterol (HDL-C), sodium, potassium, chloride, fasting blood glucose (FBG), glycated hemoglobin (HbA1c), serum C-peptide, and cortisol levels were significantly correlated with HOMA2-%B. Similarly, BW, BMI, aspartate transaminase levels, alanine transaminase (ALT) levels, triglyceride levels, HDL-C levels, FBG levels, serum C-peptide levels, renin activity, and plasma aldosterone concentration (PAC) were significantly correlated with HOMA2-IR. Multiple regression analysis revealed BMI, HbA1c levels, and cortisol levels as predictors of HOMA2-%B, whereas ALT levels and the PAC were predictors of HOMA2-IR. CONCLUSION Serum cortisol levels are associated with insulin secretion, and the PAC is associated with insulin resistance in patients with untreated type 2 diabetes. These findings suggest that aldosterone blockade may represent a potential therapeutic approach for reducing insulin resistance in patients with type 2 diabetes.
Collapse
Affiliation(s)
- Masahiro Ohira
- Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Toho University Ohashi Medical Center, 2-22-36 Ohashi, Meguro-ku, Tokyo, 153-8515, Japan.
| | - Naoyuki Kawagoe
- Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Toho University Ohashi Medical Center, 2-22-36 Ohashi, Meguro-ku, Tokyo, 153-8515, Japan
| | - Chisato Kameyama
- Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Toho University Ohashi Medical Center, 2-22-36 Ohashi, Meguro-ku, Tokyo, 153-8515, Japan
| | - Yuko Kondou
- Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Toho University Ohashi Medical Center, 2-22-36 Ohashi, Meguro-ku, Tokyo, 153-8515, Japan
| | - Madoka Igarashi
- Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Toho University Ohashi Medical Center, 2-22-36 Ohashi, Meguro-ku, Tokyo, 153-8515, Japan
| | - Hajime Ueshiba
- Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Toho University Ohashi Medical Center, 2-22-36 Ohashi, Meguro-ku, Tokyo, 153-8515, Japan
| |
Collapse
|
|
2
|
Tijani OK, Moreno-Lopez M, Louvet I, Acosta-Montalvo A, Coddeville A, Gmyr V, Kerr-Conte J, Pattou F, Vantyghem MC, Saponaro C, Bonner C, Espiard S. Impact of therapeutic doses of prednisolone and other glucocorticoids on insulin secretion from human islets. ANNALES D'ENDOCRINOLOGIE 2025; 86:101676. [PMID: 39643079 DOI: 10.1016/j.ando.2024.101676] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Revised: 11/11/2024] [Accepted: 11/25/2024] [Indexed: 12/09/2024]
Abstract
INTRODUCTION Glucocorticoid-induced diabetes (GCID) is a prevalent health issue, generally attributed to insulin resistance. High doses of dexamethasone (DEX) are known to inhibit glucose-stimulated insulin secretion (GSIS), but the effects of lower doses, commonly used in chronic therapy, and equipotent doses of other glucocorticoids (GCs) such as hydrocortisone (HC) and prednisone (PRED) remain underexplored. This study aimed to investigate these effects in vitro, and explore variations between patients. MATERIALS AND METHODS Dynamic perifusion assays were conducted on human islets to evaluate the impact of different GCs on GSIS. The islets were treated for 24h with 250nM PRED and other GCs at equipotent anti-inflammatory doses (HC: 1μM; DEX: 38nM). RESULTS In 11 human islet donor preparations, 250nM PRED, corresponding to a clinical oral dose of 5mg/day, significantly inhibited the first and second phase of GSIS: area under the curve (AUC) decreased by 32.3% (P<0.001), first phase by 41.5% (P<0.001), and second phase by 38.4% (P<0.001). Despite interindividual differences in GSIS response to PRED, no significant differences were observed according to body mass index, gender or age. Comparing the effects of GCs at equipotent anti-inflammatory doses, DEX had a more pronounced inhibitory effect on GSIS than HC or PRED. CONCLUSIONS In vitro, low-dose PRED treatment significantly impacted GSIS. DEX had a more unfavorable impact on GSIS than HC or PRED, indicating that metabolic effects do not align with anti-inflammatory potency.
Collapse
Affiliation(s)
- Omolara Khadijat Tijani
- University of Lille, CHU de Lille, Inserm U1190, EGID, Institut Pasteur de Lille, 59000 Lille, France
| | - Maria Moreno-Lopez
- University of Lille, CHU de Lille, Inserm U1190, EGID, Institut Pasteur de Lille, 59000 Lille, France
| | - Isaline Louvet
- University of Lille, CHU de Lille, Inserm U1190, EGID, Institut Pasteur de Lille, 59000 Lille, France
| | - Ana Acosta-Montalvo
- University of Lille, CHU de Lille, Inserm U1190, EGID, Institut Pasteur de Lille, 59000 Lille, France
| | - Anaïs Coddeville
- University of Lille, CHU de Lille, Inserm U1190, EGID, Institut Pasteur de Lille, 59000 Lille, France
| | - Valery Gmyr
- University of Lille, CHU de Lille, Inserm U1190, EGID, Institut Pasteur de Lille, 59000 Lille, France
| | - Julie Kerr-Conte
- University of Lille, CHU de Lille, Inserm U1190, EGID, Institut Pasteur de Lille, 59000 Lille, France
| | - François Pattou
- University of Lille, CHU de Lille, Inserm U1190, EGID, Institut Pasteur de Lille, 59000 Lille, France
| | - Marie-Christine Vantyghem
- University of Lille, CHU de Lille, Inserm U1190, EGID, Institut Pasteur de Lille, 59000 Lille, France
| | - Chiara Saponaro
- University of Lille, CHU de Lille, Inserm U1190, EGID, Institut Pasteur de Lille, 59000 Lille, France
| | - Caroline Bonner
- University of Lille, CHU de Lille, Inserm U1190, EGID, Institut Pasteur de Lille, 59000 Lille, France.
| | - Stéphanie Espiard
- University of Lille, CHU de Lille, Inserm U1190, EGID, Institut Pasteur de Lille, 59000 Lille, France.
| |
Collapse
|
|
3
|
Okuno Y, Fukuhara A, Shimomura I. The role of oxidative stress, glucocorticoid receptor and ARMC5 in lipid metabolism. Endocr J 2024; 71:1097-1101. [PMID: 38925988 PMCID: PMC11778357 DOI: 10.1507/endocrj.ej24-0177] [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: 03/25/2024] [Accepted: 06/03/2024] [Indexed: 06/28/2024] Open
Abstract
Lipid metabolism includes lipogenesis, lipolysis, and cholesterol metabolism and it exerts a wide range of biological effects. We previously found novel roles of adipocyte oxidative stress in diet-induced obesity, adipocyte glucocorticoid receptor in Cushing syndrome, and ARMC5 in adrenocortical cells. Using genetically modified mice in which oxidative stress was eliminated or augmented specifically in adipose tissues, we have been able to elucidate that obesity-induced oxidative stress inhibited healthy adipose expansion and ameliorated insulin sensitivity. Using adipocyte-specific glucocorticoid receptor knockout mice, we found that glucocorticoids also inhibited healthy adipose expansion and decreased insulin sensitivity. This was partly due to the transcriptional upregulation of ATGL. We identified ARMC5 as a novel ubiquitin E3 ligase of full-length SREBF, a master regulator of lipid metabolism. In adrenocortical cells, ARMC5 suppresses SREBF2 activity, and loss of ARMC5 may lead to cholesterol accumulation and the development of primary bilateral macronodular adrenal hyperplasia.
Collapse
Affiliation(s)
- Yosuke Okuno
- Department of Metabolic Medicine, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
| | - Atsunori Fukuhara
- Department of Metabolic Medicine, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
- Department of Adipose Management, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
| | - Iichiro Shimomura
- Department of Metabolic Medicine, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
| |
Collapse
|
|
4
|
Yue L, Li J, Yao M, Song S, Zhang X, Wang Y. Cutting edge of immune response and immunosuppressants in allogeneic and xenogeneic islet transplantation. Front Immunol 2024; 15:1455691. [PMID: 39346923 PMCID: PMC11427288 DOI: 10.3389/fimmu.2024.1455691] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Accepted: 08/27/2024] [Indexed: 10/01/2024] Open
Abstract
As an effective treatment for diabetes, islet transplantation has garnered significant attention and research in recent years. However, immune rejection and the toxicity of immunosuppressive drugs remain critical factors influencing the success of islet transplantation. While immunosuppressants are essential in reducing immune rejection reactions and can significantly improve the survival rate of islet transplants, improper use of these drugs can markedly increase mortality rates following transplantation. Additionally, the current availability of islet organ donations fails to meet the demand for organ transplants, making xenotransplantation a crucial method for addressing organ shortages. This review will cover the following three aspects: 1) the immune responses occurring during allogeneic islet transplantation, including three stages: inflammation and IBMIR, allogeneic immune response, and autoimmune recurrence; 2) commonly used immunosuppressants in allogeneic islet transplantation, including calcineurin inhibitors (Cyclosporine A, Tacrolimus), mycophenolate mofetil, glucocorticoids, and Bortezomib; and 3) early and late immune responses in xenogeneic islet transplantation and the immune effects of triple therapy (ECDI-fixed donor spleen cells (ECDI-SP) + anti-CD20 + Sirolimus) on xenotransplantation.
Collapse
Affiliation(s)
- Liting Yue
- Center of Critical Care Medicine, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
| | - Jisong Li
- Department of Gastrointestinal Surgery, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Mingjun Yao
- Center of Critical Care Medicine, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
| | - Siyuan Song
- Department of Neuroscience, Baylor College of Medicine, Houston, TX, United States
| | - Xiaoqin Zhang
- Center of Critical Care Medicine, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
| | - Yi Wang
- Center of Critical Care Medicine, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
- Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Sichuan Provincial People’s Hospital, Chengdu, China
| |
Collapse
|
|
5
|
Moore-Vasram S, Sawhney M, Houlden RL, Groome PA, Goldie C, Li W, Hay AE, Tranmer J. Determining the Associations Between Glucocorticoid Use During Hematologic Chemotherapy Treatment and New-onset Diabetes and Hyperglycemia and Mortality: A Population-based Cohort Study. Can J Diabetes 2024; 48:195-203.e1. [PMID: 38211830 DOI: 10.1016/j.jcjd.2024.01.001] [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: 02/27/2023] [Revised: 08/09/2023] [Accepted: 01/04/2024] [Indexed: 01/13/2024]
Abstract
OBJECTIVES The aim of this study was to determine the associations between glucocorticoid administration during chemotherapy for hematologic malignancy and hyperglycemia, new-onset diabetes, and mortality in Ontario, Canada. Hospitalization and emergency room utilization during the chemotherapy treatment period were also described. METHODS We conducted a retrospective cohort study using health administrative data from ICES, Ontario, to assess risk of new-onset diabetes, new-onset hyperglycemia, and hyperglycemia for individuals with leukemia, non-Hodgkin lymphoma (NHL), and Hodgkin lymphoma (HL) receiving glucocorticoids during chemotherapy between 2006 and 2016. Using multivariable regression models, we determined the associations between glucocorticoid exposure and our outcomes of interest, controlling for age, sex, marginalization, and comorbidities. RESULTS Our cohort included 19,530 individuals; 71.1% (n=13,893) received a glucocorticoid. The highest proportion of hyperglycemia occurred with leukemia (25.4%, n=1,301). Of the 15,580 individuals with no history of diabetes, those with leukemia had the highest rate of new-onset diabetes (7.1%, n=279) and new-onset hyperglycemia (18.1%, n=641), and glucocorticoid exposure increased the risk of new-onset diabetes (hazard ratio [HR] 1.29, 95% confidence interval [CI] 1.01 to 1.64, p=0.04) and new-onset hyperglycemia (HR 1.28, 95% CI 1.09 to 1.5, p=0.003). Hyperglycemia during chemotherapy increased the risk of all-cause mortality for the combined (HR 1.18, 95% CI 1.09 to 1.27, p<0.0001) and NHL (HR 1.16, 95% CI 1.04 to 1.28, p=0.007) cohorts. CONCLUSIONS Hyperglycemia is common during hematologic chemotherapy treatment and is associated with a modest increased risk of all-cause mortality. Routine screening, monitoring, and management of hyperglycemia should be an integral part of treatment plans for leukemia, NHL, or HL, with or without glucocorticoid administration.
Collapse
Affiliation(s)
| | - Monakshi Sawhney
- School of Nursing, Queen's University, Kingston, Ontario, Canada
| | - Robyn L Houlden
- Division of Endocrinology and Metabolism, Queen's University, Kingston Health Sciences Centre, Kingston, Ontario, Canada
| | - Patti A Groome
- Division of Cancer Care and Epidemiology, Queen's Cancer Research Institute, Queen's University, Kingston, Ontario, Canada; ICES, formerly the Institute for Clinical Evaluative Sciences, Queen's University Site, Kingston, Ontario, Canada
| | - Catherine Goldie
- School of Nursing, Queen's University, Kingston, Ontario, Canada
| | - Wenbin Li
- ICES, formerly the Institute for Clinical Evaluative Sciences, Queen's University Site, Kingston, Ontario, Canada
| | - Annette E Hay
- Division of Hematology, Queen's University, Kingston, Ontario, Canada
| | - Joan Tranmer
- School of Nursing, Queen's University, Kingston, Ontario, Canada; ICES, formerly the Institute for Clinical Evaluative Sciences, Queen's University Site, Kingston, Ontario, Canada
| |
Collapse
|
|
6
|
Heurtebize MA, Faillie JL. Drug-induced hyperglycemia and diabetes. Therapie 2024; 79:221-238. [PMID: 37985310 DOI: 10.1016/j.therap.2023.09.010] [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: 07/18/2023] [Accepted: 09/14/2023] [Indexed: 11/22/2023]
Abstract
BACKGROUND Drug-induced hyperglycemia and diabetes have negative and potentially serious health consequences but can often be unnoticed. METHODS We reviewed the literature searching Medline database for articles addressing drug-induced hyperglycemia and diabetes up to January 31, 2023. We also selected drugs that could induce hyperglycemia or diabetes according official data from drug information databases Thériaque and Micromedex. For each selected drug or pharmacotherapeutic class, the mechanisms of action potentially involved were investigated. For drugs considered to be at risk of hyperglycemia or diabetes, disproportionality analyses were performed using data from the international pharmacovigilance database VigiBase. In order to detect new pharmacovigilance signals, additional disproportionality analyses were carried out for drug classes with more than 100 cases reported in VigiBase, but not found in the literature or official documents. RESULTS The main drug classes found to cause hyperglycemia are glucocorticoids, HMG-coA reductase inhibitors, thiazide diuretics, beta-blockers, antipsychotics, fluoroquinolones, antiretrovirals, antineoplastic agents and immunosuppressants. The main mechanisms involved are alterations in insulin secretion and sensitivity, direct cytotoxic effects on pancreatic cells and increases in glucose production. Pharmacovigilance signal were found for a majority of drugs or pharmacological classes identified as being at risk of diabetes or hyperglycemia. We identified new pharmacovigilance signals with drugs not known to be at risk according to the literature or official data: phosphodiesterase type 5 inhibitors, endothelin receptor antagonists, sodium oxybate, biphosphonates including alendronic acid, digoxin, sartans, linosipril, diltiazem, verapamil, and darbepoetin alpha. Further studies will be needed to confirm these signals. CONCLUSIONS The risks of induced hyperglycemia vary from one drug to another, and the underlying mechanisms are multiple and potentially complex. Clinicians need to be vigilant when using at-risk drugs in order to detect and manage these adverse drug reactions. However, it is to emphasize that the benefits of appropriately prescribed treatments most often outweigh their metabolic risks.
Collapse
Affiliation(s)
- Marie-Anne Heurtebize
- CHU de Montpellier, Medical Pharmacology and Toxicology Department, 34000 Montpellier, France
| | - Jean-Luc Faillie
- CHU de Montpellier, Medical Pharmacology and Toxicology Department, 34000 Montpellier, France; IDESP, Université de Montpellier, Inserm, 34295 Montpellier, France.
| |
Collapse
|
|
7
|
Scanes CG, Pierzchała-Koziec K, Gajewska A. Effects of Restraint Stress on Circulating Corticosterone and Met Enkephalin in Chickens: Induction of Shifts in Insulin Secretion and Carbohydrate Metabolism. Animals (Basel) 2024; 14:752. [PMID: 38473137 DOI: 10.3390/ani14050752] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Revised: 02/20/2024] [Accepted: 02/22/2024] [Indexed: 03/14/2024] Open
Abstract
This study examined the effects of acute restraint stress in the presence or absence of naltrexone on the circulating concentrations of insulin, glucose, Met-enkephalin and corticosterone in 14-week-old chickens [design: 2 sex × 2 stress/non-stress × 2 +/- naltrexone]. In chickens (five male and five females per treatment) subjected to restraint for 30 min, there were increases in the plasma concentrations of corticosterone and Met-enkephalin. The plasma concentrations of insulin and glucose were also increased in the chickens during restraint. Moreover, there were increases in the plasma concentrations of insulin and glucose in the chickens. The patterns of expression of the proenkephalin gene (PENK) in both the anterior pituitary gland and the adrenal gland were very similar to that of plasma Met-enkephalin. There were relationships between the plasma concentrations of corticosterone, Met-enkephalin, insulin and glucose after 30 min of restraint. The effects of naltrexone treatment on both untreated and stressed chickens were also examined, with naltrexone attenuating the stress-induced increases in the plasma concentrations of corticosterone, Met-enkephalin and glucose but not in those of insulin. The present study demonstrates that stress increases insulin secretion in chickens but also induces insulin resistance.
Collapse
Affiliation(s)
- Colin G Scanes
- Department of Biological Science, University of Wisconsin Milwaukee, Milwaukee, WI 53211, USA
| | - Krystyna Pierzchała-Koziec
- Department of Animal Physiology and Endocrinology, University of Agriculture, Mickiewicza 24/28, 30-059 Kraków, Poland
| | - Alina Gajewska
- Kielanowski Institute of Animal Physiology and Nutrition, Polish Academy of Sciences, 05-110 Jablonna, Poland
| |
Collapse
|
|
8
|
Wilson NK, Kataria AD. Immunosuppression in solid organ-transplant recipients and impact on nutrition support. Nutr Clin Pract 2024; 39:109-116. [PMID: 38030572 DOI: 10.1002/ncp.11099] [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: 09/15/2023] [Revised: 10/28/2023] [Accepted: 11/06/2023] [Indexed: 12/01/2023] Open
Abstract
A key component to nutrition support is to consider immunosuppressive agents, the interaction with nutrients, and how the side effects of the medications influence nutrition support. The immunosuppression of the solid organ-transplant recipient involves the individualized titration of multiple therapeutic agents to prevent allorecognition and, thus, rejection of the transplanted organ. Induction immunosuppression includes the agents used at the time of transplant to prevent early rejection. Maintenance immunosuppression typically consists of oral medications taken for life. Regular therapeutic monitoring of immunosuppression is necessary to balance the risk of rejection with that of infections and malignancy. In the acute-care setting, multidisciplinary collaboration, including pharmacy and nutrition, is needed to optimize the route of administration, titration, and side effects of immunosuppression. Long-term nutrition management after transplant is also vital to prevent exacerbating adverse effects of immunosuppressive therapies, including diabetes mellitus, hypertension, dyslipidemia, obesity, and bone loss. This review summarizes common immunosuppressive agents currently utilized in solid organ-transplant recipients and factors that may influence decisions on nutrition support.
Collapse
Affiliation(s)
- Nicole K Wilson
- Department of Pharmacy, Baylor University Medical Center, Dallas, Texas, USA
| | - Ann D Kataria
- Department of Pharmacy, Baylor University Medical Center, Dallas, Texas, USA
| |
Collapse
|
|
9
|
Martinez GJ, Appleton M, Kipp ZA, Loria AS, Min B, Hinds TD. Glucocorticoids, their uses, sexual dimorphisms, and diseases: new concepts, mechanisms, and discoveries. Physiol Rev 2024; 104:473-532. [PMID: 37732829 PMCID: PMC11281820 DOI: 10.1152/physrev.00021.2023] [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: 05/22/2023] [Revised: 08/07/2023] [Accepted: 09/10/2023] [Indexed: 09/22/2023] Open
Abstract
The normal stress response in humans is governed by the hypothalamic-pituitary-adrenal (HPA) axis through heightened mechanisms during stress, raising blood levels of the glucocorticoid hormone cortisol. Glucocorticoids are quintessential compounds that balance the proper functioning of numerous systems in the mammalian body. They are also generated synthetically and are the preeminent therapy for inflammatory diseases. They act by binding to the nuclear receptor transcription factor glucocorticoid receptor (GR), which has two main isoforms (GRα and GRβ). Our classical understanding of glucocorticoid signaling is from the GRα isoform, which binds the hormone, whereas GRβ has no known ligands. With glucocorticoids being involved in many physiological and cellular processes, even small disruptions in their release via the HPA axis, or changes in GR isoform expression, can have dire ramifications on health. Long-term chronic glucocorticoid therapy can lead to a glucocorticoid-resistant state, and we deliberate how this impacts disease treatment. Chronic glucocorticoid treatment can lead to noticeable side effects such as weight gain, adiposity, diabetes, and others that we discuss in detail. There are sexually dimorphic responses to glucocorticoids, and women tend to have a more hyperresponsive HPA axis than men. This review summarizes our understanding of glucocorticoids and critically analyzes the GR isoforms and their beneficial and deleterious mechanisms and the sexual differences that cause a dichotomy in responses. We also discuss the future of glucocorticoid therapy and propose a new concept of dual GR isoform agonist and postulate why activating both isoforms may prevent glucocorticoid resistance.
Collapse
Affiliation(s)
- Genesee J Martinez
- Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, Kentucky, United States
| | - Malik Appleton
- Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, Kentucky, United States
| | - Zachary A Kipp
- Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, Kentucky, United States
| | - Analia S Loria
- Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, Kentucky, United States
- Barnstable Brown Diabetes Center, University of Kentucky College of Medicine, Lexington, Kentucky, United States
| | - Booki Min
- Department of Microbiology and Immunology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
| | - Terry D Hinds
- Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, Kentucky, United States
- Barnstable Brown Diabetes Center, University of Kentucky College of Medicine, Lexington, Kentucky, United States
- Markey Cancer Center, University of Kentucky, Lexington, Kentucky, United States
| |
Collapse
|
|
10
|
Dodonova SA, Zhidkova EM, Kryukov AA, Valiev TT, Kirsanov KI, Kulikov EP, Budunova IV, Yakubovskaya MG, Lesovaya EA. Synephrine and Its Derivative Compound A: Common and Specific Biological Effects. Int J Mol Sci 2023; 24:17537. [PMID: 38139366 PMCID: PMC10744207 DOI: 10.3390/ijms242417537] [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: 11/25/2023] [Revised: 12/12/2023] [Accepted: 12/13/2023] [Indexed: 12/24/2023] Open
Abstract
This review is focused on synephrine, the principal phytochemical found in bitter orange and other medicinal plants and widely used as a dietary supplement for weight loss/body fat reduction. We examine different aspects of synephrine biology, delving into its established and potential molecular targets, as well as its mechanisms of action. We present an overview of the origin, chemical composition, receptors, and pharmacological properties of synephrine, including its anti-inflammatory and anti-cancer activity in various in vitro and animal models. Additionally, we conduct a comparative analysis of the molecular targets and effects of synephrine with those of its metabolite, selective glucocorticoid receptor agonist (SEGRA) Compound A (CpdA), which shares a similar chemical structure with synephrine. SEGRAs, including CpdA, have been extensively studied as glucocorticoid receptor activators that have a better benefit/risk profile than glucocorticoids due to their reduced adverse effects. We discuss the potential of synephrine usage as a template for the synthesis of new generation of non-steroidal SEGRAs. The review also provides insights into the safe pharmacological profile of synephrine.
Collapse
Affiliation(s)
- Svetlana A. Dodonova
- Research Institute of Experimental Medicine, Department of Pathophysiology, Kursk State Medical University, 305041 Kursk, Russia; (S.A.D.); (A.A.K.)
| | - Ekaterina M. Zhidkova
- Department of Chemical Carcinogenesis, N.N. Blokhin National Medical Research Center of Oncology, 115478 Moscow, Russia; (E.M.Z.); (T.T.V.); (K.I.K.); (M.G.Y.)
| | - Alexey A. Kryukov
- Research Institute of Experimental Medicine, Department of Pathophysiology, Kursk State Medical University, 305041 Kursk, Russia; (S.A.D.); (A.A.K.)
| | - Timur T. Valiev
- Department of Chemical Carcinogenesis, N.N. Blokhin National Medical Research Center of Oncology, 115478 Moscow, Russia; (E.M.Z.); (T.T.V.); (K.I.K.); (M.G.Y.)
| | - Kirill I. Kirsanov
- Department of Chemical Carcinogenesis, N.N. Blokhin National Medical Research Center of Oncology, 115478 Moscow, Russia; (E.M.Z.); (T.T.V.); (K.I.K.); (M.G.Y.)
- Faculty of Oncology, Ryazan State Medical University Named after Academician I.P. Pavlov, 390026 Ryazan, Russia
| | - Evgeny P. Kulikov
- Laboratory of Single Cell Biology, Russian University of People’s Friendship (RUDN) University, 117198 Moscow, Russia;
| | - Irina V. Budunova
- Department of Dermatology, Northwestern University, Chicago, IL 60611, USA;
| | - Marianna G. Yakubovskaya
- Department of Chemical Carcinogenesis, N.N. Blokhin National Medical Research Center of Oncology, 115478 Moscow, Russia; (E.M.Z.); (T.T.V.); (K.I.K.); (M.G.Y.)
- Faculty of Oncology, Ryazan State Medical University Named after Academician I.P. Pavlov, 390026 Ryazan, Russia
| | - Ekaterina A. Lesovaya
- Department of Chemical Carcinogenesis, N.N. Blokhin National Medical Research Center of Oncology, 115478 Moscow, Russia; (E.M.Z.); (T.T.V.); (K.I.K.); (M.G.Y.)
- Faculty of Oncology, Ryazan State Medical University Named after Academician I.P. Pavlov, 390026 Ryazan, Russia
- Laboratory of Single Cell Biology, Russian University of People’s Friendship (RUDN) University, 117198 Moscow, Russia;
| |
Collapse
|
|
11
|
Tanday N, Coulter-Parkhill A, Moffett RC, Suruli K, Dubey V, Flatt PR, Irwin N. Sex-based impact of pancreatic islet stressors in GluCreERT2/Rosa26-eYFP mice. J Endocrinol 2023; 259:e230174. [PMID: 37650517 PMCID: PMC10563506 DOI: 10.1530/joe-23-0174] [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: 05/31/2023] [Accepted: 08/29/2023] [Indexed: 09/01/2023]
Abstract
The present study examines differences in metabolic and pancreatic islet adaptative responses following streptozotocin (STZ) and hydrocortisone (HC) administration in male and female transgenic GluCreERT2/Rosa26-eYFP mice. Mice received five daily doses of STZ (50 mg/kg, i.p.) or 10 daily doses of HC (70 mg/kg, i.p.), with parameters assessed on day 11. STZ-induced hyperglycaemia was evident in both sexes, alongside impaired glucose tolerance and reduced insulin concentrations. HC also had similar metabolic effects in male and female mice resulting in classical increases of circulating insulin indicative of insulin resistance. Control male mice had larger pancreatic islets than females and displayed a greater reduction of islet and beta-cell area in response to STZ insult. In addition, female STZ mice had lower levels of beta-cell apoptosis than male counterparts. Following HC administration, female mouse islets contained a greater proportion of alpha cells when compared to males. All HC mice presented with relatively comparable increases in beta- and alpha-cell turnover rates, with female mice being slightly more susceptible to HC-induced beta-cell apoptosis. Interestingly, healthy control female mice had inherently increased alpha-to-beta-cell transdifferentiation rates, which was decreased by HC treatment. The number of glucagon-positive alpha cells altering their lineage to insulin-positive beta cells was increased in male, but not female, STZ mice. Taken together, although there was no obvious sex-specific alteration of metabolic profile in STZ or HC mice, subtle differences in pancreatic islet morphology emphasises the impact of sex hormones on islets and importance of taking care when interpreting observations between males and females.
Collapse
Affiliation(s)
- Neil Tanday
- Diabetes Research Centre, Ulster University, Coleraine, Londonderry, Northern Ireland
| | | | - R Charlotte Moffett
- Diabetes Research Centre, Ulster University, Coleraine, Londonderry, Northern Ireland
| | - Karthick Suruli
- Diabetes Research Centre, Ulster University, Coleraine, Londonderry, Northern Ireland
| | - Vaibhav Dubey
- Diabetes Research Centre, Ulster University, Coleraine, Londonderry, Northern Ireland
| | - Peter R Flatt
- Diabetes Research Centre, Ulster University, Coleraine, Londonderry, Northern Ireland
| | - Nigel Irwin
- Diabetes Research Centre, Ulster University, Coleraine, Londonderry, Northern Ireland
| |
Collapse
|
|
12
|
Gupta SK, Mostofsky E, Motiwala SR, Hage A, Mittleman MA. Induction immunosuppression and post-transplant diabetes mellitus: a propensity-matched cohort study. Front Endocrinol (Lausanne) 2023; 14:1248940. [PMID: 37929038 PMCID: PMC10623448 DOI: 10.3389/fendo.2023.1248940] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Accepted: 10/02/2023] [Indexed: 11/07/2023] Open
Abstract
Introduction Post-transplant diabetes mellitus (PTDM) is a common complication among cardiac transplant recipients, causing diabetes-related complications and death. While certain maintenance immunosuppressive drugs increase PTDM risk, it is unclear whether induction immunosuppression can do the same. Therefore, we evaluated whether induction immunosuppression with IL-2 receptor antagonists, polyclonal anti-lymphocyte antibodies, or Alemtuzumab given in the peri-transplant period is associated with PTDM. Methods We used the Scientific Registry of Transplant Recipients database to conduct a cohort study of US adults who received cardiac transplants between January 2008-December 2018. We excluded patients with prior or multiple organ transplants and those with a history of diabetes, resulting in 17,142 recipients. We created propensity-matched cohorts (n=7,412) using predictors of induction immunosuppression and examined the association between post-transplant diabetes and induction immunosuppression by estimating hazard ratios using Cox proportional-hazards models. Results In the propensity-matched cohort, the average age was 52.5 (SD=13.2) years, 28.7% were female and 3,706 received induction immunosuppression. There were 867 incident cases of PTDM during 26,710 person-years of follow-up (32.5 cases/1,000 person-years). There was no association between induction immunosuppression and post-transplant diabetes (Hazard Ratio= 1.04, 95% confidence interval 0.91 - 1.19). Similarly, no associations were observed for each class of induction immunosuppression agents and post-transplant diabetes. Conclusion The use of contemporary induction immunosuppression in cardiac transplant patients was not associated with post-transplant diabetes.
Collapse
Affiliation(s)
- Suruchi K. Gupta
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, United States
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, United States
- Harvard Medical School, Boston, MA, United States
| | - Elizabeth Mostofsky
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, United States
| | - Shweta R. Motiwala
- Harvard Medical School, Boston, MA, United States
- Division of Cardiovascular Medicine, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, United States
| | - Ali Hage
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, United States
- London Health Sciences Centre, Schulich School of Medicine, Western University, London, ON, Canada
| | - Murray A. Mittleman
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, United States
- Harvard Medical School, Boston, MA, United States
- Division of Cardiovascular Medicine, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, United States
| |
Collapse
|
|
13
|
Udagawa H, Funahashi N, Nishimura W, Uebanso T, Kawaguchi M, Asahi R, Nakajima S, Nammo T, Hiramoto M, Yasuda K. Glucocorticoid receptor-NECAB1 axis can negatively regulate insulin secretion in pancreatic β-cells. Sci Rep 2023; 13:17958. [PMID: 37863964 PMCID: PMC10589354 DOI: 10.1038/s41598-023-44324-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Accepted: 10/06/2023] [Indexed: 10/22/2023] Open
Abstract
The mechanisms of impaired glucose-induced insulin secretion from the pancreatic β-cells in obesity have not yet been completely elucidated. Here, we aimed to assess the effects of adipocyte-derived factors on the functioning of pancreatic β-cells. We prepared a conditioned medium using 3T3-L1 cell culture supernatant collected at day eight (D8CM) and then exposed the rat pancreatic β-cell line, INS-1D. We found that D8CM suppressed insulin secretion in INS-1D cells due to reduced intracellular calcium levels. This was mediated by the induction of a negative regulator of insulin secretion-NECAB1. LC-MS/MS analysis results revealed that D8CM possessed steroid hormones (cortisol, corticosterone, and cortisone). INS-1D cell exposure to cortisol or corticosterone increased Necab1 mRNA expression and significantly reduced insulin secretion. The increased expression of Necab1 and reduced insulin secretion effects from exposure to these hormones were completely abolished by inhibition of the glucocorticoid receptor (GR). NECAB1 expression was also increased in the pancreatic islets of db/db mice. We demonstrated that the upregulation of NECAB1 was dependent on GR activation, and that binding of the GR to the upstream regions of Necab1 was essential for this effect. NECAB1 may play a novel role in the adipoinsular axis and could be potentially involved in the pathophysiology of obesity-related diabetes mellitus.
Collapse
Affiliation(s)
- Haruhide Udagawa
- Department of Metabolic Disorder, Diabetes Research Center, Research Institute, National Center for Global Health and Medicine, Shinjuku-ku, Tokyo, 162-8655, Japan
- Department of Registered Dietitians, Faculty of Health and Nutrition, Bunkyo University, 1100 Namegaya, Chigasaki, Kanagawa, 253-8550, Japan
| | - Nobuaki Funahashi
- Department of Life Science and Technology, Tokyo Institute of Technology, Yokohama, Japan
| | - Wataru Nishimura
- Department of Molecular Biology, International University of Health and Welfare School of Medicine, Narita, Chiba, 286-8686, Japan
- Division of Anatomy, Bio-Imaging and Neuro-Cell Science, Jichi Medical University, Shimotsuke, Tochigi, 329-0498, Japan
| | - Takashi Uebanso
- Department of Preventive Environment and Nutrition, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, 770-8503, Japan
| | - Miho Kawaguchi
- Department of Metabolic Disorder, Diabetes Research Center, Research Institute, National Center for Global Health and Medicine, Shinjuku-ku, Tokyo, 162-8655, Japan
| | - Riku Asahi
- Department of Registered Dietitians, Faculty of Health and Nutrition, Bunkyo University, 1100 Namegaya, Chigasaki, Kanagawa, 253-8550, Japan
| | - Shigeru Nakajima
- Department of Registered Dietitians, Faculty of Health and Nutrition, Bunkyo University, 1100 Namegaya, Chigasaki, Kanagawa, 253-8550, Japan
| | - Takao Nammo
- Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Suita, Japan
- Department of Diabetes Care Medicine, Graduate School of Medicine, Osaka University, Suita, Japan
| | - Masaki Hiramoto
- Department of Biochemistry, Tokyo Medical University, Tokyo, 160-8402, Japan
| | - Kazuki Yasuda
- Department of Metabolic Disorder, Diabetes Research Center, Research Institute, National Center for Global Health and Medicine, Shinjuku-ku, Tokyo, 162-8655, Japan.
- Department of Diabetes, Endocrinology and Metabolism, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo, 181-8611, Japan.
| |
Collapse
|
|
14
|
Wu T, Shao Y, Li X, Wu T, Yu L, Liang J, Zhang Y, Wang J, Sun T, Zhu Y, Chang X, Wang S, Chen F, Han X. NR3C1/Glucocorticoid receptor activation promotes pancreatic β-cell autophagy overload in response to glucolipotoxicity. Autophagy 2023; 19:2538-2557. [PMID: 37039556 PMCID: PMC10392762 DOI: 10.1080/15548627.2023.2200625] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Revised: 03/20/2023] [Accepted: 04/04/2023] [Indexed: 04/12/2023] Open
Abstract
Diabetes is a complex and heterogeneous disorder characterized by chronic hyperglycemia. Its core cause is progressively impaired insulin secretion by pancreatic β-cell failures, usually upon a background of preexisting insulin resistance. Recent studies demonstrate that macroautophagy/autophagy is essential to maintain architecture and function of β-cells, whereas excessive autophagy is also involved in β-cell dysfunction and death. It has been poorly understood whether autophagy plays a protective or harmful role in β-cells, while we report here that it is dependent on NR3C1/glucocorticoid receptor activation. We proved that deleterious hyperactive autophagy happened only upon NR3C1 activation in β-cells under glucolipotoxic conditions, which eventually promoted diabetes. The transcriptome and the N6-methyladenosine (m6A) methylome revealed that NR3C1-enhancement upregulated the RNA demethylase FTO (fat mass and obesity associated) protein in β-cells, which caused diminished m6A modifications on mRNAs of four core Atg (autophagy related) genes (Atg12, Atg5, Atg16l2, Atg9a) and, hence, hyperactive autophagy and defective insulin output; by contrast, FTO inhibition, achieved by the specific FTO inhibitor Dac51, prevented NR3C1-instigated excessive autophagy activation. Importantly, Dac51 effectively alleviated impaired insulin secretion and glucose intolerance in hyperglycemic β-cell specific NR3C1 overexpression mice. Our results determine that the NR3C1-FTO-m6A modifications-Atg genes axis acts as a key mediator of balanced autophagic flux in pancreatic β-cells, which offers a novel therapeutic target for the treatment of diabetes.Abbreviations: 3-MA: 3-methyladenine; AAV: adeno-associated virus; Ac: acetylation; Ad: adenovirus; AL: autolysosome; ATG: autophagy related; AUC: area under curve; Baf A1: bafilomycin A1; βNR3C1 mice: pancreatic β-cell-specific NR3C1 overexpression mice; cFBS: charcoal-stripped FBS; Ctrl: control; ER: endoplasmic reticulum; FTO: fat mass and obesity associated; GC: glucocorticoid; GRE: glucocorticoid response element; GSIS: glucose-stimulated insulin secretion assay; HFD: high-fat diet; HG: high glucose; HsND: non-diabetic human; HsT2D: type 2 diabetic human; i.p.: intraperitoneal injected; KSIS: potassium-stimulated insulin secretion assay; m6A: N6-methyladenosine; MeRIP-seq: methylated RNA immunoprecipitation sequencing; NR3C1/GR: nuclear receptor subfamily 3, group C, member 1; NR3C1-Enhc.: NR3C1-enhancement; NC: negative control; Palm.: palmitate; RNA-seq: RNA sequencing; T2D: type 2 diabetes; TEM: transmission electron microscopy; UTR: untranslated region; WT: wild-type.
Collapse
Affiliation(s)
- Tijun Wu
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yixue Shao
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Xirui Li
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Tao Wu
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Ling Yu
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Jin Liang
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yaru Zhang
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Jiahui Wang
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Tong Sun
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yunxia Zhu
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Xiaoai Chang
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Shusen Wang
- Organ Transplant Center, Tianjin First Central Hospital, Nankai University, Tianjin, China
| | - Fang Chen
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Xiao Han
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China
| |
Collapse
|
|
15
|
Robertson RP. Endocrine Function and Metabolic Outcomes After Pancreas and Islet Transplantation. TRANSPLANTATION OF THE PANCREAS 2023:801-815. [DOI: 10.1007/978-3-031-20999-4_57] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
|
|
16
|
Fathi FEZM, Sadek KM, Khafaga AF, Al Senosy AW, Ghoniem HA, Fayez S, Zeweil MF. Vitamin D regulates insulin and ameliorates apoptosis and oxidative stress in pancreatic tissues of rats with streptozotocin-induced diabetes. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2022; 29:90219-90229. [PMID: 35864405 PMCID: PMC9722851 DOI: 10.1007/s11356-022-22064-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Accepted: 07/13/2022] [Indexed: 06/15/2023]
Abstract
This study was designed to evaluate the potential therapeutic efficacy of vitamin D (Vit D) in averting the harmful effects of type 2 diabetes mellitus (T2D). Forty male Wistar rats were allotted into four groups: (1) the control, (2) Vit D, (3) streptozotocin (STZ), and (4) STZ + Vit D groups. Rats co-treated with Vit D had significantly (p < 0.05) decreased levels of cortisol; proinflammatory cytokines, including interleukin-6 (IL-6); and malondialdehyde (MDA). Meanwhile, the levels of insulin significantly (p < 0.05) increased, whereas the activity of the antioxidant system, including glutathione (GSH), superoxide dismutase (SOD), catalase, and total antioxidant capacity (TAC), significantly (p < 0.05) decreased. Histopathological examination revealed the destruction of beta cells in the islets of Langerhans in rats with diabetes. Meanwhile, immunoexpression revealed an increase in the immunoreactivity of caspase-3 and endothelial nitric oxide synthase and a reduction in the immunoreactivity of insulin in rats with diabetes. In conclusion, Vit D ameliorated the harmful biochemical impact of diabetes mellitus, probably by increasing insulin secretion and sensitivity, ameliorating β-cell function, and decreasing cortisol levels; also, the anti-inflammatory effect of Vit D reduces the number of proinflammatory cytokines (e.g., IL-6) and increases the activity of the antioxidant system, such as GSH, SOD, TAC, and catalase while reducing lipid peroxidation enzymes (e.g., MDA).
Collapse
Affiliation(s)
- Fatima El Zahra M Fathi
- Department of Biochemistry, Faculty of Veterinary Medicine, Damanhur University, Damanhour, 22516, Egypt
| | - Kadry M Sadek
- Department of Biochemistry, Faculty of Veterinary Medicine, Damanhur University, Damanhour, 22516, Egypt
| | - Asmaa F Khafaga
- Department of Pathology, Faculty of Veterinary Medicine, Alexandria University, Edfina, 22758, Egypt.
| | - Abdel Wahab Al Senosy
- Department of Histology, Faculty of Veterinary Medicine, Damanhur University, Damanhour, 22516, Egypt
| | - Hanan A Ghoniem
- Department of Histology, Faculty of Veterinary Medicine, Damanhur University, Damanhour, 22516, Egypt
| | - Sahar Fayez
- Department of Histology, Faculty of Veterinary Medicine, Damanhur University, Damanhour, 22516, Egypt
| | - Mohamed F Zeweil
- Department of Biochemistry, Faculty of Veterinary Medicine, Damanhur University, Damanhour, 22516, Egypt
| |
Collapse
|
|
17
|
Nishiyama M, Iwasaki Y, Makino S. Animal Models of Cushing's Syndrome. Endocrinology 2022; 163:6761324. [PMID: 36240318 DOI: 10.1210/endocr/bqac173] [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: 09/01/2022] [Indexed: 11/19/2022]
Abstract
Endogenous Cushing's syndrome is characterized by unique clinical features and comorbidities, and progress in the analysis of its genetic pathogenesis has been achieved. Moreover, prescribed glucocorticoids are also associated with exogenous Cushing's syndrome. Several animal models have been established to explore the pathophysiology and develop treatments for Cushing's syndrome. Here, we review recent studies reporting animal models of Cushing's syndrome with different features and complications induced by glucocorticoid excess. Exogenous corticosterone (CORT) administration in drinking water is widely utilized, and we found that CORT pellet implantation in mice successfully leads to a Cushing's phenotype. Corticotropin-releasing hormone overexpression mice and adrenal-specific Prkar1a-deficient mice have been developed, and AtT20 transplantation methods have been designed to examine the medical treatments for adrenocorticotropic hormone-producing pituitary neuroendocrine tumors. We also review recent advances in the molecular pathogenesis of glucocorticoid-induced complications using animal models.
Collapse
Affiliation(s)
- Mitsuru Nishiyama
- Health Care Center, Kochi University, Kochi city, Kochi 780-8520, Japan
- Department of Endocrinology, Metabolism and Nephrology, Kochi Medical School, Kochi University, Nankoku city, Kochi 783-8505, Japan
| | - Yasumasa Iwasaki
- Department of Endocrinology, Metabolism and Nephrology, Kochi Medical School, Kochi University, Nankoku city, Kochi 783-8505, Japan
- Department of Clinical Nutrition, Faculty of Health Science, Suzuka University of Medical Science, Suzuka city, Mie 510-0293Japan
| | - Shinya Makino
- Department of Endocrinology, Metabolism and Nephrology, Kochi Medical School, Kochi University, Nankoku city, Kochi 783-8505, Japan
- Department of Internal Medicine, Osaka Gyomeikan Hospital, Osaka city, Osaka 554-0012Japan
| |
Collapse
|
|
18
|
Salehidoost R, Korbonits M. Glucose and lipid metabolism abnormalities in Cushing's syndrome. J Neuroendocrinol 2022; 34:e13143. [PMID: 35980242 DOI: 10.1111/jne.13143] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Accepted: 04/15/2022] [Indexed: 11/30/2022]
Abstract
Prolonged excess of glucocorticoids (GCs) has adverse systemic effects leading to significant morbidities and an increase in mortality. Metabolic alterations associated with the high level of the GCs are key risk factors for the poor outcome. These include GCs causing excess gluconeogenesis via upregulation of key enzymes in the liver, a reduction of insulin sensitivity in skeletal muscle, liver and adipose tissue by inhibiting the insulin receptor signalling pathway, and inhibition of insulin secretion in beta cells leading to dysregulated glucose metabolism. In addition, chronic GC exposure leads to an increase in visceral adipose tissue, as well as an increase in lipolysis resulting in higher circulating free fatty acid levels and in ectopic fat deposition. Remission of hypercortisolism improves these metabolic changes, but very often does not result in full resolution of the abnormalities. Therefore, long-term monitoring of metabolic variables is needed even after the resolution of the excess GC levels.
Collapse
Affiliation(s)
- Rezvan Salehidoost
- Centre for Endocrinology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Márta Korbonits
- Centre for Endocrinology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| |
Collapse
|
|
19
|
Kethireddy R, Gandhi D, Kichloo A, Patel L. Challenges in hyperglycemia management in critically ill patients with COVID-19. World J Crit Care Med 2022; 11:219-227. [PMID: 36051939 PMCID: PMC9305683 DOI: 10.5492/wjccm.v11.i4.219] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Revised: 08/10/2021] [Accepted: 05/08/2022] [Indexed: 02/06/2023] Open
Abstract
Hyperglycemia is commonly associated with adverse outcomes especially in patients requiring intensive care unit stay. Data from the corona virus disease 2019 (COVID-19) pandemic indicates that individuals with diabetes appear to be at similar risk for COVID-19 infection to those without diabetes but are more likely to experience increased morbidity and mortality. The proposed hypothesis for hyperglycemia in COVID-19 include insulin resistance, critical illness hyperglycemia (stress- induced hyperglycemia) secondary to high levels of hormones like cortisol and catecholamines that counteract insulin action, acute cytokine storm and pancreatic cell dysfunction. Diabetic patients are more likely to have severe hyperglycemic complications including diabetic ketoacidosis and hyperosmolar hyperglycemic state. Management of hyperglycemia in COVID-19 is often complicated by use of steroids, prolonged total parenteral or enteral nutrition, frequent acute hyperglycemic events, and restrictions with fluid management due to acute respiratory distress syndrome. While managing hyperglycemia special attention should be paid to mode of insulin delivery, frequency of glucose monitoring based on patient and caregiver safety thereby minimizing exposure and conserving personal protective equipment. In this article we describe the pathophysiology of hyperglycemia, challenges encountered in managing hyperglycemia, and review some potential solutions to address them.
Collapse
Affiliation(s)
- Rajesh Kethireddy
- Division of Hospital Medicine, Abbott Northwestern Hospital, Allina Health, Minneapolis, MN 55407, United States
| | - Darshan Gandhi
- Department of Diagnostic Radiology, University of Tennessee Health Science Center, Memphis, TN 38103, United States
| | - Asim Kichloo
- Internal Medicine, Central Michigan University School of Medicine, Mt Pleasant, MI 48859, United States
| | - Love Patel
- Division of Hospital Medicine, Abbott Northwestern Hospital, Allina Health, Minneapolis, MN 55407, United States
| |
Collapse
|
|
20
|
Tholen S, Patel R, Agas A, Kovary KM, Rabiee A, Nicholls HT, Bielczyk-Maczyńska E, Yang W, Kraemer FB, Teruel MN. Flattening of circadian glucocorticoid oscillations drives acute hyperinsulinemia and adipocyte hypertrophy. Cell Rep 2022; 39:111018. [PMID: 35767959 PMCID: PMC9391061 DOI: 10.1016/j.celrep.2022.111018] [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: 06/28/2021] [Revised: 04/14/2022] [Accepted: 06/08/2022] [Indexed: 11/03/2022] Open
Abstract
Disruption of circadian glucocorticoid oscillations in Cushing's disease and chronic stress results in obesity and adipocyte hypertrophy, which is believed to be a main source of the harmful effects of obesity. Here, we recapitulate stress due to jet lag or work-life imbalances by flattening glucocorticoid oscillations in mice. Within 3 days, mice achieve a metabolic state with persistently high insulin, but surprisingly low glucose and fatty acids in the bloodstream, that precedes a more than 2-fold increase in brown and white adipose tissue mass within 3 weeks. Transcriptomic and Cd36-knockout mouse analyses show that hyperinsulinemia-mediated de novo fatty acid synthesis and Cd36-mediated fatty acid uptake drive fat mass increases. Intriguingly, this mechanism by which glucocorticoid flattening causes acute hyperinsulinemia and adipocyte hypertrophy is unexpectedly beneficial in preventing high levels of circulating fatty acids and glucose for weeks, thus serving as a protective response to preserve metabolic health during chronic stress.
Collapse
Affiliation(s)
- Stefan Tholen
- Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305, USA
| | - Roma Patel
- Department of Biochemistry and the Gale and Ira Drukier Institute of Children's Health, Weill Cornell Medical College of Cornell University, New York, NY, USA
| | - Agnieszka Agas
- Department of Biochemistry and the Gale and Ira Drukier Institute of Children's Health, Weill Cornell Medical College of Cornell University, New York, NY, USA
| | - Kyle M Kovary
- Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305, USA
| | - Atefeh Rabiee
- Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305, USA
| | - Hayley T Nicholls
- Weill Center for Metabolic Health, Division of Endocrinology, Diabetes and Metabolism, Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medical College of Cornell University, New York, NY, USA
| | - Ewa Bielczyk-Maczyńska
- Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305, USA
| | - Wenting Yang
- Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305, USA
| | - Fredric B Kraemer
- Department of Medicine, Division of Endocrinology, Stanford University, Stanford, CA, USA; VA Palo Alto Health Care System, Palo Alto, CA 94305, USA
| | - Mary N Teruel
- Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305, USA; Department of Bioengineering, Stanford University, Stanford, CA 94305, USA; Department of Biochemistry and the Gale and Ira Drukier Institute of Children's Health, Weill Cornell Medical College of Cornell University, New York, NY, USA; Weill Center for Metabolic Health, Division of Endocrinology, Diabetes and Metabolism, Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medical College of Cornell University, New York, NY, USA.
| |
Collapse
|
|
21
|
Kim S, Park ES, Chen PR, Kim E. Dysregulated Hypothalamic–Pituitary–Adrenal Axis Is Associated With Increased Inflammation and Worse Outcomes After Ischemic Stroke in Diabetic Mice. Front Immunol 2022; 13:864858. [PMID: 35784349 PMCID: PMC9243263 DOI: 10.3389/fimmu.2022.864858] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Accepted: 05/09/2022] [Indexed: 01/08/2023] Open
Abstract
Diabetic patients have larger infarcts, worse neurological deficits, and higher mortality rate after an ischemic stroke. Evidence shows that in diabetes, the hypothalamic–pituitary–adrenal (HPA) axis was dysregulated and levels of cortisol increased. Based on the role of the HPA axis in immunity, we hypothesized that diabetes-dysregulated stress response exacerbates stroke outcomes via regulation of inflammation. To test this hypothesis, we assessed the regulation of the HPA axis in diabetic mice before and after stroke and determined its relevance in the regulation of post-stroke injury and inflammation. Diabetes was induced in C57BL/6 mice by feeding a high-fat diet and intraperitoneal injection of streptozotocin (STZ), and then the mice were subjected to 30 min of middle cerebral artery occlusion (MCAO). Infarct volume and neurological scores were measured in the ischemic mice. The inflammatory cytokine and chemokine levels were also determined in the ischemic brain. To assess the effect of diabetes on the stroke-modulated HPA axis, we measured the expression of components in the HPA axis including corticotropin-releasing hormone (CRH) in the hypothalamus, proopiomelanocortin (POMC) in the pituitary, and plasma adrenocorticotropic hormone (ACTH) and corticosterone. Diabetic mice had larger infarcts and worse neurological scores after stroke. The exacerbated stroke outcomes in diabetic mice were accompanied by the upregulated expression of inflammatory factors (including IL-1β, TNF-α, IL-6, CCR2, and MCP-1) in the ischemic brain. We also confirmed increased levels of hypothalamic CRH, pituitary POMC, and plasma corticosterone in diabetic mice before and after stroke, suggesting the hyper-activated HPA axis in diabetic conditions. Finally, we confirmed that post-stroke treatment of metyrapone (an inhibitor of glucocorticoid synthesis) reduced IL-6 expression and the infarct size in the ischemic brain of diabetic mice. These results elucidate the mechanisms in which the HPA axis in diabetes exacerbates ischemic stroke. Maintaining an optimal level of the stress response by regulating the HPA axis may be an effective approach to improving stroke outcomes in patients with diabetes.
Collapse
|
|
22
|
Abstract
Drug-induced diabetes mellitus is a growing problem in clinical practice. New, potent medications contribute to this problem in a population already at high risk of developing glucose disturbances because of poor lifestyle habits and high prevalence of being overweight/obese. The present review focuses on four important pharmacological classes: glucocorticoids; antipsychotics, especially second generation; antiretroviral therapies, which revolutionised the management of individuals with HIV; and immune checkpoint inhibitors, recently used for the immunotherapy of cancer. For each class, the prevalence of drug-induced diabetes will be evaluated, the most common clinical presentations will be described, the underlying mechanisms leading to hyperglycaemia will be briefly analysed, and some recommendations for appropriate monitoring and management will be proposed.
Collapse
Affiliation(s)
- Bruno Fève
- Department of Endocrinology, CRMR PRISIS, Saint-Antoine Hospital, AP-HP, Paris, France.
- Centre de Recherche Saint-Antoine, Institute of Cardiometabolism and Nutrition, Sorbonne University-Inserm, Paris, France.
| | - André J Scheen
- Division of Diabetes, Nutrition and Metabolic Disorders, Department of Medicine, CHU Liège, Liège, Belgium.
- Division of Clinical Pharmacology, Center for Interdisciplinary Research on Medicines (CIRM), University of Liège, Liège, Belgium.
| |
Collapse
|
|
23
|
Ji LN, Wu S, Fu DQ, Fang SJ, Xie GQ, Fan YS, Bao J. Jieduquyuziyin Prescription alleviates hepatic gluconeogenesis via PI3K/Akt/PGC-1α pathway in glucocorticoid-induced MRL/lpr mice. JOURNAL OF ETHNOPHARMACOLOGY 2022; 284:114815. [PMID: 34763039 DOI: 10.1016/j.jep.2021.114815] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Revised: 10/25/2021] [Accepted: 11/04/2021] [Indexed: 06/13/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Jieduquyuziyin prescription (JP) is a traditional Chinese medicine (TCM) formula. According to both TCM theory and more than a decade of clinical practice, JP has been testified to be effective for systemic lupus erythematosus (SLE) treatment as an approved hospital prescription in China. AIM OF THE STUDY To determine the effect of JP on the treatment of SLE by glucocorticoid (GC) and to further examine the molecular mechanisms. MATERIALS AND METHODS We conducted in vivo experiments to estimate the effect of JP on hepatic gluconeogenesis in MRL/lpr mice treated with GC. Additionally, isoproterenol (ISO) induced hepatic gluconeogenesis model and GC-treated MRL/lpr mouse hepatocytes were carried out in vitro experiments to verify the effect of JP on gluconeogenesis. RESULTS The results showed that JP combined with GC could effectively alleviate the lupus symptoms in MRL/lpr mice and improve the pathological changes of the kidney and liver. And the combination of JP reduced the side effects caused by GC, which was related to the inhibition of GC-induced hepatic gluconeogenesis in MRL/lpr mice. Specifically, JP up-regulated the expression of glucocorticoid receptor (GR) α, phosphoinositide-3-kinase (PI3K) and Akt restrained by GC to reduce the production of forkhead box O1 (FoxO1), peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α), and the gluconeogenic genes phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase). In vivo, the use of JP either alone or with GC could reduce spleen enlargement, high levels of serum antibodies, aggravated urine protein and renal pathological damage in MRL/lpr mice. Furthermore, the glucose content was reduced in the liver of MRL/lpr mice treated with JP, and the liver damage and steatosis were also alleviated. In vitro, the expressions of PI3K and Akt increased and the expressions of FoxO1, PGC-1α, PEPCK and G6Pase decreased after JP treatment in ISO-treated hepatocytes. Compared with MRL/MP mice, we found that JP could significantly inhibit the expression of gluconeogenesis in the hepatocytes of MRL/lpr mice induced by GC to a greater extent. CONCLUSIONS The therapeutic effect of JP on GC-induced is likely related to hepatic gluconeogenesis, which provides a new perspective to reveal the positive role of JP in SLE.
Collapse
Affiliation(s)
- Li-Na Ji
- The First College of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, China.
| | - Shan Wu
- The First College of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, China.
| | - Dan-Qing Fu
- School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, China.
| | - Si-Jia Fang
- The First College of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, China.
| | - Guan-Qun Xie
- School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, China.
| | - Yong-Sheng Fan
- School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, China.
| | - Jie Bao
- School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, China.
| |
Collapse
|
|
24
|
Fairman CM, Lønbro S, Cardaci TD, VanderVeen BN, Nilsen TS, Murphy AE. Muscle wasting in cancer: opportunities and challenges for exercise in clinical cancer trials. JCSM RAPID COMMUNICATIONS 2022; 5:52-67. [PMID: 36118249 PMCID: PMC9481195 DOI: 10.1002/rco2.56] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/04/2023]
Abstract
BACKGROUND Low muscle in cancer is associated with an increase in treatment-related toxicities and is a predictor of cancer-related and all-cause mortality. The mechanisms of cancer-related muscle loss are multifactorial, including anorexia, hypogonadism, anaemia, inflammation, malnutrition, and aberrations in skeletal muscle protein turnover and metabolism. METHODS In this narrative review, we summarise relevant literature to (i) review the factors influencing skeletal muscle mass regulation, (ii) provide an overview of how cancer/treatments negatively impact these, (iii) review factors beyond muscle signalling that can impact the ability to participate in and respond to an exercise intervention to counteract muscle loss in cancer, and (iv) provide perspectives on critical areas of future research. RESULTS Despite the well-known benefits of exercise, there remains a paucity of clinical evidence supporting the impact of exercise in cancer-related muscle loss. There are numerous challenges to reversing muscle loss with exercise in clinical cancer settings, ranging from the impact of cancer/treatments on the molecular regulation of muscle mass, to clinical challenges in responsiveness to an exercise intervention. For example, tumour-related/treatment-related factors (e.g. nausea, pain, anaemia, and neutropenia), presence of comorbidities (e.g. diabetes, arthritis, and chronic obstructive pulmonary disease), injuries, disease progression and bone metastases, concomitant medications (e.g., metformin), can negatively affect an individual's ability to exercise safely and limit subsequent adaptation. CONCLUSIONS This review identifies numerous gaps and oppportunities in the area of low muscle and muscle loss in cancer. Collaborative efforts between preclinical and clinical researchers are imperative to both understanding the mechanisms of atrophy, and develop appropriate therapeutic interventions.
Collapse
Affiliation(s)
- Ciaran M. Fairman
- Department of Exercise Science, University of South Carolina, Columbia, South Carolina 29033, USA
- Correspondence to: Ciaran Fairman, Department of Exercise Science, University of South Carolina, Columbia, SC 29033, USA.
| | - Simon Lønbro
- Department of Public Health, Section for Sports Science, Aarhus University, Aarhus, Denmark
| | - Thomas D. Cardaci
- Department of Exercise Science, University of South Carolina, Columbia, South Carolina 29033, USA
| | - Brandon N. VanderVeen
- Department of Pathology, Microbiology and Immunology, School of Medicine, University of South Carolina, Columbia, South Carolina, USA
| | - Tormod S. Nilsen
- Department of Physical Performance, Norwegian School of Sports Sciences, Oslo, Norway
| | - Angela E. Murphy
- Department of Pathology, Microbiology and Immunology, School of Medicine, University of South Carolina, Columbia, South Carolina, USA
| |
Collapse
|
|
25
|
Ambalal SM. Metabolic Syndrome and Skin: Interactions and Implications. Indian J Dermatol 2022; 67:138-145. [PMID: 36092223 PMCID: PMC9455100 DOI: 10.4103/ijd.ijd_155_21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
The metabolic syndrome (MetS) has become a global crisis and is believed to affect almost one-quarter of the world's population. Its prevalence has been rising, especially in the younger age group. The interactions of the skin and MetS are myriad. Physiological functions of the skin may confer a protective role, whereas cutaneous diseases may play the role of MetS initiator or amplifier. Cutaneous signs may be some of the earliest manifestations of insulin resistance, the basic pathophysiology behind MetS. Skin changes are also prominent in type 2 diabetes mellitus, the consequence of MetS. Drugs used in dermatological disorders can lead to metabolic dysfunction. Awareness about the risk factors and early lifestyle interventions can help delay or even prevent the life-threatening complications of this syndrome. Dermatologists are in a unique position to predict and prevent MetS or its complications, a long time before the patient visits a physician for systemic problems. To write this review, an internet search was made focusing on articles on skin problems associated with MetS and its components, its risk factors, pathogenesis, and ways to prevent it. Information relevant to dermatological practice was compiled.
Collapse
Affiliation(s)
- Sujata Mehta Ambalal
- From the Skin Clinic @ Sumeru, SHREI (Skin and Hair Research and Education Initiative), Navrangpura, Ahmedabad, Gujarat, India,Address for correspondence: Dr. Sujata Mehta Ambalal, Skin Clinic @ Sumeru, Opp. Campus Corner Building, St. Xavier's College Corner, Navrangpura, Ahmedabad, Gujarat - 380 009, India. E-mail:
| |
Collapse
|
|
26
|
Delangre E, Liu J, Tolu S, Maouche K, Armanet M, Cattan P, Pommier G, Bailbé D, Movassat J. Underlying mechanisms of glucocorticoid-induced β-cell death and dysfunction: a new role for glycogen synthase kinase 3. Cell Death Dis 2021; 12:1136. [PMID: 34876563 PMCID: PMC8651641 DOI: 10.1038/s41419-021-04419-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Revised: 11/10/2021] [Accepted: 11/18/2021] [Indexed: 11/08/2022]
Abstract
Glucocorticoids (GCs) are widely prescribed for their anti-inflammatory and immunosuppressive properties as a treatment for a variety of diseases. The use of GCs is associated with important side effects, including diabetogenic effects. However, the underlying mechanisms of GC-mediated diabetogenic effects in β-cells are not well understood. In this study we investigated the role of glycogen synthase kinase 3 (GSK3) in the mediation of β-cell death and dysfunction induced by GCs. Using genetic and pharmacological approaches we showed that GSK3 is involved in GC-induced β-cell death and impaired insulin secretion. Further, we unraveled the underlying mechanisms of GC-GSK3 crosstalk. We showed that GSK3 is marginally implicated in the nuclear localization of GC receptor (GR) upon ligand binding. Furthermore, we showed that GSK3 regulates the expression of GR at mRNA and protein levels. Finally, we dissected the proper contribution of each GSK3 isoform and showed that GSK3β isoform is sufficient to mediate the pro-apoptotic effects of GCs in β-cells. Collectively, in this work we identified GSK3 as a viable target to mitigate GC deleterious effects in pancreatic β-cells.
Collapse
Affiliation(s)
- Etienne Delangre
- Université de Paris, BFA, UMR 8251, CNRS, Team « Biologie et Pathologie du Pancréas Endocrine », Paris, France
| | - Junjun Liu
- Université de Paris, BFA, UMR 8251, CNRS, Team « Biologie et Pathologie du Pancréas Endocrine », Paris, France
- Shandong Institute of Endocrine & Metabolic Diseases, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
| | - Stefania Tolu
- Université de Paris, BFA, UMR 8251, CNRS, Team « Biologie et Pathologie du Pancréas Endocrine », Paris, France
| | - Kamel Maouche
- Université de Paris, BFA, UMR 8251, CNRS, Team « Biologie et Pathologie du Pancréas Endocrine », Paris, France
| | - Mathieu Armanet
- Cell Therapy Unit, Saint-Louis hospital, AP-HP, and Université de Paris, Paris, France
| | - Pierre Cattan
- Cell Therapy Unit, Saint-Louis hospital, AP-HP, and Université de Paris, Paris, France
| | - Gaëlle Pommier
- Université de Paris, BFA, UMR 8251, CNRS, Team « Biologie et Pathologie du Pancréas Endocrine », Paris, France
| | - Danielle Bailbé
- Université de Paris, BFA, UMR 8251, CNRS, Team « Biologie et Pathologie du Pancréas Endocrine », Paris, France
| | - Jamileh Movassat
- Université de Paris, BFA, UMR 8251, CNRS, Team « Biologie et Pathologie du Pancréas Endocrine », Paris, France.
| |
Collapse
|
|
27
|
Reshad RAI, Riana SH, Chowdhury MAB, Moin AT, Miah F, Sarkar B, Jewel NA. Diabetes in COVID-19 patients: challenges and possible management strategies. THE EGYPTIAN JOURNAL OF BRONCHOLOGY 2021. [PMCID: PMC8642747 DOI: 10.1186/s43168-021-00099-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Background The recent pandemic of coronavirus disease 19 (COVID-19) has been causing intense stress among the global population. In the case of hospitalized and ICU-admitted COVID-19 patients with comorbidities, it has been observed that a major portion of them are diabetic. Therefore, researchers had indicated a link between diabetes mellitus (DM) and COVID-19. Furthermore, DM is a potential risk factor for the severity of COVID-19 cases. Thus, in this study, the correlation existing between diabetic patients and COVID-19 was summarized. Main body of the abstract Diabetic patients have a weaker immune system, less viral clearance rate, malfunctions of metabolic activity due to their high blood glucose level, and other associated problems. This does not increase the susceptibility for the patients to be infected with COVID-19. However, the severity of COVID-19 can worsen due to the comorbidity of DM. Short conclusion Proper management, appropriate use of drugs that do not increase the ACE2 expression, lowering blood glucose level, decreasing the susceptibility of SARS-CoV-2, and maintaining a healthy lifestyle could be effective.
Collapse
|
|
28
|
Abstract
Pathogenesis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induced COVID-19 implied the presence of excessive proinflammatory cytokines and chemokines in patients causing significant morbidity and mortality. To diminish systemic hyper inflammation, a few physicians and researchers have utilized corticosteroids. Corticosteroid implementation has increased after the publication of interim guidelines regarding corticosteroid use in COVID-19 patients by WHO, despite the remaining controversies regarding long-term side effects and disease progression capability of corticosteroids. In different studies, the implementation of corticosteroids on COVID-19 patients revealed controversial results, which require further intensive research. This review will present the current outcomes and possibilities of using corticosteroids to treat COVID-19 patients.
Collapse
|
|
29
|
Satin LS, Soleimanpour SA, Walker EM. New Aspects of Diabetes Research and Therapeutic Development. Pharmacol Rev 2021; 73:1001-1015. [PMID: 34193595 PMCID: PMC8274312 DOI: 10.1124/pharmrev.120.000160] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Both type 1 and type 2 diabetes mellitus are advancing at exponential rates, placing significant burdens on health care networks worldwide. Although traditional pharmacologic therapies such as insulin and oral antidiabetic stalwarts like metformin and the sulfonylureas continue to be used, newer drugs are now on the market targeting novel blood glucose-lowering pathways. Furthermore, exciting new developments in the understanding of beta cell and islet biology are driving the potential for treatments targeting incretin action, islet transplantation with new methods for immunologic protection, and the generation of functional beta cells from stem cells. Here we discuss the mechanistic details underlying past, present, and future diabetes therapies and evaluate their potential to treat and possibly reverse type 1 and 2 diabetes in humans. SIGNIFICANCE STATEMENT: Diabetes mellitus has reached epidemic proportions in the developed and developing world alike. As the last several years have seen many new developments in the field, a new and up to date review of these advances and their careful evaluation will help both clinical and research diabetologists to better understand where the field is currently heading.
Collapse
Affiliation(s)
- Leslie S Satin
- Department of Pharmacology (L.S.S.), Division of Metabolism, Endocrinology, and Diabetes, Department of Internal Medicine (L.S.S., S.A.S., E.M.W.), and Brehm Diabetes Center (L.S.S., S.A.S., E.M.W.), University of Michigan Medical School, Ann Arbor, Michigan; and VA Ann Arbor Healthcare System, Ann Arbor, Michigan (S.A.S.) ; ;
| | - Scott A Soleimanpour
- Department of Pharmacology (L.S.S.), Division of Metabolism, Endocrinology, and Diabetes, Department of Internal Medicine (L.S.S., S.A.S., E.M.W.), and Brehm Diabetes Center (L.S.S., S.A.S., E.M.W.), University of Michigan Medical School, Ann Arbor, Michigan; and VA Ann Arbor Healthcare System, Ann Arbor, Michigan (S.A.S.)
| | - Emily M Walker
- Department of Pharmacology (L.S.S.), Division of Metabolism, Endocrinology, and Diabetes, Department of Internal Medicine (L.S.S., S.A.S., E.M.W.), and Brehm Diabetes Center (L.S.S., S.A.S., E.M.W.), University of Michigan Medical School, Ann Arbor, Michigan; and VA Ann Arbor Healthcare System, Ann Arbor, Michigan (S.A.S.) ; ;
| |
Collapse
|
|
30
|
Hong P, Song YG, Paek S. Possible effects of agent orange and posttraumatic stress disorder on hyperglycemia in Korean veterans from the US-Vietnam war. Medicine (Baltimore) 2021; 100:e26508. [PMID: 34160471 PMCID: PMC8238358 DOI: 10.1097/md.0000000000026508] [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: 09/29/2020] [Accepted: 05/12/2021] [Indexed: 01/04/2023] Open
Abstract
This study was conducted to examine whether Korean veterans from the US-Vietnam War who had a diagnosis of type II diabetes mellitus (T2DM) as well as past history of exposure to agent orange (AO) are vulnerable to hyperglycemia when receiving intra-articular corticosteroid injection (IACI) for pain relief.The current study included a total of 49 patients (n = 49) who received an injection of triamcinolone 20 or 40 mg to the shoulder under sonographic guidance or did that of dexamethasone 10 mg or triamcinolone 40 mg combined with dexamethasone 20 mg to the spine under fluoroscopic guidance. Their 7-day fasting blood glucose (FBG) levels were measured and then averaged, serving as baseline levels. This is followed by measurement of FBG levels for 14 days of IACI. Respective measurements were compared with baseline levels. The patients were also evaluated for whether there are increases in FBG levels depending on insulin therapy as well as HbA1c ≥ 7% or HbA1c < 7%.Overall, there were significant increases in FBG levels by 64.7 ± 42.5 mg/dL at 1 day of IACI from baseline (P < .05). HbA1c ≥ 7% and HbA1c < 7% showed increases in FBG levels by 106.1 ± 49.0 mg/dL and 46.5 ± 3.8 mg/dL, respectively, at 1 day of IACI from baseline (P < .05). In the presence and absence of insulin therapy, there were significant increases in them by 122.6 ± 48.7 mg/dL and 48.0 ± 20.4 mg/dL, respectively, at 1 day of IACI from baseline (P < .05). But there were decreases in them to baseline levels at 2 days of IACI.Clinicians should consider the possibility of hyperglycemia when using corticosteroids for relief of musculoskeletal pain in Korean veterans from the US-Vietnam War who had a history of exposure to AO.
Collapse
Affiliation(s)
- Pa Hong
- Department of Radiology, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon
| | - Yun Gyu Song
- Department of Radiology, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon
| | - Sungwoo Paek
- Department of Rehabilitation Medicine, Konkuk University Chungju Hospital, Konkuk University School of Medicine, Chungju, Korea
| |
Collapse
|
|
31
|
Wang X, Heinrich DA, Kunz SL, Heger N, Sturm L, Uhl O, Beuschlein F, Reincke M, Bidlingmaier M. Characteristics of preoperative steroid profiles and glucose metabolism in patients with primary aldosteronism developing adrenal insufficiency after adrenalectomy. Sci Rep 2021; 11:11181. [PMID: 34045650 PMCID: PMC8160266 DOI: 10.1038/s41598-021-90901-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Accepted: 05/18/2021] [Indexed: 11/28/2022] Open
Abstract
Treatment of choice in patients with unilateral aldosterone producing adenoma (APA) is adrenalectomy. Following surgery, most patients retain normal adrenal function, while some develop adrenal insufficiency (AI). To facilitate early detection and treatment of AI, we aimed to identify variables measured pre-operatively that are associated with post-operative AI. Variables obtained from 66 patients before and after surgery included anthropometrical data, clinical chemistry, endocrine work-up. LC–MS/MS steroid hormone profiles from tests before surgery (ACTH-stimulation, saline infusion, dexamethasone suppression) were obtained. Based on 78 variables, machine-learning methods were used in model fitting for classification and regression to predict ACTH-stimulated cortisol after surgery. Among the 78 variables, insulin concentration during pre-operative oral glucose tolerance test (OGTT) correlated positively, and dexamethasone suppressed glucocorticoids correlated negatively with ACTH-stimulated cortisol after surgery. Inclusion of LC–MS/MS measurements allowed construction of better models associated with the occurrence of AI in the training data, but did not allow reliable prediction in cross-validation. Our results suggest that glucocorticoid co-secretion (low insulin during pre-operative OGTT and insufficient suppression of glucocorticoids following dexamethasone) are correlated with the development of post-operative AI. Addition of steroid profiles improved the accuracy of prediction, but cross validation revealed lack of reliability in the prediction of AI.
Collapse
Affiliation(s)
- Xiao Wang
- Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Ziemssenstraße 1, 80336, Munich, Germany
| | - Daniel A Heinrich
- Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Ziemssenstraße 1, 80336, Munich, Germany.
| | - Sonja L Kunz
- Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Ziemssenstraße 1, 80336, Munich, Germany
| | - Nina Heger
- Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Ziemssenstraße 1, 80336, Munich, Germany
| | - Lisa Sturm
- Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Ziemssenstraße 1, 80336, Munich, Germany
| | - Olaf Uhl
- Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Ziemssenstraße 1, 80336, Munich, Germany.,Division of Metabolic and Nutritional Medicine, Dr. von Hauner Children's Hospital, Lindwurmstr. 4, 80337, Munich, Germany
| | - Felix Beuschlein
- Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Ziemssenstraße 1, 80336, Munich, Germany.,Klinik für Endokrinologie, Diabetologie und Klinische Ernährung, Rämistrasse 100, 8091, Zurich, Switzerland
| | - Martin Reincke
- Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Ziemssenstraße 1, 80336, Munich, Germany
| | - Martin Bidlingmaier
- Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Ziemssenstraße 1, 80336, Munich, Germany
| |
Collapse
|
|
32
|
Gubbi S, Muniyappa R, Sharma ST, Grewal S, McGlotten R, Nieman LK. Mifepristone Improves Adipose Tissue Insulin Sensitivity in Insulin Resistant Individuals. J Clin Endocrinol Metab 2021; 106:1501-1515. [PMID: 33507248 PMCID: PMC8063260 DOI: 10.1210/clinem/dgab046] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Indexed: 01/03/2023]
Abstract
BACKGROUND Increased tissue cortisol availability has been implicated in abnormal glucose and fat metabolism in patients with obesity, metabolic syndrome, and type 2 diabetes (T2DM). Our objective was to evaluate whether blockade of glucocorticoid receptor (GR) with mifepristone ameliorates insulin resistance (IR) in overweight/obese subjects with glucose intolerance. METHODS We conducted a randomized, double-blinded, placebo-controlled, crossover study in overweight/obese individuals (n = 16, 44% female) with prediabetes or mild T2DM but not clinical hypercortisolism. Mifepristone (50 mg every 6 h) or placebo was administered for 9 days, followed by crossover to the other treatment arm after a washout period of 6 to 8weeks. At baseline and following each treatment, oral glucose tolerance test (OGTT) and frequently sampled intravenous glucose tolerance test (FSIVGTT) were performed. Insulin sensitivity was measured using FSIVGTT [primary outcome: insulin sensitivity index (SI)] and OGTT [Matsuda index (MI) and oral glucose insulin sensitivity index (OGIS)]. Hepatic and adipose insulin resistance were assessed using hepatic insulin resistance index (HIRI), and adipose tissue insulin sensitivity index (Adipo-SI) and adipo-IR, derived from the FSIVGTT. RESULTS Mifepristone administration did not alter whole-body glucose disposal indices of insulin sensitivity (SI, MI, and OGIS). GR blockade significantly improved Adipo-SI (61.7 ± 32.9 vs 42.8 ± 23.9; P = 0.002) and reduced adipo-IR (49.9 ± 45.9 vs 65.5 ± 43.8; P = 0.004), and HIRI (50.2 ± 38.7 vs 70.0 ± 44.3; P = 0.08). Mifepristone increased insulin clearance but did not affect insulin secretion or β-cell glucose sensitivity. CONCLUSION Short-term mifepristone administration improves adipose and hepatic insulin sensitivity among obese individuals with hyperglycemia without hypercortisolism.
Collapse
Affiliation(s)
- Sriram Gubbi
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Ranganath Muniyappa
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Susmeeta T Sharma
- Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
- MedStar Washington Hospital Center, Washington, DC, USA
| | - Shivraj Grewal
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Raven McGlotten
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
- Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
| | - Lynnette K Nieman
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
- Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
- Correspondence: Lynnette K. Nieman, M.D., 10 Center Drive, Building 10, CRC, Rm 1-3140, Bethesda, MD 20892-1613.
| |
Collapse
|
|
33
|
Binayi F, Zardooz H, Ghasemi R, Hedayati M, Askari S, Pouriran R, Sahraei M. The chemical chaperon 4-phenyl butyric acid restored high-fat diet- induced hippocampal insulin content and insulin receptor level reduction along with spatial learning and memory deficits in male rats. Physiol Behav 2021; 231:113312. [PMID: 33412188 DOI: 10.1016/j.physbeh.2021.113312] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Revised: 01/01/2021] [Accepted: 01/02/2021] [Indexed: 12/18/2022]
Abstract
This study assessed the effect of a chronic high-fat diet (HFD) on plasma and hippocampal insulin and corticosterone levels, the hippocampus insulin receptor amount, and spatial learning and memory with or without receiving 4-phenyl butyric acid (4-PBA) in male rats. Rats were divided into high-fat and normal diet groups, then each group was subdivided into dimethyl sulfoxide (DMSO) and 4-PBA groups. After weaning, the rats were fed with HFD for 20 weeks. Then, 4-PBA or DMSO were injected for 3 days. Subsequently, oral glucose tolerance test was done. On the following day, spatial memory tests were performed. Then the hippocampus Bip, Chop, insulin, corticosterone, and insulin receptor levels were determined. HFD increased plasma glucose, leptin and corticosterone concentrations, hippocampus Bip, Chop and corticosterone levels, food intake, abdominal fat weight and body weight along with impaired glucose tolerance. It decreased plasma insulin, and insulin content, and its receptor amount in hippocampus. HFD lengthened escape latency and shortened the duration spent in target zone. 4-PBA administration improved the HFD- induced adverse changes. Chronic HFD possibly through the induction of endoplasmic reticulum (ER) stress and subsequent changes in the levels of hippocampal corticosterone, insulin and insulin receptor along with possible leptin resistance caused spatial learning and memory deficits.
Collapse
Affiliation(s)
- Fateme Binayi
- Department of Physiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Neurophysiology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Homeira Zardooz
- Department of Physiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Neurophysiology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Cellular and Molecular Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Rasoul Ghasemi
- Department of Physiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Neurophysiology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mehdi Hedayati
- Cellular and Molecular Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Sahar Askari
- Department of Physiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ramin Pouriran
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Sahraei
- School of Dentistry, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| |
Collapse
|
|
34
|
Corticosteroid-binding-globulin (CBG)-deficient mice show high pY216-GSK3β and phosphorylated-Tau levels in the hippocampus. PLoS One 2021; 16:e0246930. [PMID: 33592009 PMCID: PMC7886218 DOI: 10.1371/journal.pone.0246930] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Accepted: 01/28/2021] [Indexed: 12/16/2022] Open
Abstract
Corticosteroid-binding globulin (CBG) is the specific carrier of circulating glucocorticoids, but evidence suggests that it also plays an active role in modulating tissue glucocorticoid activity. CBG polymorphisms affecting its expression or affinity for glucocorticoids are associated with chronic pain, chronic fatigue, headaches, depression, hypotension, and obesity with an altered hypothalamic pituitary adrenal axis. CBG has been localized in hippocampus of humans and rodents, a brain area where glucocorticoids have an important regulatory role. However, the specific CBG function in the hippocampus is yet to be established. The aim of this study was to investigate the effect of the absence of CBG on hippocampal glucocorticoid levels and determine whether pathways regulated by glucocorticoids would be altered. We used cbg-/- mice, which display low total-corticosterone and high free-corticosterone blood levels at the nadir of corticosterone secretion (morning) and at rest to evaluate the hippocampus for total- and free-corticosterone levels; 11β-hydroxysteroid dehydrogenase expression and activity; the expression of key proteins involved in glucocorticoid activity and insulin signaling; microtubule-associated protein tau phosphorylation, and neuronal and synaptic function markers. Our results revealed that at the nadir of corticosterone secretion in the resting state the cbg-/- mouse hippocampus exhibited slightly elevated levels of free-corticosterone, diminished FK506 binding protein 5 expression, increased corticosterone downstream effectors and altered MAPK and PI3K pathway with increased pY216-GSK3β and phosphorylated tau. Taken together, these results indicate that CBG deficiency triggers metabolic imbalance which could lead to damage and long-term neurological pathologies.
Collapse
|
|
35
|
Molecular Mechanisms of Glucocorticoid-Induced Insulin Resistance. Int J Mol Sci 2021; 22:ijms22020623. [PMID: 33435513 PMCID: PMC7827500 DOI: 10.3390/ijms22020623] [Citation(s) in RCA: 110] [Impact Index Per Article: 27.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Revised: 12/29/2020] [Accepted: 01/02/2021] [Indexed: 12/12/2022] Open
Abstract
Glucocorticoids (GCs) are steroids secreted by the adrenal cortex under the hypothalamic-pituitary-adrenal axis control, one of the major neuro-endocrine systems of the organism. These hormones are involved in tissue repair, immune stability, and metabolic processes, such as the regulation of carbohydrate, lipid, and protein metabolism. Globally, GCs are presented as ‘flight and fight’ hormones and, in that purpose, they are catabolic hormones required to mobilize storage to provide energy for the organism. If acute GC secretion allows fast metabolic adaptations to respond to danger, stress, or metabolic imbalance, long-term GC exposure arising from treatment or Cushing’s syndrome, progressively leads to insulin resistance and, in fine, cardiometabolic disorders. In this review, we briefly summarize the pharmacological actions of GC and metabolic dysregulations observed in patients exposed to an excess of GCs. Next, we describe in detail the molecular mechanisms underlying GC-induced insulin resistance in adipose tissue, liver, muscle, and to a lesser extent in gut, bone, and brain, mainly identified by numerous studies performed in animal models. Finally, we present the paradoxical effects of GCs on beta cell mass and insulin secretion by the pancreas with a specific focus on the direct and indirect (through insulin-sensitive organs) effects of GCs. Overall, a better knowledge of the specific action of GCs on several organs and their molecular targets may help foster the understanding of GCs’ side effects and design new drugs that possess therapeutic benefits without metabolic adverse effects.
Collapse
|
|
36
|
SIRT1 functional polymorphisms (rs12778366, rs3758391) as genetic biomarkers of susceptibility to type 2 diabetes mellitus in Iranians: a case-control study and computational analysis. Int J Diabetes Dev Ctries 2021. [DOI: 10.1007/s13410-020-00898-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
|
|
37
|
Quattrocelli M, Zelikovich AS, Salamone IM, Fischer JA, McNally EM. Mechanisms and Clinical Applications of Glucocorticoid Steroids in Muscular Dystrophy. J Neuromuscul Dis 2021; 8:39-52. [PMID: 33104035 PMCID: PMC7902991 DOI: 10.3233/jnd-200556] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Glucocorticoid steroids are widely used as immunomodulatory agents in acute and chronic conditions. Glucocorticoid steroids such as prednisone and deflazacort are recommended for treating Duchenne Muscular Dystrophy where their use prolongs ambulation and life expectancy. Despite this benefit, glucocorticoid use in Duchenne Muscular Dystrophy is also associated with significant adverse consequences including adrenal suppression, growth impairment, poor bone health and metabolic syndrome. For other forms of muscular dystrophy like the limb girdle dystrophies, glucocorticoids are not typically used. Here we review the experimental evidence supporting multiple mechanisms of glucocorticoid action in dystrophic muscle including their role in dampening inflammation and myofiber injury. We also discuss alternative dosing strategies as well as novel steroid agents that are in development and testing, with the goal to reduce adverse consequences of prolonged glucocorticoid exposure while maximizing beneficial outcomes.
Collapse
Affiliation(s)
- Mattia Quattrocelli
- Center for Genetic Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.,Molecular Cardiovascular Biology Division, Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Aaron S Zelikovich
- Center for Genetic Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Isabella M Salamone
- Center for Genetic Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Julie A Fischer
- Center for Genetic Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Elizabeth M McNally
- Center for Genetic Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| |
Collapse
|
|
38
|
Brix JM, Tura A, Herz CT, Feder A, Krzizek EC, Parzer V, Pacini G, Ludvik B. The Association of Cortisol Excretion with Weight and Metabolic Parameters in Nondiabetic Patients with Morbid Obesity. Obes Facts 2021; 14:510-519. [PMID: 34496367 PMCID: PMC8546449 DOI: 10.1159/000517766] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Accepted: 05/28/2021] [Indexed: 11/19/2022] Open
Abstract
INTRODUCTION Cortisol is involved in the regulation of gluconeogenesis and glucose utilization. In morbid obesity (MO), the association of cortisol excretion with metabolic parameters is not well-characterized. In our study, we evaluated cortisol excretion in nondiabetic subjects with MO and its effect on glucose metabolism. METHODS We included 1,249 nondiabetic patients with MO (79.8% females, mean BMI 44.9 ± 6.5 kg/m2, mean age 38 ± 11 years). Anthropometric data and cardiovascular risk factors were assessed, and an oral glucose tolerance test for calculation of insulin resistance was performed. Cortisol excretion was assessed on 2 consecutive days (24 h urine specimens). RESULTS Regarding cortisol excretion, patients were divided into 3 tertiles (urinary cortisol ≤51.6, >51.6 and <117.6, and ≥117.6 μg/24 h, respectively). Patients in the highest tertile were younger (p = 0.003), more obese (BMI: p = 0.040), had lower diastolic blood pressure ([DBP]; p = 0.012), lower total (p = 0.032) and LDL cholesterol (p = 0.021), fasting (p = 0.049) and 2-h glycemia (p = 0.028), 2-h insulinemia (p = 0.020), and HbA1c (p < 0.001), and a higher estimated glomerular filtration rate (eGFR) (p < 0.001). The glucose (p < 0.001) and insulin (p = 0.011) area under the curve (AUC) were also lower. Urinary cortisol excretion adjusted for age, sex, and eGFR was positively correlated with body weight (BW, beta = 0.076, p = 0.004) and overall glucose tolerance (oral disposition index, beta = 0.090, p = 0.011), and negatively with HbA1c (beta = -0.179, p < 0.001), 2-h glycemia (beta = -0.075, p = 0.032), AUC glucose (beta = -0.103, p = 0.002), and DBP (beta = -0.139, p < 0.001). HbA1c, BW, and DBP remained significant after multivariable analysis. DISCUSSION/CONCLUSION Despite being more obese, patients with higher cortisol excretion have a more favorable metabolic profile. These results deserve further attention regarding the respective mechanisms.
Collapse
Affiliation(s)
- Johanna Maria Brix
- Department of Medicine I, Klinik Landstraße, Vienna, Austria
- Karl Landsteiner Institute for Obesity and Metabolic Disorders, Vienna, Austria
- *Johanna Maria Brix,
| | - Andrea Tura
- CNR Institute of Neuroscience, Metabolix Unit, Padova, Italy
| | - Carsten Thilo Herz
- Department of Medicine III, Division for Nephrology and Dialysis, Medical University Vienna, Vienna, Austria
| | - Astrid Feder
- Department of Medicine I, Klinik Landstraße, Vienna, Austria
- Karl Landsteiner Institute for Obesity and Metabolic Disorders, Vienna, Austria
| | - Eva-Christina Krzizek
- Department of Medicine I, Klinik Landstraße, Vienna, Austria
- Karl Landsteiner Institute for Obesity and Metabolic Disorders, Vienna, Austria
| | - Verena Parzer
- Department of Medicine I, Klinik Landstraße, Vienna, Austria
| | - Giovanni Pacini
- CNR Institute of Neuroscience, Metabolix Unit, Padova, Italy
| | - Bernhard Ludvik
- Department of Medicine I, Klinik Landstraße, Vienna, Austria
- Karl Landsteiner Institute for Obesity and Metabolic Disorders, Vienna, Austria
| |
Collapse
|
|
39
|
Koorneef LL, Kroon J, Viho EMG, Wahl LF, Heckmans KML, van Dorst MMAR, Hoekstra M, Houtman R, Hunt H, Meijer OC. The selective glucocorticoid receptor antagonist CORT125281 has tissue-specific activity. J Endocrinol 2020; 246:79-92. [PMID: 32369774 PMCID: PMC7274539 DOI: 10.1530/joe-19-0486] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Accepted: 05/04/2020] [Indexed: 12/19/2022]
Abstract
Glucocorticoids mediate numerous essential processes in the human body via binding to the glucocorticoid receptor (GR). Excessive GR signaling can cause disease, and GR antagonists can be used to treat many symptoms of glucocorticoid-induced pathology. The purpose of this study was to characterize the tissue-specific properties of the selective GR antagonist CORT125281. We evaluated the antagonistic effects of CORT125281 upon acute and subchronic corticosterone exposure in mice. In the acute corticosterone setting, hypothalamus-pituitary-adrenal-axis activity was investigated by measurement of basal- and stress-induced corticosterone levels, adrenocorticotropic hormone levels and pituitary proopiomelanocortin expression. GR signaling was evaluated by RT-PCR analysis of GR-responsive transcripts in liver, muscle, brown adipose tissue (BAT), white adipose tissue (WAT) and hippocampus. Pretreatment with a high dose of CORT125281 antagonized GR activity in a tissue-dependent manner. We observed complete inhibition of GR-induced target gene expression in the liver, partial blockade in muscle and BAT and no antagonism in WAT and hippocampus. Tissue distribution only partially explained the lack of effective antagonism. CORT125281 treatment did not disinhibit the hypothalamus-pituitary-adrenal neuroendocrine axis. In the subchronic corticosterone setting, CORT125281 partially prevented corticosterone-induced hyperinsulinemia, but not hyperlipidemia and immune suppression. In conclusion, CORT125281 antagonizes GR transcriptional activity in a tissue-dependent manner and improves corticosterone-induced hyperinsulinemia. Tailored dosing of CORT125281 may allow tissue-specific inhibition of GR transcriptional activity.
Collapse
Affiliation(s)
- Lisa L Koorneef
- Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, The Netherlands
- Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands
| | - Jan Kroon
- Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, The Netherlands
- Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands
| | - Eva M G Viho
- Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, The Netherlands
- Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands
| | - Lucas F Wahl
- Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, The Netherlands
- Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands
| | - Kim M L Heckmans
- Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, The Netherlands
- Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands
| | - Marloes M A R van Dorst
- Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, The Netherlands
- Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands
| | - Menno Hoekstra
- Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands
| | - René Houtman
- Pamgene International, Den Bosch, The Netherlands
| | - Hazel Hunt
- Corcept Therapeutics, Menlo Park, California, USA
| | - Onno C Meijer
- Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, The Netherlands
- Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands
- Correspondence should be addressed to O C Meijer:
| |
Collapse
|
|
40
|
Rothe N, Steffen J, Penz M, Kirschbaum C, Walther A. Examination of peripheral basal and reactive cortisol levels in major depressive disorder and the burnout syndrome: A systematic review. Neurosci Biobehav Rev 2020; 114:232-270. [DOI: 10.1016/j.neubiorev.2020.02.024] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2019] [Revised: 01/27/2020] [Accepted: 02/19/2020] [Indexed: 12/15/2022]
|
|
41
|
Srivastava SP, Goodwin JE. Cancer Biology and Prevention in Diabetes. Cells 2020; 9:cells9061380. [PMID: 32498358 PMCID: PMC7349292 DOI: 10.3390/cells9061380] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Revised: 05/25/2020] [Accepted: 05/30/2020] [Indexed: 02/07/2023] Open
Abstract
The available evidence suggests a complex relationship between diabetes and cancer. Epidemiological data suggest a positive correlation, however, in certain types of cancer, a more complex picture emerges, such as in some site-specific cancers being specific to type I diabetes but not to type II diabetes. Reports share common and differential mechanisms which affect the relationship between diabetes and cancer. We discuss the use of antidiabetic drugs in a wide range of cancer therapy and cancer therapeutics in the development of hyperglycemia, especially antineoplastic drugs which often induce hyperglycemia by targeting insulin/IGF-1 signaling. Similarly, dipeptidyl peptidase 4 (DPP-4), a well-known target in type II diabetes mellitus, has differential effects on cancer types. Past studies suggest a protective role of DPP-4 inhibitors, but recent studies show that DPP-4 inhibition induces cancer metastasis. Moreover, molecular pathological mechanisms of cancer in diabetes are currently largely unclear. The cancer-causing mechanisms in diabetes have been shown to be complex, including excessive ROS-formation, destruction of essential biomolecules, chronic inflammation, and impaired healing phenomena, collectively leading to carcinogenesis in diabetic conditions. Diabetes-associated epithelial-to-mesenchymal transition (EMT) and endothelial-to-mesenchymal transition (EndMT) contribute to cancer-associated fibroblast (CAF) formation in tumors, allowing the epithelium and endothelium to enable tumor cell extravasation. In this review, we discuss the risk of cancer associated with anti-diabetic therapies, including DPP-4 inhibitors and SGLT2 inhibitors, and the role of catechol-o-methyltransferase (COMT), AMPK, and cell-specific glucocorticoid receptors in cancer biology. We explore possible mechanistic links between diabetes and cancer biology and discuss new therapeutic approaches.
Collapse
Affiliation(s)
- Swayam Prakash Srivastava
- Department of Pediatrics, Yale University School of Medicine, Yale University, New Haven, CT 06520-8064, USA
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT 06520-8066, USA
- Correspondence: (S.P.S.); (J.E.G.)
| | - Julie E. Goodwin
- Department of Pediatrics, Yale University School of Medicine, Yale University, New Haven, CT 06520-8064, USA
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT 06520-8066, USA
- Correspondence: (S.P.S.); (J.E.G.)
| |
Collapse
|
|
42
|
Nagaraju R, Joshi AKR, Vamadeva SG, Rajini PS. Deregulation of hepatic lipid metabolism associated with insulin resistance in rats subjected to chronic monocrotophos exposure. J Biochem Mol Toxicol 2020; 34:e22506. [PMID: 32267039 DOI: 10.1002/jbt.22506] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2019] [Revised: 02/24/2020] [Accepted: 03/26/2020] [Indexed: 12/19/2022]
Abstract
In our previous study, we demonstrated the potential of monocrotophos (MCP), an organophosphorus insecticide (OPI), to induce glucose intolerance, insulin resistance (IR), and dyslipidemia with hyperinsulinemia in rats after chronic exposure. As hyperinsulinemia is likely to exert an impact on hepatic lipid metabolism, we carried out this study to establish the effect of chronic MCP exposure (0.9 and 1.8 mg/kg/day for 180 days) on hepatic lipid metabolism in rats. The state of IR induced by MCP in rats was associated with an increase in the liver lipid content (triglyceride and cholesterol) and expression levels of sterol regulatory element-binding proteins, PPARγ, acetyl-CoA carboxylase, and fatty acid synthase in the liver. Similarly, activities of key enzymes (acetyl-COA carboxylase, fatty acid synthase, lipin 1, malic enzyme, glucose-6-phosphate dehydrogenase, and glycerol-3-phosphate dehydrogenase), which regulate lipogenesis, were enhanced in livers of pesticide-treated rats. A strong correlation was observed between insulin levels, hepatic lipid content, and plasma lipid profile in treated rats. Our study suggests that long-term exposure to OPIs not only has a propensity to induce a state of hyperinsulinemic IR, but it is also associated with augmented hepatic lipogenesis, which may explain dyslipidemia induced by chronic exposure to MCP.
Collapse
Affiliation(s)
- Raju Nagaraju
- Food Protectants and Infestation Control Department, CSIR-Central Food Technological Research Institute, Mysore, Karnataka, India
| | - Apurva K R Joshi
- Food Protectants and Infestation Control Department, CSIR-Central Food Technological Research Institute, Mysore, Karnataka, India
| | - Sowmya G Vamadeva
- Food Protectants and Infestation Control Department, CSIR-Central Food Technological Research Institute, Mysore, Karnataka, India
| | - Padmanabhan S Rajini
- Food Protectants and Infestation Control Department, CSIR-Central Food Technological Research Institute, Mysore, Karnataka, India
| |
Collapse
|
|
43
|
Kooptiwut S, Samon K, Semprasert N, Suksri K, Yenchitsomanus PT. Prunetin Protects Against Dexamethasone-Induced Pancreatic Β-Cell Apoptosis via Modulation of p53 Signaling Pathway. Nat Prod Commun 2020. [DOI: 10.1177/1934578x20916328] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Long-term administration of dexamethasone results in insulin resistance and pancreatic β-cell apoptosis. Prunetin (an O-methylated isoflavone, a type of flavonoid) is demonstrated to protect diabetes, but the molecular mechanism of this protection is still unclear. This study thus aims to investigate how prunetin protects against dexamethasone-induced pancreatic β-cell apoptosis. Rat insulinoma (INS-1) cells were cultured in medium with or without dexamethasone in the presence or absence of prunetin or pifithrin-α, a p53 inhibitor. Cell apoptosis was measured by Annexin V/propidium iodide staining. Dexamethasone significantly induced INS-1 apoptosis but dexamethasone plus prunetin significantly reduced INS-1 apoptosis. Dexamethasone-treated INS-1 upregulated p53 protein expression; the induction of p53 was also reduced in the presence of RU486, a glucocorticoid receptor (GR) inhibitor. This suggested that dexamethasone induced P53 via GR. Dexamethasone-treated INS-1 significantly increased p53, Bax, and Rb protein expressions, whereas treatments of dexamethasone plus prunetin or pifithrin-α significantly decreased these protein expressions. In addition, dexamethasone significantly decreased B-cell lymphoma 2 (Bcl2), while dexamethasone plus prunetin or pifithrin-α significantly increased Bcl2. Dexamethasone significantly increased caspase-3 activity while co-treatment of dexamethasone plus prunetin or pifithrin-α significantly decreased caspase-3 activity to the control level. Taken together, our results revealed that prunetin protected against dexamethasone-induced pancreatic β-cells apoptosis via modulation of the p53 signaling pathway.
Collapse
Affiliation(s)
- Suwattanee Kooptiwut
- Department of Physiology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Kanokwan Samon
- Department of Physiology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Namoiy Semprasert
- Department of Physiology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Kanchana Suksri
- Department of Physiology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Pa-Thai Yenchitsomanus
- Division of Molecular Medicine, Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| |
Collapse
|
|
44
|
Akane Y, Yamamoto M, Igarashi K, Takebayashi A, Hori T. Permanent insulin-dependent diabetes mellitus in a patient with acute lymphoblastic leukemia. Pediatr Int 2020; 62:403-405. [PMID: 32022381 DOI: 10.1111/ped.14079] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2019] [Revised: 11/18/2019] [Accepted: 11/29/2019] [Indexed: 11/29/2022]
Affiliation(s)
- Yusuke Akane
- Department of Pediatrics, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Masaki Yamamoto
- Department of Pediatrics, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Keita Igarashi
- Department of Pediatrics, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Akira Takebayashi
- Department of Pediatrics, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Tsukasa Hori
- Department of Pediatrics, Sapporo Medical University School of Medicine, Sapporo, Japan
| |
Collapse
|
|
45
|
Cobo-Vuilleumier N, Gauthier BR. Time for a paradigm shift in treating type 1 diabetes mellitus: coupling inflammation to islet regeneration. Metabolism 2020; 104:154137. [PMID: 31904355 DOI: 10.1016/j.metabol.2020.154137] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Revised: 12/26/2019] [Accepted: 12/29/2019] [Indexed: 02/07/2023]
Abstract
Type 1 diabetes mellitus (T1DM) is an autoimmune disease that targets the destruction of islet beta-cells resulting in insulin deficiency, hyperglycemia and death if untreated. Despite advances in medical devices and longer-acting insulin, there is still no robust therapy to substitute and protect beta-cells that are lost in T1DM. Attempts to refrain from the autoimmune attack have failed to achieve glycemic control in patients highlighting the necessity for a paradigm shift in T1DM treatment. Paradoxically, beta-cells are present in T1DM patients indicating a disturbed equilibrium between the immune attack and beta-cell regeneration reminiscent of unresolved wound healing that under normal circumstances progression towards an anti-inflammatory milieu promotes regeneration. Thus, the ultimate T1DM therapy should concomitantly restore immune self-tolerance and replenish the beta-cell mass similar to wound healing. Recently the agonistic activation of the nuclear receptor LRH-1/NR5A2 was shown to induce immune self-tolerance, increase beta-cell survival and promote regeneration through a mechanism of alpha-to-beta cell phenotypic switch. This trans-regeneration process appears to be facilitated by a pancreatic anti-inflammatory environment induced by LRH-1/NR5A2 activation. Herein, we review the literature on the role of LRH1/NR5A2 in immunity and islet physiology and propose that a cross-talk between these cellular compartments is mandatory to achieve therapeutic benefits.
Collapse
Affiliation(s)
- Nadia Cobo-Vuilleumier
- Andalusian Center for Molecular Biology and Regenerative Medicine-CABIMER, Junta de Andalucia-University of Pablo de Olavide-University of Seville-CSIC, Seville, Spain
| | - Benoit R Gauthier
- Andalusian Center for Molecular Biology and Regenerative Medicine-CABIMER, Junta de Andalucia-University of Pablo de Olavide-University of Seville-CSIC, Seville, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, 28029 Spain.
| |
Collapse
|
|
46
|
Esguerra JLS, Ofori JK, Nagao M, Shuto Y, Karagiannopoulos A, Fadista J, Sugihara H, Groop L, Eliasson L. Glucocorticoid induces human beta cell dysfunction by involving riborepressor GAS5 LincRNA. Mol Metab 2020; 32:160-167. [PMID: 32029226 PMCID: PMC6976904 DOI: 10.1016/j.molmet.2019.12.012] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2019] [Revised: 12/08/2019] [Accepted: 12/20/2019] [Indexed: 12/25/2022] Open
Abstract
OBJECTIVE A widely recognized metabolic side effect of glucocorticoid (GC) therapy is steroid-induced diabetes mellitus (DM). However, studies on the molecular basis of GC-induced pancreatic beta cell dysfunction in human beta cells are lacking. The significance of non-coding RNAs in various cellular processes is emerging. In this study, we aimed to show the direct negative impact of GC on beta cell function and elucidate the role of riborepressor GAS5 lincRNA in the GC signaling pathway in human pancreatic beta cells. METHODS Patients undergoing two weeks of high-dose prednisolone therapy were monitored for C-peptide levels. Human pancreatic islets and the human beta cell line EndoC-βH1 were incubated in pharmacological concentrations of dexamethasone. The GAS5 level was modulated using anti-sense LNA gapmeR or short oligonucleotides with GAS5 HREM (hormone response element motif). Immunoblotting and/or real-time PCR were used to assess changes in protein and RNA expression, respectively. Functional characterization included glucose-stimulated insulin secretion and apoptosis assays. Correlation analysis was performed on RNAseq data of human pancreatic islets. RESULTS We found reduced C-peptide levels in patients undergoing high-dose GC therapy. Human islets and the human beta cell line EndoC-βH1 exposed to GC exhibited reduced insulin secretion and increased apoptosis. Concomitantly, reduced expression of important beta cell transcription factors, PDX1 and NKX6-1, as well as exocytotic protein SYT13 were observed. The expression of the glucocorticoid receptor was decreased, while that of serum and glucocorticoid-regulated kinase 1 (SGK1) was elevated. The expression of these genes was found to significantly correlate with GAS5 in human islet transcriptomics data. Increasing GAS5 levels using GAS5 HREM alleviated the inhibitory effects of dexamethasone on insulin secretion. CONCLUSIONS The direct adverse effect of glucocorticoid in human beta cell function is mediated via important beta cell proteins and components of the GC signaling pathway in an intricate interplay with GAS5 lincRNA, a potentially novel therapeutic target to counter GC-mediated beta cell dysfunction.
Collapse
Affiliation(s)
- Jonathan L S Esguerra
- Islet Cell Exocytosis, Department of Clinical Sciences-Malmö, Lund University, Malmö, Sweden; Lund University Diabetes Centre, Skåne University Hospital, Malmö, Sweden.
| | - Jones K Ofori
- Islet Cell Exocytosis, Department of Clinical Sciences-Malmö, Lund University, Malmö, Sweden; Lund University Diabetes Centre, Skåne University Hospital, Malmö, Sweden
| | - Mototsugu Nagao
- Islet Cell Exocytosis, Department of Clinical Sciences-Malmö, Lund University, Malmö, Sweden; Department of Endocrinology, Diabetes and Metabolism, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan; Lund University Diabetes Centre, Skåne University Hospital, Malmö, Sweden
| | - Yuki Shuto
- Department of Endocrinology, Diabetes and Metabolism, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan
| | - Alexandros Karagiannopoulos
- Islet Cell Exocytosis, Department of Clinical Sciences-Malmö, Lund University, Malmö, Sweden; Lund University Diabetes Centre, Skåne University Hospital, Malmö, Sweden
| | - Joao Fadista
- Department of Epidemiology Research, Statens Serum Institut, 2300, Copenhagen S, Denmark
| | - Hitoshi Sugihara
- Department of Endocrinology, Diabetes and Metabolism, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan
| | - Leif Groop
- Diabetes and Endocrinology, Department of Clinical Sciences-Malmö, Lund University, Malmö, Sweden; Lund University Diabetes Centre, Skåne University Hospital, Malmö, Sweden
| | - Lena Eliasson
- Islet Cell Exocytosis, Department of Clinical Sciences-Malmö, Lund University, Malmö, Sweden; Lund University Diabetes Centre, Skåne University Hospital, Malmö, Sweden
| |
Collapse
|
|
47
|
Akalestou E, Genser L, Rutter GA. Glucocorticoid Metabolism in Obesity and Following Weight Loss. Front Endocrinol (Lausanne) 2020; 11:59. [PMID: 32153504 PMCID: PMC7045057 DOI: 10.3389/fendo.2020.00059] [Citation(s) in RCA: 65] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2019] [Accepted: 01/30/2020] [Indexed: 01/08/2023] Open
Abstract
Glucocorticoids are steroid hormones produced by the adrenal cortex and are essential for the maintenance of various metabolic and homeostatic functions. Their function is regulated at the tissue level by 11β-hydroxysteroid dehydrogenases and they signal through the glucocorticoid receptor, a ligand-dependent transcription factor. Clinical observations have linked excess glucocorticoid levels with profound metabolic disturbances of intermediate metabolism resulting in abdominal obesity, insulin resistance and dyslipidaemia. In this review, we discuss the physiological mechanisms of glucocorticoid secretion, regulation and function, and survey the metabolic consequences of excess glucocorticoid action resulting from elevated release and activation or up-regulated signaling. Finally, we summarize the reported impact of weight loss by diet, exercise, or bariatric surgery on circulating and tissue-specific glucocorticoid levels and examine the therapeutic possibility of reversing glucocorticoid-associated metabolic disorders.
Collapse
Affiliation(s)
- Elina Akalestou
- Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Metabolism, Digestion and Reproduction, Imperial Centre for Translational and Experimental Medicine, Imperial College London, London, United Kingdom
| | - Laurent Genser
- Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Metabolism, Digestion and Reproduction, Imperial Centre for Translational and Experimental Medicine, Imperial College London, London, United Kingdom
- Department of Digestive and Hepato-Pancreato-Biliary Surgery, Liver Transplantation, Assistance Publique-Hôpitaux de Paris, Pitié-Salpêtrière University Hospital, Institut Hospitalo-Universitaire ICAN, Sorbonne Université, Paris, France
| | - Guy A. Rutter
- Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Metabolism, Digestion and Reproduction, Imperial Centre for Translational and Experimental Medicine, Imperial College London, London, United Kingdom
- *Correspondence: Guy A. Rutter
| |
Collapse
|
|
48
|
Han M, Cao X, Zhao C, Yang L, Yin N, Shen P, Zhang J, Gao F, Ren Y, Liang D, Yang J, Zhang Y, Liu Y. Assessment of Glycometabolism Impairment and Glucose Variability Using Flash Glucose Monitoring System in Patients With Adrenal Diseases. Front Endocrinol (Lausanne) 2020; 11:544752. [PMID: 33101192 PMCID: PMC7546367 DOI: 10.3389/fendo.2020.544752] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2020] [Accepted: 09/08/2020] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND This study aimed to investigate the characteristics and extent of glycometabolism impairment in patients with adrenal diseases, including Cushing syndrome, primary aldosteronism, pheochromocytoma, and nonfunctional adrenal incidentaloma. METHODS This study enrolled thirty-two patients with adrenal diseases as adrenal disease groups and eight healthy individuals as healthy controls. Blood glucose levels were indicated by glucose concentration in interstitial fluid, which was documented using flash glucose monitoring system. According to flash glucose monitoring system data, parameters representing general blood glucose alterations, within-day and day-to-day glucose variability, and glucose-target-rate were calculated. Furthermore, blood glucose levels at nocturnal, fasting, and postprandial periods were analyzed. Besides, islet β-cell function and insulin resistance were assessed. RESULTS Analysis of flash glucose monitoring system-related parameters indicated impaired glycometabolism in patients with adrenal diseases compared with that of healthy controls at general blood glucose, within-day and day-to-day glucose variability, and glucose-target-rate levels. Furthermore, the dynamic glucose monitoring data revealed that significantly affected blood glucose levels compared with that of healthy controls were observed at postprandial periods in the Cushing syndrome and primary aldosteronism groups; at nocturnal, fasting and postprandial periods in the pheochromocytoma group. Significant insulin resistance and abnormal β-cell function were observed in the Cushing syndrome group compared with that in healthy controls. CONCLUSION Adrenal diseases can negatively affect glucose metabolism. Patients diagnosed with adrenal diseases should receive timely and appropriate treatment to avoid adverse cardiovascular events linked to hyperglycemia and insulin resistance.
Collapse
Affiliation(s)
- Minmin Han
- First Clinical Medical College, Shanxi Medical University, Taiyuan, China
- Department of Endocrinology, First Hospital of Shanxi Medical University, Taiyuan, China
| | - Xiaoming Cao
- Department of Urology, First Hospital of Shanxi Medical University, Taiyuan, China
| | - Changjian Zhao
- Department of Urology, First Hospital of Shanxi Medical University, Taiyuan, China
| | - Luyang Yang
- Department of Endocrinology, First Hospital of Shanxi Medical University, Taiyuan, China
| | - Nan Yin
- Department of Urology, First Hospital of Shanxi Medical University, Taiyuan, China
| | - Pengliang Shen
- Department of Urology, First Hospital of Shanxi Medical University, Taiyuan, China
| | - Jin Zhang
- Department of Endocrinology, First Hospital of Shanxi Medical University, Taiyuan, China
| | - Fei Gao
- Department of Endocrinology, First Hospital of Shanxi Medical University, Taiyuan, China
| | - Yi Ren
- Department of Endocrinology, First Hospital of Shanxi Medical University, Taiyuan, China
| | - Dong Liang
- Department of Endocrinology, First Hospital of Shanxi Medical University, Taiyuan, China
| | - Jing Yang
- Department of Endocrinology, First Hospital of Shanxi Medical University, Taiyuan, China
| | - Yi Zhang
- Department of Pharmacology, Shanxi Medical University, Taiyuan, China
- *Correspondence: Yi Zhang, ; Yunfeng Liu,
| | - Yunfeng Liu
- Department of Endocrinology, First Hospital of Shanxi Medical University, Taiyuan, China
- *Correspondence: Yi Zhang, ; Yunfeng Liu,
| |
Collapse
|
|
49
|
Ortiz R, Kluwe B, Odei J, Echouffo Tcheugui JB, Sims M, Kalyani RR, Bertoni AG, Golden SH, Joseph JJ. The association of morning serum cortisol with glucose metabolism and diabetes: The Jackson Heart Study. Psychoneuroendocrinology 2019; 103:25-32. [PMID: 30623794 PMCID: PMC6450778 DOI: 10.1016/j.psyneuen.2018.12.237] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2018] [Revised: 12/23/2018] [Accepted: 12/27/2018] [Indexed: 01/09/2023]
Abstract
BACKGROUND Serum cortisol levels have been associated with type 2 diabetes (T2D). However, the role of cortisol in glycemia and T2D is not fully elucidated among African Americans (AAs). We hypothesized that among AAs morning serum cortisol would be positively associated with glycemic measures and prevalent T2D. METHODS We examined the cross-sectional association of baseline morning serum cortisol with fasting plasma glucose (FPG), hemoglobin A1c (HbA1c), homeostasis model assessment of insulin resistance (HOMA-IR), β-cell function (HOMA-β), and prevalent T2D in the Jackson Heart Study. Linear regression models were used to examine the association of log-transformed cortisol with glycemic traits, stratified by T2D status. Logistic regression was used to examine the association of log-transformed cortisol with prevalent T2D. Models were adjusted for age, sex, education, occupation, systolic blood pressure, waist circumference, physical activity, smoking, beta-blocker/hormone replacement medications and cortisol collection time. RESULTS Among 4,206 AAs (mean age 55 ± 13 years, 64% female), 19% had prevalent T2D. A 100% increase in cortisol among participants without diabetes was associated with 2.7 mg/dL (95% CI: 2.0, 3.3) higher FPG and a 10.0% (95% CI: -14.0, -6.0) lower HOMA-β with no significant association with HbA1c or HOMA-IR. In participants with diabetes, a 100% increase in cortisol was associated with a 23.6 mg/dL (95% CI: 13.6, 33.7) higher FPG and a 0.6% (95% CI: 0.3, 0.9) higher HbA1c. Among all participants, quartile 4 vs. 1 of cortisol was associated with a 1.26-fold (95% CI: 1.75, 2.91) higher odds of prevalent T2D. CONCLUSION Higher morning serum cortisol was associated with higher FPG and lower β-cell function among participants without T2D and higher FPG and HbA1c in participants with diabetes. Among all participants, higher cortisol was associated with higher odds of T2D. These findings support a role for morning serum cortisol in glucose metabolism among AAs.
Collapse
Affiliation(s)
- Robin Ortiz
- Departments of Internal Medicine and Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD
| | | | - James Odei
- Division of Biostatistics, The Ohio State University College of Public Health, Columbus, OH
| | | | - Mario Sims
- Department of Medicine, University of Mississippi Medical Center, Jackson, MS
| | - Rita R. Kalyani
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Alain G. Bertoni
- Division of Public Health Sciences, Wake Forest School of Medicine, Winston Salem, NC
| | - Sherita H. Golden
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Joshua J. Joseph
- Department of Medicine, The Ohio State University College of Medicine, Columbus, OH
| |
Collapse
|
|
50
|
Combination Therapy with Empagliflozin and Insulin Results in Successful Glycemic Control: A Case Report of Uncontrolled Diabetes Caused by Autoimmune Pancreatitis and Subsequent Steroid Treatment. Case Rep Endocrinol 2019; 2019:9415347. [PMID: 30895163 PMCID: PMC6393920 DOI: 10.1155/2019/9415347] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2018] [Accepted: 02/01/2019] [Indexed: 12/24/2022] Open
Abstract
A 66-year-old Japanese male presented with thirst, polyuria, and hemoglobin A1c and postprandial glucose levels (13.1% and 529 mg/dL, respectively) that indicated severe hyperglycemia. Based on his high immunoglobulin G4 level and the results of magnetic resonance imaging and magnetic resonance cholangiopancreatography, we diagnosed him with autoimmune pancreatitis. Insulin was initiated to control his diabetes. One month later, the patient commenced on prednisolone therapy for the treatment of autoimmune pancreatitis, after which his total insulin dosage increased to a maximum of 52 units/day. When the prednisolone dosage was later tapered, the patient's total dosage of insulin was reduced to 42 units/day. However, he had gained 3.6 kg from the start of prednisolone therapy, and 42 units/day was insufficient for maintaining glycemic control. Thus, empagliflozin, a sodium-dependent glucose transporter 2 (SGLT2) inhibitor, was added. Thereafter, we were able to reduce the patient's total dosage of insulin; it was eventually discontinued with good glycemic control and weight loss. Such results suggest that the combination of insulin with an SGLT2 inhibitor may be a viable option for the treatment of diabetic patients on prednisolone therapy.
Collapse
|