β-Cell–Derived Angiopoietin-1 Regulates Insulin Secretion and Glucose Homeostasis by Stabilizing the Islet Microenvironment

Abstract

Islets are highly vascularized for prompt insulin secretion. Although angiopoietin-1 (Ang1) is a wellknown angiogenic factor, its role in glucose homeostasis remains largely unknown. The objective of this study was to investigate whether and how Ang1 contributes to glucose homeostasis in response to metabolic challenge. We used inducible systemic Ang1 knockout (Ang1 sys2/2) and b-cellspecific Ang1 knockout (Ang1 b-cell2/2) mice fed a high-fat diet for 24 weeks. Although the degree of insulin sensitivity did not differ between Ang1 sys2/2 and Ang1 sys+/+ mice, serum insulin levels were lower in Ang1 sys2/2 mice, resulting in significant glucose intolerance. Similar results were observed in Ang1 b-cell2/2 mice, suggesting a critical role of b-cell-derived Ang1 in glucose homeostasis. There were no differences in b-cell area or vasculature density, but glucosestimulated insulin secretion was significantly decreased, and PDX-1 expression and GLUT2 localization were altered in Ang1 b-cell2/2 compared with Ang1 b-cell+/+ mice. These effects were associated with less pericyte coverage, disorganized endothelial cell ultrastructure, and enhanced infiltration of inflammatory cells and upregulation of adhesion molecules in the islets of Ang1 b-cell2/2 mice. In conclusion, b-cell-derived Ang1 regulates insulin secretion and glucose homeostasis by stabilizing the blood vessels in the islet and may be a novel therapeutic target for diabetes treatment in the future.

Functional Characterization of the Human Islet Microvasculature Using Living Pancreas Slices

“…Pancreatic islets are endocrine mini-organs rich in blood vessels ( 1 , 2 ). Close interactions between islet endocrine cells and vascular cells are established early on during development and maintained throughout life, by providing mutual trophic and functional support ( 2 – 7 ). Indeed, as any other endocrine organ, islets depend on their blood vessels to function properly ( 8 ).…”

Systemic AAV10.COMP-Ang1 rescues renal glomeruli and pancreatic islets in type 2 diabetic mice

“… 39 Meanwhile, a defect in ß-cell-derived Ang1 induced islet inflammation, disrupted the normal intraislet vascular ultrastructure and impaired the insulin secretory mechanism in response to a high fat diet. 40 Although the mouse high fat diet model differs from human patients with respect to the development of T2DM, these reports nonetheless indicate that the balance of Ang1 and Ang2 governs the microenvironment and function of islets under metabolic challenge. Importantly, the dysregulation of the secretion of Ang1/2 equilibrium by either decreased Ang1 or increased Ang2 levels has been clinically associated with T2DM and vascular dysfunction, 9 41 underscoring the question of whether altered Ang1-Tie2 signaling contributes to impaired pancreatic islet vasculature, homeostasis and diabetes progression.…”

The vascular endothelium plays a role in insulin action

“…In the pancreas, insulin resistance by HFD induces dilation of pancreatic islet vasculature, rather than angiogenesis, and islet endothelial dysfunction may be associated with reduced insulin release in isolated islets . Interestingly a potent angiogenic factor released by pancreatic beta‐cells did not increase vascular density but maintains endothelial cell ultrastructure . This stabilizes the blood vessels in the islet, regulating islet morphology, insulin secretion, and therefore glucose homeostasis .…”

“…82 Interestingly a potent angiogenic factor released by pancreatic beta-cells did not increase vascular density but maintains endothelial cell ultrastructure. 83 This stabilizes the blood vessels in the islet, regulating islet morphology, insulin secretion, and therefore glucose homeostasis. 83,84 Plasma hyperinsulinaemia is a combination of the release of insulin by the pancreas, and clearance, primarily by the liver, yet these two tissues are also exposed to the hyperinsulinaemia they induce, which can affect their function.…”

“…83 This stabilizes the blood vessels in the islet, regulating islet morphology, insulin secretion, and therefore glucose homeostasis. 83,84 Plasma hyperinsulinaemia is a combination of the release of insulin by the pancreas, and clearance, primarily by the liver, yet these two tissues are also exposed to the hyperinsulinaemia they induce, which can affect their function. The relationship between hyperinsulinaemia and the endothelial function is not clear.…”