beta-cell function in morbidly obese subjects during free living: long-term effects of weight loss.
Insulin hypersecretion and insulin resistance are physiologically linked features of obesity. We tested whether extreme hypersecretion impairs beta-cell function under free-living conditions and whether major weight loss modifies insulin hypersecretion, insulin sensitivity, and beta-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 beta-cell function: rate sensitivity, beta-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 micromol.min(-1) . kg(FFM)(-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, beta-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 micromol.min(-1).kg(FFM)(-1)) were normalized. At 2 years (weight loss = 50 +/- 8 kg), insulin sensitivity was supernormal (68.7 +/- 3.3 micromol.min(-1).kg(FFM)(-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 beta-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.
Camastra
Stefania
S
Department of Internal Medicine, Metabolism Unit, National Research Council Institute of Clinical Physiology, University of Pisa, Pisa, Italy.
Manco
Melania
M
Mari
Andrea
A
Baldi
Simona
S
Gastaldelli
Amalia
A
Greco
Aldo V
AV
Mingrone
Gertrude
G
Ferrannini
Ele
E
D000328:Adult; D015904:Biliopancreatic Diversion; D001786:Blood Glucose / Q000032:analysis; D015992:Body Mass Index; D002096:C-Peptide / Q000097:blood; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005260:Female; D015309:Glucose Clamp Technique; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000503:physiopathology*; D008297:Male; D009767:Obesity, Morbid / Q000503:physiopathology* / Q000601:surgery; D015431:Weight Loss / Q000502:physiology*
D001786:Blood Glucose; D002096:C-Peptide; D005230:Fatty Acids, Nonesterified; D007328:Insulin