Sweet taste receptors regulate basal insulin secretion and contribute to compensatory insulin hypersecretion during the development of diabetes in male mice.
β-Cells rapidly secrete insulin in response to acute increases in plasma glucose but, upon further continuous exposure to glucose, insulin secretion progressively decreases. Although the mechanisms are unclear, this mode of regulation suggests the presence of a time-dependent glucosensory system that temporarily attenuates insulin secretion. Interestingly, early-stage β-cell dysfunction is often characterized by basal (ie, fasting) insulin hypersecretion, suggesting a disruption of these related mechanisms. Because sweet taste receptors (STRs) on β-cells are implicated in the regulation of insulin secretion and glucose is a bona fide STR ligand, we tested whether STRs mediate this sensory mechanism and participate in the regulation of basal insulin secretion. We used mice lacking STR signaling (T1R2(-/-) knockout) and pharmacologic inhibition of STRs in human islets. Mouse and human islets deprived of STR signaling hypersecrete insulin at short-term fasting glucose concentrations. Accordingly, 5-hour fasted T1R2(-/-) mice have increased plasma insulin and lower glucose. Exposure of isolated wild-type islets to elevated glucose levels reduced STR expression, whereas islets from diabetic (db/db) or diet-induced obese mouse models show similar down-regulation. This transcriptional reprogramming in response to hyperglycemia correlates with reduced STR function in these mouse models, leading to insulin hypersecretion. These findings reveal a novel mechanism by which insulin secretion is physiologically regulated by STRs and also suggest that, during the development of diabetes, STR function is compromised by hyperglycemia leading to hyperinsulinemia. These observations further suggest that STRs might be a promising therapeutic target to prevent and treat type 2 diabetes.
Diabetes and Obesity Research Center (G.A.K., K.R.S., B.T., T.H., R.E.P.) Sanford-Burnham Medical Research Institute, Orlando, Florida 32827; Translational Research Institute for Metabolism and Diabetes (G.A.K., R.E.P.), Florida Hospital, Orlando, Florida 32804; and Translational Science (B.T.), Cardiovascular and Metabolic Disease, Mölndal, AstraZeneca, Sweden.
George A
GA
Kyriazis
Kathleen R
KR
Smith
Björn
B
Tyrberg
Tania
T
Hussain
Richard E
RE
Pratley
D000818:Animals; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D008297:Male; D051379:Mice; D060888:Real-Time Polymerase Chain Reaction; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*
D007328:Insulin; D043562:Receptors, G-Protein-Coupled; C431926:taste receptors, type 1