From Genetic Association to Molecular Mechanisms for Islet-cell Dysfunction in Type 2 Diabetes

The prevalence of Type 2 diabetes is increasing dramatically as a result of the obesity epidemic, and poses a major health and socio-economic burden. Type 2 diabetes develops in individuals who fail to compensate for insulin resistance by increasing pancreatic insulin secretion. This insulin deficiency results from pancreatic β-cell dysfunction and death. Western diets rich in saturated fats cause obesity and insulin resistance, and increase levels of circulating NEFAs [non-esterified (‘free’) fatty acids]. In addition, they contribute to β-cell failure in genetically predisposed individuals. NEFAs cause β-cell apoptosis and may thus contribute to progressive β-cell loss in Type 2 diabetes. The molecular pathways and regulators involved in NEFA-mediated β-cell dysfunction and apoptosis are beginning to be understood. We have identified ER (endoplasmic reticulum) stress as one of the molecular mechanisms implicated in NEFA-induced β-cell apoptosis. ER stress was also proposed as a mechanism linking high-fat-diet-induced obesity with insulin resistance. This cellular stress response may thus be a common molecular pathway for the two main causes of Type 2 diabetes, namely insulin resistance and β-cell loss. A better understanding of the molecular mechanisms contributing to pancreatic β-cell loss will pave the way for the development of novel and targeted approaches to prevent Type 2 diabetes.

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Insights into pancreatic islet cell dysfunction from type 2 diabetes mellitus genetics

Nature Reviews Endocrinology ◽

10.1038/s41574-020-0325-0 ◽

2020 ◽

Vol 16 (4) ◽

pp. 202-212 ◽

Cited By ~ 17

Author(s):

Nicole A. J. Krentz ◽

Anna L. Gloyn

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Pancreatic Islet ◽

Islet Cell ◽

Pancreatic Islet Cell ◽

Cell Dysfunction

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SINGLE-CELL TRANSCRIPTOMICS OF AGING MOUSE ISLET REVEALS AGE-RELATED RECRUITMENT OF ISLET-RESIDENT MACROPHAGE

Innovation in Aging ◽

10.1093/geroni/igz038.960 ◽

2019 ◽

Vol 3 (Supplement_1) ◽

pp. S257-S257

Author(s):

Jia Nie ◽

Nicolas Musi

Keyword(s):

Single Cell ◽

Islet Cell ◽

Molecular Mechanisms ◽

Cell Composition ◽

Cell Dysfunction ◽

Cell Clustering ◽

Age Related ◽

And Function ◽

Old Mice

Abstract Type 2 diabetes (T2D) prevalence increases with age. The notion of inevitable progression of T2D has been challenged by reports of remission in some human T2D cases; however, this remission is dependent on islet function reserve. To elucidate the molecular mechanisms driving islet cell dysfunction, it is necessary to understand islet cell composition, diversity, and function throughout the lifespan. We generated a single-cell transcriptomic atlas of healthy islets isolated from young (5 weeks old), middle-aged (12 months old), and older-aged (25 months old) mice. Cell clustering identified 13 initial cell clusters that were further sub-clustered. This single-cell RNAseq profile showed that each cell type/group has different markers and functional characteristics and that age causes a remarkable shift in islet cell composition, diversity, and number. By comparing macrophages from young and old mice, we also found that aged islets contain a higher number of islet-resident macrophages. Overall, this single-cell islet atlas covers nearly all cells in the normal islet and allows a comprehensive exploration of all transcriptional states throughout the lifespan.

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The involvement of microRNAs in Type 2 diabetes

Biochemical Society Transactions ◽

10.1042/bst0381565 ◽

2010 ◽

Vol 38 (6) ◽

pp. 1565-1570 ◽

Cited By ~ 59

Author(s):

David Ferland-McCollough ◽

Susan E. Ozanne ◽

Kenneth Siddle ◽

Anne E. Willis ◽

Martin Bushell

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Molecular Mechanisms ◽

Genetic Factors ◽

Β Cells ◽

Major Health ◽

Cell Dysfunction ◽

Metabolic Genes ◽

Major Health Issue

T2D (Type 2 diabetes mellitus) is a major health issue that has reached epidemic status worldwide. T2D is a progressive metabolic disorder characterized by reduced insulin sensitivity, insulin resistance and pancreatic β-cell dysfunction. Improper treatment of TD2 can lead to severe complications such as heart disease, stroke, kidney failure, blindness and nerve damage. The aetiology and molecular mechanisms of T2D are not fully understood, but compelling evidence points to a link between T2D, obesity, dyslipidaemia and insulin resistance. Although T2D seems to be strongly linked to environmental factors such as nutrition and lifestyle, studies have shown that genetic factors, such as polymorphisms associated with metabolic genes, imprinting, fetal programming and miRNA (microRNA) expression, could also contribute to the development of this disease. miRNAs are small 22–25-nt-long untranslated RNAs that negatively regulate the translation of mRNAs. miRNAs are involved in a large number of biological functions such as development, metabolism, immunity and diseases such as cancer, cardiovascular diseases and diabetes. The present review examines the various miRNAs that have been identified as being potentially involved in T2D, focusing on the insulin-sensitive organs: white adipose tissue, liver, skeletal muscle and the insulin-producing pancreatic β-cells.

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Alpha and Beta Cell Dysfunction Improves With Effective Insulin Therapy in Treatment Naive Type 2 Diabetes - a Prospective Observational Study

Journal of the Endocrine Society ◽

10.1210/jendso/bvab048.951 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. A466-A466

Author(s):

Jayanthy Ramesh ◽

Ashok Chakravarthy Makineni ◽

Madhubabu Mudimela ◽

Srivalli Madhira

Keyword(s):

Type 2 Diabetes ◽

Beta Cell ◽

Insulin Therapy ◽

Islet Cell ◽

Cell Function ◽

Beta Cell Dysfunction ◽

Newly Diagnosed ◽

C Peptide ◽

Cell Dysfunction

Abstract Abstract: Type 2 diabetes mellitus is characterized by insulin resistance and progressive beta cell decline. Elevated glucagon levels and impaired incretin axis also contribute to the poor glycemic status. Early intensive glycemic control, reduces long-term vascular complications and may preserve β-cell function. Clinical studies of effect of early insulin therapy on combined alpha and beta cell function are lacking. Objective: To determine the effect of early insulin therapy on combined alpha and beta cell dysfunction (islet cell dysfunction) in newly diagnosed type 2 diabetes. Methods: 56 newly diagnosed type 2 diabetes patients, attending the endocrinology OPD at a tertiary teaching hospital were enrolled in this treatment related follow up study after institutional ethical committee clearance, conducted between May 2017 to December 2018. Patients with HbA1C > 8.5% to <12.5% (n=56) were included in the study. Metabolic (FPG, PPG, HbA1c), and Hormonal parameters (plasma glucagon levels,fasting and 2 hour mixed meal stimulated C peptide and levels) were assessed both at baseline and after 6 months of insulin treatment. Initiating dose of insulin was 0.5 U/kg/day and the dose was titrated according to FPG and 2 hr PPG in order to maintain glycemic goals as per ADA standards. Results: The study included 56 subjects with mean age of 41.24 ± 5.64 years and a mean BMI of 25.5 kg/m2. At the end of 6 months of the study, a significant reduction in the mean FPG, PPG, HbA1C were observed,[FPG (139±14.47 mg/dl), PPG (179.89 ± 19.42mg/dl),HbA1c (7.54± 0.63%)] as compared to baseline mean FPG, (216.30 ± 42.35 mg/dl),2 hour PPG (338.44 ±62.89 mg/dl), HbA1C (10.39 ± 1.56 %) (p <0.001). Baseline glucagon levels were high (197.68± 49.09 pg/ml), and were significantly reduced at 6 months of insulin therapy (107.06±49.09 pg/ml).(p <0.001). In comparison to the baseline a significant increase in both fasting (0.73±0.27 ng/ml) and stimulated c-peptide (1.54±1.02 ng/ml) (p<0.001) levels was observed at end of the study. Conclusion: Combined alpha and beta cell (Islet) dysfunction prevails in newly diagnosed T2DM. And early insulin therapy significantly improves both these defects. The documentation of this novel beneficial effect on islet cell dysfunction in our study strengthens the concept of early insulin therapy in newly diagnosed Type 2 diabetes patients.

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Comparison of Sleeve Gastrectomy and Conservatory Treatment Effect on Biochemical and Hormonal Profile of Obese Type 2 Diabetes Subjects: CREDOR Randomized Controlled Study Results

Revista de Chimie ◽

10.37358/rc.17.7.5730 ◽

2017 ◽

Vol 68 (7) ◽

pp. 1622-1627 ◽

Cited By ~ 1

Author(s):

Diana Simona Stefan ◽

Andrada Mihai ◽

Daiana Bajko ◽

Daniela Lixandru ◽

Laura Petcu ◽

...

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Weight Loss ◽

Sleeve Gastrectomy ◽

Beta Cell ◽

Beta Cell Dysfunction ◽

Control Group ◽

Cell Dysfunction ◽

Randomized Controlled

Metabolic surgery is the most efficacious method for the treatment of morbid obesity and was recently included among the antidiabetes treatments recommended in obese type 2 diabetes (T2D) patients. The aim of this study was to compare in a randomized controlled trial the effect of sleeve gastrectomy (SG) to that of intensive lifestyle intervention plus pharmacologic treatment on some markers of insulin resistance and beta cell function as well as some appetite controlling hormones in a group of male obese T2D subjects. The study groups comprised 20 subjects for SG and 21 control subjects. Fasting blood glucose, insulin, proinsulin, adiponectin, leptin, ghrelin, HOMA-IR, HOMA-%B, proinsulin-to-insulin ratio and proinsulin-to-adiponectin ratio were evaluated at baseline and after one year follow-up. Overall, patients in the SG group lost 78.98% of excess weight loss (%EWL) in comparison with 9.45% in the control group. This was accompanied by a significant improvement of insulin resistance markers, including increase of adiponectin and decrease of HOMA-IR, while no changes were recorded in the control group. Weight loss was also associated with a significant improvement of proinsulin-to-insulin and proinsulin-to-adiponectin ratio, both surrogate markers of beta cell dysfunction. These also improved in the control group, but were only marginally significant. Our findings suggest that improved insulin resistance and decreased beta cell dysfunction after sleeve gastrectomy might explain diabetes remission associated with metabolic surgery.

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279 – A study of the genetic association between schizophrenia and type-2 diabetes mellitus

Schizophrenia Research ◽

10.1016/j.schres.2007.12.346 ◽

2008 ◽

Vol 98 ◽

pp. 148

Author(s):

A. Mathur ◽

M.H. Law ◽

I.L. Megson ◽

J. Wei

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Genetic Association

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MicroRNAs and Oxidative Stress: An Intriguing Crosstalk to Be Exploited in the Management of Type 2 Diabetes

Antioxidants ◽

10.3390/antiox10050802 ◽

2021 ◽

Vol 10 (5) ◽

pp. 802

Author(s):

Teresa Vezza ◽

Aranzazu M. de Marañón ◽

Francisco Canet ◽

Pedro Díaz-Pozo ◽

Miguel Marti ◽

...

Keyword(s):

Oxidative Stress ◽

Type 2 Diabetes ◽

Signaling Pathways ◽

Current Knowledge ◽

Critical Role ◽

Cell Dysfunction ◽

Non Coding Rnas ◽

And Oxidative Stress ◽

Molecular Crosstalk

Type 2 diabetes is a chronic disease widespread throughout the world, with significant human, social, and economic costs. Its multifactorial etiology leads to persistent hyperglycemia, impaired carbohydrate and fat metabolism, chronic inflammation, and defects in insulin secretion or insulin action, or both. Emerging evidence reveals that oxidative stress has a critical role in the development of type 2 diabetes. Overproduction of reactive oxygen species can promote an imbalance between the production and neutralization of antioxidant defence systems, thus favoring lipid accumulation, cellular stress, and the activation of cytosolic signaling pathways, and inducing β-cell dysfunction, insulin resistance, and tissue inflammation. Over the last few years, microRNAs (miRNAs) have attracted growing attention as important mediators of diverse aspects of oxidative stress. These small endogenous non-coding RNAs of 19–24 nucleotides act as negative regulators of gene expression, including the modulation of redox signaling pathways. The present review aims to provide an overview of the current knowledge concerning the molecular crosstalk that takes place between oxidative stress and microRNAs in the physiopathology of type 2 diabetes, with a special emphasis on its potential as a therapeutic target.

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