Altered Islet Morphology but Normal Islet Secretory Function In Vitro in a Mouse Model with Microvascular Alterations in the Pancreas

Elena Kostromina,Xiaorui Wang,Weiping Han,Aimin Xu

doi:10.1371/journal.pone.0071277

Abstract

BackgroundOur previous studies have shown that signal transducer and activator of transcription 3 (STAT3) signaling is important for the development of pancreatic microvasculature via its regulation of vascular endothelial growth factor-A (VEGF-A). Pancreas-specific STAT3-KO mice exhibit glucose intolerance and impaired insulin secretion in vivo, along with microvascular alterations in the pancreas. However, the specific role of STAT3 signaling in the regulation of pancreatic islet development and function is not entirely understood.Methodology/Principal FindingsTo investigate the role of STAT3 signaling in the formation and maintenance of pancreatic islets, we studied pancreas-specific STAT3-KO mice. Histological analysis showed that STAT3 deficiency affected pancreatic islet morphology. We found an increased proportion of small-sized islets and a reduced fraction of medium-sized islets, indicating abnormal islet development in STAT3-KO mice. Interestingly, the islet area relative to the whole pancreas area in transgenic and control mice was not significantly different. Immunohistochemical analysis on pancreatic cryosections revealed abnormalities in islet architecture in STAT3-KO mice: the pattern of peripheral distribution of glucagon-positive α-cells was altered. At the same time, islets belonging to different size categories isolated from STAT3-KO mice exhibited normal glucose-stimulated insulin secretion in perifusion experiments in vitro when compared to control mice.ConclusionsOur data demonstrate that STAT3 signaling in the pancreas is required for normal islet formation and/or maintenance. Altered islet size distribution in the KO mice does not result in an impaired islet secretory function in vitro. Therefore, our current study supports that the glucose intolerance and in vivo insulin secretion defect in pancreas-specific STAT3-KO mice is due to altered microvasculature in the pancreas, and not intrinsic beta-cell function.

Highlights

Insulin secretion and its regulation by glucose and other physiological stimuli are vital to the maintenance of glucose homeostasis
Our current study supports that the glucose intolerance and in vivo insulin secretion defect in pancreas-specific signal transducer and activator of transcription 3 (STAT3)-KO mice is due to altered microvasculature in the pancreas, and not intrinsic beta-cell function
STAT3 signaling plays a direct role in the regulation of vascular endothelial growth factor-A (VEGF-A) expression [13], and its activation is essential for VEGF-A overexpression in pancreatic cancer, a key regulator in abnormal tumor angiogenesis [14]

Summary

Introduction

Insulin secretion and its regulation by glucose and other physiological stimuli are vital to the maintenance of glucose homeostasis. Using a mouse model with Pdx-Cre– mediated STAT3 inactivation [15] we showed that pancreatic STAT3 signaling is essential for the development of highly organized islet microvascular network through its regulation of VEGF-A expression under normal physiological conditions. A dichotomy of impaired glucose-stimulated insulin secretion in vivo and normal islet secretory function in vitro, as revealed in our p-KO mice, has been reported for mice lacking VEGF-A signaling in pancreatic b-cells [17]. Abnormal development of microvascular network in pancreatic islets, due to reduced expression of VEGF-A, is an important factor that affects insulin output from islets in response to secretagogues, leading to impaired insulin release in vivo without impairment of b-cell secretory function [19,20]. The specific role of STAT3 signaling in the regulation of pancreatic islet development and function is not entirely understood

Methods

Results

Conclusion