Reduced hepatic insulin extraction in response to gastric inhibitory polypeptide compensates for reduced insulin secretion in normal-weight and normal glucose tolerant first-degree relatives of type 2 diabetic patients

Our objective was to study whether young first-degree relatives of patients with type 2 diabetes (FDRs) have altered insulin secretion and insulin clearance in response to gastric inhibitory polypeptide (GIP) in combination with glucose and arginine. A hyperglycemic clamp (11.1 mmol/l for 115 min), followed by addition of GIP (2 pmol . kg(-1) . min(-1), 60-115 min) and an arginine bolus and infusion (10 mg . kg(-1) . min(-1), 90-115 min), was conducted on 14 healthy volunteers and 13 FDRs. Both groups had normal glucose tolerance. FDRs were more insulin resistant (HOMA(IR)) under basal conditions (P = 0.003). FDRs demonstrated significant global impairment in insulin secretion capacity, which was not specific for one of the secretagogues. Insulin clearance was significantly reduced in the group of FDRs under basal conditions and in response to GIP, but there was no general defect in insulin clearance in response to glucose and arginine. The HOMAIR correlated negatively (P < 0.01) with insulin clearance under basal conditions (r = -0.96) and under GIP infusion (r = -0.56). We propose that impairment in insulin secretion capacity and decreased insulin sensitivity is compensated for several mechanisms, one of which includes a GIP-dependent reduction of the insulin clearance that will increase peripheral insulin levels to maintain normoglycemia.