Modelling of dysregulated glucagon secretion in type 2 diabetes by considering mitochondrial alterations in pancreatic α-cells.

Vladimir Grubelnik,Marko Gosak,Gerd Leitinger,Saška Lipovšek,Andraž Stožer,Ismael Valladolid-Acebes,Rene Markovič,Per-Olof Berggren,Matjaž Perc,Jurij Dolenšek,Marko Marhl

doi:10.1098/rsos.191171

Abstract

Type 2 diabetes mellitus (T2DM) has been associated with insulin resistance and the failure of β-cells to produce and secrete enough insulin as the disease progresses. However, clinical treatments based solely on insulin secretion and action have had limited success. The focus is therefore shifting towards α-cells, in particular to the dysregulated secretion of glucagon. Our qualitative electron-microscopy-based observations gave an indication that mitochondria in α-cells are altered in Western-diet-induced T2DM. In particular, α-cells extracted from mouse pancreatic tissue showed a lower density of mitochondria, a less expressed matrix and a lower number of cristae. These deformities in mitochondrial ultrastructure imply a decreased efficiency in mitochondrial ATP production, which prompted us to theoretically explore and clarify one of the most challenging problems associated with T2DM, namely the lack of glucagon secretion in hypoglycaemia and its oversecretion at high blood glucose concentrations. To this purpose, we constructed a novel computational model that links α-cell metabolism with their electrical activity and glucagon secretion. Our results show that defective mitochondrial metabolism in α-cells can account for dysregulated glucagon secretion in T2DM, thus improving our understanding of T2DM pathophysiology and indicating possibilities for new clinical treatments.

Highlights

For several decades, diabetes research has been focusing on insulin resistance and the consequent defects in pancreatic β-cells and insulin secretion
The systemic tests on Western diet (WD)-fed mice showed that after eight weeks, male C57BL6/J mice become obese and develop partially decompensated type 2 diabetes mellitus (T2DM) with hyperglycaemia and hyperinsulinaemia, which is in agreement with previously reported data [52]
The basic premise of the model is that the effectiveness of mitochondrial function is altered upon a specific diet and that the mitochondrial dysfunction is linked to the pathological morphological changes

Summary

Introduction

Diabetes research has been focusing on insulin resistance and the consequent defects in pancreatic β-cells and insulin secretion. It has been shown that glucose inhibits glucagon release at concentrations below the threshold for β-cell activation and insulin secretion, which would point more to intrinsic mechanisms of glucagon secretion in α-cells, at least in hypoglycaemic conditions [4] Several concepts of this intrinsic glucagon secretion have been evolved, from store-operated models [5,6] to KATP-channel-centred models [7,8,9]; for a recent review of these α-cell-intrinsic models for glucagon secretion, see [2]. The open probability of KATP channels decreases even more, causing a further membrane depolarization, closing the voltagedependent Na+ channels, and decreasing the amplitude of action potential firing This in turn reduces the amplitude of P/Q-type Ca2+-currents and glucagon secretion [10]

Methods

Results

Conclusion