Impaired insulin secretion and β-cell loss in tissue-specific knockout mice with mitochondrial 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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Glucose Intolerance and Impaired Insulin Secretion in Pancreas-Specific Signal Transducer and Activator of Transcription-3 Knockout Mice Are Associated with Microvascular Alterations in the Pancreas

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jcem.95.4.9987 ◽

2010 ◽

Vol 95 (4) ◽

pp. 2004-2004

Author(s):

Elena Kostromina ◽

Natalia Gustavsson ◽

Xiaorui Wang ◽

Chun-Yan Lim ◽

George K. Radda ◽

...

Keyword(s):

Insulin Secretion ◽

Glucose Intolerance ◽

Knockout Mice ◽

Signal Transducer ◽

Specific Signal ◽

Impaired Insulin Secretion ◽

Impaired Insulin ◽

Microvascular Alterations ◽

Transcription 3

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Unrestricted Feed Intake Induces β-Cell Death and Impairs Insulin Secretion in Broiler Breeder Hens

Animals ◽

10.3390/ani10111969 ◽

2020 ◽

Vol 10 (11) ◽

pp. 1969

Author(s):

Yu-Feng Huang ◽

Ling-Chu Chang ◽

Chung-Yu Chen ◽

Yu-Hui Chen ◽

Rosemary L. Walzem ◽

...

Keyword(s):

Insulin Secretion ◽

Feed Intake ◽

Cell Apoptosis ◽

Glucose Disposal ◽

Β Cell ◽

Broiler Breeder ◽

Impaired Insulin Secretion ◽

Breeder Hens ◽

Impaired Insulin ◽

Broiler Breeder Hens

Past studies regarding to insulin secretion and glucose disposal in chickens were focused on rapidly growing juvenile broilers and may not reflect glucose/insulin physiology in adulthood. The study aimed to assess insulin secretion and glucose disposal in respect to restricted (R) vs. ad libitum (Ad) feed intake for obesity development in broiler breeder hens. Hens at age of 26 weeks were continued on R rations, or allowed Ad-feed intake up to 45 weeks. Results from prandial changes and glucose tolerance test suggested that Ad-feed intake to 45 weeks impaired insulin secretion and glucose clearance, and, thus, caused hyperglycemia in accompany with transient hyperinsulinemia at age of 33 weeks (p < 0.05). The alterations were shown operating at both transcript and protein level of insulin gene expression per se and at ATP supply for insulin release as evidenced by consistent changes of enzyme expression and activity in pyruvate anaplerosis in the β-islets (p < 0.05). Ad-feed intake also increased β-islet triacylglycerol and ceramide accumulation and provoked interleukin-1β (IL-1β) production (p < 0.05), which were further manifested by a detrimental increase of caspase 3/7 activity and cell apoptosis (p < 0.05). Results support the conclusion that release to Ad-feed intake in broiler breeder hens transiently induced hyperinsulinemia along rapid bodyweight gain and adiposity, but later provoked lipotoxicity and inflammation leading to β-cell apoptosis and ultimately impaired insulin secretion and glucose disposal.

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Regulatory roles for small G proteins in the pancreatic β-cell: lessons from models of impaired insulin secretion

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00196.2003 ◽

2003 ◽

Vol 285 (4) ◽

pp. E669-E684 ◽

Cited By ~ 44

Author(s):

Anjaneyulu Kowluru

Keyword(s):

Insulin Secretion ◽

G Proteins ◽

Posttranslational Modifications ◽

Protein Function ◽

Future Research ◽

Signaling Proteins ◽

Β Cell ◽

Impaired Insulin Secretion ◽

Impaired Insulin ◽

Histidine Phosphorylation

Emerging evidence suggests that GTP-binding proteins (G proteins) play important regulatory roles in physiological insulin secretion from the islet β-cell. Such conclusions were drawn primarily from experimental data derived through the use of specific inhibitors of G protein function. Data from gene depletion experiments appear to further substantiate key roles for these signaling proteins in the islet metabolism. The first part of this review will focus on findings supporting the hypothesis that activation of specific G proteins is essential for insulin secretion, including regulation of their function by posttranslational modifications at their COOH-terminal cysteines (e.g., isoprenylation). The second part will overview novel, non-receptor-dependent mechanism(s) whereby glucose might activate specific G proteins via protein histidine phosphorylation. The third section will review findings that appear to link abnormalities in the expression and/or functional activation of these key signaling proteins to impaired insulin secretion. It is hoped that this review will establish a basis for future research in this area of islet signal transduction, which presents a significant potential, not only in identifying key signaling proteins that are involved in physiological insulin secretion, but also in examining potential abnormalities in this signaling cascade that lead to islet dysfunction and onset of diabetes.

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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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