scholarly journals A human antibody against pathologic IAPP aggregates protects beta cells in type 2 diabetes

2021 ◽  
Author(s):  
Fabrice Heitz ◽  
Fabian Wirth ◽  
Christine Seeger ◽  
Ioana Combaluzier ◽  
Karin Breu ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Beta Cell ◽  
Beta Cells ◽  
Pancreatic Beta Cells ◽  
Cell Function ◽  
Human Monoclonal Antibody ◽  
Human Antibody ◽  
Cell Protection ◽  
Antibody Treatment

Abstract In patients with type 2 diabetes, pancreatic beta cells progressively degenerate and gradually lose their ability to produce insulin and regulate blood glucose. Beta cell dysfunction and loss is associated with an accumulation of aggregated forms of islet amyloid polypeptide (IAPP) consisting of soluble prefibrillar IAPP oligomers as well as insoluble IAPP fibrils in pancreatic islets. Here, we describe a novel human monoclonal antibody selectively targeting IAPP oligomers and neutralizing IAPP aggregate toxicity by preventing membrane disruption and apoptosis in vitro. Antibody treatment in rats and mice transgenic for human IAPP, and human islet-engrafted mouse models of type 2 diabetes triggered clearance of IAPP oligomers resulting in beta cell protection and improved glucose control. These results provide new evidence for the pathological role of IAPP oligomers and suggest that antibody-mediated removal of IAPP oligomers could be a pharmaceutical strategy to support beta cell function in type 2 diabetes.

scholarly journals Arginase 2 and Polyamines in Human Pancreatic Beta Cells: Possible Role in the Pathogenesis of Type 2 Diabetes

2021 ◽  
Vol 22 (22) ◽  
pp. 12099
Author(s):  
Lorella Marselli ◽  
Emanuele Bosi ◽  
Carmela De Luca ◽  
Silvia Del Guerra ◽  
Marta Tesi ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Beta Cell ◽  
Beta Cells ◽  
Beta Cell Function ◽  
Pancreatic Beta Cells ◽  
Cell Function ◽  
Pancreas Development ◽  
Tissue Specific

Arginase 2 (ARG2) is a manganese metalloenzyme involved in several tissue specific processes, from physiology to pathophysiology. It is variably expressed in extra-hepatic tissues and is located in the mitochondria. In human pancreatic beta cells, ARG2 is downregulated in type 2 diabetes. The enzyme regulates the synthesis of polyamines, that are involved in pancreas development and regulation of beta cell function. Here, we discuss several features of ARG2 and polyamines, which can be relevant to the pathophysiology of type 2 diabetes.

DPP-4 is expressed in human pancreatic beta cells and its direct inhibition improves beta cell function and survival in type 2 diabetes

2018 ◽  
Vol 473 ◽  
pp. 186-193 ◽  
Author(s):  
Marco Bugliani ◽  
Farooq Syed ◽  
Flavia M.M. Paula ◽  
Bilal A. Omar ◽  
Mara Suleiman ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Beta Cell ◽  
Beta Cells ◽  
Beta Cell Function ◽  
Pancreatic Beta Cells ◽  
Cell Function ◽  
Direct Inhibition

scholarly journals Imprinted Genes Impact Upon Beta Cell Function in the Current (and Potentially Next) Generation

2021 ◽  
Vol 12 ◽  
Author(s):  
Chelsie Villanueva-Hayes ◽  
Steven J. Millership
Keyword(s):  
Type 2 Diabetes ◽  
Beta Cell ◽  
Beta Cells ◽  
Cell Function ◽  
Monoallelic Expression ◽  
Imprinted Genes ◽  
Nutritional Regulation ◽  
Next Generation ◽  
The Impact

Beta cell failure lies at the centre of the aetiology and pathogenesis of type 2 diabetes and the epigenetic control of the expression of critical beta cell genes appears to play a major role in this decline. One such group of epigenetically-controlled genes, termed ‘imprinted’ genes, are characterised by transgenerational monoallelic expression due to differential allelic DNA methylation and play key functional roles within beta cells. Here, we review the evidence for this functional importance of imprinted genes in beta cells as well as their nutritional regulation by the diet and their altered methylation and/or expression in rodent models of diabetes and in type 2 diabetic islets. We also discuss imprinted genes in the context of the next generation, where dietary overnutrition in the parents can lead to their deregulation in the offspring, alongside beta cell dysfunction and defective glucose handling. Both the modulation of imprinted gene expression and the likelihood of developing type 2 diabetes in adulthood are susceptible to the impact of nutritional status in early life. Imprinted loci, therefore, represent an excellent opportunity with which to assess epigenomic changes in beta cells due to the diet in both the current and next generation.

scholarly journals ER stress increases store-operated Ca2+ entry (SOCE) and augments basal insulin secretion in pancreatic beta cells

2020 ◽  
Vol 295 (17) ◽  
pp. 5685-5700
Author(s):  
Irina X. Zhang ◽  
Jianhua Ren ◽  
Suryakiran Vadrevu ◽  
Malini Raghavan ◽  
Leslie S. Satin
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Beta Cell ◽  
Er Stress ◽  
Beta Cells ◽  
Beta Cell Function ◽  
Cell Function ◽  
Critical Role ◽  
Beta Cell Apoptosis

Type 2 diabetes mellitus (T2DM) is characterized by impaired glucose-stimulated insulin secretion and increased peripheral insulin resistance. Unremitting endoplasmic reticulum (ER) stress can lead to beta-cell apoptosis and has been linked to type 2 diabetes. Although many studies have attempted to link ER stress and T2DM, the specific effects of ER stress on beta-cell function remain incompletely understood. To determine the interrelationship between ER stress and beta-cell function, here we treated insulin-secreting INS-1(832/13) cells or isolated mouse islets with the ER stress–inducer tunicamycin (TM). TM induced ER stress as expected, as evidenced by activation of the unfolded protein response. Beta cells treated with TM also exhibited concomitant alterations in their electrical activity and cytosolic free Ca2+ oscillations. As ER stress is known to reduce ER Ca2+ levels, we tested the hypothesis that the observed increase in Ca2+ oscillations occurred because of reduced ER Ca2+ levels and, in turn, increased store-operated Ca2+ entry. TM-induced cytosolic Ca2+ and membrane electrical oscillations were acutely inhibited by YM58483, which blocks store-operated Ca2+ channels. Significantly, TM-treated cells secreted increased insulin under conditions normally associated with only minimal release, e.g. 5 mm glucose, and YM58483 blocked this secretion. Taken together, these results support a critical role for ER Ca2+ depletion–activated Ca2+ current in mediating Ca2+-induced insulin secretion in response to ER stress.

scholarly journals MicroRNA Sequences Modulated by Beta Cell Lipid Metabolism: Implications for Type 2 Diabetes Mellitus

Biology ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 534
Author(s):  
Jamie M. R. Tarlton ◽  
Steven Patterson ◽  
Annette Graham
Keyword(s):  
Gene Expression ◽  
Type 2 Diabetes ◽  
Lipid Metabolism ◽  
Beta Cell ◽  
Beta Cells ◽  
Beta Cell Function ◽  
Cell Function ◽  
Therapeutic Strategies ◽  
Predictive Analysis

Alterations in lipid metabolism within beta cells and islets contributes to dysfunction and apoptosis of beta cells, leading to loss of insulin secretion and the onset of type 2 diabetes. Over the last decade, there has been an explosion of interest in understanding the landscape of gene expression which influences beta cell function, including the importance of small non-coding microRNA sequences in this context. This review sought to identify the microRNA sequences regulated by metabolic challenges in beta cells and islets, their targets, highlight their function and assess their possible relevance as biomarkers of disease progression in diabetic individuals. Predictive analysis was used to explore networks of genes targeted by these microRNA sequences, which may offer new therapeutic strategies to protect beta cell function and delay the onset of type 2 diabetes.

scholarly journals The Role of Vegan Diets in Lipotoxicity-Induced Beta-Cell Dysfunction in Type-2-Diabetes

2020 ◽  
Vol 27 (SP2) ◽  
pp. e22-e38
Author(s):  
Maximilian Andreas Storz
Keyword(s):  
Type 2 Diabetes ◽  
Fatty Acids ◽  
Fatty Acid ◽  
Beta Cell ◽  
Beta Cells ◽  
Beta Cell Function ◽  
Cell Function ◽  
Beta Cell Dysfunction ◽  
Cell Dysfunction

Type-2-diabetes is considered the new plague of the current century and both, its incidence and prevalence are rapidly increasing. Chronic insulin resistance and a progressive decline in beta-cell function are discussed as the root causes of type-2-diabetes. Both were associated with obesity and pathologically elevated concentrations of circulating free fatty acids in the blood. The harmful effects of chronically elevated free fatty acid levels on glucose homeostasis and non-adipose tissues are referred to as lipotoxicity. Pancreatic beta-cells appear to be particularly vulnerable and both, dietary fat quantity and quality may impact beta-cell function. Diets high in saturated fats are especially harmful to beta-cells while (poly-)unsaturated fatty acids were associated with beta-cell protective effects. This review examined how a dietary modification towards a low-fat vegan diet, which is particularly low in saturated and trans-fats, could help to prevent or reduce lipotoxicity-induced beta cell dysfunction. Several potential mechanisms of action were identified including: (1) reduced total fat intake (fat quantity), (2) a more favorable polyunsaturated fatty acid to saturated fatty acid ratio (fat quality), (3) improved body weight and a reduction in adipose tissue mass, and finally (4) improved glycemic control. The latter appears of paramount importance in light of the accumulating evidence that lipotoxic events are tightly coupled to excess glucose levels. All four mechanisms are likely to contribute complementarily to improved beta-cell function in individuals with type-2-diabetes and may reduce the likelihood of lipotoxic events to occur. Physicians must consider these findings when counseling patients on lifestyle and nutrition.

Targeting type 2 diabetes: lessons from a knockout model of insulin receptor substrate 2

2014 ◽  
Vol 92 (8) ◽  
pp. 613-620 ◽  
Author(s):  
Joana Moitinho Oliveira ◽  
Sandra A. Rebuffat ◽  
Rosa Gasa ◽  
Ramon Gomis
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Beta Cell ◽  
Insulin Receptor ◽  
Beta Cells ◽  
Pancreatic Beta Cells ◽  
Mitogen Activated Protein Kinase ◽  
Insulin Receptor Substrate ◽  
Beta Cell Failure

Insulin receptor substrate 2 (IRS2) is a widely expressed protein that regulates crucial biological processes including glucose metabolism, protein synthesis, and cell survival. IRS2 is part of the insulin – insulin-like growth factor (IGF) signaling pathway and mediates the activation of the phosphotidylinositol 3-kinase (PI3K)–Akt and the Ras–mitogen-activated protein kinase (MAPK) cascades in insulin target tissues and in the pancreas. The best evidence of this is that systemic elimination of the Irs2 in mice (Irs2−/−) recapitulates the pathogenesis of type 2 diabetes (T2D), in that diabetes arises as a consequence of combined insulin resistance and beta-cell failure. Indeed, work using this knockout mouse has confirmed the importance of IRS2 in the control of glucose homeostasis and especially in the survival and function of pancreatic beta-cells. These studies have shown that IRS2 is critically required for beta-cell compensation in conditions of increased insulin demand. Importantly, islets isolated from T2D patients exhibit reduced IRS2 expression, which supports the likely contribution of altered IRS2-dependent signaling to beta-cell failure in human T2D. For all these reasons, the Irs2−/− mouse has been and will be essential for elucidating the inter-relationship between beta-cell function and insulin resistance, as well as to delineate therapeutic strategies to protect beta-cells during T2D progression.

scholarly journals A genome-wide CRISPR screen identifies regulators of beta cell function involved in type 2 diabetes risk

2021 ◽  
Author(s):  
Antje K Grotz ◽  
Elena Navarro-Guerrero ◽  
Romina J Bevacqua ◽  
Roberta Baronio ◽  
Soren K Thomsen ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Beta Cell ◽  
Beta Cell Function ◽  
Pancreatic Beta Cells ◽  
Complex Disease ◽  
Cell Function ◽  
Pancreatic Islet Cell ◽  
Genome Wide ◽  
A Genome

Identification of the genes and processes mediating genetic association signals for complex disease represents a major challenge. Since many of the genetic signals for type 2 diabetes exert their effects through pancreatic islet-cell dysfunction, we performed a genome-wide pooled CRISPR loss-of-function screen in human pancreatic beta cells. We focused on the regulation of insulin content as a disease-relevant readout of beta cell function. We identified 580 genes influencing this phenotype: integration with genetic and genomic data provided experimental support for 20 candidate type 2 diabetes effector transcripts including the autophagy receptor CALCOCO2. Our study highlights how cellular screens can augment existing multi-omic efforts to accelerate biological and translational inference at GWAS loci.

scholarly journals microRNA-483 protects pancreatic beta-cells by targeting ALDH1A3

Endocrinology ◽  
2021 ◽  
Author(s):  
Zhihong Wang ◽  
Ramkumar Mohan ◽  
Xinqian Chen ◽  
Katy Matson ◽  
Jackson Waugh ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Beta Cell ◽  
Pancreatic Beta Cells ◽  
Cell Function ◽  
Β Cell ◽  
Blood Lipid Profile ◽  
Cell Dedifferentiation ◽  
Knockout Mouse Model ◽  
Genetic Ablation

Abstract Pancreatic β-cell dysfunction is central to the development and progression of type 2 diabetes. Dysregulation of miRNAs has been associated with pancreatic islet dysfunction in type 2 diabetes. Previous study has shown that miR-483 is expressed relatively higher in β-cells than in α-cells. To explore the physiological function of miR-483, we generated a beta-cell specific knockout mouse model of miR-483. Loss of miR-483 enhances high-fat diet-induced hyperglycemia and glucose intolerance by the attenuation of diet-induced insulin release. Intriguingly, mice with miR-483 deletion exhibited loss of β-cell features, as indicated by elevated expression of aldehyde dehydrogenase family 1, subfamily A3 (Aldh1a3), a marker of beta-cell dedifferentiation. Moreover, Aldh1a3 was validated as a direct target of miR-483 and overexpression of miR-483 repressed Aldh1a3 expression. Genetic ablation of miR-483 also induced alterations in blood lipid profile. Collectively, these data suggest that miR-483 is critical in protecting β-cell function by repressing β-cell disallowed gene Aldh1a3. The dysregulated miR-483 may impair insulin secretion and initiate β-cell dedifferentiation during the development of type 2 diabetes.

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