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Nutrient sensing in pancreatic islets: lessons from congenital hyperinsulinism and monogenic diabetes
Author(s) -
Lu Ming,
Li Changhong
Publication year - 2018
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1111/nyas.13448
Subject(s) - glucokinase , congenital hyperinsulinism , medicine , endocrinology , hyperinsulinism , beta cell , insulin , hypoglycemia , diabetes mellitus , glut2 , sulfonylurea receptor , maturity onset diabetes of the young , biology , islet , glucose transporter , insulin resistance , type 2 diabetes , glibenclamide
Abstract Pancreatic beta cells sense changes in nutrients during the cycles of fasting and feeding and release insulin accordingly to maintain glucose homeostasis. Abnormal beta cell nutrient sensing resulting from gene mutations leads to hypoglycemia or diabetes. Glucokinase (GCK) plays a key role in beta cell glucose sensing. As one form of congenital hyperinsulinism (CHI), activating mutations of GCK result in a decreased threshold for glucose‐stimulated insulin secretion and hypoglycemia. In contrast, inactivating mutations of GCK result in diabetes, including a mild form (MODY2) and a severe form (permanent neonatal diabetes mellitus (PNDM)). Mutations of beta cell ion channels involved in insulin secretion regulation also alter glucose sensing. Activating or inactivating mutations of ATP‐dependent potassium (K ATP ) channel genes result in severe but completely opposite clinical phenotypes, including PNDM and CHI. Mutations of the other ion channels, including voltage‐gated potassium channels (K v 7.1) and voltage‐gated calcium channels, also lead to abnormal glucose sensing and CHI. Furthermore, amino acids can stimulate insulin secretion in a glucose‐independent manner in some forms of CHI, including activating mutations of the glutamate dehydrogenase gene, HDAH deficiency, and inactivating mutations of K ATP channel genes. These genetic defects have provided insight into a better understanding of the complicated nature of beta cell fuel‐sensing mechanisms.