Offspring of Mice Exposed to a Low-Protein Diet in Utero Demonstrate Changes in mTOR Signaling in Pancreatic Islets of Langerhans, Associated with Altered Glucagon and Insulin Expression and a Lower β-Cell Mass.

Renee King,Brenda Strutt,Mark Russell,Jessica Hill,Yuzhen Tong,David Hill,Sarah Richardson,Noel Morgan,Bibek Saha

doi:10.3390/nu11030605

Renee King, Brenda Strutt + Show 7 more

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https://doi.org/10.3390/nu11030605

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Abstract

Low birth weight is a risk factor for gestational and type 2 diabetes (T2D). Since mammalian target of rapamycin (mTOR) controls pancreatic β-cell mass and hormone release, we hypothesized that nutritional insult in utero might permanently alter mTOR signaling. Mice were fed a low-protein (LP, 8%) or control (C, 20%) diet throughout pregnancy, and offspring examined until 130 days age. Mice receiving LP were born 12% smaller and β-cell mass was significantly reduced throughout life. Islet mTOR levels were lower in LP-exposed mice and localized predominantly to α-rather than β-cells. Incubation of isolated mouse islets with rapamycin significantly reduced cell proliferation while increasing apoptosis. mRNA levels for mTORC complex genes mTOR, Rictor and Raptor were elevated at 7 days in LP mice, as were the mTOR and Raptor proteins. Proglucagon gene expression was similarly increased, but not insulin or the immune/metabolic defense protein STING. In human and mouse pancreas STING was strongly associated with islet β-cells. Results support long-term changes in islet mTOR signaling in response to nutritional insult in utero, with altered expression of glucagon and insulin and a reduced β-cell mass. This may contribute to an increased risk of gestational or type 2 diabetes.

Highlights

Dietary restriction during human pregnancy results in a reduction in birth weight [1], leading to permanent changes in organ development including the endocrine pancreas [2], and contributing to an adult predisposition to type 2 diabetes and cardio-vascular disease [3]
The purpose of this study was to examine changes in the expression and function of proteins involved in mammalian target of rapamycin (mTOR) signaling in islets from mice exposed to LP vs. control diet in utero, to determine if prenatal programming of the pancreatic islet mTOR axis might contribute to the longer-term phenotype of decreased β-cell mass, function and adaptability to metabolic stress that could contribute to gestational diabetes
The abundance of mTOR protein in isolated islets relative to β-actin, as determined by Western blot, was significantly lower in the mice exposed to LP diet in utero than control-fed animals at 30 and 130 days of age

Summary

Introduction

Dietary restriction during human pregnancy results in a reduction in birth weight [1], leading to permanent changes in organ development including the endocrine pancreas [2], and contributing to an adult predisposition to type 2 diabetes and cardio-vascular disease [3]. The dietary insult resulted in reduced β-cell mass in the offspring due to a lower β-cell proliferation rate and a greater incidence of apoptosis, the latter seen under basal conditions as well as following exposure to cytotoxic cytokines [4,9]. We and others observed in mice that offspring of LP-fed dams were unable to adequately undergo the adaptive change in β-cell mass that normally occurs during pregnancy, resulting in impaired glucose tolerance during the final week of gestation [11,12]. This was associated with an inability to appropriately increase β-cell proliferation. Exposure to a LP diet in utero is associated with mice being unable to adequately regenerate β-cell mass after injury, to maintain β-cell viability in the presence of cytotoxic cytokines, and to increase β-cell mass to compensate for the metabolic demands of pregnancy

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