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)
Poor growth of MIN-6 cells in 5mM glucose under 20% O2 could be improved by reducing the concentration of tissue culture oxygen to 10%, implicating oxygen stress (Supplementary Figure 4B)
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. 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.
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