Cholinergic augmentation of insulin release requires ankyrin-B.
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.
Healy
Jane A
JA
1Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC 27710, USA.
Nilsson
Kent R
KR
Hohmeier
Hans E
HE
Berglund
Jelena
J
Davis
Jonathan
J
Hoffman
Janis
J
Kohler
Martin
M
Li
Luo-Sheng
LS
Berggren
Per-Olof
PO
Newgard
Christopher B
CB
Bennett
Vann
V
D000818:Animals; D017487:Ankyrins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002217:Carbachol / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D015151:Immunoblotting; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D051379:Mice; D008856:Microscopy, Fluorescence; D020125:Mutation, Missense; D010275:Parasympathetic Nervous System / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012307:Risk Factors
C498995:Ank2 protein, mouse; D017487:Ankyrins; D053496:Inositol 1,4,5-Trisphosphate Receptors; D007328:Insulin; D034741:RNA, Small Interfering; D002217:Carbachol; D005947:Glucose; D002118:Calcium