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Abstract
Type 2 diabetes develops when beta cells are not able to fulfill insulin needs. The role of the endoplasmic reticulum–mitochondria junction in coordinating the functions of these two organelles throughout the natural history of type 2 diabetes is determinant and may explain the alterations of insulin biosynthesis. Our goal was to study endoplasmic reticulum and mitochondrial interactions in human beta cells from organ donors with type 2 diabetes. Pancreas samples were obtained via the network for pancreatic organ donors with diabetes (nPOD) based on disease status with 12 subjects with type 2 diabetes and 9 non-diabetic controls. We examined pancreatic specimens by immunofluorescence, in situ hybridization and in situ proximity ligation assay and compared the results to an in vitro model of beta-cell dysfunction. Expression of proteins that enable tethering and exchanges between endoplasmic reticulum (ER) and mitochondria and quantification of interconnection through mitochondria associated membranes (MAM) was investigated. In beta cells from type 2 diabetic cases as compared to controls, there was a significant increase in reticular expression of inositol triphosphate receptor-2 (IP3R2) both at the protein and mRNA levels, no difference in mitochondrial transit peptide receptor TOM20 and mitofusin-2 expressions, and a decrease in the expression of voltage-dependent anion channel-1 (VDAC-1). The number of IP3R2-VDAC-1 complexes identified by in situ proximity ligation assay was significantly lower in diabetic islets and in beta cells of diabetics as compared to controls. Treatment of Min6-B1 cells with palmitate altered glucose-stimulated insulin secretion, increased ER stress and significantly reduced ER-mitochondrial interactions. We can conclude that specific changes in reticular and mitochondrial beta cell proteins characterize human type 2 diabetes with reduction in organelle interactions. This finding opens new targets of intervention.
Highlights
Type 2 diabetes is characterized by beta cells being unable to produce sufficient amounts of insulin in the context of insulin resistance
Because beta cells are subjected to high insulin demand in response to hyperglycemia and peripheral insulin resistance, we postulated that expressions of proteins involved at the ERmitochondrion interface were increased during type 2 diabetes
We studied by in situ hybridization (ISH) experiments, the number of ITPR2 transcripts per islet cell with a representative figure shown in S3A Fig in comparison to positive and negative controls using PPIB and DapB probes, as shown in S3B and S3C Fig respectively
Summary
Type 2 diabetes is characterized by beta cells being unable to produce sufficient amounts of insulin in the context of insulin resistance. Interrelated stressors alter beta cells with different proportions among diabetic individuals that include lipid accumulation, inflammation, endoplasmic reticulum (ER) stress, oxidative stress and amyloid deposits which lead to beta cell apoptosis [1, 2]. This sequence of events are largely extrapolated from animal models as well as from in vitro studies using cell lines or primary islet cell cultures and reinforces the need to intervene as early as possible in the course of the disease to prevent beta cell loss. There is an important heterogeneity among patients due to genetic polymorphisms that control insulin synthesis as well as disparities between the levels of nutritional load and body’s insulin sensitivity
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