Differential sensitivity of human islets from obese versus lean donors to chronic high glucose or palmitate.

Françoise Castex,René Gross,Jeremy Leroy,Christophe Broca,Anne Wojtusciszyn,Flore Duranton,Karima Mezghenna,Vanessa Lavallard,Anne‐Dominique Lajoix,Fanny Lebreton

doi:10.1111/1753-0407.13026

Françoise Castex, René Gross + Show 8 more

Open Access

https://doi.org/10.1111/1753-0407.13026

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Abstract

Due to the shortage of multi-organ donors, human pancreatic islet transplantation has now been extended to islets originating from obese subjects. In this study, our aim is to compare the respective sensitivity of human islets from lean vs obese donors to chronic high glucose or high palmitate. Human islets were isolated from pancreases harvested from brain-dead multi-organ donors. Islets were cultured during 72 hours in the presence of moderate (16.7 mmol/L) or high (28 mmoL/L) glucose concentrations, or glucose (5.6 mmoL/L) and palmitate (0.4 mmoL/L), before measurement of their response to glucose. We first observed a greater insulin response in islets from obese donors under both basal and high-glucose conditions, confirming their hyperresponsiveness to glucose. When islets from obese donors were cultured in the presence of moderate or high glucose concentrations, insulin response to glucose remained unchanged or was slightly reduced, as opposed to that observed in lean subjects. Moreover, culturing islets from obese donors with high palmitate also induced less reduction in insulin response to glucose than in lean subjects. This partial protection of obese islets is associated with less induction of inducible nitric oxide synthase in islets, together with a greater expression of the transcription factor forkhead box O1 (FOXO1). Our data suggest that in addition to an increased sensitivity to glucose, islets from obese subjects can be considered as more resistant to glucose and fatty acid excursions and are thus valuable candidates for transplantation.

Highlights

Human pancreatic islet transplantation is considered as an effective cell replacement therapy for the management of certain categories of type 1 diabetes.[1]
As inducible nitric oxide synthase (iNOS) has been previously shown to be induced by high glucose and to modulate insulin secretion,[17] we investigated whether the chronic exposure to high glucose could differently affect iNOS expression in islets from lean or obese subjects
During the silent phase preceding the onset of type 2 diabetes, pancreatic β-cells compensate for insulin resistance by upregulating insulin secretion, which allows the maintenance of normoglycemia

Summary

| INTRODUCTION

Human pancreatic islet transplantation is considered as an effective cell replacement therapy for the management of certain categories of type 1 diabetes.[1]. A major hurdle to this procedure is the access to deceased multi-organ donors and the need of several islet transplants to achieve insulin independence For these reasons, indications for pancreas removal have been extended to initially excluded donors, namely obese subjects (body mass index, BMI > 30 kg/m2).[3,4] isolation of pancreatic islets from obese donors gives higher yields of islets, with an improved purity as compared to lean donors.[5,6] Isolated islets from obese donors display a comparable viability and allow achieving normoglycemia when transplanted to streptozotocininduced diabetic nude mice.[6] the risk of certain complications is significantly increased with obese donors, such as surgical thrombosis and infections.[7] when transplantation is technically successful, the same graft survival as for lean donors is achieved at 1 and 3 years.[7]. In the present study, our objective is to compare the respective sensitivity of human islets from lean vs obese donors to chronic high glucose or high palmitate, in relation to iNOS expression, and to allow better selection of pancreases for islets grafts

| METHODS

| RESULTS

Findings

| DISCUSSION