c-Myc directly induces both impaired insulin secretion and loss of β-cell mass, independently of hyperglycemia in vivo

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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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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Follow-up of GK rats during prediabetes highlights increased insulin action and fat deposition despite low insulin secretion

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00501.2007 ◽

2008 ◽

Vol 294 (1) ◽

pp. E168-E175 ◽

Cited By ~ 32

Author(s):

Jamileh Movassat ◽

Danièle Bailbé ◽

Cécile Lubrano-Berthelier ◽

Françoise Picarel-Blanchot ◽

Eric Bertin ◽

...

Keyword(s):

Body Composition ◽

Insulin Secretion ◽

Insulin Sensitivity ◽

Cell Function ◽

Cell Mass ◽

The Body ◽

Whole Body ◽

Β Cell ◽

Gk Rats

The adult Goto-Kakizaki (GK) rat is characterized by impaired glucose-induced insulin secretion in vivo and in vitro, decreased β-cell mass, decreased insulin sensitivity in the liver, and moderate insulin resistance in muscles and adipose tissue. GK rats do not exhibit basal hyperglycemia during the first 3 wk after birth and therefore could be considered prediabetic during this period. Our aim was to identify the initial pathophysiological changes occurring during the prediabetes period in this model of type 2 diabetes (T2DM). To address this, we investigated β-cell function, insulin sensitivity, and body composition in normoglycemic prediabetic GK rats. Our results revealed that the in vivo secretory response of GK β-cells to glucose is markedly reduced and the whole body insulin sensitivity is increased in the prediabetic GK rats in vivo. Moreover, the body composition of suckling GK rats is altered compared with age-matched Wistar rats, with an increase of the number of adipocytes before weaning despite a decreased body weight and lean mass in the GK rats. None of these changes appeared to be due to the postnatal nutritional environment of GK pups as demonstrated by cross-fostering GK pups with nondiabetic Wistar dams. In conclusion, in the GK model of T2DM, β-cell dysfunction associated with increased insulin sensitivity and the alteration of body composition are proximal events that might contribute to the establishment of overt diabetes in adult GK rats.

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Measurements of insulin responses as predictive markers of pancreatic β-cell mass in normal and β-cell-reduced lean and obese Göttingen minipigs in vivo

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00251.2005 ◽

2006 ◽

Vol 290 (4) ◽

pp. E670-E677 ◽

Cited By ~ 27

Author(s):

Marianne O. Larsen ◽

Bidda Rolin ◽

Jeppe Sturis ◽

Michael Wilken ◽

Richard D. Carr ◽

...

Keyword(s):

Insulin Secretion ◽

Cell Mass ◽

Insulin Response ◽

Study Groups ◽

Β Cell ◽

Intravenous Glucose ◽

Body Weights ◽

In Vivo Tests ◽

Insulin Responses

At present, the best available estimators of β-cell mass in humans are those based on measurement of insulin levels or appearance rates in the circulation. In several animal models, these estimators have been validated against β-cell mass in lean animals. However, as many diabetic humans are obese, a correlation between in vivo tests and β-cell mass must be evaluated over a range of body weights to include different levels of insulin sensitivity. For this purpose, obese ( n = 10) and lean ( n = 25) Göttingen minipigs were studied. β-Cell mass had been reduced ( n = 16 lean, n = 5 obese) with a combination of nicotinamide (67 mg/kg) and streptozotocin (125 mg/kg), acute insulin response (AIR) to intravenous glucose and/or arginine was tested, pulsatile insulin secretion was evaluated by deconvolution ( n = 30), and β-cell mass was determined histologically. AIR to 0.3 ( r2= 0.4502, P < 0.0001) or 0.6 g/kg glucose ( r2= 0.6806, P < 0.0001), 67 mg/kg arginine ( r2= 0.5730, P < 0.001), and maximum insulin concentration ( r2= 0.7726, P < 0.0001) were all correlated to β-cell mass when evaluated across study groups, and regression lines were not different between lean and obese groups except for AIR to 0.3 g/kg glucose. Baseline pulse mass was not significantly correlated to β-cell mass across the study groups ( r2= 0.1036, NS), whereas entrained pulse mass did show a correlation across groups ( r2= 0.4049, P < 0.001). This study supports the use of in vivo tests of insulin responses to evaluate β-cell mass over a range of body weights in the minipig. Extensive stimulation of insulin secretion by a combination of glucose and arginine seems to give the best correlation to β-cell mass.

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Overexpression of FoxO1 in the Hypothalamus and Pancreas Causes Obesity and Glucose Intolerance

Endocrinology ◽

10.1210/en.2011-1635 ◽

2012 ◽

Vol 153 (2) ◽

pp. 659-671 ◽

Cited By ~ 30

Author(s):

Hye-Jin Kim ◽

Masaki Kobayashi ◽

Tsutomu Sasaki ◽

Osamu Kikuchi ◽

Kosuke Amano ◽

...

Keyword(s):

Metabolic Syndrome ◽

Insulin Secretion ◽

Glucose Intolerance ◽

Insulin Signaling ◽

Uncoupling Protein ◽

Cell Mass ◽

Peroxisome Proliferator ◽

Β Cells ◽

Impaired Insulin Secretion ◽

Impaired Insulin

Recent studies have revealed that insulin signaling in pancreatic β-cells and the hypothalamus is critical for maintaining nutrient and energy homeostasis, the failure of which are hallmarks of metabolic syndrome. We previously reported that forkhead transcription factor forkhead box-containing protein of the O subfamily (FoxO)1, a downstream effector of insulin signaling, plays important roles in β-cells and the hypothalamus when we investigated the roles of FoxO1 independently in the pancreas and hypothalamus. However, because metabolic syndrome is caused by the combined disorders in hypothalamus and pancreas, to elucidate the combined implications of FoxO1 in these organs, we generated constitutively active FoxO1 knockin (KI) mice with specific activation in both the hypothalamus and pancreas. The KI mice developed obesity, insulin resistance, glucose intolerance, and hypertriglyceridemia due to increased food intake, decreased energy expenditure, and impaired insulin secretion, which characterize metabolic syndrome. The KI mice also had increased hypothalamic Agouti-related protein and neuropeptide Y levels and decreased uncoupling protein 1 and peroxisome proliferator-activated receptor γ coactivator 1α levels in adipose tissue and skeletal muscle. Impaired insulin secretion was associated with decreased expression of pancreatic and duodenum homeobox 1 (Pdx1), muscyloaponeurotic fibrosarcoma oncogene homolog A (MafA), and neurogenic differentiation 1 (NeuroD) in islets, although β-cell mass was paradoxically increased in KI mice. Based on these results, we propose that uncontrolled FoxO1 activation in the hypothalamus and pancreas accounts for the development of obesity and glucose intolerance, hallmarks of metabolic syndrome.

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Impaired insulin secretion associated with near normoglycemia. Study in normal rats with 96-h in vivo glucose infusions

Diabetes ◽

10.2337/diabetes.36.4.459 ◽

1987 ◽

Vol 36 (4) ◽

pp. 459-464 ◽

Cited By ~ 14

Author(s):

J. L. Leahy ◽

H. E. Cooper ◽

G. C. Weir

Keyword(s):

Insulin Secretion ◽

Impaired Insulin Secretion ◽

Impaired Insulin

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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

Endocrinology ◽

10.1210/en.2009-1199 ◽

2010 ◽

Vol 151 (5) ◽

pp. 2050-2059 ◽

Cited By ~ 18

Author(s):

Elena Kostromina ◽

Natalia Gustavsson ◽

Xiaorui Wang ◽

Chun-Yan Lim ◽

George K. Radda ◽

...

Keyword(s):

Insulin Secretion ◽

Glucose Intolerance ◽

Endocrine Pancreas ◽

Isolated Islets ◽

Signal Transducer ◽

Microvascular Network ◽

Impaired Insulin Secretion ◽

Stat3 Signaling ◽

Impaired Insulin

Maintenance of glucose homeostasis depends on adequate amount and precise pattern of insulin secretion, which is determined by both β-cell secretory processes and well-developed microvascular network within endocrine pancreas. The development of highly organized microvasculature and high degrees of capillary fenestrations in endocrine pancreas is greatly dependent on vascular endothelial growth factor-A (VEGF-A) from islet cells. However, it is unclear how VEGF-A production is regulated in endocrine pancreas. To understand whether signal transducer and activator of transcription (STAT)-3 is involved in VEGF-A regulation and subsequent islet and microvascular network development, we generated a mouse line carrying pancreas-specific deletion of STAT3 (p-KO) and performed physiological analyses both in vivo and using isolated islets, including glucose and insulin tolerance tests, and insulin secretion measurements. We also studied microvascular network and islet development by using immunohistochemical methods. The p-KO mice exhibited glucose intolerance and impaired insulin secretion in vivo but normal insulin secretion in isolated islets. Microvascular density in the pancreas was reduced in p-KO mice, along with decreased expression of VEGF-A, but not other vasotropic factors in islets in the absence of pancreatic STAT3 signaling. Together, our study suggests that pancreatic STAT3 signaling is required for the normal development and maintenance of endocrine pancreas and islet microvascular network, possibly through its regulation of VEGF-A.

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AWRK6, a Novel GLP-1 Receptor Agonist, Attenuates Diabetes by Stimulating Insulin Secretion

International Journal of Molecular Sciences ◽

10.3390/ijms19103053 ◽

2018 ◽

Vol 19 (10) ◽

pp. 3053

Author(s):

Qiuyu Wang ◽

Chunlin Zhao ◽

Lili Jin ◽

Hanyu Zhang ◽

Qifan Miao ◽

...

Keyword(s):

Insulin Secretion ◽

Cell Mass ◽

Membrane Integrity ◽

The Body ◽

Oral Glucose ◽

Diabetic Mice ◽

Β Cell ◽

Min6 Cells

Diabetes is a metabolic disorder leading to many complications. The treatment of diabetes mainly depends on hypoglycemic drugs, often with side effects, which drive us to develop novel agents. AWRK6 was a peptide developed from the antimicrobial peptide Dybowskin-2CDYa in our previous study, and the availability of AWRK6 on diabetes intervention was unknown. Here, in vivo and in vitro experiments were carried out to investigate the effects of AWRK6 against diabetes. In diabetic mice, induced by high-fat diet followed by streptozocin (STZ) administration, the daily administration of AWRK6 presented acute and sustained hypoglycemic effects. The plasma insulin was significantly elevated by AWRK6 during an oral glucose tolerance test (OGTT). The relative β cell mass in diabetic mice was increased by AWRK6 treatment. The body weight and food intake were remarkably reduced by AWRK6 administration. In the mouse pancreatic β cell line Min6 cells, the intracellular calcium concentration was found to be enhanced under the treatment with AWRK6, and protein kinase A (PKA) inhibitor H-89 and Epac2 inhibitor HJC0350 represented inhibitory effects of the insulinotropic function of AWRK6. By FITC-AWRK6 incubation and GLP-1 receptor (GLP-1R) knockdown, AWRK6 proved to be a novel GLP-1R agonist. In addition, AWRK6 showed no toxicity in cell viability and membrane integrity in Min6 cells, and no hypoglycemia risk and no lethal toxicity in mice. In summary, AWRK6 was found as a novel agonist of GLP-1R, which could stimulate insulin secretion to regulate blood glucose and energy metabolism, via cAMP-calcium signaling pathway, without significant toxicity. The peptide AWRK6 might become a novel candidate for diabetes treatment.

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

Biochemistry and Cell Biology ◽

10.1139/bcb-2015-0057 ◽

2015 ◽

Vol 93 (5) ◽

pp. 511-521 ◽

Cited By ~ 15

Author(s):

Tasnim Dayeh ◽

Charlotte Ling

Keyword(s):

Risk Factors ◽

Type 2 Diabetes ◽

Insulin Secretion ◽

Β Cells ◽

Β Cell ◽

Cell Dysfunction ◽

Impaired Insulin Secretion ◽

Expression Of Genes ◽

Impaired Insulin

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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