Channeling glycemia: The role of islet TALK-1 gain- and loss-of-function channels in Ca2+ handling, metabolism, hormone secretion, and insulin sensitivity

Abstract

Pancreatic islet insulin secretion is impaired during diabetes pathogenesis, due in part to disruption of β-cell Ca2+ handling. TALK-1 K+ channels are key regulators of ꞵ-cell electrical excitability, Ca2+ entry, and glucose-stimulated insulin secretion (GSIS). KCNK16, the gene encoding TALK-1 is the most abundant ꞵ-cell K+ channel transcript and the most islet-restricted ion channel. Furthermore, there is strong genetic evidence linking KCNK16 to diabetic phenotypes; including a gain-of-function (GOF) polymorphism (rs1535500) that causes a predisposition for type-2 diabetes (T2D) and a GOF mutation (p. L114P) associated with maturity-onset diabetes of the young (MODY). Here, using mouse models with TALK-1 loss-of-function (LOF) and TALK-1 GOF we tested the roles of TALK-1 in islet function and glucose homeostasis. Neonatal mice harboring the TALK-1-L114P GOF mutation exhibit severe hyperglycemia, lack of GSIS, and increased neonatal lethality. Whereas in adult mice, TALK-1-L114P blunts glucose-stimulated β-cell electrical activity, Ca2+ handling, and GSIS, thus significantly impairing glucose tolerance resulting in a MODY-like phenotype. This confirms that increased TALK-1 activity leads to a diabetic phenotype. Interestingly, mice with β-cell TALK-1 ablation are protected from glucose dyshomeostasis on a diabetogenic diet. As these mice also exhibit less GSIS on a diabetogenic diet, this suggests that TALK-1 control of β-cell insulin secretion may impact hepatic and/or peripheral insulin demand. Finally, to test if TALK-1 could be selectively targeted utilizing pharmacology, we developed a high-throughput screening approach and identified 78 small-molecule TALK-1-selective inhibitors. The identified inhibitors impact islet Ca2+ handling and, thus, could be utilized to test TALK-1 inhibition as a therapeutic approach to treat diabetes. In summary, this thesis determined that changes in TALK-1 activity are an important regulator of islet hormone secretion, insulin sensitivity, and glucose homeostasis, suggesting that modulation of TALK-1 function should be explored as a strategy for diabetes treatment.