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Piona C, Passanisi S, Bombaci B, Marigliano M, Lombardo F, Mancioppi V, Morandi A, Maffeis C, Salzano G. Time in tight range in automated insulin delivery system users: Real-world data from children and adolescents with type 1 diabetes. Diabetes Obes Metab 2024; 26:4767-4771. [PMID: 39021339 DOI: 10.1111/dom.15791] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2024] [Revised: 06/27/2024] [Accepted: 06/28/2024] [Indexed: 07/20/2024]
Affiliation(s)
- Claudia Piona
- Pediatric Diabetes and Metabolic Disorders Unit, Regional Center for Pediatric Diabetes, University City Hospital, Verona, Italy
| | - Stefano Passanisi
- Department of Human Pathology in Adult and Developmental Age "Gaetano Barresi", University of Messina, Messina, Italy
| | - Bruno Bombaci
- Department of Human Pathology in Adult and Developmental Age "Gaetano Barresi", University of Messina, Messina, Italy
| | - Marco Marigliano
- Pediatric Diabetes and Metabolic Disorders Unit, Regional Center for Pediatric Diabetes, University City Hospital, Verona, Italy
| | - Fortunato Lombardo
- Department of Human Pathology in Adult and Developmental Age "Gaetano Barresi", University of Messina, Messina, Italy
| | - Valentina Mancioppi
- Pediatric Diabetes and Metabolic Disorders Unit, Regional Center for Pediatric Diabetes, University City Hospital, Verona, Italy
| | - Anita Morandi
- Pediatric Diabetes and Metabolic Disorders Unit, Regional Center for Pediatric Diabetes, University City Hospital, Verona, Italy
| | - Claudio Maffeis
- Pediatric Diabetes and Metabolic Disorders Unit, Regional Center for Pediatric Diabetes, University City Hospital, Verona, Italy
| | - Giuseppina Salzano
- Department of Human Pathology in Adult and Developmental Age "Gaetano Barresi", University of Messina, Messina, Italy
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Lee YM, Lin PR, Sia HK. Oral antidiabetic therapy versus early insulinization on glycemic control in newly diagnosed type 2 diabetes patients: a retrospective matched cohort study. Sci Rep 2024; 14:15491. [PMID: 38969701 PMCID: PMC11226661 DOI: 10.1038/s41598-024-66468-1] [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: 02/29/2024] [Accepted: 07/01/2024] [Indexed: 07/07/2024] Open
Abstract
Our study aims to compare the efficacy of oral antidiabetic therapy to early insulinization on glycemic control among newly diagnosed type 2 diabetes patients in real-world clinical practice. A retrospective cohort study conducted at a medical center in Taiwan analyzed 1256 eligible patients from January 2007 to December 2017. Propensity score matching resulted in well-balanced groups of 94 patients each in the oral antidiabetic drug (OAD) and early insulinization cohorts. Glycemic outcomes were assessed in both groups. Patients exclusively using OAD showed consistently lower glycated hemoglobin (HbA1c) levels at 3, 12, 24, and 36 months compared to insulin users. At later periods, 77.7% of OAD users achieved glycemic control versus 64.9% of insulin users, with a marginally significant difference. Subgroup analyses suggested a trend favoring well-controlled diabetes in the OAD group, though not statistically significant. Our study finds oral antidiabetic therapy is not inferior to early insulinization for glycemic control in newly diagnosed type 2 diabetes patients, irrespective of initial HbA1c levels. This supports oral therapy as a rational treatment option, even in cases with elevated HbA1c at diagnosis.
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Affiliation(s)
- Yang-Ming Lee
- Department of Internal Medicine, Changhua Christian Hospital, Changhua, Taiwan.
- Department of Endocrinology and Metabolism, Changhua Christian Hospital, 135 Nanhsiao Street, Changhua, 500, Taiwan.
| | - Pei Ru Lin
- Big Data Center, Changhua Christian Hospital, Changhua, 500, Taiwan
- Graduate Institute of Statistics and Information Science, National Changhua University of Education, Changhua, 500, Taiwan
| | - Hon-Ke Sia
- Department of Endocrinology and Metabolism, Changhua Christian Hospital, 135 Nanhsiao Street, Changhua, 500, Taiwan.
- Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung, Taiwan.
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Adu FA, Poku CA, Adu AP, Owusu LB. The role of social support and self-management on glycemic control of type 2 diabetes mellitus with complications in Ghana: A cross-sectional study. Health Sci Rep 2024; 7:e2054. [PMID: 38650722 PMCID: PMC11033339 DOI: 10.1002/hsr2.2054] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Revised: 02/08/2024] [Accepted: 04/02/2024] [Indexed: 04/25/2024] Open
Abstract
Background and Aims Diabetes mellitus (DM) can result in detrimental complications which are connected with long-term impairments and disabilities. Chronic complications are well-known consequences of type 2 diabetes mellitus (T2DM) progression, which reduce patient quality of life, place a burden on the healthcare system, and increase mortality. Measures to promote health outcomes for people with DM are scanty; the study therefore aimed at determining the effects of self-management and social support on glycemic control of T2DM with complications in Ghana. Methods A cross-sectional design using convenience sampling was conducted on 400 T2DM patients using Hensarling's Diabetes Family Support Scale and Summary of Diabetes Self‑Care Activities scale. Data analysis was conducted using descriptive, Pearson Moment Product Correlation and Binary Logistic Regression on self-management, social support, and glycemic control in T2DM patients. Results Social support among participants was high and there was a positive correlation or relationship between social support and T2DM self-management. There was a correlation between social support and self-management (r = 0.149, p < 0.05) and diet control (r = 0.221, p < 0.05). The results also showed a significant correlation between medication adherence and glycemic management (r = 0.116, p < 0.05) while female T2DM participants, individuals with at least primary education were less likely to have low self-management relative to T2DM. Conclusion Though the level of T2DM self-management was high it does not translate to good glycemic control. Focused health education programs should be incorporated into patients' care plans which will be particularly relevant for patients with T2DM and will contribute to positive physiological and psychological outcomes. Furthermore, a more robust monitoring and follow-up scheme should be scaled up or instituted for patients with T2DM.
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Affiliation(s)
- Frank Amankwah Adu
- Medical Technology in the Xiangya School of NursingCentral South UniversityChangshaChina
- Department of NursingKwame Nkrumah University of Science and TechnologyKumasiGhana
| | - Collins Atta Poku
- Department of NursingKwame Nkrumah University of Science and TechnologyKumasiGhana
| | - Amanda Parko Adu
- Department of NursingKwame Nkrumah University of Science and TechnologyKumasiGhana
| | - Lydia Boampong Owusu
- Department of NursingKwame Nkrumah University of Science and TechnologyKumasiGhana
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Dunn TC, Ajjan RA, Bergenstal RM, Xu Y. Is It Time to Move Beyond TIR to TITR? Real-World Data from Over 20,000 Users of Continuous Glucose Monitoring in Patients with Type 1 and Type 2 Diabetes. Diabetes Technol Ther 2024; 26:203-210. [PMID: 38444315 PMCID: PMC10877396 DOI: 10.1089/dia.2023.0565] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/07/2024]
Abstract
The growing use of continuous glucose monitoring (CGM) has been supported by expert consensus and clinical guidelines on glycemic management in diabetes with time in range (TIR 70-180 mg/dL) representing a key CGM-derived glucose metric. Time in tight range (TITR) has also been proposed for clinical use, spanning largely normal glucose levels of 70-140 mg/dL. However, keeping such narrow glucose ranges can be challenging, and understanding the factors modulating TITR can help achieve these tight glycemic targets. Our real-life study aimed to evaluate the relationship between average glucose (AG) and TIR/TITR in a large cohort (n = 22,006) of CGM users, divided into four groups: self-identified as having type 1 diabetes (T1D) treated with insulin using multiple daily injections (MDI) or pumps; type 2 diabetes (T2D) on MDI or insulin pumps; T2D on basal insulin only; and T2D not on insulin treatment. The T2D groups, regardless of treatment type, displayed the highest TIR and TITR values, associated with lowest glycemic variability measured as glucose coefficient of variation (CV; 23-30%). The T1D group showed the lowest TIR and TITR, associated with the highest CVs (36-38%). Overall, higher CV was associated with lower TIR and TITR for AG values below 180 and 140 mg/dL, respectively, with the reverse holding true for AG values above these thresholds. The discordance between AG and TIR/TITR was less pronounced in T2D compared with T1D, attributed to lower CV in the former group. It was also observed that TITR has advantages over TIR for assessing glycemia status and progress toward more stringent A1C, particularly when approaching normal glucose levels. The data detail how CV affects the AG relationship with TIR/TITR, which has implications for CGM interpretation. In many instances TITR, rather than TIR, may be preferable to employ once AG falls below 140 mg/dL and near-normal glucose levels are required clinically.
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Affiliation(s)
- Timothy C. Dunn
- Clinical Affairs, Abbott Diabetes Care, Alameda, California, USA
| | - Ramzi A. Ajjan
- The LIGHT Laboratories, Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, United Kingdom
| | - Richard M. Bergenstal
- International Diabetes Center, HealthPartners Institute, Minneapolis, Minnesota, USA
| | - Yongjin Xu
- Clinical Affairs, Abbott Diabetes Care, Alameda, California, USA
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Shinjo T, Onizuka S, Zaitsu Y, Ishikado A, Park K, Li Q, Yokomizo H, Zeze T, Sato K, St-Louis R, Fu J, I-Hsien W, Mizutani K, Hasturk H, Van Dyke TE, Nishimura F, King GL. Dysregulation of CXCL1 Expression and Neutrophil Recruitment in Insulin Resistance and Diabetes-Related Periodontitis in Male Mice. Diabetes 2023; 72:986-998. [PMID: 37058471 PMCID: PMC10281234 DOI: 10.2337/db22-1014] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2022] [Accepted: 04/05/2023] [Indexed: 04/15/2023]
Abstract
Insulin resistance and hyperglycemia are risk factors for periodontitis and poor wound healing in diabetes, which have been associated with selective loss of insulin activation of the PI3K/Akt pathway in the gingiva. This study showed that insulin resistance in the mouse gingiva due to selective deletion of smooth muscle and fibroblast insulin receptor (SMIRKO mice) or systemic metabolic changes induced by a high-fat diet (HFD) in HFD-fed mice exacerbated periodontitis-induced alveolar bone loss, preceded by delayed neutrophil and monocyte recruitment and impaired bacterial clearance compared with their respective controls. The immunocytokines, CXCL1, CXCL2, MCP-1, TNFα, IL-1β, and IL-17A, exhibited delayed maximal expression in the gingiva of male SMIRKO and HFD-fed mice compared with controls. Targeted overexpression of CXCL1 in the gingiva by adenovirus normalized neutrophil and monocyte recruitment and prevented bone loss in both mouse models of insulin resistance. Mechanistically, insulin enhanced bacterial lipopolysaccharide-induced CXCL1 production in mouse and human gingival fibroblasts (GFs), via Akt pathway and NF-κB activation, which were reduced in GFs from SMIRKO and HFD-fed mice. These results provided the first report that insulin signaling can enhance endotoxin-induced CXCL1 expression to modulate neutrophil recruitment, suggesting CXCL1 as a new therapeutic direction for periodontitis or wound healing in diabetes. ARTICLE HIGHLIGHTS The mechanism for the increased risks for periodontitis in the gingival tissues due to insulin resistance and diabetes is unclear. We investigated how insulin action in gingival fibroblasts modulates the progression of periodontitis in resistance and diabetes. Insulin upregulated the lipopolysaccharide-induced neutrophil chemoattractant, CXCL1, production in gingival fibroblasts via insulin receptors and Akt activation. Enhancing CXCL1 expression in the gingiva normalized diabetes and insulin resistance-induced delays in neutrophils recruitment and periodontitis. Targeting dysregulation of CXCL1 in fibroblasts is potentially therapeutic for periodontitis and may also improve wound healing in insulin resistance and diabetes.
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Affiliation(s)
- Takanori Shinjo
- Section of Vascular Cell Biology, Joslin Diabetes Center, Harvard Medical School, Boston, MA
- Section of Periodontology, Faculty of Dental Science, Kyushu University, Fukuoka, Japan
| | - Satoru Onizuka
- Section of Vascular Cell Biology, Joslin Diabetes Center, Harvard Medical School, Boston, MA
| | - Yumi Zaitsu
- Section of Vascular Cell Biology, Joslin Diabetes Center, Harvard Medical School, Boston, MA
| | - Atsushi Ishikado
- Section of Vascular Cell Biology, Joslin Diabetes Center, Harvard Medical School, Boston, MA
| | - Kyoungmin Park
- Section of Vascular Cell Biology, Joslin Diabetes Center, Harvard Medical School, Boston, MA
| | - Qian Li
- Section of Vascular Cell Biology, Joslin Diabetes Center, Harvard Medical School, Boston, MA
| | - Hisashi Yokomizo
- Section of Vascular Cell Biology, Joslin Diabetes Center, Harvard Medical School, Boston, MA
| | - Tatsuro Zeze
- Section of Periodontology, Faculty of Dental Science, Kyushu University, Fukuoka, Japan
| | - Kohei Sato
- Section of Periodontology, Faculty of Dental Science, Kyushu University, Fukuoka, Japan
| | - Ronald St-Louis
- Section of Vascular Cell Biology, Joslin Diabetes Center, Harvard Medical School, Boston, MA
| | - Jialin Fu
- Section of Vascular Cell Biology, Joslin Diabetes Center, Harvard Medical School, Boston, MA
| | - Wu I-Hsien
- Section of Vascular Cell Biology, Joslin Diabetes Center, Harvard Medical School, Boston, MA
| | - Koji Mizutani
- Department of Periodontology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Hatice Hasturk
- Department of Applied Oral Science, The Forsyth Institute, Cambridge, MA
| | - Thomas E. Van Dyke
- Department of Applied Oral Science, The Forsyth Institute, Cambridge, MA
| | - Fusanori Nishimura
- Section of Periodontology, Faculty of Dental Science, Kyushu University, Fukuoka, Japan
| | - George L. King
- Section of Vascular Cell Biology, Joslin Diabetes Center, Harvard Medical School, Boston, MA
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Xia L, Cheng L, Jiang T, Liu C, Zhang S, Hu H, Dai F, Zhang Q, Lu Y. Estimation of the prevalence of type 2 diabetes in combination with diabetic kidney disease and identification of the associated factors in patients attending primary hospitals in Anhui Province, China. J Int Med Res 2021; 49:3000605211051225. [PMID: 34670424 PMCID: PMC8544780 DOI: 10.1177/03000605211051225] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023] Open
Abstract
Objective To evaluate the prevalence of type 2 diabetes mellitus (T2DM) with chronic kidney disease (DM-CKD) and identify the associated factors in patients attending primary hospitals in Anhui Province, China. Methods A multi-stage sampling method was used to collect the demographic information, general clinical data, and details of the kidney disease of patients in 2019 through a questionnaire survey, physical examination, and laboratory examination. Results A total of 1067 patients with T2DM were studied, of whom 345 had chronic kidney disease (CKD; 32.33%); 18.8%, 12.2%, 58.0%, 9.9% and 1.2% of the participants had stages 1 to 5 CKD. Fifty-point-three percent of the participants were female and they were 59 ± 11.3 years old. Multivariate regression analysis revealed that age, systolic blood pressure, the duration of diabetes, hyperlipidaemia, and smoking were associated with DM-CKD. The duration of diabetes was positively associated with body mass index, 2-hour postprandial glucose, fasting blood glucose concentration, glycosylated haemoglobin, total cholesterol concentration and triglyceride concentration. Conclusions The incidence of DM-CKD is relatively high in primary hospitals in Anhui Province. Appropriate preventive and therapeutic measures should be instituted according to the age, the duration of diabetes, sex, hypertension, smoking habits, and lipidaemia of patients.
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Affiliation(s)
- Li Xia
- Endocrinology Department, 12485Anhui Medical University, First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Lanlan Cheng
- Endocrinology Department, 12485Anhui Medical University, First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Tian Jiang
- Endocrinology Department, 12485Anhui Medical University, First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Chao Liu
- Endocrinology Department, 12485Anhui Medical University, First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Shiqi Zhang
- Endocrinology Department, 12485Anhui Medical University, First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Honglin Hu
- Endocrinology Department, 12485Anhui Medical University, First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Fang Dai
- Endocrinology Department, 12485Anhui Medical University, First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Qiu Zhang
- Endocrinology Department, 12485Anhui Medical University, First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Yunxia Lu
- Department of Biochemistry and Molecular Biology, Anhui Medical University, Hefei, China
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Li GY, Li HY, Li Q. Use of glycated albumin for the identification of diabetes in subjects from northeast China. World J Diabetes 2021; 12:149-157. [PMID: 33594334 PMCID: PMC7839171 DOI: 10.4239/wjd.v12.i2.149] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Revised: 12/10/2020] [Accepted: 12/23/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Metabolic memory is important for the diagnosis and treatment of diabetes in the early stage, and in maintaining blood glucose concentrations within the normal range. The clinical diagnosis of diabetes mellitus is currently made using fasting plasma glucose, 2 h-plasma glucose (2h-PG) during a 75 g oral glucose tolerance test, and hemoglobin A1c (HbA1c) level. However, the fasting plasma glucose test requires fasting, which is a barrier to screening, and reproducibility of the 2h-PG level is poor. HbA1c is affected by a shortened red blood cell lifespan. In patients with anemia and hemoglobinopathies, the measured HbA1c levels may be inaccurate. Compared with HbA1c, glycated albumin (GA) is characterized by more rapid and greater changes, and can be used to diagnose new-onset diabetes especially if urgent early treatment is required, for example in gestational diabetes. In this study, we provided cutoff values for GA and evaluated its utility as a screening and diagnostic tool for diabetes in a large high-risk group study.
AIM To evaluate the utility of GA in identifying subjects with diabetes in northeast China, and to assess the diagnostic accuracy of the proposed GA cutoff in the diagnosis of diabetes mellitus.
METHODS This cross-sectional study included 1935 subjects, with suspected diabetes or in high-risk groups, from 2014 to 2015 in the Second Affiliated Hospital of Harbin Medical University (Harbin, China). The use of GA to identify diabetes was investigated using the area under the receiver operating characteristic curve (AUC). The GA cutoffs were derived from different 2h-PG values with hemoglobin A1c cutoffs used as a calibration curve.
RESULTS The GA cutoff for the diagnosis of diabetes mellitus was 15.15% from the receiver operating characteristic (ROC) curve. ROC analysis demonstrated that GA was an efficient marker for detecting diabetes, with an AUC of 90.3%.
CONCLUSION Our study supports the use of GA as a biomarker for the diagnosis of diabetes.
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Affiliation(s)
- Guo-Yan Li
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Harbin Medical University, Harbin 150080, Heilongjiang Province, China
| | - Hao-Yu Li
- Faculty of Population Health Sciences, University College London, London WC1E 6BT, United Kingdom
| | - Qiang Li
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Harbin Medical University, Harbin 150080, Heilongjiang Province, China
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Liebisch M, Wolf G. AGE-Induced Suppression of EZH2 Mediates Injury of Podocytes by Reducing H3K27me3. Am J Nephrol 2020; 51:676-692. [PMID: 32854097 DOI: 10.1159/000510140] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Accepted: 07/12/2020] [Indexed: 01/11/2023]
Abstract
BACKGROUND Chronic hyperglycemia, a pivotal feature of diabetes mellitus (DM), initiates the formation of advanced glycation end products (AGEs) and the dysregulation of epigenetic mechanisms, which may cause injury to renal podocytes, a central feature of diabetic kidney disease (DKD). Previous data of our group showed that AGEs significantly reduce the expression of NIPP1 (nuclear inhibitor of protein phosphatase 1) in podocytes in vitro as well as in human and murine DKD. NIPP1 was shown by others to interact with enhancer of zeste homolog 2 (EZH2), which catalyzes the repressive methylation of H3K27me3 on histone 3. Therefore, we hypothesized that AGEs can directly induce epigenetic changes in podocytes. METHODS We analyzed the relevance of AGEs on EZH2 expression and activity in a murine podocyte cell line. Cells were treated with 5 mg/mL glycated BSA for 24 h. To determine the meaning of EZH2 suppression, EZH2 activity was inhibited by incubating the cells with the pharmacological methyltransferase inhibitor 3-deazaneplanocin A; EZH2 expression was repressed with siRNA. mRNA expression was analyzed with real-time PCR, and protein expression with Western blot. EZH2 expression and level of H3K27 trimethylation in podocytes of diabetic db/db mice, a mouse model for type 2 DM, were analyzed using immunofluorescence. RESULTS Our data demonstrated that AGEs decrease EZH2 expression in podocytes and consequently reduce H3K27me3. This suppression of EZH2 mimicked the AGE effects and caused an upregulated expression of pathological factors that contribute to podocyte injury in DKD. In addition, analyses of db/db mice showed significantly reduced H3K27me3 and EZH2 expression in podocytes. Moreover, the suppression of NIPP1 and EZH2 showed similar effects regarding podocyte injury. CONCLUSIONS Our studies provide a novel pathway how AGEs contribute to podocyte injury and the formation of the so-called metabolic memory in DKD.
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Affiliation(s)
- Marita Liebisch
- Department of Internal Medicine III, University Hospital Jena, Jena, Germany
| | - Gunter Wolf
- Department of Internal Medicine III, University Hospital Jena, Jena, Germany,
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Wang H, Tang W, Zhang P, Zhang Z, He J, Zhu D, Bi Y. Modulation of gut microbiota contributes to effects of intensive insulin therapy on intestinal morphological alteration in high-fat-diet-treated mice. Acta Diabetol 2020; 57:455-467. [PMID: 31749050 DOI: 10.1007/s00592-019-01436-0] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2019] [Accepted: 10/03/2019] [Indexed: 02/07/2023]
Abstract
AIMS Disturbance of intestinal homeostasis promotes the development of type 2 diabetes. Although intensive insulin therapy has been shown to promote extended glycemic remission in newly diagnosed type 2 diabetic patients through multiple mechanisms, its effect on intestinal homeostasis remains unknown. METHODS This study evaluated the effects of intensive insulin therapy on intestinal morphometric parameters in a hyperglycemic mice model induced by high-fat diet (HFD). 16S rRNA V4 region sequencing and multivariate analysis were utilized to evaluate the structural changes of gut microbiota. RESULTS HFD-induced increases in the lengths of villus, microvillus and crypt depth were significantly reversed after intensive insulin therapy. Moreover, intestinal proliferation was notably decreased after intensive insulin therapy, whereas intestinal apoptosis was further increased. Importantly, intensive insulin therapy significantly shifted the overall structure of the HFD-disrupted gut microbiota toward that of mice fed a normal diet and changed the gut microbial composition. The abundances of 54 operational taxonomic units (OTUs) were changed by intensive insulin therapy. Thirty altered OTUs correlated with two or more intestinal morphometric parameters and were designated 'functionally relevant phylotypes.' CONCLUSIONS For the first time, our data indicate that intensive insulin therapy recovers diabetes-associated gut structural abnormalities and restores the microbiome landscape. Moreover, specific altered 'functionally relevant phylotypes' correlates with improvement in diabetes-associated gut structural alterations.
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Affiliation(s)
- Hongdong Wang
- Department of Endocrinology, Drum Tower Hospital Affiliated to Nanjing University Medical School, 321 Zhongshan Road, Nanjing, 210008, China
| | - Wenjuan Tang
- Department of Endocrinology, Drum Tower Hospital Affiliated to Nanjing University Medical School, 321 Zhongshan Road, Nanjing, 210008, China
| | - Pengzi Zhang
- Department of Endocrinology, Drum Tower Hospital Affiliated to Nanjing University Medical School, 321 Zhongshan Road, Nanjing, 210008, China
| | - Zhou Zhang
- Department of Endocrinology, Drum Tower Hospital Affiliated to Nanjing University Medical School, 321 Zhongshan Road, Nanjing, 210008, China
| | - Jielei He
- Department of Endocrinology, Drum Tower Hospital Affiliated to Nanjing University Medical School, 321 Zhongshan Road, Nanjing, 210008, China
| | - Dalong Zhu
- Department of Endocrinology, Drum Tower Hospital Affiliated to Nanjing University Medical School, 321 Zhongshan Road, Nanjing, 210008, China
| | - Yan Bi
- Department of Endocrinology, Drum Tower Hospital Affiliated to Nanjing University Medical School, 321 Zhongshan Road, Nanjing, 210008, China.
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Abstract
Background Organisms can be primed by metabolic exposures to continue expressing response genes even once the metabolite is no longer available, and can affect the speed and magnitude of responsive gene expression during subsequent exposures. This “metabolic transcriptional memory” can have a profound impact on the survivability of organisms in fluctuating environments. Scope of review Here I present several examples of metabolic transcriptional memory in the microbial world and discuss what is known so far regarding the underlying mechanisms, which mainly focus on chromatin modifications, protein inheritance, and broad changes in metabolic network. From these lessons learned in microbes, some insights into the yet understudied human metabolic memory can be gained. I thus discuss the implications of metabolic memory in disease progression in humans – i.e., the memory of high blood sugar exposure and the resulting effects on diabetic complications. Major conclusions Carbon source shifts from glucose to other less preferred sugars such as lactose, galactose, and maltose for energy metabolism as well as starvation of a signal transduction precursor sugar inositol are well-studied examples of metabolic transcriptional memory in Escherichia coli and Saccharomyces cerevisiae. Although the specific factors guiding metabolic transcriptional memory are not necessarily conserved from microbes to humans, the same basic mechanisms are in play, as is observed in hyperglycemic memory. Exploration of new metabolic transcriptional memory systems as well as further detailed mechanistic analyses of known memory contexts in microbes is therefore central to understanding metabolic memory in humans, and may be of relevance for the successful treatment of the ever-growing epidemic of diabetes.
Metabolic exposures can prime genes to have memory. Memory of carbon source shifts occurs in all kingdoms of life. Memory is maintained through multiple mechanisms including chromatin modifications, proteins, and metabolic network. Metabolic transcriptional memory in unicellular organisms is a part of “bet-hedging” strategies to ensure survival. Hyperglycemic memory in humans contributes to diabetes and aging.
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Affiliation(s)
- Poonam Bheda
- Institute of Functional Epigenetics, Helmholtz Zentrum München, Neuherberg, Germany.
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Huang YS, Zheng Q, Yang H, Fu X, Zhang X, Xia C, Zhu Z, Liu YN, Liu WJ. Efficacy of Intermittent or Continuous Very Low-Energy Diets in Overweight and Obese Individuals with Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analyses. J Diabetes Res 2020; 2020:4851671. [PMID: 32090119 PMCID: PMC7008267 DOI: 10.1155/2020/4851671] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2019] [Accepted: 01/07/2020] [Indexed: 01/29/2023] Open
Abstract
OBJECTIVE This study is aimed at investigating the efficacy of a very low-energy diet (VLED) in overweight and obese individuals with type 2 diabetes mellitus (T2DM). METHODS We thoroughly searched eight electronic resource databases of controlled studies concerning the efficacy and acceptability of intermittent or continuous VLEDs in patients with T2DM compared with other energy restriction interventions. RESULTS Eighteen studies (11 randomized and seven nonrandomized controlled trials) with 911 participants were included. The meta-analyses showed that compared with a low-energy diet (LED) and mild energy restriction (MER), VLED is superior in the reduction of body weight (mean difference (MD) MDLED = -2.77, 95% confidence interval (CI) CILED = -4.81 to - 0.72, P LED = 0.008; MDMER = -6.72, 95%CIMER = -10.05 to - 3.39, P LED = 0.008; MDMER = -6.72, 95%CIMER = -10.05 to - 3.39, P LED = 0.008; MDMER = -6.72, 95%CIMER = -10.05 to - 3.39, P LED = 0.008; MDMER = -6.72, 95%CIMER = -10.05 to - 3.39, P LED = 0.008; MDMER = -6.72, 95%CIMER = -10.05 to - 3.39, P LED = 0.008; MDMER = -6.72, 95%CIMER = -10.05 to - 3.39, P LED = 0.008; MDMER = -6.72, 95%CIMER = -10.05 to - 3.39, I 2 = 0%) and TG level (MD = -0.25, 95%CI = -0.55 to 0.06, P LED = 0.008; MDMER = -6.72, 95%CIMER = -10.05 to - 3.39, I 2 = 0%) and TG level (MD = -0.25, 95%CI = -0.55 to 0.06, P LED = 0.008; MDMER = -6.72, 95%CIMER = -10.05 to - 3.39, P LED = 0.008; MDMER = -6.72, 95%CIMER = -10.05 to - 3.39, P LED = 0.008; MDMER = -6.72, 95%CIMER = -10.05 to - 3.39, P LED = 0.008; MDMER = -6.72, 95%CIMER = -10.05 to - 3.39, P LED = 0.008; MDMER = -6.72, 95%CIMER = -10.05 to - 3.39. CONCLUSION Dietary intervention through VLEDs is an effective therapy for rapid weight loss, glycemic control, and improved lipid metabolism in overweight and obese individuals with T2DM. Thus, VLEDs should be encouraged in overweight and obese individuals with T2DM who urgently need weight loss and are unsuitable or unwilling to undergo surgery. As all outcome indicators have low or extremely low quality after GRADE evaluation, further clinical trials that focus on the remission effect of VLEDs on T2DM are needed.
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Affiliation(s)
- Yi Shan Huang
- Renal Research Institution of Beijing University of Chinese Medicine, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing 100700, China
| | - Qiyan Zheng
- Renal Research Institution of Beijing University of Chinese Medicine, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing 100700, China
| | - Huisheng Yang
- Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Xinwen Fu
- Renal Research Institution of Beijing University of Chinese Medicine, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing 100700, China
| | - Xueqin Zhang
- Renal Research Institution of Beijing University of Chinese Medicine, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing 100700, China
| | - Chenhui Xia
- Renal Research Institution of Beijing University of Chinese Medicine, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing 100700, China
| | - Zebing Zhu
- Renal Research Institution of Beijing University of Chinese Medicine, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing 100700, China
| | - Yu Ning Liu
- Renal Research Institution of Beijing University of Chinese Medicine, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing 100700, China
- Department of Endocrinology Nephropathy, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing 100700, China
| | - Wei Jing Liu
- Renal Research Institution of Beijing University of Chinese Medicine, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing 100700, China
- Institute of Nephrology, Zhanjiang Key Laboratory of Prevention and Management of Chronic Kidney Disease, Guangdong Medical University, Zhanjiang, Guangdong 524001, China
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Huang JX, Liao YF, Li YM. Clinical Features and Microvascular Complications Risk Factors of Early-onset Type 2 Diabetes Mellitus. Curr Med Sci 2019; 39:754-758. [PMID: 31612393 DOI: 10.1007/s11596-019-2102-7] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2019] [Revised: 09/02/2019] [Indexed: 12/16/2022]
Abstract
The aim of this research was to study the clinical features and microvascular complications risk factors of early-onset type 2 diabetes mellitus (T2DM). We analyzed the clinical data from 1421 T2DM inpatients at Wuhan Union Hospital. Subjects were divided into early-onset T2DM group (diagnostic age <40 years) and late-onset T2DM group (diagnostic age >40 years). All subjects underwent a standardized assessment of microvascular complications. Data were compared with independent-samples t test or Chi-square test. Multiple logistic regression was used to determine the risk factors of microvascular complications. Patients with early-onset T2DM were more inclined to have a lower systolic blood pressure (SBP), a longer duration of diabetes and higher levels of body mass index (BMI), uric acid (UA), fasting plasma glucose (FPG), total cholesterol (TC)- triglyceride (TG) and glycosylated hemoglobin (HbA1c) than those with late-onset T2DM (P<0.05). The prevalence of diabetic retinopathy (DR) was significantly higher and that of diabetic peripheral neuropathy (DPN) was significantly lower in early-onset group than in late-onset group (P<0.05). For DN, UA was an independent risk factor in early-onset T2DM. SBP and TG were independent risk factors in late-onset T2DM. For DR, duration of diabetes and SBP were independent risk factors in early-onset T2DM. Duration of diabetes, SBP and HbA1c were independent risk factors in late-onset T2DM. This study demonstrated that the clinical characteristics of early-onset T2DM were metabolic disorders, including glucose metabolism, lipid metabolism and amino acid metabolism. Early-onset T2DM was more likely to be associated with DR. The potential pathogenesis of early and late-onset T2DM might be different. The management of metabolic risk factors especially HbA1c, SBP, TG and UA is advised to be performed in the early stage of diabetes.
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Affiliation(s)
- Jia-Xin Huang
- Department of Ultrasound, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.,Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Yun-Fei Liao
- Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Yu-Ming Li
- Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
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Arambewela MH, Somasundaram NP, Jayasekara HBPR, Kumbukage MP, Jayasena PMS, Chandrasekara CMPH, Fernando KRAS, Kusumsiri DP. Prevalence of Chronic Complications, Their Risk Factors, and the Cardiovascular Risk Factors among Patients with Type 2 Diabetes Attending the Diabetic Clinic at a Tertiary Care Hospital in Sri Lanka. J Diabetes Res 2018; 2018:4504287. [PMID: 29951551 PMCID: PMC5989171 DOI: 10.1155/2018/4504287] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2017] [Revised: 03/23/2018] [Accepted: 04/15/2018] [Indexed: 12/17/2022] Open
Abstract
Diabetes incurs heavy burden to patients and the healthcare system. Assessment of disease burden is important in taking necessary precautions and management decisions. We aimed to determine the prevalence of macro- and microvascular complications, their risk factors, and coronary artery disease (CAD) risk factors among patients with type 2 diabetes mellitus (T2DM). A descriptive cross-sectional single-centre study was carried out among 3000 patients with T2DM attending the diabetic clinic at the National Hospital of Sri Lanka from January to July 2016. The study population had 72.7% females and 27.3% males. Mean age and disease duration were 58.3 ± 10.3 and 10.8 ± 7 years, respectively. Prevalence of CAD, stroke, and peripheral vascular disease were 10.6%, 1.1%, and 4.7% while diabetic retinopathy, neuropathy, nephropathy, diabetic foot, and lower extremity amputation (LEA) were 26.1%, 62.6%, 50.8%, 2.6%, and 1.3%, respectively. Prevalence of overweight/obesity, hypertension, dyslipidemia, and smoking were 80%, 77.6%, 76.7%, and 11%, respectively. Increased age, disease duration, and HBA1c were risk factors for microvascular disease and diabetic foot while age was the only risk factor for macrovascular complications. Occurrence of CAD, peripheral neuropathy, diabetic foot, and LEA was significantly higher among males than when compared to females. This study highlights the major burden of chronic complications and high prevalence of CAD risk factors in this population.
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Affiliation(s)
- Maulee Hiromi Arambewela
- Department of Diabetes and Endocrinology, National Hospital of Sri Lanka, Colombo, Sri Lanka
- Faculty of Medical Sciences, University of Sri Jayewardenepura, Nugegoda, Sri Lanka
| | - Noel P. Somasundaram
- Department of Diabetes and Endocrinology, National Hospital of Sri Lanka, Colombo, Sri Lanka
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Mobbs CV. Glucose-Induced Transcriptional Hysteresis: Role in Obesity, Metabolic Memory, Diabetes, and Aging. Front Endocrinol (Lausanne) 2018; 9:232. [PMID: 29892261 PMCID: PMC5985453 DOI: 10.3389/fendo.2018.00232] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2018] [Accepted: 04/23/2018] [Indexed: 01/30/2023] Open
Abstract
During differentiation transient, inducers produce permanent changes in gene expression. A similar phenomenon, transcriptional hysteresis, produced by transient or prolonged exposure to glucose, leads to cumulative, persistent, and largely irreversible effects on glucose-regulated gene expression, and may drive key aspects of metabolic memory, obesity, diabetes, and aging, and explain the protective effects of dietary restriction during aging. The most relevant effects of glucose-induced transcriptional hysteresis are the persistent effects of elevated glucose on genes that control glucose metabolism itself. A key observation is that, as with the lac operon, glucose induces genes that promote glycolysis and inhibits gene expression of alternative metabolic pathways including the pentose pathway, beta oxidation, and the TCA cycle. A similar pattern of metabolic gene expression is observed during aging, suggesting that cumulative exposure to glucose during aging produces this metabolic shift. Conversely, dietary restriction, which increases lifespan and delays age-related impairments, produces the opposite metabolic profile, leading to a shift away from glycolysis and toward the use of alternative substrates, including lipid and ketone metabolisms. The effect of glucose on gene expression leads to a positive feedback loop that leads to metastable persistent expression of genes that promote glycolysis and inhibit alternative pathways, a phenomenon first observed in the regulation of the lac operon. On the other hand, this pattern of gene expression can also be inhibited by activation of peroxisome proliferator activating receptor transcription factors that promote beta oxidation and inhibit metabolism of glucose-derived carbon bonds in the TCA cycle. Several pathological consequences may arise from glucose-induced transcriptional hysteresis. First, elevated glucose induces glycolytic genes in pancreatic beta cells, which induces a semi-stable persistent increase in insulin secretion, which could drive obesity and insulin resistance, and also due to glucose toxicity could eventually lead to beta-cell decompensation and diabetes. Diabetic complications persist even after complete normalization of glucose, a phenomenon known as metabolic memory. This too can be explained by persistent bistable expression of glucose-induced glycolytic genes.
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15
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Ogawa S, Okawa Y, Sawada K, Goto Y, Hosoba S, Fukaya S. MicroRNA and hyperglycemic memory in the diabetic heart. J Thorac Dis 2017; 8:E1473-E1474. [PMID: 28066634 DOI: 10.21037/jtd.2016.11.68] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Affiliation(s)
- Shinji Ogawa
- Department of Cardiovascular Surgery, Toyohashi Heart Center, Toyohashi, Japan
| | - Yasuhide Okawa
- Department of Cardiovascular Surgery, Toyohashi Heart Center, Toyohashi, Japan
| | - Koshi Sawada
- Department of Cardiovascular Surgery, Toyohashi Heart Center, Toyohashi, Japan
| | - Yoshihiro Goto
- Department of Cardiovascular Surgery, Toyohashi Heart Center, Toyohashi, Japan
| | - Soh Hosoba
- Department of Cardiovascular Surgery, Toyohashi Heart Center, Toyohashi, Japan
| | - Syunsuke Fukaya
- Department of Cardiovascular Surgery, Toyohashi Heart Center, Toyohashi, Japan
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Xu W, Wang F, Yu Z, Xin F. Epigenetics and Cellular Metabolism. GENETICS & EPIGENETICS 2016; 8:43-51. [PMID: 27695375 PMCID: PMC5038610 DOI: 10.4137/geg.s32160] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/15/2016] [Revised: 07/25/2016] [Accepted: 08/01/2016] [Indexed: 01/03/2023]
Abstract
Living eukaryotic systems evolve delicate cellular mechanisms for responding to various environmental signals. Among them, epigenetic machinery (DNA methylation, histone modifications, microRNAs, etc.) is the hub in transducing external stimuli into transcriptional response. Emerging evidence reveals the concept that epigenetic signatures are essential for the proper maintenance of cellular metabolism. On the other hand, the metabolite, a main environmental input, can also influence the processing of epigenetic memory. Here, we summarize the recent research progress in the epigenetic regulation of cellular metabolism and discuss how the dysfunction of epigenetic machineries influences the development of metabolic disorders such as diabetes and obesity; then, we focus on discussing the notion that manipulating metabolites, the fuel of cell metabolism, can function as a strategy for interfering epigenetic machinery and its related disease progression as well.
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Affiliation(s)
- Wenyi Xu
- Institute of Food Science and Technology, Chinese Academy of Agricultural Sciences (CAAS), Beijing, China
| | - Fengzhong Wang
- Institute of Food Science and Technology, Chinese Academy of Agricultural Sciences (CAAS), Beijing, China
| | - Zhongsheng Yu
- Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA
| | - Fengjiao Xin
- Institute of Food Science and Technology, Chinese Academy of Agricultural Sciences (CAAS), Beijing, China
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17
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Datta-Nemdharry P, Thomson A, Beynon J, Donegan K. Patterns of anti-diabetic medication use in patients with type 2 diabetes mellitus in England and Wales. Pharmacoepidemiol Drug Saf 2016; 26:127-135. [DOI: 10.1002/pds.4092] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2016] [Revised: 05/13/2016] [Accepted: 08/10/2016] [Indexed: 12/19/2022]
Affiliation(s)
| | - Andrew Thomson
- Vigilance and Risk Management of Medicines (VRMM); MHRA; London UK
| | - Julie Beynon
- Vigilance and Risk Management of Medicines (VRMM); MHRA; London UK
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18
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Clements MA, Foster NC, Maahs DM, Schatz DA, Olson BA, Tsalikian E, Lee JM, Burt-Solorzano CM, Tamborlane WV, Chen V, Miller KM, Beck RW. Hemoglobin A1c (HbA1c) changes over time among adolescent and young adult participants in the T1D exchange clinic registry. Pediatr Diabetes 2016; 17:327-36. [PMID: 26153338 DOI: 10.1111/pedi.12295] [Citation(s) in RCA: 170] [Impact Index Per Article: 18.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2014] [Revised: 06/04/2015] [Accepted: 06/09/2015] [Indexed: 12/17/2022] Open
Abstract
OBJECTIVE Hemoglobin A1c (HbA1c) levels among individuals with type 1 diabetes (T1D) influence the longitudinal risk for diabetes-related complications. Few studies have examined HbA1c trends across time in children, adolescents, and young adults with T1D. This study examines changes in glycemic control across the specific transition periods of pre-adolescence-to-adolescence and adolescence-to-young adulthood, and the demographic and clinical factors associated with these changes. RESEARCH DESIGN AND METHODS Available HbA1c lab results for up to 10 yr were collected from medical records at 67 T1D Exchange clinics. Two retrospective cohorts were evaluated: the pre-adolescent-to-adolescent cohort consisting of 85 016 HbA1c measurements from 6574 participants collected when the participants were 8-18 yr old and the adolescent-to-young adult cohort, 2200 participants who were 16-26 yr old at the time of 17 279 HbA1c measurements. RESULTS HbA1c in the 8-18 cohort increased over time after age 10 yr until ages 16-17; followed by a plateau. HbA1c levels in the 16-26 cohort remained steady from 16-18, and then gradually declined. For both cohorts, race/ethnicity, income, health insurance, and pump use were all significant in explaining individual variations in age-centered HbA1c (p < 0.001). For the 8-18 cohort, insulin pump use, age of onset, and health insurance were significant in predicting individual HbA1c trajectory. CONCLUSIONS Glycemic control among patients 8-18 yr old worsens over time, through age 16. Elevated HbA1c levels observed in 18 yr-olds begin a steady improvement into early adulthood. Focused interventions to prevent deterioration in glucose control in pre-adolescence, adolescence, and early adulthood are needed.
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Affiliation(s)
- Mark A Clements
- Pediatrics (Endocrinology), Children's Mercy Hospitals and Clinics, Kansas City, MO, 64018, USA
| | - Nicole C Foster
- Jaeb Center for Health Research, T1D Exchange, Tampa, FL, 33647, USA
| | - David M Maahs
- Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, CO, 80045, USA
| | - Desmond A Schatz
- University of Florida College of Medicine, Division of Endocrinology, Gainesville, FL, 32610, USA
| | - Beth A Olson
- Park Nicollet International Diabetes Center, Minneapolis, MN, 55416, USA
| | - Eva Tsalikian
- University of Iowa Children's Hospital, Department of Pediatrics, Iowa City, IA, 52242, USA
| | - Joyce M Lee
- Pediatric Endocrinology, University of Michigan, Department of Pediatrics and Communicable Diseases, Ann Arbor, MI, 48109, USA
| | | | | | - Vincent Chen
- Jaeb Center for Health Research, T1D Exchange, Tampa, FL, 33647, USA
| | - Kellee M Miller
- Jaeb Center for Health Research, T1D Exchange, Tampa, FL, 33647, USA
| | - Roy W Beck
- Jaeb Center for Health Research, T1D Exchange, Tampa, FL, 33647, USA
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Yu TY, Lee DH. Dizziness and Syncope Related with Diabetic Autonomic Neuropathy. INTERNATIONAL JOURNAL OF ARRHYTHMIA 2016. [DOI: 10.18501/arrhythmia.2016.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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20
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Li FF, Fu LY, Zhang WL, Su XF, Wu JD, Sun J, Ye L, Ma JH. Blood Glucose Fluctuations in Type 2 Diabetes Patients Treated with Multiple Daily Injections. J Diabetes Res 2015; 2016:1028945. [PMID: 26839889 PMCID: PMC4709669 DOI: 10.1155/2016/1028945] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2015] [Accepted: 10/28/2015] [Indexed: 01/04/2023] Open
Abstract
To compare blood glucose fluctuations in type 2 diabetes mellitus (T2DM) patients were treated using three procedures: insulin intensive therapy which is continuous subcutaneous insulin infusion (CSII), MDI3 (three injections daily), and MDI4 (four injections daily). T2DM patients were hospitalized and were randomly assigned to CSII, aspart 30-based MDI3, and glargine based MDI4. Treatments were maintained for 2-3 weeks after the glycaemic target was reached. After completing the baseline assessment, 6-day continuous glucose monitoring (CGM) was performed before and after completion of insulin treatment. Treatment with CSII provided a greater improvement of blood glucose fluctuations than MDI (MDI3 or MDI4) therapy either in newly diagnosed or in long-standing T2DM patients. In long-standing diabetes patients, the MDI4 treatment group had significantly greater improvement of mean amplitude glycemic excursion (MAGE) than the MDI3 treatment group. However, in patients with newly diagnosed diabetes, there were no significant differences in the improvement of MAGE between MDI3 and MDI4 groups. Glargine based MDI4 therapy provided better glucose fluctuations than aspart 30-based MDI3 therapy, especially in long-standing T2DM patients, if CSII therapy was not available.
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Affiliation(s)
- Feng-fei Li
- Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210012, China
| | - Li-yuan Fu
- Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Wen-li Zhang
- Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210012, China
| | - Xiao-fei Su
- Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210012, China
| | - Jin-dan Wu
- Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210012, China
| | - Jin Sun
- Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210012, China
| | - Lei Ye
- National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore 169606
| | - Jian-hua Ma
- Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210012, China
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Li FF, Xu XH, Fu LY, Su XF, Wu JD, Lu CF, Ye L, Ma JH. Influence of Acarbose on Plasma Glucose Fluctuations in Insulin-Treated Patients with Type 2 Diabetes: A Pilot Study. Int J Endocrinol 2015; 2015:903524. [PMID: 26640487 PMCID: PMC4658413 DOI: 10.1155/2015/903524] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2015] [Revised: 10/20/2015] [Accepted: 10/21/2015] [Indexed: 11/18/2022] Open
Abstract
Background and Aims. To evaluate the effect of adding acarbose on glycemic excursions measured by continuous glucose monitoring system (CGMS) in patients with type 2 diabetes mellitus (T2DM) already on insulin therapy. Materials and Methods. This was an opened and unblended study. 134 patients with T2DM were recruited. After initial rapidly corrected hyperglycaemia by continuous subcutaneous insulin infusion (CSII) for 7 d, a 4-6-day premixed insulin titration period subsequently followed. Patients were then randomized 1 : 1 to acarbose plus insulin group or insulin therapy group for 2 weeks. CGMS was used to measure glucose fluctuations for at least 3 days after therapy cessation. Results. Patients in acarbose plus insulin group achieved a significant improvement of MAGE compared to that of insulin therapy only group (5.56 ± 2.16 versus 7.50 ± 3.28 mmol/L, P = 0.044), accompanied by a significant decrease in the incremental AUC of plasma glucose concentration above 10.0 mmol/L (0.5 [0.03, 0.9] versus 0.85 [0.23,1.4] mmol/L per day, P = 0.037). Conclusions. Add-on acarbose to insulin therapy further improves glucose fluctuation in patients with T2DM. This study was registered with ClinicalTrials.gov registration number ChiCTR-TRC-11001218.
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Affiliation(s)
- Feng-fei Li
- Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210012, China
| | - Xiao-hua Xu
- Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210012, China
| | - Li-yuan Fu
- Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Xiao-fei Su
- Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210012, China
| | - Jin-dan Wu
- Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210012, China
| | - Chun-feng Lu
- Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210012, China
| | - Lei Ye
- National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore 169606
| | - Jian-hua Ma
- Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210012, China
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ZHAO SHUZHI, LI JUN, WANG NA, ZHENG BINGQING, LI TAO, GU QING, XU XUN, ZHENG ZHI. Fenofibrate suppresses cellular metabolic memory of high glucose in diabetic retinopathy via a sirtuin 1-dependent signalling pathway. Mol Med Rep 2015; 12:6112-8. [DOI: 10.3892/mmr.2015.4164] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2014] [Accepted: 06/22/2015] [Indexed: 11/06/2022] Open
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Tallapragada DSP, Karpe PA, Tikoo K. Long-lasting partnership between insulin resistance and endothelial dysfunction: role of metabolic memory. Br J Pharmacol 2015; 172:4012-23. [PMID: 25825057 DOI: 10.1111/bph.13145] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2014] [Revised: 03/17/2015] [Accepted: 03/25/2015] [Indexed: 01/13/2023] Open
Abstract
BACKGROUND AND PURPOSE The persistence of deleterious effects of hyperglycaemia even after glucose normalization is referred to as 'metabolic memory'. However, similar persistent effects of the metabolic consequences of a high fat diet (HFD) have not been described. EXPERIMENTAL APPROACH Rats were given a normal pellet diet (NPD) or a HFD for 3 months. The animals from the HFD group were then returned to the NPD to observe the long-term effects of insulin resistance. Endothelial dysfunction was assessed by carbachol-mediated vasorelaxation and eNOS phosphorylation. KEY RESULTS As expected, HFD consumption resulted in insulin resistance and endothelial dysfunction. Phosphorylation of eNOS at S1177 was decreased in HFD rats, compared with that in the NPD group. Rats on 3 months of HFD showed glucose intolerance and impaired insulin sensitivity and were then switched back to NPD (REV group) . Levels of cholesterol and triglyceride, and adiposity returned to normal in REV rats. However, endothelium-dependent vascular responses to carbachol which were impaired in HFD rats, continued to be impaired in REV rats. Similarly, decreased eNOS phosphorylation after HFD was not improved after 1 or 6 months of REV. CONCLUSIONS AND IMPLICATIONS Our data indicate that returning to NPD did not improve the insulin sensitivity or the endothelial dysfunction induced by HFD. Although some biochemical parameters responsible for insulin resistance and endothelial dysfunction were normalized, molecular and vascular abnormalities, involving NO, persisted for several months, highlighting the long-lasting effects of metabolic memory.
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Affiliation(s)
- Divya Sri Priyanka Tallapragada
- Laboratory of Epigenetics and Diseases, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Mohali, Punjab, India
| | - Pinakin Arun Karpe
- Laboratory of Epigenetics and Diseases, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Mohali, Punjab, India
| | - Kulbhushan Tikoo
- Laboratory of Epigenetics and Diseases, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Mohali, Punjab, India
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Li J, Feng Z, Li Q, He Y, Zhao C, He J. Insulin glargine effectively achieves glycemic control and improves insulin resistance in patients with early type 2 diabetes that exhibit a high risk for cardiovascular disease. Exp Ther Med 2014; 8:147-152. [PMID: 24944613 PMCID: PMC4061209 DOI: 10.3892/etm.2014.1688] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2013] [Accepted: 03/13/2014] [Indexed: 01/08/2023] Open
Abstract
In the present study, the clinical efficacy and safety of administering insulin glargine to early type 2 diabetes (T2D) mellitus patients with a high risk for cardiovascular disease were assessed. A total of 42 early T2D patients at a high risk for cardiovascular disease were randomly divided into an insulin-glargine group and a standard-care group. The patients in the insulin-glargine group received oral antidiabetic agents plus glargine once a day via a subcutaneous injection. The patients in the standard-care group were administered oral antidiabetic agents according to the diabetic treatment guidelines. The median follow-up period was 6.4 years. Comparisons were made between the two groups with regard to levels of plasma glucose, glycosylated hemoglobin (HbA1c) and plasma lipids, the homeostasis model assessment-insulin secretion index (HOMA-β) and HOMA-insulin resistance index (HOMA-IR), as well as the incidence of hypoglycemia, adverse cardiovascular events and body mass index (BMI). The fasting plasma glucose level in the insulin-glargine group was significantly lower than that observed in the standard-care group. However, the levels of 2-h postprandial glucose, HbA1c and plasma lipids, as well as the BMI, were similar when comparing the two groups. Although the level of the HOMA-β did not differ between the two groups, the level of HOMA-IR in the insulin-glargine group was significantly lower than that observed in the standard-care group. During the follow-up period, the incidence of hypoglycemia in the insulin-glargine group was significantly higher when compared with the standard-care group, however, no significant difference in the incidence of adverse cardiovascular events was observed. Therefore, the results of the present study indicated that insulin glargine may effectively achieve glycemic control and improve insulin resistance without increasing the risk for cardiovascular events in early T2D patients that were considered to be at a high risk for cardiovascular disease.
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Affiliation(s)
- Jiling Li
- Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
| | - Zhengping Feng
- Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
| | - Qifu Li
- Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
| | - Yan He
- Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
| | - Changhong Zhao
- Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
| | - Jun He
- Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
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Moon JS, Ha KS, Yoon JS, Lee HW, Lee HC, Won KC. The effect of glargine versus glimepiride on pancreatic β-cell function in patients with type 2 diabetes uncontrolled on metformin monotherapy: open-label, randomized, controlled study. Acta Diabetol 2014; 51:277-85. [PMID: 24445656 DOI: 10.1007/s00592-013-0553-z] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2013] [Accepted: 12/30/2013] [Indexed: 01/09/2023]
Abstract
The aim of present study is to assess whether if basal insulin, glargine, could improve insulin secretory function of β-cells compared with glimepiride when metformin alone was failed. This was an open-label and multi-center study for 52 weeks in Korean patients with uncontrolled type 2 diabetes by metformin monotherapy. Subjects were randomized to glargine or glimepiride groups (n = 38 vs. 36, respectively). The primary endpoint was to compare changes in c-peptide via glucagon test after 48 weeks. Glycemic efficacy and safety endpoints (glycated hemoglobin (HbA1c), HOMA-B, fasting plasma glucose (FPG), lipid profiles, and hypoglycemic events) were also checked. The mean disease duration of all subjects was 88.2 months. Changes in C-peptide was no significant different between groups (P = 0.73), even though insulin secretion was not worsened in both groups at the endpoint. Glargine was not superior to glimepiride in other β-cell function indexes such as HOMA-B (P = 0.28). HbA1c and FPG reduced significantly in each groups but not different between two groups. Although, severe hypoglycemia did not occur, symptomatic hypoglycemia was more frequent in glimepiride group (P = 0.01). Insulin glargine was as effective as glimepiride in controlling hyperglycemia and maintaining β-cell function in Korean patients with type 2 diabetes during 48 weeks study period, after failure of metformin monotherapy. Hypoglycemic profile was favorable in the insulin glargine group and less weight gain was observed in the glimepiride group. Our results suggest that glargine and glimepiride can be considered after failure of metformin monotherapy.
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Affiliation(s)
- Jun Sung Moon
- Department of Internal Medicine, Yeungnam University College of Medicine, 170 Hyunchung-ro, Nam-gu, Daegu, 705-717, Republic of Korea
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Abstract
OBJECTIVE To review and discuss the risks and impact of hypoglycemia and provide guidance for the prevention of hypoglycemia in type 2 diabetes (T2DM). METHODS We review and discuss the risks and impact of hypoglycemia, providing specific guidance regarding the prevention of hypoglycemia and judicial selection of glucose-lowering agents in individuals with T2DM. RESULTS Hypoglycemia in T2DM is underrecognized and underreported. Emerging evidence from large clinical trials suggest that hypoglycemia may be an important risk factor for morbidity and mortality in T2DM. In addition, hypoglycemia is associated with reduced quality of life, greater healthcare utilization costs, and poor adherence to medical regiments. CONCLUSION These findings have led professional organizations to emphasize the prevention of hypoglycemia as an important consideration when initiating or intensifying treatment regimens. In clinical settings, particular attention should be paid to a patient's risk for hypoglycemia when initiating or intensifying the pharmacological treatment regimen. The endocrinologist can play an important role in educating not only the patient, but also other members of the diabetes-management team regarding the need for individualized therapy.
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Affiliation(s)
- Etie Moghissi
- Department of Medicine, University of California, Marina Del Rey, California 90292, USA.
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Dimitropoulos G, Tahrani AA, Stevens MJ. Cardiac autonomic neuropathy in patients with diabetes mellitus. World J Diabetes 2014; 5:17-39. [PMID: 24567799 PMCID: PMC3932425 DOI: 10.4239/wjd.v5.i1.17] [Citation(s) in RCA: 188] [Impact Index Per Article: 17.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2013] [Revised: 12/02/2013] [Accepted: 12/12/2013] [Indexed: 02/05/2023] Open
Abstract
Cardiac autonomic neuropathy (CAN) is an often overlooked and common complication of diabetes mellitus. CAN is associated with increased cardiovascular morbidity and mortality. The pathogenesis of CAN is complex and involves a cascade of pathways activated by hyperglycaemia resulting in neuronal ischaemia and cellular death. In addition, autoimmune and genetic factors are involved in the development of CAN. CAN might be subclinical for several years until the patient develops resting tachycardia, exercise intolerance, postural hypotension, cardiac dysfunction and diabetic cardiomyopathy. During its sub-clinical phase, heart rate variability that is influenced by the balance between parasympathetic and sympathetic tones can help in detecting CAN before the disease is symptomatic. Newer imaging techniques (such as scintigraphy) have allowed earlier detection of CAN in the pre-clinical phase and allowed better assessment of the sympathetic nervous system. One of the main difficulties in CAN research is the lack of a universally accepted definition of CAN; however, the Toronto Consensus Panel on Diabetic Neuropathy has recently issued guidance for the diagnosis and staging of CAN, and also proposed screening for CAN in patients with diabetes mellitus. A major challenge, however, is the lack of specific treatment to slow the progression or prevent the development of CAN. Lifestyle changes, improved metabolic control might prevent or slow the progression of CAN. Reversal will require combination of these treatments with new targeted therapeutic approaches. The aim of this article is to review the latest evidence regarding the epidemiology, pathogenesis, manifestations, diagnosis and treatment for CAN.
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Verrotti A, Prezioso G, Scattoni R, Chiarelli F. Autonomic neuropathy in diabetes mellitus. Front Endocrinol (Lausanne) 2014; 5:205. [PMID: 25520703 PMCID: PMC4249492 DOI: 10.3389/fendo.2014.00205] [Citation(s) in RCA: 102] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2014] [Accepted: 11/17/2014] [Indexed: 12/14/2022] Open
Abstract
Diabetic autonomic neuropathy (DAN) is a serious and common complication of diabetes, often overlooked and misdiagnosed. It is a systemic-wide disorder that may be asymptomatic in the early stages. The most studied and clinically important form of DAN is cardiovascular autonomic neuropathy defined as the impairment of autonomic control of the cardiovascular system in patients with diabetes after exclusion of other causes. The reported prevalence of DAN varies widely depending on inconsistent definition, different diagnostic method, different patient cohorts studied. The pathogenesis is still unclear and probably multifactorial. Once DAN becomes clinically evident, no form of therapy has been identified, which can effectively stop or reverse it. Prevention strategies are based on strict glycemic control with intensive insulin treatment, multifactorial intervention, and lifestyle modification including control of hypertension, dyslipidemia, stop smoking, weight loss, and adequate physical exercise. The present review summarizes the latest knowledge regarding clinical presentation, epidemiology, pathogenesis, and management of DAN, with some mention to childhood and adolescent population.
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Affiliation(s)
| | | | | | - Francesco Chiarelli
- Department of Pediatrics, University of Chieti, Chieti, Italy
- *Correspondence: Francesco Chiarelli, Department of Pediatrics, University of Chieti, Via dei Vestini 5, Chieti 66013, Italy e-mail:
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Abd-Allha E, Hassan BB, Abduo M, Omar SA, Sliem H. Small dense low-density lipoprotein as a potential risk factor of nephropathy in type 2 diabetes mellitus. Indian J Endocrinol Metab 2014; 18:94-98. [PMID: 24701437 PMCID: PMC3968741 DOI: 10.4103/2230-8210.126585] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
BACKGROUND The risk for diabetic nephropathy in type 2 diabetes is about 30-40%, and it is considered the leading cause of end-stage renal disease. Small dense low-density lipoprotein (sdLDL) particles are believed to be atherogenic, and its predominance has been accepted as an emerging cardiovascular risk factor. This study aimed to assess small dense LDL as a potential risk factor and a possible predictor for diabetic nephropathy in type 2 diabetic patients. PATIENTS AND METHODS According to microalbuminuria test, 40 diabetic patients were categorized into two groups: Diabetic patients without nephropathy (microalbuminuria negative group) and diabetic patients with nephropathy (microalbuminuria positive group), each group consists of 20 patients and all were non-obese and normotensive. The patients were re-classified into three sub-groups depending on the glomerular filtration rate (GFR). RESULTS The mean of small dense LDL level in the microalbuminuria positive group was higher than that in the microalbuminuria negative group, but without statistical significance. It was significantly higher in patients with either mild or moderate decrease in estimated GFR than in patients with normal estimated GFR. There was statistically significant correlation between small dense LDL and albuminuria and significant inverse correlation between small dense LDL and estimated GFR in all patients in the study. Based on microalbuminuria, the sensitivity and specificity of small dense LDL in the diagnosis of diabetic nephropathy was 40% and 80%, respectively, with cutoff values of small dense LDL >55.14 mg/dl. On the other hand, based on GFR, the sensitivity and specificity were 88.24% and 73.91% respectively, with cutoff values of small dense LDL >41.89 mg/dl. CONCLUSION Small dense LDL is correlated with the incidence and severity of diabetic nephropathy in type 2 diabetic patients. It should be considered as a potential risk factor and as a diagnostic biomarker to be used in conjunction with other biochemical markers for early diagnosis, assessment, and follow-up of diabetic nephropathy.
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Affiliation(s)
- Essam Abd-Allha
- Department of Clinical Pathology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt
| | - Basma Badr Hassan
- Department of Clinical Pathology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt
| | - Mohamad Abduo
- Department of Internal Medicine, Faculty of Medicine, Suez Canal University, Ismailia, Egypt
| | - Seham Ahmed Omar
- Department of Internal Medicine, Faculty of Medicine, Suez Canal University, Ismailia, Egypt
| | - Hamdy Sliem
- Department of Internal Medicine, Faculty of Medicine, Suez Canal University, Ismailia, Egypt
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Xu W, Weng J. Current role of short-term intensive insulin strategies in newly diagnosed type 2 diabetes. J Diabetes 2013; 5:268-74. [PMID: 23551748 DOI: 10.1111/1753-0407.12054] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2012] [Revised: 02/26/2013] [Accepted: 03/27/2013] [Indexed: 01/09/2023] Open
Abstract
Type 2 diabetes mellitus (T2DM) is a progressive disease characterized by worsening insulin resistance and a decline in β-cell function. Achieving good glycemic control becomes more challenging as β-cell function continues to deteriorate throughout the disease process. The traditional management paradigm emphasizes a stepwise approach, and insulin has generally been reserved as a final armament. However, mounting evidence indicates that short-term intensive insulin therapy used in the early stages of type 2 diabetes could improve β-cell function, resulting in better glucose control and more extended glycemic remission than oral antidiabetic agents. Improvements in insulin sensitivity and lipid profile were also seen after the early initiation of short-term intensive insulin therapy. Thus, administering short-term intensive insulin therapy to patients with newly diagnosed T2DM has the potential to delay the natural process of this disease, and should be considered when clinicians initiate treatment. Although the early use of insulin is advocated by some guidelines, the optimal time to initiate insulin therapy is not clearly defined or easily recognized, and a pragmatic approach is lacking. Herein we summarize the current understanding of early intensive insulin therapy in patients with newly diagnosed T2DM, focusing on its clinical benefit and problems, as well as possible biological mechanisms of action, and discuss our perspective.
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Affiliation(s)
- Wen Xu
- Department of Endocrinology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
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Malmgren S, Spégel P, Danielsson APH, Nagorny CL, Andersson LE, Nitert MD, Ridderstråle M, Mulder H, Ling C. Coordinate changes in histone modifications, mRNA levels, and metabolite profiles in clonal INS-1 832/13 β-cells accompany functional adaptations to lipotoxicity. J Biol Chem 2013; 288:11973-87. [PMID: 23476019 DOI: 10.1074/jbc.m112.422527] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Lipotoxicity is a presumed pathogenetic process whereby elevated circulating and stored lipids in type 2 diabetes cause pancreatic β-cell failure. To resolve the underlying molecular mechanisms, we exposed clonal INS-1 832/13 β-cells to palmitate for 48 h. We observed elevated basal insulin secretion but impaired glucose-stimulated insulin secretion in palmitate-exposed cells. Glucose utilization was unchanged, palmitate oxidation was increased, and oxygen consumption was impaired. Halting exposure of the clonal INS-1 832/13 β-cells to palmitate largely recovered all of the lipid-induced functional changes. Metabolite profiling revealed profound but reversible increases in cellular lipids. Glucose-induced increases in tricarboxylic acid cycle intermediates were attenuated by exposure to palmitate. Analysis of gene expression by microarray showed increased expression of 982 genes and decreased expression of 1032 genes after exposure to palmitate. Increases were seen in pathways for steroid biosynthesis, cell cycle, fatty acid metabolism, DNA replication, and biosynthesis of unsaturated fatty acids; decreases occurred in the aminoacyl-tRNA synthesis pathway. The activity of histone-modifying enzymes and histone modifications of differentially expressed genes were reversibly altered upon exposure to palmitate. Thus, Insig1, Lss, Peci, Idi1, Hmgcs1, and Casr were subject to epigenetic regulation. Our analyses demonstrate that coordinate changes in histone modifications, mRNA levels, and metabolite profiles accompanied functional adaptations of clonal β-cells to lipotoxicity. It is highly likely that these changes are pathogenetic, accounting for loss of glucose responsiveness and perturbed insulin secretion.
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Affiliation(s)
- Siri Malmgren
- Department of Clinical Sciences, Units of Molecular Metabolism, Scania University Hospital, 205 02 Malmö, Sweden
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Han D, Yamamoto Y, Munesue S, Motoyoshi S, Saito H, Win MTT, Watanabe T, Tsuneyama K, Yamamoto H. Induction of receptor for advanced glycation end products by insufficient leptin action triggers pancreatic β-cell failure in type 2 diabetes. Genes Cells 2013; 18:302-14. [PMID: 23410183 DOI: 10.1111/gtc.12036] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2012] [Accepted: 12/18/2012] [Indexed: 12/31/2022]
Abstract
Glucolipotoxicity, which is exerted by free fatty acids (FFA) and prolonged hyperglycemia, is implicated in pancreatic β-cell failure in diabetes. Pattern recognition receptors such as receptor for advanced glycation end products (RAGE) and toll-like receptors 2 and 4 could mediate danger signals in β-cells. We examined whether RAGE contributes to β-cell failure in a type 2 diabetes mouse model. Pancreatic islets were isolated from ob/ob, db/db, diet-induced obesity (DIO), RAGE-null (RAGE(-/-) ), and RAGE(+/+) wild-type (WT) control mice and dispersed into single cells for flow cytometry. RAGE expression was detected in insulin-positive β-cells of ob/ob and db/db mice, but not of WT, DIO, or RAGE(-/-) mice: thus, inadequate leptin receptor signaling and RAGE expression may be linked. Compared with RAGE(+/+) db/db mice, RAGE(-/-) db/db mice showed higher β-cell number and mass with less apoptosis as well as glucose tolerance with higher insulin secretion without any differences in serum levels of FFA and adiponectin. Palmitate or oleate pretreatment combined with a leptin antagonist induced RAGE expression, AGE-elicited apoptosis, and impaired glucose-stimulated insulin secretion by advanced glycation end products (AGE) in MIN6 cells. FFA elevation with concomitant AGE formation during prolonged hyperglycemia could cause β-cell damage through insufficient leptin action and subsequent RAGE induction in type 2 diabetes.
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Affiliation(s)
- Dong Han
- Department of Biochemistry and Molecular Vascular Biology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, 920-8640, Japan
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Reach G, Le Pautremat V, Gupta S. Determinants and consequences of insulin initiation for type 2 diabetes in France: analysis of the National Health and Wellness Survey. Patient Prefer Adherence 2013; 7:1007-23. [PMID: 24143079 PMCID: PMC3797252 DOI: 10.2147/ppa.s51299] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND The aim of the study was to identify the intrinsic patient characteristics and extrinsic environmental factors predicting prescription and use and, more specifically, early initiation (up to 5 years of disease duration) of insulin for type 2 diabetes in France. A secondary objective was to evaluate the impact of insulin therapy on mental and physical quality of life and patient adherence. METHODS The data used in this study were derived from the 2008, 2010, and 2011 France National Health and Wellness Survey. This survey is an annual, cross-sectional, self-administered, Internet-based questionnaire among a nationwide representative sample of adults (aged 18 years or older). Of the total of 45,958 persons recruited in France, 1,933 respondents (deduped) were identified as diagnosed with type 2 diabetes. All unique respondents from the three waves, currently using insulin or oral bitherapy or tritherapy at the time of assessment, were included in this analysis. RESULTS Early (versus late) initiation of insulin therapy was 9.9 times more likely to be prescribed by an endocrinologist or diabetologist than by a primary care physician (P < 0.0001). Younger age at diagnosis and current smoking habits were significant predictors of early (versus late) insulin initiation (odds ratio [OR] 1.031, 95% confidence interval [CI] 1.005-1.059, P = 0.0196, and OR 2.537, 95% CI 1.165-5.524, P = 0.0191, respectively). Patients with a yearly income ≥€50,000 were less likely to be put on insulin early (P = 0.0399). A link between insulin prescription and complications was shown only in univariate analysis. Mental quality of life was lower in patients on early (versus late) insulin, but only in patients with diabetes-related complications. Insulin users (versus oral bitherapy or tritherapy users) had 3.0 times greater odds of being adherent than uncontrolled oral bitherapy or tritherapy users (OR 2.983, 95% CI 1.37-6.495, P = 0.0059). CONCLUSION This study confirms the role of specialists in early initiation of insulin, and the data presented herein reflect the fact that early initiation is more frequent in younger patients, patients with diabetes-related complications, and current smokers, and less frequent in patients with a higher income. Moreover, we observed that being treated with insulin was not associated with deterioration in quality of life, and insulin-treated patients were more often adherent than uncontrolled oral bitherapy or tritherapy users. These data suggest that doctors' concerns about patient adherence and detrimental effects on quality of life should not be a barrier to their decision regarding early initiation of insulin therapy. Due to the nature of this cross-sectional survey (eg, inability to assess treatment flow), further research is needed to confirm its findings.
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Affiliation(s)
- Gérard Reach
- Department of Endocrinology, Diabetes, and Metabolic Diseases, Avicenne Hospital APHP, and EA 3412, CRNH-IdF, Paris 13 University, Sorbonnne Paris Cité, Bobigny, France
- Correspondence: Gérard Reach Service d’Endocrinologie, Diabétologie, Maladies Métaboliques, Hôpital Avicenne APHP, 125 route de Stalingrad, 93000 Bobigny, France, Tel +331 4895 5158, Fax +331 4895 5560, Email
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Pittenger GL, Mehrabyan A, Simmons K, Amandarice, Dublin C, Barlow P, Vinik AI. Small fiber neuropathy is associated with the metabolic syndrome. Metab Syndr Relat Disord 2012; 3:113-21. [PMID: 18370718 DOI: 10.1089/met.2005.3.113] [Citation(s) in RCA: 81] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
BACKGROUND The etiology of sensory neuropathies is often not found. We tested the hypothesis that the metabolic syndrome (MS) may be associated with painful neuropathy, in the absence of frank diabetes. METHODS Clinical and quantitative neuropathy assessments were performed on 10 neuropathy patients with MS, 20 with MS with type 2 diabetes (10 recent onset and 10 of >5 years in duration), and 10 healthy, age-matched subjects. Intraepidermal nerve fiber density (IENF) and mean dendrite length (MDL) were determined by quantitative immunofluorescence on skin biopsies using antibody to PGP 9.5. RESULTS In metabolic syndrome, MDL was reduced and correlated negatively with sensory symptoms, signs, HDL-C, and sural nerve amplitude. The strongest inverse metabolic correlate of the metabolic syndrome neuropathy was HDL-C, which also correlated negatively with sensory symptoms, signs, and sural nerve amplitudes. The strongest metabolic correlate of diabetic sensorimotor neuropathy was HbA1c, which was associated with reduced IENF in patients with >5 years in duration of disease as well as reduced peroneal nerve amplitudes. CONCLUSIONS These data indicate that metabolic features, including HDL-C in metabolic syndrome, are associated with small fiber neuropathy and that MDL is an early marker of sensory neuropathy in patients with MS. Reductions in IENF reflect a longer duration of diabetes, with hyperglycemia leading to a sensorimotor neuropathy. These findings support the possibility that there is a sensory neuropathy with reduced intraepidermal nerve fiber length, which cosegregates with features of metabolic syndrome.
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Affiliation(s)
- Gary L Pittenger
- The Strelitz Diabetes Institutes, Department of Internal Medicine, and Department of Pathology and Anatomy, Eastern Virginia Medical School, Norfolk, Virginia
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Hamasaki H, Mishima S, Yanai H. Hyperinsulinemia and insulin resistance in a patient with type 2 diabetes complicated with myelofibrosis. World J Diabetes 2012; 3:156-7. [PMID: 22912917 PMCID: PMC3423639 DOI: 10.4239/wjd.v3.i8.156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2012] [Revised: 07/18/2012] [Accepted: 08/08/2012] [Indexed: 02/05/2023] Open
Abstract
Inflammation induces insulin resistance and hyperinsulinemia due to elevation of serum cytokines such as tumor necrosis factor-α and interleukins. Chronic myeloproliferative diseases including myelofibrosis show higher serum interleukin levels than healthy subjects, which has been suggested to be the useful markers for disease activity. However, an association between myelofibrosis and insulin resistance has not ever been discussed anywhere. Here we report a case of type 2 diabetes showing remarkable hyperinsulinemia and insulin resistance possibly due to myelofibrosis.
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Affiliation(s)
- Hidetaka Hamasaki
- Hidetaka Hamasaki, Shuichi Mishima, Hidekatsu Yanai, Department of Internal Medicine, Kohnodai Hospital, National Center for Global Health and Medicine, Chiba 272-8516, Japan
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Abstract
Although the terms "metabolic memory" and "legacy effect" have been used to describe the prolonged benefits of good blood glucose control, the former is now recognized as a phenomenon related to the prolonged harm produced mainly by hyperglycemia. At least three randomized clinical trials (Diabetes Control and Complications Trial in type 1 diabetes, United Kingdom Prospective Diabetes Study and Steno-2 in type 2 diabetes) have demonstrated that patients treated intensively for a period of time have a lower risk of micro- and macrovascular complications that persists during subsequent follow-up, even after their tight control has relented and the levels of glycated hemoglobin in the conventionally treated group improve. The mechanisms are not fully understood but most probably relate to the physiopathology of vascular complications of diabetes, and in recent years a unifying theory has been emerging to understand them. The excess superoxide anion produced by the mitochondria in response to hyperglycemia leads through disturbances at the nuclear level to the accumulation of potentially harmful substances such as advanced glycated end-products, protein kinase C, and nuclear factor κB, which are directly implicated in the development of vascular complications in diabetes. These adverse effects are not reversed when the high blood glucose is corrected, and some may be permanent because of epigenetic changes. Some antidiabetes drugs and antioxidant substances have produced partial reversibility of the mechanisms involved in the metabolic memory at the experimental level, but probably the best strategy is to optimize the metabolic control as early as possible, even before diabetes is diagnosed.
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Affiliation(s)
- Pablo J Aschner
- Javeriana Pontificia University, San Ignacio University Hospital, Bogota, Colombia.
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Abstract
Diabetic autonomic neuropathies are a heterogeneous and progressive disease entity and commonly complicate both type 1 and type 2 diabetes mellitus. Although the aetiology is not entirely understood, hyperglycaemia, insulin deficiency, metabolic derangements and potentially autoimmune mechanisms are thought to play an important role. A subgroup of diabetic autonomic neuropathy, cardiovascular autonomic neuropathy (CAN), is one of the most common diabetes-associated complications and is ultimately clinically important because of its correlation with increased mortality. The natural history of CAN is unclear, but is thought to progress from a subclinical stage characterized by impaired baroreflex sensitivity and abnormalities of spectral analysis of heart rate variability to a clinically apparent stage with diverse and disabling symptoms. Early diagnosis of CAN, using spectral analysis of heart rate variability or scintigraphic imaging techniques, might enable identification of patients at highest risk for the development of clinical CAN and, thereby, enable the targeting of intensive therapeutic approaches. This Review discusses methods for diagnosis, epidemiology, natural history and potential causes and consequences of CAN.
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Affiliation(s)
- Michael Kuehl
- Cardiovascular Research Department, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
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Kellow NJ, Savige GS, Khalil H. Predictors of poor glycaemic control during the initial five years post-diagnosis in rural adults with type 2 diabetes. Aust J Rural Health 2012; 19:267-74. [PMID: 21933370 DOI: 10.1111/j.1440-1584.2011.01222.x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
Abstract
OBJECTIVE To identify factors predicting suboptimal glycaemic control in rural adults during the initial five years post-type 2 diabetes diagnosis. DESIGN Retrospective medical record audit. Quantitative study. SETTING Rural community-based primary health service, South Gippsland, Victoria, Australia. PARTICIPANTS Two hundred and seventy-two de-identified medical records randomly selected from the type 2 diabetes outpatient database. MAIN OUTCOME MEASURES Demographic, biochemical, anthropometric, pharmacological, co-morbidity and lifestyle data during the first five years post-diabetes diagnosis were retrospectively collected. Univariate analysis was performed to identify variables associated with poor diabetes control (HbA1c ≥ 7%). RESULTS Independent predictors of poor glycaemic control in this rural cohort were elevated fasting glucose at diagnosis (odds ratio (OR) 1.97, 95% confidence interval (CI) 1.31-2.97, P < 0.001), weight gain during the initial 2.5 years of diabetes (OR 1.33, 95% CI 1.11-1.59, P < 0.01), excessive body weight at diagnosis (OR 1.07, 95% CI 1.03-1.12, P < 0.001) and younger age at diagnosis (OR 0.94, 95% CI 0.88-1.00, P < 0.05). These variables combined explained 48% of the variation in HbA1c. Gender, body mass index, waist circumference and lifestyle factors at diagnosis were not significant predictors of diabetes control. CONCLUSIONS Young-middle-aged adults (≤58 years) with elevated fasting glucose (≥9.0 mmol L(-1) ) and excessive body weight (≥93.1 kg) at type 2 diabetes diagnosis and those unable to lose weight early in the course of the disease are more likely to experience a rapid deterioration in glucose control. Rural clinicians should target these individuals for aggressive diabetes management from the time of diagnosis.
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Affiliation(s)
- Nicole J Kellow
- Department of Rural and Indigenous Health, Monash University, Melbourne, Australia.
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Association of socioeconomic status with mortality in type 1 diabetes: the Pittsburgh epidemiology of diabetes complications study. Ann Epidemiol 2011; 21:367-73. [PMID: 21458730 DOI: 10.1016/j.annepidem.2011.02.011] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2010] [Revised: 01/23/2011] [Accepted: 02/21/2011] [Indexed: 11/23/2022]
Abstract
PURPOSE Socioeconomic status (SES) as a risk factor for mortality in type 1 diabetes (T1D) has not been adequately studied prospectively. METHODS Complete clinical and SES (income, education, occupation) data were available for 317 T1D participants in the Pittsburgh Epidemiology of Diabetes Complications Study within 4 years of age 28 (chosen to maximize income, education, and occupational potential, and to minimize the SES effect of advanced diabetes complications). Vital status was determined as of 1/1/2008. RESULTS Over a median 16 years of follow-up, 34 (10.7%) deaths occurred (standardized mortality ratios [SMRs] = 4.1, 95% confidence interval [CI]: 2.7-5.5). SMRs did not differ from the general population for those in the highest education and income groups, whereas in those with low SES, SMRs were increased. Mortality rates were three times lower for individuals with a college degree versus without a college degree (p = 0.004) and nearly four times lower for the highest income versus lower income groups (p = 0.04). In Cox models adjusting for diabetes duration and sex, education was the only SES measure predictive of mortality (hazard ratio [HR] = 3.0, 95% CI: 1.2-7.8), but lost significance after adjusting for HbA(1c), non-HDL cholesterol, hypertension, and microalbuminuria (HR = 2.1, 95% CI: 0.8-5.6). CONCLUSIONS The strong association of education with mortality in T1D is partially mediated by better glycemic, lipid, and blood pressure control.
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Abstract
It has long been recognized that cardiac autonomic neuropathy increases morbidity and mortality in diabetes and may have greater predictive power than traditional risk factors for cardiovascular events. Significant morbidity and mortality can now be attributable to autonomic imbalance between the sympathetic and parasympathetic nervous system regulation of cardiovascular function. New and emerging syndromes include orthostatic tachycardia, orthostatic bradycardia and an inability to use heart rate as a guide to exercise intensity because of the resting tachycardia. Recent studies have shown that autonomic imbalance may be a predictor of risk of sudden death with intensification of glycaemic control. This review examines an association of autonomic dysregulation and the role of inflammatory cytokines and adipocytokines that promote cardiovascular risk. In addition, conditions of autonomic imbalance associated with cardiovascular risk are discussed. Potential treatment for restoration of autonomic balance is outlined.
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Affiliation(s)
- A I Vinik
- Eastern Virginia Medical School, Strelitz Diabetes Research Center and Neuroendocrine Unit, 855 W Brambleton Avenue, Norfolk, VA 23510, USA.
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Sun W, Bi Y, Liang H, Cai M, Chen X, Zhu Y, Li M, Xu F, Yu Q, He X, Ye J, Weng J. Inhibition of obesity-induced hepatic ER stress by early insulin therapy in obese diabetic rats. Endocrine 2011; 39:235-41. [PMID: 21088934 PMCID: PMC4148044 DOI: 10.1007/s12020-010-9429-y] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2010] [Accepted: 11/01/2010] [Indexed: 12/27/2022]
Abstract
To understand the mechanism by which early insulin therapy improves insulin sensitivity in type 2 diabetes, we investigated endoplasmic reticulum (ER) stress in the liver of type 2 diabetic rats. A high fat diet plus a low dose of streptozotocin (STZ) in Sprague-Dawley (SD) rats was implemented to create an animal model mimicking diabetes. After 3 weeks of insulin treatment, the rats were examined for insulin sensitivity and ER stress in the liver. To investigate insulin sensitivity within the liver, serine phosphorylation of IRS-1 (Ser307) and Akt (Ser473) and expression of gluconeogenic genes, PEPCK and G6Pase, were tested. Protein levels of ER stress markers, such as immunoglobulin binding protein (Bip), inositol-requiring protein 1 alpha (IRE1α), and unspliced and spliced x-box binding protein-1 (XBP-1), were determined to assess ER stress. In the diabetic (DM) group, IRS-1 phosphorylation was increased (P < 0.05), Akt phosphorylation was reduced (P < 0.05), expression of PEPCK and G6Pase was elevated (P < 0.05), and ER stress markers were up-regulated (P < 0.05) relative to the non-diabetic rats. In the insulin (INS) therapy group, all of aforementioned changes were attenuated or reversed (P < 0.05). In addition, c-Jun N-terminal kinase (JNK) activity and SREBP-1 expression were decreased (P < 0.05). Adipose tissue mass was increased (P < 0.05). These data suggest that short-term insulin therapy relieved ER stress and enhanced insulin sensitivity in the liver of diabetic rats. The mechanism is likely related to fat redistribution from liver to adipose tissue. These cellular and molecular responses may represent a mechanism for improvement of insulin sensitivity in type 2 diabetic rats by insulin therapy.
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Affiliation(s)
- Weiping Sun
- Department of Endocrinology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, China
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Affiliation(s)
- Aaron Vinik
- From the Strelitz Diabetes Center, Eastern Virginia Medical School, Norfolk, Virginia
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Youssef-Elabd EM, McGee KC, Tripathi G, Aldaghri N, Abdalla MS, Sharada HM, Ashour E, Amin AI, Ceriello A, O'Hare JP, Kumar S, McTernan PG, Harte AL. Acute and chronic saturated fatty acid treatment as a key instigator of the TLR-mediated inflammatory response in human adipose tissue, in vitro. J Nutr Biochem 2011; 23:39-50. [PMID: 21414768 PMCID: PMC3243902 DOI: 10.1016/j.jnutbio.2010.11.003] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2010] [Revised: 10/14/2010] [Accepted: 11/18/2010] [Indexed: 01/28/2023]
Abstract
A post-prandial increase in saturated fatty acids (SFAs) and glucose (Glc) activates an inflammatory response, which may be prolonged following restoration of physiological SFAs and Glc levels--a finding referred to as 'metabolic memory'. This study examined chronic and oscillating SFAs and Glc on the inflammatory signalling pathway in human adipose tissue (AT) and adipocytes (Ads) and determined whether Ads are subject to "metabolic memory." Abdominal (Abd) subcutaneous (Sc) explants and Ads were treated with chronic low glucose (L-Glc): 5.6 mM and high glucose (H-Glc): 17.5 mM, with low (0.2 mM) and high (2 mM) SFA for 48 h. Abd Sc explants and Ads were also exposed to the aforementioned treatment regimen for 12-h periods, with alternating rest periods of 12 h in L-Glc. Chronic treatment with L-Glc and high SFAs, H-Glc and high SFAs up-regulated key factors of the nuclear factor-κB (NFκB) pathway in Abd Sc AT and Ads (TLR4, NFκB; P<.05), whilst down-regulating MyD88. Oscillating Glc and SFA concentrations increased TLR4, NFκB, IKKβ (P<.05) in explants and Ads and up-regulated MyD88 expression (P<.05). Both tumor necrosis factor α and interleukin 6 (P<.05) secretion were markedly increased in chronically treated Abd Sc explants and Ads whilst, with oscillating treatments, a sustained inflammatory effect was noted in absence of treatment. Therefore, SFAs may act as key instigators of the inflammatory response in human AT via NFκB activation, which suggests that short-term exposure of cells to uncontrolled levels of SFAs and Glc leads to a longer-term inflammatory insult within the Ad, which may have important implications for patients with obesity and Type 2 diabetes.
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Testa R, Bonfigli AR, Marra M, Testa I. In the Light of the Metabolic Memory Theory, Should Not All Aged People with Dysglycemia Be Treated? Rejuvenation Res 2010; 13:599-605. [DOI: 10.1089/rej.2010.1024] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Affiliation(s)
- Roberto Testa
- Metabolic and Nutrition Research Centre on Diabetes, INRCA-IRCCS, Ancona, Italy
| | - Anna Rita Bonfigli
- Metabolic and Nutrition Research Centre on Diabetes, INRCA-IRCCS, Ancona, Italy
| | - Maurizio Marra
- Metabolic and Nutrition Research Centre on Diabetes, INRCA-IRCCS, Ancona, Italy
| | - Ivano Testa
- Metabolic and Nutrition Research Centre on Diabetes, INRCA-IRCCS, Ancona, Italy
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Liu Z, Fu C, Wang W, Xu B. Prevalence of chronic complications of type 2 diabetes mellitus in outpatients - a cross-sectional hospital based survey in urban China. Health Qual Life Outcomes 2010; 8:62. [PMID: 20579389 PMCID: PMC2906445 DOI: 10.1186/1477-7525-8-62] [Citation(s) in RCA: 155] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2010] [Accepted: 06/26/2010] [Indexed: 02/06/2023] Open
Abstract
Background Chronic complications are the major outcome of type 2 diabetes mellitus progress, which reduce the quality of life of patients, incur heavy burdens to the health care system, and increase diabetic mortality. The aims of this study were to describe the prevalence of chronic complications among urban Chinese type 2 diabetic outpatients; and to analyze the associations between chronic complications and patients' demographics, diabetic related clinical characteristics. Methods This cross-sectional hospital-based study was carried out in 4 major Chinese cities: - Shanghai, Chengdu, Beijing and Guangzhou. The survey was conducted from March to July in 2007 among 1,524 type 2 diabetic outpatients. The subjects were interviewed face-to-face by trained interviewers using a questionnaire to capture information on demographics, disease presentations and complications. All the subjects were invited to have a HbA1c test free of charge by the standardized method with Bio-Rad Variant II. Results Of the 1,524 study subjects, 637 (41.8%) were male, and the mean age was 63.3 ± 10.2 years. At least one chronic complication was diagnosed in 792 individuals (52.0%) of the study subjects; 509 (33.4%) presented with macrovascular complications and 528 (34.7%) with microvascular complications. The prevalence of cardiovascular and cerebrovascular conditions, neuropathy, nephropathy, ocular lesions and foot disease were 30.1%, 6.8%, 17.8%, 10.7%, 14.8% and 0.8%, respectively. The prevalence of chronic complications varied between cities, and significantly increased with age and duration of diagnosed diabetes. The mean of HbA1c in diabetic patients with chronic complications was 8.2% ± 1.6% and 63.0% of the subjects with type 2 diabetes related complications had a poor glycemic control with the HbA1c > 7.5%. Conclusions Chronic complications are highly prevalent among type 2 diabetic outpatients, the glycemic control of diabetic patients with chronic complications was poor, and future efforts should be directed at intensive blood glucose control, strengthening early diagnosis and improving case management to prevent and minimize the occurrence of complications.
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Affiliation(s)
- Zhaolan Liu
- Department of Epidemiology, School of Public Health, Fudan University, Shanghai 200032, PR China
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Drel VR, Lupachyk S, Shevalye H, Vareniuk I, Xu W, Zhang J, Delamere NA, Shahidullah M, Slusher B, Obrosova IG. New therapeutic and biomarker discovery for peripheral diabetic neuropathy: PARP inhibitor, nitrotyrosine, and tumor necrosis factor-{alpha}. Endocrinology 2010; 151:2547-55. [PMID: 20357221 PMCID: PMC2875829 DOI: 10.1210/en.2009-1342] [Citation(s) in RCA: 69] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
This study evaluated poly(ADP-ribose) polymerase (PARP) inhibition as a new therapeutic approach for peripheral diabetic neuropathy using clinically relevant animal model and endpoints, and nitrotyrosine (NT), TNF-alpha, and nitrite/nitrate as potential biomarkers of the disease. Control and streptozotocin-diabetic rats were maintained with or without treatment with orally active PARP inhibitor 10-(4-methyl-piperazin-1-ylmethyl)-2H-7-oxa-1,2-diaza-benzo[de]anthracen-3-one (GPI-15,427), 30 mg kg(-1) d(-1), for 10 wk after first 2 wk without treatment. Therapeutic efficacy was evaluated by poly(ADP-ribosyl)ated protein expression (Western blot analysis), motor and sensory nerve conduction velocities, and tibial nerve morphometry. Sciatic nerve and spinal cord NT, TNF-alpha, and nitrite/nitrate concentrations were measured by ELISA. NT localization in peripheral nervous system was evaluated by double-label fluorescent immunohistochemistry. A PARP inhibitor treatment counteracted diabetes-induced motor and sensory nerve conduction slowing, axonal atrophy of large myelinated fibers, and increase in sciatic nerve and spinal cord NT and TNF-alpha concentrations. Sciatic nerve NT and TNF-alpha concentrations inversely correlated with motor and sensory nerve conduction velocities and myelin thickness, whereas nitrite/nitrate concentrations were indistinguishable between control and diabetic groups. NT accumulation was identified in endothelial and Schwann cells of the peripheral nerve, neurons, astrocytes, and oligodendrocytes of the spinal cord, and neurons and glial cells of the dorsal root ganglia. The findings identify PARP as a compelling drug target for prevention and treatment of both functional and structural manifestations of peripheral diabetic neuropathy and provide rationale for detailed evaluation of NT and TNF-alpha as potential biomarkers of its presence, severity, and progression.
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Affiliation(s)
- Viktor R Drel
- Pennington Biomedical Research Center, Louisiana State University System, 6400 Perkins Road, Baton Rouge, Louisiana 70808, USA
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High-fat diet-induced neuropathy of prediabetes and obesity: effect of PMI-5011, an ethanolic extract of Artemisia dracunculus L. Mediators Inflamm 2010; 2010:268547. [PMID: 20396384 PMCID: PMC2852597 DOI: 10.1155/2010/268547] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2009] [Revised: 01/20/2010] [Accepted: 01/21/2010] [Indexed: 12/16/2022] Open
Abstract
Artemisia species are a rich source of herbal remedies with antioxidant and anti-inflammatory properties. We evaluated PMI-5011, an ethanolic extract of Artemisia dracunculus L., on neuropathy in high-sfat diet-fed mice, a model of prediabetes and obesity developing oxidative stress and proinflammatory changes in peripheral nervous system. C57Bl6/J mice fed high-fat diet for 16 weeks developed obesity, moderate nonfasting hyperglycemia, nerve conduction deficit, thermal and mechanical hypoalgesia, and tactile allodynia. They displayed 12/15-lipoxygenase overexpression, 12(S)-hydroxyeicosatetraenoic acid accumulation, and nitrosative stress in peripheral nerve and spinal cord. PMI-5011 (500 mgkg−1d−1, 7 weeks) normalized glycemia, alleviated nerve conduction slowing and sensory neuropathy, and reduced 12/15-lipoxygenase upregulation and nitrated protein expression in peripheral nervous system. PMI-5011, a safe and nontoxic botanical extract, may find use in treatment of neuropathic changes at the earliest stage of disease.
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Metabolic memory and diabetic retinopathy: role of inflammatory mediators in retinal pericytes. Exp Eye Res 2010; 90:617-23. [PMID: 20170650 DOI: 10.1016/j.exer.2010.02.006] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2009] [Revised: 01/06/2010] [Accepted: 02/11/2010] [Indexed: 01/09/2023]
Abstract
Diabetic retinopathy shares many characteristics features of a low grade chronic inflammatory disease. Its progression resists arrest when good metabolic control is re-established after a period of poor metabolic control, suggesting a 'metabolic memory' phenomenon. The aim of this study is to investigate the effect of reversal of high glucose to normal glucose on the inflammatory mediators in pericytes, the site of histopathology in diabetic retinopathy. Bovine retinal pericytes were incubated in high glucose (20 mM) for 2 days followed by normal glucose (5 mM) for 4 days (2 --> 4), or in high glucose for 4 days followed by normal glucose for 4 days (4 --> 4) or 8 days (4 --> 8). Pericytes incubated in continuous normal or high glucose for 2-12 days served as controls. Continuous high glucose exposure for 2-12 days significantly elevated gene expressions and protein concentrations of IL-1 beta, NF-kB, VEGF, TNF-alpha, TGF-beta and ICAM-1 in retinal pericytes. Four days of normal glucose that followed 2 days of high glucose (2 --> 4) had marginal, but significant, beneficial effect on the increases in these inflammatory mediators. Four days of normal glucose in 4 --> 4 group failed to reverse increases in inflammatory mediators and cell apoptosis remained elevated, but addition of dexamethasone during normal glucose exposure ameliorated such increases. However, when normal glucose exposure, after 4 days of high glucose was extended to 8 days (4 --> 8), increases in these mediators were significantly decreased. Hyperglycemia-induced elevations in inflammatory mediators in retinal microvascular cells resist reversal after re-institution of normal glucose conditions. Both, the duration of the initial exposure to high glucose, and normal glucose that follows high glucose, are critical in determining the outcome of the alterations in the inflammatory mediators.
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Chan PS, Kanwar M, Kowluru RA. Resistance of retinal inflammatory mediators to suppress after reinstitution of good glycemic control: novel mechanism for metabolic memory. J Diabetes Complications 2010; 24:55-63. [PMID: 19056300 PMCID: PMC2804951 DOI: 10.1016/j.jdiacomp.2008.10.002] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2008] [Revised: 09/11/2008] [Accepted: 10/15/2008] [Indexed: 10/21/2022]
Abstract
Diabetic retinopathy resists arrest of its progression after reestablishment of good glycemic control that follows a profound period of poor glycemic control. The objective of this study was to elucidate the role of inflammation in the resistance of retinopathy to arrest after termination of hyperglycemia. Streptozotocin-diabetic rats were (a) maintained either in poor glycemic control [PC group; glycated hemoglobin (GHb)>11%] or in good glycemic control (GC group; GHb<7%) for 12 months or (b) allowed to be in poor glycemic control for 6 months followed by good glycemic control for 6 additional months. At 12 months, retina was analyzed for pro-inflammatory mediators. Twelve months of PC increased retinal interleukin 1beta (IL-1beta) mRNA by 2-fold and its protein expression by 25% compared with the values obtained from normal rat retina. Tumor necrosis factor alpha (TNF-alpha) was elevated approximately 3-fold (both mRNA and protein), and the receptors for IL-1beta and TNF-alpha were increased by 40% each. The concentrations of intercellular cell adhesion molecule 1 and vascular cell adhesion molecule 1 were elevated by 40% and 150%, respectively, and inducible nitric oxide synthase transcripts were elevated by 6-fold. Six months of good glycemic control that followed 6 months of poor glycemic control failed to reverse the elevations in IL-1beta, TNF receptor type I, and intercellular cell adhesion molecule 1 but had some beneficial effects on TNF-alpha, inducible nitric oxide synthase, and vascular cell adhesion molecule 1, however these mediators remained significantly elevated. However, the GC group showed no significant change in the retinal pro-inflammatory mediators compared with the normal rats. Failure to reverse retinal inflammatory mediators supports their important role in the resistance of retinopathy to arrest after cessation of hyperglycemia.
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Affiliation(s)
- Pooi-See Chan
- Kresge Eye Institute, Wayne State University, Detroit, MI
| | - Mamta Kanwar
- Kresge Eye Institute, Wayne State University, Detroit, MI
| | - Renu A Kowluru
- Kresge Eye Institute, Wayne State University, Detroit, MI
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Vinik A. Advancing therapy in type 2 diabetes mellitus with early, comprehensive progression from oral agents to insulin therapy. Clin Ther 2009; 29:1236-53. [PMID: 18036387 DOI: 10.1016/j.clinthera.2007.07.005] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/13/2007] [Indexed: 12/18/2022]
Abstract
BACKGROUND Early and intensive glycemic control is necessary to prevent or minimize the development of microvascular and macrovascular complications in individuals with type 2 diabetes mellitus. However, many patients are unable to attain glycemic control, partly due to protracted treatment with oral antidiabetic drugs (OADs) despite inadequate control and barriers to initiating insulin therapy. Patients at different stages of disease may benefit from the early introduction of intensive glycemic control. OBJECTIVE This article discusses some of the potential barriers to achieving and maintaining optimal glycemic levels in patients whose blood glucose is sub-optimally controlled with OADs and reviews the benefits of early introduction of intensive glycemic control in patients at various stages of disease, with an emphasis on insulin therapy. METHODS Relevant English-language articles published from 1996 to 2006 were identified through searches of the National Center for Biotechnology PubMed database. Search terms included insulin, insulin therapy, type 2 diabetes, insulin analogs, early insulinization, and diabetes prevention, among others. Studies were assessed regarding designs, primary and secondary efficacy parameters, glycosylated hemoglobin (HbAM(lc)), fasting plasma glucose, incidence of hypoglycemia, and other safety assessments. Inclusion criteria were multicenter, randomized, open-label, parallel-group trials, as well as retrospective observational studies, conducted in Europe or the United States. Additional analyses and guideline-based recommendations are included. RESULTS The landmark results of the United Kingdom Prospective Diabetes Study, which found that an intensive strategy in 3867 newly diagnosed patients with type 2 diabetes was associated with stricter glycemic control than was conventional care (HbA(lc) over 10 years, 7.0% vs 7.9%; P < 0.001), as well as a 25% reduction in the risk for microvascular complications (P = 0.01). Early initiation of insulin therapy concomitantly with OADs appeared well tolerated in the populations studied, was effective in recently diagnosed patients, and may also confer anti-inflammatory and antiatherogenic effects. Characteristics associated with newer formulations of insulin (eg, basal insulin analogues as well as rapid-acting insulin analogues, the insulin pump, or inhaled insulin) may help overcome barriers associated with initiating insulin therapy. CONCLUSIONS Based on the literature, early and persistent intensification of antidiabetic therapy is an approach that most likely will achieve optimal glycemic control in patients with type 2 diabetes and help prevent associated complications. Greater clinical experience with newer therapeutic approaches, including incretin mimetics and dipeptidyl peptidase-IV inhibitors, will provide insight into their place in the spectrum of diabetes treatments.
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Affiliation(s)
- Aaron Vinik
- Strefitz Diabetes Research Institute, Eastern Virginia Medical School, Norfolk, Virginia, USA.
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