Does epigenetic dysregulation of pancreatic islets contribute to impaired insulin secretion and type 2 diabetes?

β cell dysfunction is central to the development and progression of type 2 diabetes (T2D). T2D develops when β cells are not able to compensate for the increasing demand for insulin caused by insulin resistance. Epigenetic modifications play an important role in establishing and maintaining β cell identity and function in physiological conditions. On the other hand, epigenetic dysregulation can cause a loss of β cell identity, which is characterized by reduced expression of genes that are important for β cell function, ectopic expression of genes that are not supposed to be expressed in β cells, and loss of genetic imprinting. Consequently, this may lead to β cell dysfunction and impaired insulin secretion. Risk factors that can cause epigenetic dysregulation include parental obesity, an adverse intrauterine environment, hyperglycemia, lipotoxicity, aging, physical inactivity, and mitochondrial dysfunction. These risk factors can affect the epigenome at different time points throughout the lifetime of an individual and even before an individual is conceived. The plasticity of the epigenome enables it to change in response to environmental factors such as diet and exercise, and also makes the epigenome a good target for epigenetic drugs that may be used to enhance insulin secretion and potentially treat diabetes.

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Visceral Adiposity Index is associated with Insulin Resistance, impaired Insulin Secretion, and β-cell dysfunction in subjects at risk for Type 2 Diabetes

Diabetes Epidemiology and Management ◽

10.1016/j.deman.2021.100013 ◽

2021 ◽

pp. 100013

Author(s):

Froylan David Martínez-Sánchez ◽

Valerie Paola Vargas-Abonce ◽

Andrea Rocha-Haro ◽

Romina Flores-Cardenas ◽

Milagros Fernández-Barrio ◽

...

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

At Risk ◽

Insulin Secretion ◽

Visceral Adiposity ◽

Visceral Adiposity Index ◽

Β Cell ◽

Cell Dysfunction ◽

Impaired Insulin

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Analysis of compensatory β-cell response in mice with combined mutations of Insr and Irs2

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00430.2006 ◽

2007 ◽

Vol 292 (6) ◽

pp. E1694-E1701 ◽

Cited By ~ 17

Author(s):

Jane J. Kim ◽

Yoshiaki Kido ◽

Philipp E. Scherer ◽

Morris F. White ◽

Domenico Accili

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Insulin Secretion ◽

Cell Response ◽

Cell Mass ◽

Comprehensive Treatment ◽

Β Cell ◽

Cell Dysfunction ◽

Impaired Insulin

Type 2 diabetes results from impaired insulin action and β-cell dysfunction. There are at least two components to β-cell dysfunction: impaired insulin secretion and decreased β-cell mass. To analyze how these two variables contribute to the progressive deterioration of metabolic control seen in diabetes, we asked whether mice with impaired β-cell growth due to Irs2 ablation would be able to mount a compensatory response in the background of insulin resistance caused by Insr haploinsufficiency. As previously reported, ∼70% of mice with combined Insr and Irs2 mutations developed diabetes as a consequence of markedly decreased β-cell mass. In the initial phases of the disease, we observed a robust increase in circulating insulin levels, even as β-cell mass gradually declined, indicating that replication-defective β-cells compensate for insulin resistance by increasing insulin secretion. These data provide further evidence for a heterogeneous β-cell response to insulin resistance, in which compensation can be temporarily achieved by increasing function when mass is limited. The eventual failure of compensatory insulin secretion suggests that a comprehensive treatment of β-cell dysfunction in type 2 diabetes should positively affect both aspects of β-cell physiology.

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Reduced PDX-1 expression impairs islet response to insulin resistance and worsens glucose homeostasis

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00252.2004 ◽

2005 ◽

Vol 288 (4) ◽

pp. E707-E714 ◽

Cited By ~ 62

Author(s):

Marcela Brissova ◽

Michael Blaha ◽

Cathi Spear ◽

Wendell Nicholson ◽

Aramandla Radhika ◽

...

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Insulin Secretion ◽

Glucose Homeostasis ◽

Cell Mass ◽

Glucose Disposal ◽

Β Cell ◽

Impaired Insulin Secretion ◽

Impaired Insulin

In type 2 diabetes mellitus, insulin resistance and an inadequate pancreatic β-cell response to the demands of insulin resistance lead to impaired insulin secretion and hyperglycemia. Pancreatic duodenal homeodomain-1 (PDX-1), a transcription factor required for normal pancreatic development, also plays a key role in normal insulin secretion by islets. To investigate the role of PDX-1 in islet compensation for insulin resistance, we examined glucose disposal, insulin secretion, and islet cell mass in mice of four different genotypes: wild-type mice, mice with one PDX-1 allele inactivated (PDX-1+/−, resulting in impaired insulin secretion), mice with one GLUT4 allele inactivated (GLUT4+/−, resulting in insulin resistance), and mice heterozygous for both PDX-1 and GLUT4 (GLUT4+/−;PDX-1+/−). The combination of PDX-1 and GLUT4 heterozygosity markedly prolonged glucose clearance. GLUT4+/−;PDX-1+/− mice developed β-cell hyperplasia but failed to increase their β-cell insulin content. These results indicate that PDX-1 heterozygosity (∼60% of normal protein levels) abrogates the β-cell's compensatory response to insulin resistance, impairs glucose homeostasis, and may contribute to the pathogenesis of type 2 diabetes.

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1516-P: A Comparison of the Contributions of Impaired Insulin Secretion and Insulin Resistance to the Development of Type 2 Diabetes in a Japanese Community: The Hisayama Study

Diabetes ◽

10.2337/db19-1516-p ◽

2019 ◽

Vol 68 (Supplement 1) ◽

pp. 1516-P

Author(s):

MASAHITO YOSHINARI ◽

YOICHIRO HIRAKAWA ◽

JUN HATA ◽

MAYU HIGASHIOKA ◽

TAKANORI HONDA ◽

...

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Insulin Secretion ◽

Impaired Insulin Secretion ◽

Impaired Insulin

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TYK2 Promoter Variant, a Putative Virus-Induced Diabetes Susceptibility Gene, Is Associated with Impaired Insulin Secretion and Lower Insulin Resistance in Japanese Type 2 Diabetes Patients

SSRN Electronic Journal ◽

10.2139/ssrn.3667638 ◽

2020 ◽

Author(s):

Hitoe Mori ◽

Hirokazu Takahashi ◽

Keiichiro Mine ◽

Ken Higashimoto ◽

Kanako Inoue ◽

...

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Insulin Secretion ◽

Susceptibility Gene ◽

Diabetes Susceptibility ◽

Impaired Insulin Secretion ◽

Diabetes Susceptibility Gene ◽

Impaired Insulin ◽

Diabetes Patients

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RFX6-mediated dysregulation defines human β cell dysfunction in early type 2 diabetes

10.1101/2021.12.16.466282 ◽

2021 ◽

Author(s):

John T Walker ◽

Diane C Saunders ◽

Vivek Rai ◽

Chunhua Dai ◽

Peter Orchard ◽

...

Keyword(s):

Type 2 Diabetes ◽

Insulin Secretion ◽

Association Studies ◽

Critical Role ◽

Regulatory Elements ◽

Genome Wide Association Studies ◽

Β Cells ◽

Β Cell ◽

Gene Regulatory

A hallmark of type 2 diabetes (T2D), a major cause of world-wide morbidity and mortality, is dysfunction of insulin-producing pancreatic islet β cells. T2D genome-wide association studies (GWAS) have identified hundreds of signals, mostly in the non-coding genome and overlapping β cell regulatory elements, but translating these into biological mechanisms has been challenging. To identify early disease-driving events, we performed single cell spatial proteomics, sorted cell transcriptomics, and assessed islet physiology on pancreatic tissue from short-duration T2D and control donors. Here, through integrative analyses of these diverse modalities, we show that multiple gene regulatory modules are associated with early-stage T2D β cell-intrinsic defects. One notable example is the transcription factor RFX6, which we show is a highly connected β cell hub gene that is reduced in T2D and governs a gene regulatory network associated with insulin secretion defects and T2D GWAS variants. We validated the critical role of RFX6 in β cells through direct perturbation in primary human islets followed by physiological and single nucleus multiome profiling, which showed reduced dynamic insulin secretion and large-scale changes in the β cell transcriptome and chromatin accessibility landscape. Understanding the molecular mechanisms of complex, systemic diseases necessitates integration of signals from multiple molecules, cells, organs, and individuals and thus we anticipate this approach will be a useful template to identify and validate key regulatory networks and master hub genes for other diseases or traits with GWAS data.

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