Autocrine IGF2 programmes \u03b2-cell plasticity under conditions of increased metabolic demand

Ionel Sandovici,Gema Medina-Gómez,Susan E Ozanne,Antonio Vidal-Puig,Constanze M Hammerle,Yurena Vivas-Garcia,Sam Virtue,Adriana Izquierdo-Lahuerta,Miguel Constância

doi:10.1038/s41598-021-87292-x

Abstract

When exposed to nutrient excess and insulin resistance, pancreatic β-cells undergo adaptive changes in order to maintain glucose homeostasis. The role that growth control genes, highly expressed in early pancreas development, might exert in programming β-cell plasticity in later life is a poorly studied area. The imprinted Igf2 (insulin-like growth factor 2) gene is highly transcribed during early life and has been identified in recent genome-wide association studies as a type 2 diabetes susceptibility gene in humans. Hence, here we investigate the long-term phenotypic metabolic consequences of conditional Igf2 deletion in pancreatic β-cells (Igf2βKO) in mice. We show that autocrine actions of IGF2 are not critical for β-cell development, or for the early post-natal wave of β-cell remodelling. Additionally, adult Igf2βKO mice maintain glucose homeostasis when fed a chow diet. However, pregnant Igf2βKO females become hyperglycemic and hyperinsulinemic, and their conceptuses exhibit hyperinsulinemia and placentomegalia. Insulin resistance induced by congenital leptin deficiency also renders Igf2βKO females more hyperglycaemic compared to leptin-deficient controls. Upon high-fat diet feeding, Igf2βKO females are less susceptible to develop insulin resistance. Based on these findings, we conclude that in female mice, autocrine actions of β-cell IGF2 during early development determine their adaptive capacity in adult life.

Highlights

When exposed to nutrient excess and insulin resistance, pancreatic β-cells undergo adaptive changes in order to maintain glucose homeostasis
Paternal Igf2βKO resulted in ~ 96% reduction of its mRNA levels in pancreatic β-cells isolated by Fluorescence Activated Cell Sorting (FACS) at postnatal day 2 (P2) (Fig. 1b)
Igf2βKO females became hyperglycaemic at E15, with normal levels of insulin and normal clearance of glucose from periphery during oral glucose tolerance tests (OGTTs)

Summary

Introduction

When exposed to nutrient excess and insulin resistance, pancreatic β-cells undergo adaptive changes in order to maintain glucose homeostasis. Upon high-fat diet feeding, Igf2βKO females are less susceptible to develop insulin resistance Based on these findings, we conclude that in female mice, autocrine actions of β-cell IGF2 during early development determine their adaptive capacity in adult life. Much of this evidence stems from in vitro studies or analyses performed with gain-of-function rodent models, and can be summarised as follows: (1) rat β-cells overexpressing Igf[2] from a transgene were protected from interleukin-1β (IL-1β) cytokine-induced apoptosis ex vivo[11] and islets isolated from neonatal rats were protected from cytokine-induced apoptosis when cultured in the presence of I GF212; (2) diabetic rats transplanted with islets overexpressing Igf[2] had improved glucose tolerance compared to diabetic rats transplanted with standard islets, and β-cell replication rate was higher in Igf2-overexpressing islets compared to control islets after transplantation[13]; (3) Goto-Kakizaki (GK) rats that develop spontaneous diabetes had decreased IGF2 protein levels in their pancreatic bud, prior to the onset of the β-cell mass reduction[14]; (4) transgenic mice with global Igf[2] overexpression had larger pancreatic islets at the end of gestation, with increased cell replication and reduced apoptosis[15]; (5) transgenic mice with overexpression of Igf[2] in β-cells under the control of rat insulin I promoter had a threefold expansion of β-cell mass, with disrupted islet morphology, hyperglycaemia when fed a standard chow diet and overt diabetes when fed high fat diet (HFD)[16]; and (6) conditional Igf[2] deletion in pancreatic β-cells led to reduced glucose-stimulated insulin secretion (GSIS) in 24–26 weeks-old females fed chow diet, and lower GSIS in both sexes after 18 weeks of HFD feeding, associated with reduced β-cell mass in females[17]

Methods

Results

Conclusion