Impaired insulin secretion and β-cell loss in tissue-specific knockout mice with mitochondrial diabetes

Abstract

Mitochondrial dysfunction is an important contributor to human pathology and it is estimated that mutations of mitochondrial DNA (mtDNA) cause approximately 0.5-1% of all types of diabetes mellitus. We have generated a mouse model for mitochondrial diabetes by tissue-specific disruption of the nuclear gene encoding mitochondrial transcription factor A (Tfam, previously mtTFA; ref. 7) in pancreatic beta-cells. This transcriptional activator is imported to mitochondria, where it is essential for mtDNA expression and maintenance. The Tfam-mutant mice developed diabetes from the age of approximately 5 weeks and displayed severe mtDNA depletion, deficient oxidative phosphorylation and abnormal appearing mitochondria in islets at the ages of 7-9 weeks. We performed physiological studies of beta-cell stimulus-secretion coupling in islets isolated from 7-9-week-old mutant mice and found reduced hyperpolarization of the mitochondrial membrane potential, impaired Ca(2+)-signalling and lowered insulin release in response to glucose stimulation. We observed reduced beta-cell mass in older mutants. Our findings identify two phases in the pathogenesis of mitochondrial diabetes; mutant beta-cells initially display reduced stimulus-secretion coupling, later followed by beta-cell loss. This animal model reproduces the beta-cell pathology of human mitochondrial diabetes and provides genetic evidence for a critical role of the respiratory chain in insulin secretion.

Fetal programming of glucose–insulin metabolism

“…Indeed, increased levels of ROS lead to decreased levels of glucose mediated insulin secretion (86)(87)(88), decreased beta cell proliferation (86) and decreased expression of genes vital for beta cell function, including insulin (89)(90)(91)(92)(93)(94)(95). Ultimately the viability of beta cells is at risk (96,97). Uterine artery ligation in the rat has been shown to elicit similar metabolic effects in the muscle as uteroplacental insufficiency does in humans.…”

mt-Nd2 Allele of the ALR/Lt mouse confers resistance against both chemically induced and autoimmune diabetes

“…Hence, an important axis exists between the nuclear and mitochondrial genomes in maintaining intracellular redox potential. Insulin biosynthetic and secretory capacities of pancreatic beta cells are highly dependent upon normal nuclear/mt communication [3], mt ATP generation [4], and exquisite sensitivity to ROS-mediated damage [5,6]. In this context, reports of mtDNA mutations associated with matrilineal type 2 diabetes (T2D) pedigrees in humans and rodents are becoming increasingly more frequent [7][8][9], accounting for up to 1% of human T2D.…”

Of mice and models: improved animal models for biomedical research

“…B: metabolic/endocrine dysfunction. Tissue-specific disruption of the nuclear gene encoding the mitochondrial transcription factor A (mtTFA) sets off diabetes (130). C: cardiovascular disease.…”