TALK-1-mediated alterations of β-cell mitochondrial function and insulin secretion impair glucose homeostasis on a diabetogenic diet
Sarah M. Graff, Arya Y. Nakhe, Prasanna K. Dadi, Matthew T. Dickerson, Jordyn R. Dobson, Karolina E. Zaborska, Chloe E. Ibsen, Regan B. Butterworth, Nicholas C. Vierra, David A. Jacobson
Abstract
Mitochondrial Ca 2+ ([Ca 2+ ] m ) homeostasis is critical for β-cell function and becomes disrupted during the pathogenesis of diabetes. [Ca 2+ ] m uptake is dependent on elevations in cytoplasmic Ca 2+ ([Ca 2+ ] c ) and endoplasmic reticulum Ca 2+ ([Ca 2+ ] ER ) release, both of which are regulated by the two-pore domain K + channel TALK-1. Here, utilizing a novel β-cell TALK-1-knockout (β-TALK-1-KO) mouse model, we found that TALK-1 limited β-cell [Ca 2+ ] m accumulation and ATP production. However, following exposure to a high-fat diet (HFD), ATP-linked respiration, glucose-stimulated oxygen consumption rate, and glucose-stimulated insulin secretion (GSIS) were increased in control but not TALK1-KO mice. Although β-TALK-1-KO animals showed similar GSIS before and after HFD treatment, these mice were protected from HFD-induced glucose intolerance. Collectively, these data identify that TALK-1 channel control of β-cell function reduces [Ca 2+ ] m and suggest that metabolic remodeling in diabetes drives dysglycemia.