Mitochondrial dysfunction in pancreatic β-cells in Type 2 Diabetes

Abstract

Mitochondrial metabolism controls insulin secretion from the pancreatic β-cell. Type 2 Diabetes evolves when the β-cells fail to release appropriate amounts of insulin, causing metabolic dysregulation and hyperglycemia. It is attractive to assume that mitochondrial dysfunction plays a decisive role in these processes. Indeed, while being a rare condition, genetically determined dysfunction of mitochondria causes a Type 2 Diabetes-like syndrome.Here, we review what is known about mitochondrial dysfunction in the β-cell in Type 2Diabetes. The focus is on observations in humans but relevant studies in animal models of the disease are discussed. A particular emphasis is placed on changes in metabolic enzymes and function in β-cell mitochondria and how altered structure of the organelle appears to facilitate its function. These molecular processes are subject to tight genetic as well as epigenetic control. Variations and implications of these mechanisms are reviewed. The emerging picture is that alterations in mitochondria may be a culprit in the pathogenetic processes culminating in Type 2 Diabetes. Such processes may prove to be targets for therapeutic interventions in the disease.

Sex-specific genetic dissection of diabetes in a rodent model identifies Ica1 and Ndufa4 as major candidate genes

“…Ndufa4 is also considered to be an endogenous antioxidant that protects intracellular membranes from lipid peroxidation under oxidative stress (9). Since intact mitochondrial function is required for normal insulin secretion (12,15), low expression of Ndufa4 could lead, under conditions of exceeding demand, to mitochondrial insufficiency.…”

Targeting cyclophilin D and the mitochondrial permeability transition enhances β-cell survival and prevents diabetes in Pdx1 deficiency

“…Mitochondria are implicated in the pathogenesis of diabetes mellitus (14). Recently, a connection between Pdx1 insufficiency and mitochondrial dysfunction was described, implicating dysregulation of the mitochondrial transcription factor TFAM in abnormal insulin secretion (15).…”

Common variation in oxidative phosphorylation genes is not a major cause of insulin resistance or type 2 diabetes

“…Based on the substantial evidence that mitochondrial dysfunction is linked to insulin resistance and beta cell dysfunction, and is present in multiple tissues relevant to the pathogenesis of type 2 diabetes [7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22], we hypothesised that common variation in OxPhos genes contributes to an increased risk of type 2 diabetes or influences metabolic traits related to the disease. OxPhos gene variants showing nominal association with type 2 diabetes in a meta-analysis of three GWA studies that were part of the DIAGRAM Study [28] were selected for follow-up in an independent cohort of Danish individuals.…”

“…This includes reports of reduced expression of electron transport chain (ETC) genes in adipose tissue of women with type 2 diabetes [16], and of impaired mitochondrial respiratory capacity in heart muscle [17] and liver from type 2 diabetic individuals [18]. Finally, mitochondrial ATP production is known to play a critical regulatory role in glucosestimulated insulin secretion, and several recent studies have suggested that defects in mitochondrial OxPhos could contribute to beta cell dysfunction in patients with type 2 diabetes [19][20][21][22].…”