Impaired insulin response after oral but not intravenous glucose in heart- and liver-transplant recipients.

BACKGROUND: The prevalence of diabetes is high after transplantation. We hypothesized that liver transplantation induces additional alterations of glucose homeostasis because of liver denervation. METHODS: Nondiabetic patients with a heart (n=9) or liver (n=9) transplant and healthy subjects (n=8) were assessed using a two-step hyperglycemic clamp (7.5 and 10 mmol/L). Thereafter, an oral glucose load (0.65 g/kg fat free mass) was administered while glucose was clamped at 10 mmol/L. Glucose appearance from the gut was calculated as the difference between glucose appearance (6,6 2H2 glucose) and exogenous glucose infusion. Plasma insulin, glucagon-like peptide (GLP)-1 and gastric inhibitory polypeptide(GIP) concentrations were compared after intravenous and oral glucose. RESULTS: After oral glucose, the glucose appearance from the gut was increased 52% and 81% in liver- and heart-transplant recipients (P<0.05). First-pass splanchnic glucose uptake was reduced by 39% in liver-transplant and 64% in heart-transplant patients (P<0.05). After oral but not intravenous glucose, there was an impairment of insulin secretion in both transplant groups relative to the controls. Plasma concentrations of GIP and GLP-1 increased similarly in all three groups after oral glucose. CONCLUSIONS: First-pass hepatic glucose extraction is decreased after heart and liver transplant. Insulin secretion elicited by oral, but not intravenous glucose, is significantly reduced in both groups of patients. There was no difference between liver- and heart-transplant recipients, indicating that hepatic denervation was not involved. These data suggest an impairment in the beta-cell response to neural factors or incretin hormones secondary to immunosuppressive treatment.

In normal men, free fatty acids reduce peripheral but not splanchnic glucose uptake.

Raising plasma free fatty acid (FFA) levels reduces muscle glucose uptake, but the effect of FFAs on splanchnic glucose uptake, total glucose output, and glucose cycling may also be critical to producing lipid-induced glucose intolerance. In eight normal volunteers, we measured glucose turnover and cycling rates ([2H7]glucose infusion) during a moderately hyperglycemic (7.7 mmol/l) hyperinsulinemic clamp, before and after ingestion of a labeled (dideuterated) oral glucose load (700 mg/kg). Each test was performed twice, with either a lipid or a saline infusion; four subjects also had a third test with a glycerol infusion. As shown by similar rates of exogenous glucose appearance, the lipid infusion did not reduce first-pass splanchnic glucose uptake (saline 1.48+/-0.18, lipid 1.69+/-0.17, and glycerol 1.88+/-0.17 mmol/kg per 180 min; NS), but it reduced peripheral glucose uptake by 40% (P < 0.01 vs. both saline and glycerol infusions). Before oral ingestion of glucose, total glucose output was similarly increased by the lipid and glycerol infusions. Total glucose output was significantly increased by FFAs after oral ingestion of glucose (saline 3.68+/-1.15, glycerol 3.68+/-1.70, and lipid 7.92+/-0.88 micromol x kg(-1) x min(-1); P < 0.01 vs. saline and P < 0.05 vs. glycerol). The glucose cycling rate was approximately 2.7 micromol x kg(-1) x min(-1) with the three infusions and tended to decrease all along the lipid infusion, which argues against a stimulation of glucose-6-phosphatase by FFAs. It is concluded that in situations of moderate hyperinsulinemia-hyperglycemia, FFAs reduce peripheral but not splanchnic glucose uptake. Total glucose output is increased by FFAs, by a mechanism that does not seem to involve stimulation of glucose-6-phosphatase.