A common human variant of GIPR improves systemic glucose homeostasis in a sexual dimorphic manner

Abstract

SummaryGlucose-dependent insulinotropic polypeptide (GIP), an incretin hormone, has a role in controlling postprandial metabolic tone. A GIP receptor (GIPR) variant (Q354, rs1800437) is associated with enhanced glucose tolerance and a lower BMI. To isolate the contribution of GIPR in metabolic control, we generated a mouse model of the GIPR-Q354 variant. Islets isolated from both male and female GIPR-Q variant mice have an enhanced glucose sensitivity and enhanced GIP response. In whole animal studies only female GIPR-Q variant mice are more glucose tolerant, whereas males have normal glucose tolerance but an enhanced sensitivity to GIP. In both sexes postprandial GIP levels are reduced, revealing feedback between the sensitivity of GIP target tissues and the secretion of GIP from intestinal endocrine cells. In line with the association of the variant with reduced BMI, GIPR-Q350 mice are resistant to diet-induced obesity. GIPR, a GPCR, is coupled to elevated cAMP. Prior studies have established altered post-activation traffic of the GIPR-Q variant without a change in affinity for GIP or in cAMP production. Consequently, our data link altered intracellular traffic of the GIPR-Q variant with GIP metabolic control of metabolism. Incretin hormone action is targeted in treatment of insulin-resistance, and our findings support pharmacologic targeting the GIPR to mimic the altered trafficking of the GIPR-Q variant as a potential strategy to enhance GIP metabolic effects in treatment of insulin resistance.