Noncanonical Regulation of cAMP-dependent Insulin Secretion and Its Implications in 2 Diabetes

Impaired glucose tolerance (IGT) and & beta;-cell dysfunction in insulin resistance associated with obesity lead to type 2 diabetes (T2D). Glucose-stimulated insulin secretion (GSIS) from & beta;-cells occurs via a canonical pathway that involves glucose metabolism, ATP generation, inactivation of KATP channels, plasma membrane depolarization, and increases in cytosolic concentrations of [Ca2+]c. However, optimal insulin secretion requires amplification of GSIS by increases in cyclic adeno-sine monophosphate (cAMP) signaling. The cAMP effectors protein kinase A (PKA) and exchange factor activated by cyclic-AMP (Epac) regulate membrane depolarization, gene expression, and trafficking and fusion of insulin granules to the plasma membrane for amplifying GSIS. The widely recognized lipid signaling generated within & beta;-cells by the & beta;-isoform of Ca2+-independent phospho-lipase A2 enzyme (iPLA2 & beta;) participates in cAMP-stimulated insulin secretion (cSIS). Recent work has identified the role of a G-protein coupled receptor (GPCR) activated signaling by the com-plement 1q like-3 (C1ql3) secreted protein in inhibiting cSIS. In the IGT state, cSIS is attenuated, and the & beta;-cell function is reduced. Interestingly, while & beta;-cell-specific deletion of iPLA2 & beta; reduces cAMP-mediated amplification of GSIS, the loss of iPLA2 & beta; in macrophages (Mo) confers protection against the development of glucose intolerance associated with diet-induced obesity (DIO). In this article, we discuss canonical (glucose and cAMP) and novel noncanonical (iPLA2 & beta; and C1ql3) pathways and how they may affect & beta;-cell (dys)function in the context of impaired glucose intoler-ance associated with obesity and T2D. In conclusion, we provide a perspective that in IGT states, targeting noncanonical pathways along with canonical pathways could be a more comprehen-sive approach for restoring & beta;-cell function in T2D. & COPY; 2023 American Physiological Society. Compr Physiol 13:5023-5049, 2023.

Automated summary

Impaired glucose tolerance and β-cell dysfunction in insulin resistance associated with obesity leads to the development of type 2 diabetes. Recent research suggests that both canonical and novel noncanonical pathways play a role in β-cell (dys)function. Therefore, targeting both pathways could be a more comprehensive approach for restoring β-cell function in the context of impaired glucose tolerance associated with obesity and type 2 diabetes.