Peeling the onion: another layer in the regulation of insulin secretion
Kristie I. Aamodt, Alvin C. Powers
Kristie I. Aamodt, Alvin C. Powers
View: Text | PDF
Commentary

Peeling the onion: another layer in the regulation of insulin secretion

Abstract

Insulin secretion by pancreatic β cells is a dynamic and highly regulated process due to the central importance of insulin in enabling efficient utilization and storage of glucose. Multiple regulatory layers enable β cells to adapt to acute changes in nutrient availability as well as chronic changes in metabolic demand. While epigenetic factors have been well established as regulators of chronic β cell adaptations to insulin resistance, their role in acute adaptations in response to nutrient stimulation has been relatively unexplored. In this issue of the JCI, Wortham et al. report that short-term dynamic changes in histone modifications regulated insulin secretion and acute β cell adaptations in response to fasting and feeding cycles. These findings highlight the importance of investigating whether other epigenetic mechanisms may contribute to acute physiologic adaptations in β cells.

Authors

Kristie I. Aamodt, Alvin C. Powers

×

Figure 1

Complex interactions across multiple regulatory layers generate dynamic changes in insulin secretion in response to acute and chronic metabolic stimuli.

Options: View larger image (or click on image) Download as PowerPoint
Complex interactions across multiple regulatory layers generate dynamic ...
(i) The insulin secretory mechanism intrinsic to β cells regulates the triggering phase of GSIS, where an increase in plasma glucose rapidly activates insulin secretion. Glucose metabolism generates ATP through mitochondrial oxidative metabolism and additional noncanonical pathways (dotted line) (8). This increase in intracellular ATP closes KATP channels, which depolarizes the membrane, consequently activating voltage-gated Ca2+ channels. Subsequent increases in intracellular Ca2+ trigger exocytosis of insulin secretory granules. Several mechanisms, predominantly KATP channel independent, potentiate insulin secretion during the amplifying phase via intermediary metabolites and metabolic coupling factors that further increase trafficking and secretion of insulin granules. (ii) Initiation of GSIS activates transcriptional changes in nutrient-responsive genes, allowing for β cell adaptation to acute cycles of feeding and fasting. The β cell adapts to prolonged nutrient stimulation by increasing proinsulin synthesis and compensatory hypertrophy of the ER and Golgi complex. (iii) Wortham et al. (7) identified a role for Lsd1-mediated changes of histone acetylation in regulating the expression of these nutrient-responsive genes. Other epigenetic regulators of insulin secretion, including DNA methylation, RNA modifications, and ncRNAs, play a role in chronic β cell adaptations to insulin resistance. (iv) Paracrine signals from α cells, such as glucagon, GLP-1, and acetylcholine, potentiate insulin secretion, while δ cells counterbalance GSIS via somatostatin. Glucagon and GLP-1 work through G protein–coupled receptors (GCGR and GLP-1R) to activate cAMP/pKA signaling. (v) Insulin secretion is also regulated acutely in response to circulating factors that are increased with feeding. Nutrients, including amino acids and FFAs, along with circulating incretin hormones from the gastrointestinal tract, including GLP-1 and GIP, promote insulin secretion and acute β cell adaptations. Specific circulating miRNAs have also been shown to regulate insulin secretion and chronic β cell adaptations.