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The β-cell workload increases in the setting of insulin resistance and reduced β-cell mass, which occurs in type 2 and type 1 diabetes, respectively. The prolonged elevation of insulin production and secretion during the pathogenesis of diabetes results in β-cell ER stress. The depletion of β-cell Ca 2+ ER during ER stress activates the unfolded protein response, leading to β-cell dysfunction. Ca 2+ ER is involved in many pathways that are critical to β-cell function, such as protein processing, tuning organelle and cytosolic Ca 2+ handling, and modulating lipid homeostasis. Mutations that promote β-cell ER stress and deplete Ca 2+ ER stores are associated with or cause diabetes (e.g., mutations in ryanodine receptors and insulin). Thus, improving β-cell Ca 2+ ER handling and reducing ER stress under diabetogenic conditions could preserve β-cell function and delay or prevent the onset of diabetes. This review focuses on how mechanisms that control β-cell Ca 2+ ER are perturbed during the pathogenesis of diabetes and contribute to β-cell failure.

The gain-of-function mutation in the TALK-1 K + channel (p.L114P) is associated with maturity-onset diabetes of the young (MODY). TALK-1 is a key regulator of β-cell electrical activity and glucose-stimulated insulin secretion. The KCNK16 gene encoding TALK-1 is the most abundant and β-cell-restricted K + channel transcript. To investigate the impact of KCNK16 L114P on glucose homeostasis and confirm its association with MODY, a mouse model containing the Kcnk16 L114P mutation was generated. Heterozygous and homozygous Kcnk16 L114P mice exhibit increased neonatal lethality in the C57BL/6J and the CD-1 (ICR) genetic background, respectively. Lethality is likely a result of severe hyperglycemia observed in the homozygous Kcnk16 L114P neonates due to lack of glucose-stimulated insulin secretion and can be reduced with insulin treatment. Kcnk16 L114P increased whole-cell β-cell K + currents resulting in blunted glucose-stimulated Ca 2+ entry and loss of glucose-induced Ca 2+ oscillations. Thus, adult Kcnk16 L114P mice have reduced glucose-stimulated insulin secretion and plasma insulin levels, which significantly impairs glucose homeostasis. Taken together, this study shows that the MODY-associated Kcnk16 L114P mutation disrupts glucose homeostasis in adult mice resembling a MODY phenotype and causes neonatal lethality by inhibiting islet insulin secretion during development. These data suggest that TALK-1 is an islet-restricted target for the treatment for diabetes., Competing Interests: AN, PD, JK, MD, SB, JD, SS, JC, LS, MM, DJ No competing interests declared, (© 2023, Nakhe et al.)

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., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

G i/o -coupled somatostatin or α2-adrenergic receptor activation stimulated β-cell NKA activity, resulting in islet Ca 2+ fluctuations. Furthermore, intra-islet paracrine activation of β-cell G i/o -GPCRs and NKAs by δ-cell somatostatin secretion slowed Ca 2+ oscillations, which decreased insulin secretion. β-cell membrane potential hyperpolarization resulting from G i/o -GPCR activation was dependent on NKA phosphorylation by Src tyrosine kinases. Whereas, β-cell NKA function was inhibited by cAMP-dependent PKA activity. These data reveal that NKA-mediated β-cell membrane potential hyperpolarization is the primary and conserved mechanism for G i/o -GPCR control of electrical excitability, Ca 2+ handling, and insulin secretion., (© 2022. The Author(s).)

Aim: To determine whether hyperpolarization-activated cyclic nucleotide-gated (HCN) channels impact glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) modulation of islet Ca 2+ handling and insulin secretion., Methods: The impact of liraglutide (GLP-1 analogue) on islet Ca 2+ handling, HCN currents and insulin secretion was monitored with fluorescence microscopy, electrophysiology and enzyme immunoassays, respectively. Furthermore, liraglutide-mediated β-to-δ-cell cross-communication was assessed following selective ablation of either mouse islet δ or β cells., Results: Liraglutide increased β-cell Ca 2+ oscillation frequency in mouse and human islets under stimulatory glucose conditions. This was dependent in part on liraglutide activation of HCN channels, which also enhanced insulin secretion. Similarly, liraglutide activation of HCN channels also increased β-cell Ca 2+ oscillation frequency in islets from rodents exposed to a diabetogenic diet. Interestingly, liraglutide accelerated Ca 2+ oscillations in a majority of islet δ cells, which showed synchronized Ca 2+ oscillations equivalent to β cells; therefore, we assessed if either cell type was driving this liraglutide-mediated islet Ca 2+ response. Although δ-cell loss did not impact liraglutide-mediated increase in β-cell Ca 2+ oscillation frequency, β-cell ablation attenuated liraglutide-facilitated acceleration of δ-cell Ca 2+ oscillations., Conclusion: The data presented here show that liraglutide-induced stimulation of islet HCN channels augments Ca 2+ oscillation frequency. As insulin secretion oscillates with β-cell Ca 2+ , these findings have important implications for pulsatile insulin secretion that is probably enhanced by liraglutide activation of HCN channels and therapeutics that target GLP-1Rs for treating diabetes. Furthermore, these studies suggest that liraglutide as well as GLP-1-based therapies enhance δ-cell Ca 2+ oscillation frequency and somatostatin secretion kinetics in a β-cell-dependent manner., (© 2022 John Wiley & Sons Ltd.)