Cholinergic Augmentation of Insulin Release Requires Ankyrin-B

Abstract

Parasympathetic stimulation of pancreatic islets augments glucose-stimulated insulin secretion by inducing inositol trisphosphate receptor (IP(3)R)-mediated calcium ion (Ca2+) release. Ankyrin-B binds to the IP(3)R and is enriched in pancreatic beta cells. We found that ankyrin-B-deficient islets displayed impaired potentiation of insulin secretion by the muscarinic agonist carbachol, blunted carbachol-mediated intracellular Ca2+ release, and reduced the abundance of IP3R. Ankyrin-B-haploinsufficient mice exhibited hyperglycemia after oral ingestion but not after intraperitoneal injection of glucose, consistent with impaired parasympathetic potentiation of glucose-stimulated insulin secretion. The R1788W mutation of ankyrin-B impaired its function in pancreatic islets and is associated with type 2 diabetes in Caucasians and Hispanics. Thus, defective glycemic regulation through loss of ankyrin-B-dependent stabilization of IP3R is a potential risk factor for type 2 diabetes.

ARA290 Improves Insulin Release and Glucose Tolerance in Type 2 Diabetic Goto-Kakizaki Rats

“…Following rapid transport through the β-cell plasma membrane, the hexose is phosphorylated to glucose-6-phosphate, and then further metabolized through glycolysis and citric acid cycle to yield ATP (15). The subsequent increase in the cytosolic ATP/ADP ratio leads to closure of the ATP-regulated K + channels, plasma membrane depolarization and opening of voltage-dependent L-type Ca 2+ channels (13,14). The resulting increase in [Ca 2+ ] i stimulates the exocytosis of insulin granules (16).…”

New Horizons in Cellular Regulation by Inositol Polyphosphates: Insights from the Pancreaticβ-Cell

“…In the first, acetylcholine-activated, PLC-linked M3 receptors were selectively knocked out in mouse pancreatic b-cells (Gautam et al, 2006) and, in the second, depletion of the Ins(1,4,5)P 3 receptor after the knockout of ankyrin B (Healy et al, 2010). The phenotype of both these interventions was a marked curtailment of glucose-induced insulin secretion.…”

“…In both cases, an impairment of glucosestimulated insulin secretion results in a type 2 diabetic (T2D) phenotype. The latest report comes from work on the ankyrin B knockout mouse (Healy et al, 2010). Ankyrin B is only expressed in the pancreatic b-cells and not in other islet cells, which aids interpretation of the results.…”

“…With few exceptions, there has been little characterization of partner proteins in b-cells. However, the data from both the ankyrin B (Healy et al, 2010) and b 3 -knockout mice (Berggren et al, 2004), suggest that there is much to explore in this subject area.…”

β IV -Spectrin and CaMKII facilitate Kir6.2 regulation in pancreatic beta cells

“…β-Spectrin polypeptides associate with ankyrin proteins through a conserved binding motif in the β-spectrin 15th spectrin repeat (11). Ankyrin-B (AnkB) is present within the islet and necessary for the targeting and expression of the ATP-sensitive potassium channel (K ATP ) (12) and inositol 1,4,5 trisphosphate (IP3) receptor (13). Human mutations in Kir6.2 (K ATP channel α-subunit) that block binding with AnkB are associated with neonatal diabetes mellitus (12,14), although these variants may also affect K ATP Kir6.2/SUR1 subunit coupling (15).…”