β-Cell hypersecretion and not reduced hepatic insulin extraction is the main cause of hyperinsulinemia in obese nondiabetic subjects

Abstract

Obesity is characterized by peripheral hyperinsulinemia, for which either β-cell hypersecretion, diminished hepatic insulin extraction, or both may be responsible. To clarify this issue, we investigated insulin secretion and hormone hepatic extraction in 18 nondiabetic obese patients (body mass index [BMI], 39 ± 1.3 kg/m 2) and 18 healthy, lean control subjects (BMI, 21.3 ± 0.7 kg/m 2). Body fat distribution was calculated by measuring the waist to hip ratio (WHR). A highly reduced tissue insulin sensitivity (2.4 ± 0.5 v 9.5 ± 1.5 10 4 · min −1/[μU/mL], P > .0005) and glucose effectiveness, ie, glucose's ability to stimulate its own disappearance at basal insulin (16 ± 2 v 30 ± 3 10 3 · min −1, P > .005), were found in the overweight subjects compared with the controls. The basal (76 ± 14 v 37 ± 4 pmol/L/min) and total (377,848 ± 5,562 v 16,864 ± 1,850 pmol/L) prehepatic insulin secretion and the basal (15 ± 2 v 7 ± 0.7 pmol/L/min) and total (8,286 ± 2,009 v 2,840 ± 210 pmol/L) posthepatic insulin delivery were significantly higher in the overweight subjects compared with the controls ( P < .005), whereas the mean hepatic insulin extraction did not differ (77.8% ± 2.6% v 79.5% ± 2.6%). A significant inverse correlation was found between the hepatic insulin extraction and the WHR ( r = .5, P > .04), signifying the importance of fat distribution in insulin metabolism. The obese patients were subdivided into two subgroups according to their glucose tolerance; eight patients exhibited a normal tolerance and the remaining 10 were intolerant. While glucose effectiveness was significantly lower in patients with impaired glucose tolerance, there were no significant differences in insulin sensitivity in the two subgroups. The basal and total prehepatic and posthepatic insulin secretion was found to be significantly higher in patients with impaired glucose tolerance. We conclude that hyperinsulinemia in obesity is primarily caused by pancreatic β-cell hypersecretion, whereas diminished hepatic extraction of insulin only seems to be operative in patients with extreme upper-body fat distribution. In addition, basal hyperinsulinemia and a marked reduction in the ability of glucose to stimulate glucose uptake at basal insulin levels seem to be the main defects leading to impaired glucose tolerance.