Dataset Information

Pancreatic islet vasculature adapts to insulin resistance through dilation and not angiogenesis.

ABSTRACT: Pancreatic islets adapt to insulin resistance through a complex set of changes, including ?-cell hyperplasia and hypertrophy. To determine if islet vascularization changes in response to insulin resistance, we investigated three independent models of insulin resistance: ob/ob, GLUT4(+/-), and mice with high-fat diet-induced obesity. Intravital blood vessel labeling and immunocytochemistry revealed a vascular plasticity in which islet vessel area was significantly increased, but intraislet vessel density was decreased as the result of insulin resistance. These vascular changes were independent of islet size and were only observed within the ?-cell core but not in the islet periphery. Intraislet endothelial cell fenestration, proliferation, and islet angiogenic factor/receptor expression were unchanged in insulin-resistant compared with control mice, indicating that islet capillary expansion is mediated by dilation of preexisting vessels and not by angiogenesis. We propose that the islet capillary dilation is modulated by endothelial nitric oxide synthase via complementary signals derived from ?-cells, parasympathetic nerves, and increased islet blood flow. These compensatory changes in islet vascularization may influence whether ?-cells can adequately respond to insulin resistance and prevent the development of diabetes.

SUBMITTER: Dai C

PROVIDER: S-EPMC3837044 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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Pancreatic islet vasculature adapts to insulin resistance through dilation and not angiogenesis.

Dai Chunhua C Brissova Marcela M Reinert Rachel B RB Nyman Lara L Liu Eric H EH Thompson Courtney C Shostak Alena A Shiota Masakazu M Takahashi Takamune T Powers Alvin C AC

Diabetes 20130429 12

Pancreatic islets adapt to insulin resistance through a complex set of changes, including β-cell hyperplasia and hypertrophy. To determine if islet vascularization changes in response to insulin resistance, we investigated three independent models of insulin resistance: ob/ob, GLUT4(+/-), and mice with high-fat diet-induced obesity. Intravital blood vessel labeling and immunocytochemistry revealed a vascular plasticity in which islet vessel area was significantly increased, but intraislet vessel ...[more]

PMID: 23630302

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Project description:Fibroblast growth factor (FGF) 21 is an endocrine factor that normalizes glucose homeostasis and reduces insulin resistance in diabetes. Although the pancreas is an FGF21 target organ, its role in pancreatic islets remains obscure. This study aimed to elucidate the physiological role of FGF21 in pancreatic islets using FGF21-knockout (FGF21-KO) mice. Twenty-four-week-old male global FGF21-KO mice were used in this study. Glucose and insulin tolerance were assessed. Expression of genes and proteins related to islet function and underlying mechanisms were also examined. Islet morphology and insulin-secreting capacity were further evaluated. FGF21-KO mice exhibited insulin resistance while being normoglycemic, associated with increases in beta-cell proliferation and insulin synthesis, acting as compensatory responses. This phenotype probably results from enhanced growth hormone (GH) sensitivity in FGF21-KO mouse islets. In addition, ex vivo FGF21 treatment in normal C57BL/6J mouse islets reduced GH signaling, probably via upregulation of peroxisome proliferator-activated receptor gamma (PPARγ) and cytokine-inducible SH-2 containing (CIS) protein, whereas KO mouse islets displayed reduced PPARγ and CIS expression. FGF21 treatment also reversed GH-induced insulin expression, beta-cell proliferation and GH-impaired glucose-stimulated insulin secretion (GSIS) in islets. Furthermore, distorted islet morphology and impaired GSIS were observed in KO mice, suggestive of islet dysfunction, whereas the enhanced insulin expression and impaired GSIS in FGF21-KO mouse islets could be reversed by blockade of GH signaling. Our data indicate that FGF21 is important in the regulation of beta-cell proliferation and insulin synthesis, probably via modulation of GH signaling. These findings provide evidence that FGF21 is an obligatory metabolic regulator in pancreatic islets and shed new light onto the role of endogenous FGF21 in the pathogenesis of insulin resistance and islet dysfunction.

Dataset Information

Pancreatic islet vasculature adapts to insulin resistance through dilation and not angiogenesis.

Publications

Pancreatic islet vasculature adapts to insulin resistance through dilation and not angiogenesis.

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