Abstract

Type 2 diabetes (T2D) is a metainflammatory disease characterized by impairments in mitochondrial function and ultrastructure that contribute to the overall disruption of β-cell function. Mitochondria rely on both the nuclear genome as well as their own 16.6 kilobase-pair circular genome to generate the machinery required for oxidative phosphorylation (OXPHOS). Recently, our group identified a reduction in mitochondrial DNA (mtDNA) copy number in islets from donors with T2D, indicating a disruption in mitochondrial genome stability. While mtDNA genome instability is implicated in several diseases, its impact on β-cell dysfunction in diabetes has yet to be explored. Here, we generated a mouse model prone to increased β-cell mtDNA deletions by selective expression of a dominant negative Twinkle (TwnkK320E) helicase mutant, which is essential for mtDNA maintenance. Beginning at 5 weeks, β-TwnkK320E mice exhibited impaired glucose tolerance, which progressively worsened with age. Circulating insulin concentrations following glucose stimulation were also reduced in β-TwnkK320E mice by 5 weeks of age, yet there was no difference in β-cell mass, suggestive of a β cell functional defect. Further, we observed a complete loss of MafA, a key regulator of β-cell maturity, from a subset of β cells in β-TwnkK320E mice. While mitochondrial mass was unchanged between groups, β‑TwnkK320E islets have altered expression of subunits of all OXPHOS complexes, as well as reduced glucose-stimulated oxygen consumption, indicative of impaired mitochondrial function. Together, these data suggest that the accumulation of mtDNA deletions diminishes β-cell function and support the importance of mitochondrial genome integrity to β-cell health. Disclosure R.K. Davidson: Employee; Eli Lilly and Company. J. Zhu: None. E.C. Reck: None. S. Soleimanpour: Advisory Panel; Novo Nordisk. Research Support; Ono Pharmaceutical Co., Ltd. Funding National Institutes of Health (T32DK101357)