Abstract
Background: Mitochondrial diabetes is primarily caused by β-cell failure, a cell type whose unique properties are important in pathogenesis. Methods: By reducing glucose, we induced energetic stress in two rodent β-cell models to assess effects on cellular function. Results: Culturing rat insulin-secreting INS-1 cells in low glucose conditions caused a rapid reduction in whole cell respiration, associated with elevated mitochondrial reactive oxygen species production, and an altered glucose-stimulated insulin secretion profile. Prolonged exposure to reduced glucose directly impaired mitochondrial function and reduced autophagy. Conclusions: Insulinoma cell lines have a very different bioenergetic profile to many other cell lines and provide a useful model of mechanisms affecting β-cell mitochondrial function.
Highlights
Mitochondria play a key role in glucose homeostasis[1,2]
Insulinoma cell lines are sensitive to media glucose levels with reduced glucose associated with increased mitochondrial Reactive oxygen species (ROS) production Initial experiments showed that β-cells grow poorly when media glucose levels are below 5mM (Supplementary Figure 4A)
Further studies of the origins of the oxidative stress showed the ROS resulting from incubation in low glucose medium to be of mitochondrial origin
Summary
Mitochondria play a key role in glucose homeostasis[1,2]. Maternally inherited diabetes is caused by a mtDNA mutation with a population prevalence of 1 in 3003, affecting up to 1% of patients with diabetes[4,5] and often going unrecognized by clinicians. In patients whose diabetes is associated with mitochondrial DNA mutations, reduced β-cell mass may result from islet hypoplasia[7] or apoptosis[8], the latter has never been demonstrated in vivo or post mortem tissue[9]. The limited post mortem studies suggest that the mutant load of the pathogenic 3243 A-G mtDNA mutation in t-RNA leucine is low in the pancreas compared to other affected tissues, 30% contrasting with >70% in other tissues[10]. This observation suggests that beta cells with high mutant load are likely to fail, and this is linked to reduced β-cell mass.
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