β-Cell Function in Morbidly Obese Subjects During Free Living

Abstract

Insulin hypersecretion and insulin resistance are physiologically linked features of obesity. We tested whether extreme hypersecretion impairs β-cell function under free-living conditions and whether major weight loss modifies insulin hypersecretion, insulin sensitivity, and β-cell function. Plasma glucose, C-peptide, and free fatty acid concentrations were measured at hourly intervals during 24 h of normal life (including calorie-standardized meals) in 20 morbidly obese nondiabetic patients (BMI 48.4 ± 1.7 kg/m2) and 7 nonobese age- and sex-matched control subjects; 8 of the obese patients were restudied 6 months and 2 years following biliopancreatic diversion. Insulin secretion was reconstructed from C-peptide levels by deconvolution and related to concurrent glucose levels through a mathematical model incorporating key features of β-cell function: rate sensitivity, β-cell glucose sensitivity, and potentiation. Insulin sensitivity (by the euglycemic insulin clamp technique) was reduced by 50% in obese subjects (23.1 ± 2.5 of obese subjects vs. 52.9 ± 4.9 μmol · min−1 · kgFFM−1 of control subjects, means ± SE, P = 0.0004) as was mean 24-h insulin clearance (median 809 [interquartile range 451] vs. 1,553 [520] ml · min−1 · m−2, P < 0.001) due to a 50% reduction in hepatic insulin extraction (P < 0.01). Over 24 h, insulin secretion was doubled in obese subjects (468 nmol [202] in obese subjects vs. 235 [85] of control subjects, P = 0.0002). Despite the hypersecretion, β-cell glucose sensitivity, rate sensitivity, and potentiation were similar in obese and control subjects. Six months postoperatively (weight loss = 33 ± 3 kg), both insulin hypersecretion (282 nmol [213]) and insulin sensitivity (51.6 ± 3.7 μmol · min−1 · kgFFM−1) were normalized. At 2 years (weight loss = 50 ± 8 kg), insulin sensitivity was supernormal (68.7 ± 3.3 μmol · min−1 · kgFFM−1) and insulin secretion was lower than normal (167 nmol [37]) (both P < 0.05 vs. control subjects). In conclusion, severe uncomplicated obesity is characterized by gross insulin hypersecretion and insulin resistance, but the dynamic aspects of β-cell function are intact. Malabsorptive bariatric surgery corrects both the insulin hypersecretion and the insulin resistance at a time when BMI is still high. With continued weight loss over a 2-year period, moderately obese subjects become supersensitive to insulin and, correspondingly, insulin hyposecretors.