Disruption of mitochondria-associated membranes contributes to the dysregulation of insulin secretion in undernutrition, obesity, and double burden of malnutrition

Abstract

Aims/hypothesis

Nutritional disorders directly affect the endocrine pancreas, increasing the susceptibility to type 2 diabetes mellitus. However, the molecular mechanisms underlying these alterations remain unknown. This study aims to characterize the role of endoplasmic reticulum (ER)-mitochondria contact sites, known as mitochondrial-associated membranes (MAMs), in insulin secretion dysfunctions associated with undernutrition, obesity, and the double burden of malnutrition (DBM).

Methods

Rat pancreatic INS-1E β-cells were cultured in a medium without amino acids supplemented with 1 × (control) or 0.25 × (amino acid restriction) of an amino acid solution for 48 h, and then cells were exposed to a fatty acid mix for 48 h. Male C57BL/6 mice were fed a normoprotein diet (14 % protein) or protein-restricted diet (6 % protein) for 6 weeks and subsequently a high-fat diet (35 % kcal) for 12 weeks. ER-mitochondria interactions were evaluated by in situ proximity ligation assay and transmission electronic microscopy.

Results

Our findings indicate that protein restriction reduces ER-mitochondria contacts in pancreatic beta-cells, leading to decreased mitochondrial metabolism and glucose-stimulated insulin secretion (GSIS). In contrast, obesity increases ER-mitochondria contact points, mitochondrial metabolism, and GSIS in pancreatic beta-cells, without alterations in viability. DBM results in a significant increase in ER-mitochondria contacts, elevated mitochondrial calcium levels, increased production of reactive oxygen species, and cell death, collectively contributing to impaired GSIS response in the context of obesity.

Conclusions/interpretation

These data indicates that MAMs play a crucial role in GSIS during nutritional disorders such as undernutrition, obesity, and DBM. Importantly, changes in MAMs precede GSIS impairment, therefore targeting these interactions might prevent further disruption in beta-cell function.