Spontaneous restoration of functional β-cell mass in obese SM/J mice.

Mario A Miranda,Marcus Kunzmann,Caryn Carson,Juan F Macias‐Velasco,Jing W Hughes,Celine L St Pierre,Heather Schmidt,Heather A Lawson,Jessica P Wayhart

doi:10.14814/phy2.14573

Abstract

Maintenance of functional β‐cell mass is critical to preventing diabetes, but the physiological mechanisms that cause β‐cell populations to thrive or fail in the context of obesity are unknown. High fat‐fed SM/J mice spontaneously transition from hyperglycemic‐obese to normoglycemic‐obese with age, providing a unique opportunity to study β‐cell adaptation. Here, we characterize insulin homeostasis, islet morphology, and β‐cell function during SM/J’s diabetic remission. As they resolve hyperglycemia, obese SM/J mice dramatically increase circulating and pancreatic insulin levels while improving insulin sensitivity. Immunostaining of pancreatic sections reveals that obese SM/J mice selectively increase β‐cell mass but not α‐cell mass. Obese SM/J mice do not show elevated β‐cell mitotic index, but rather elevated α‐cell mitotic index. Functional assessment of isolated islets reveals that obese SM/J mice increase glucose‐stimulated insulin secretion, decrease basal insulin secretion, and increase islet insulin content. These results establish that β‐cell mass expansion and improved β‐cell function underlie the resolution of hyperglycemia, indicating that obese SM/J mice are a valuable tool for exploring how functional β‐cell mass can be recovered in the context of obesity.

Highlights

Obesity and diabetes are a deadly combination, compounding risk for cardiovascular disease, cancer, and stroke (Centers for Disease Control and Prevention C, 2017; Esposito, Chiodini, Colao, Lenzi, & Giugliano, 2012; Ninomiya et al, 2004; Younis et al, 2016)
We describe insulin homeostasis, islet morphology, and β-cell function in obese SM/J mice as they transition from hyperglycemic to normoglycemic
We determine that increased insulin production and insulin sensitivity accompany improved glycemic control, driven by expanded β-cell mass and improved glucose-stimulated insulin secretion

Summary

| INTRODUCTION

Obesity and diabetes are a deadly combination, compounding risk for cardiovascular disease, cancer, and stroke (Centers for Disease Control and Prevention C, 2017; Esposito, Chiodini, Colao, Lenzi, & Giugliano, 2012; Ninomiya et al, 2004; Younis et al, 2016). Recent work suggests that β-cells do not respond uniformly to glycemic stress, rather they experience variable fates including dedifferentiation, replication, and apoptosis (Butler et al, 2003; Cinti et al, 2016; Georgia & Bhushan, 2004) Understanding how these changes mediate diabetic risk is complicated by β-cell heterogeneity. We have previously shown that by 30 weeks of age, high fat-fed SM/J mice enter diabetic remission, characterized by normalized fasting blood glucose, and greatly improved glucose tolerance and insulin sensitivity (Carson et al, 2019). These changes occur in the context of sustained obesity. This study focuses on how insulin homeostasis, β-cell morphology, and β-cell function change during this remarkable transition and establishes SM/J mice as a useful model for teasing apart diabetic-obese and nondiabetic-obese states

| METHODS

| RESULTS

| DISCUSSION

Findings

DISCLOSURE