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
Affiliations
Sarah M. Graff
Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USA; Department of Pharmacy and Pharmaceutical Sciences, Lipscomb University, Nashville, TN 37204, USA
Arya Y. Nakhe
Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USA
Prasanna K. Dadi
Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USA
Matthew T. Dickerson
Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USA
Jordyn R. Dobson
Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USA
Karolina E. Zaborska
Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USA
Chloe E. Ibsen
Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USA
Regan B. Butterworth
Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USA
Nicholas C. Vierra
Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USA
David A. Jacobson
Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USA; Corresponding author
Summary: Mitochondrial Ca2+ ([Ca2+]m) homeostasis is critical for β-cell function and becomes disrupted during the pathogenesis of diabetes. [Ca2+]m uptake is dependent on elevations in cytoplasmic Ca2+ ([Ca2+]c) and endoplasmic reticulum Ca2+ ([Ca2+]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 [Ca2+]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 [Ca2+]m and suggest that metabolic remodeling in diabetes drives dysglycemia.
