The effects of superphysiologic hyperinsulinemia on glucose and lipid metabolism in glucose-tolerant offspring of patients with non-insulin-dependent diabetes mellitus (NIDDM)

Abstract

First-degree relatives of patients with NIDDM manifest severe insulin resistance despite normal glucose tolerance test. To examine the mechanisms underlying the normal glucose tolerance, we evaluated the serum glucose/C-peptide/insulin dynamics and free fatty acid (FFA) as well as substrate oxidation rates and energy expenditure (EE) (indirect calorimetry) in nine young offspring of NIDDM patients (mean ± SEM age 30 ± 2.3 years, body mass index 24.2 ± 1.2 kg/m 2). Nine age-, sex- and weight-matched, normal subjects with no family history of diabetes served as the controls. Metabolic parameters were measured before, during and after a two-step glucose infusion (2 and 4 mg/kg·min) for 120 min. Mean basal serum glucose, insulin and C-peptide levels were similar in both groups. During 2 mg/kg·min glucose infusion, mean serum insulin and C-peptide rose to significantly ( P < 0.05-0.02) greater levels in the offspring vs. controls, while serum glucose levels were similar. With the 4 mg/kg·min glucose infusion, mean serum glucose, insulin and C-peptide levels were significantly ( P < 0.02-0.001) greater in the offspring at 100–120 min. Isotopically-derived ( d[3- 3H]glucose), basal hepatic glucose output (HGO) was not significantly different between the offspring vs. controls (1.86 ± 0.30 vs. 1.78 ± 0.06 mg/kg·min). During glucose infusion, basal HGO was partially suppressed by 66% at 60 min and by 100% at 120 min in the offspring. In contrast, HGO was completely (100%) suppressed at both times in the controls. Following cessation of glucose infusion, HGO rose to 1.64 ± 0.12 mg/kg·min in the offspring and 1.46 ± 0.05 mg/kg·min in the controls ( P < 0.05) between 200 and 240 min. These were 88% and 82% of the respective basal HGO values. At low glucose infusion ( t = 0–60 min), the mean absolute, nonoxidative glucose disposal remained 1.5-fold greater in the offspring while at higher glucose infusion, nonoxidative glucose metabolism was not different in both groups. Throughout the study period, oxidative glucose disposal rate was not significantly different in both groups. The mean basal FFA was significantly greater in the offspring vs. controls (865 ± 57 vs. 642 ± 45 μEq/l). It was appropriately suppressed during glucose infusion to a similar nadir in both groups (395 ± 24 vs. 375 ± 33 μEq/l). The mean basal lipid oxidation was also significantly greater in the offspring than controls (1.06 ± 0.05 vs. 0.75 ± 0.04 mg/kg·min, P < 0.05). During glucose infusion, lipid oxidation was suppressed to a similar nadir in both groups (0.62 ± 0.07 vs. 0.63 ± 0.06 ng/kg·min). FFA did not correlate with the HGO or nonoxidative and oxidative glucose disposal in either group. We found insignificant correlations between lipid and glucose oxidation rates at basal ( r = −0.422) and during glucose infusion ( r = −0.402) in the offspring. In contrast, significant ( P < 0.001) negative relationships were found between both parameters at basal ( r = −0.850, P < 0.01) and during glucose infusion ( r = −0.825) in the healthy controls. There were no significant differences in resting energy expenditure (REE), post-glucose thermic effect in the offspring and controls, despite the higher insulin levels in the former. In summary, the present study demonstrates that nondiabetic offspring of NIDDM patients manifest impaired insulin-mediated glucose, energy and FFA/lipid metabolism. We found that beta-cell hormone secretion was extraordinarily sensitive to glucose infusion in the offspring. The resultant hyperinsulinemia could be an early compensation for the insulin resistance in the glucose-tolerant offspring. At low glucose load, the offspring appear to manifest normal glucose tolerance by maintaining greater nonoxidative glucose disposal, probably due to hyperinsulinemia. However, at higher glucose challenge, this compensatory mechanism is inadequate to achieve normal glucose concentrations, thus resulting in hyperglycemia.