Altered Pancreatic Growth and Insulin Secretion in WSB/EiJ Mice

Maggie M Ho,James D Johnson,Subashini Karunakaran,Xiaoke Hu,Susanne M Clee

doi:10.1371/journal.pone.0088352

Abstract

These data suggest that insulin secretion in WSB mice is blunted specifically in vivo, either due to a reduced insulin requirement and/or due to factors that are absent or destroyed in vitro. These studies also highlight the role of post-natal growth in determining adult β-cell mass. Mice are important animal models for the study of metabolic physiology and the genetics of complex traits. Wild-derived inbred mouse strains, such as WSB/EiJ (WSB), are unrelated to the commonly studied mouse strains and are valuable tools to identify novel genes that modify disease risk. We have previously shown that in contrast to C57BL/6J (B6) mice, WSB mice fed a high fat diet do not develop hyperinsulinemia or insulin resistance, and had nearly undetectable insulin secretion in response to an intraperitoneal glucose challenge. As hyperinsulinemia may drive obesity and insulin resistance, we examined whether defects in β-cell mass or function could contribute to the low insulin levels in WSB mice. In young WSB mice, β-cell mass was similar to B6 mice. However, we found that adult WSB mice had reduced β-cell mass due to reduced pancreatic weights. Pancreatic sizes were similar between the strains when normalized to body weight, suggesting their pancreatic size is appropriate to their body size in adults, but overall post-natal pancreatic growth was reduced in WSB mice compared to B6 mice. Islet architecture was normal in WSB mice. WSB mice had markedly increased insulin secretion from isolated islets in vitro. These data suggest that insulin secretion in WSB mice is blunted specifically in vivo, either due to a reduced insulin requirement and/or due to factors that are absent or destroyed in vitro. These studies suggest that WSB mice may provide novel insight into mechanisms regulating insulin secretion and also highlight the role of post-natal growth in determining adult β-cell mass.

Highlights

Type 2 diabetes (T2D) develops when the b-cells of the pancreas cannot produce enough insulin to meet the body’s demands, which are increased when an individual becomes resistant to insulin
Islet Architecture and b-cell Mass Our previous studies found that unlike B6 mice, fasting plasma insulin levels that did not increase with age or high fat feeding in WSB mice, and that they exhibited minimal glucose-stimulated insulin secretion in response to an intraperitoneal glucose challenge in vivo [17]
We found that compared to B6 mice, WSB mice maintained low fasting plasma insulin levels over time or with high fat feeding, remained insulin sensitive and secreted minor amounts of insulin in response to a glucose challenge in vivo [17]

Summary

Introduction

Type 2 diabetes (T2D) develops when the b-cells of the pancreas cannot produce enough insulin to meet the body’s demands, which are increased when an individual becomes resistant to insulin. B-cell dysfunction is a key component of T2D [1] Both factors affecting b-cell mass and insulin secretion are important [1]. T2D has a strong genetic component [2] that could provide clues about the critical factors affecting T2D risk. Many of the factors that have recently been identified in the genome-wide association studies (GWAS) have been suggested to affect properties of b-cells [3,4]. While the arrays used in the GWAS may contain thousands of SNPs accounting for up to 50% of the variation in T2D risk [5], only ,60 of these SNPs have been identified to date, and the majority of the genetic factors contributing to T2D are still unknown [4]

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Conclusion