Intact proinsulin and beta-cell function in lean and obese subjects with and without type 2 diabetes

OBJECTIVE - Type 2 diabetes is a heterogeneous disease in which both beta-c ell dysfunction and insulin resistance are pathogenetic factors. Disproport ionate hyperproinsulinemia (elevated proinsulin/insulin) is another abnorma lity in ripe 2 diabetes whose mechanism is unknown. Increased demand due to obesity and/or insulin resistance may result in secretion of immature beta -cell granules with a higher content of intact proinsulin. RESEARCH DESIGN AND METHODS - We investigated the impact of obesity on beta -cell secretion in normal subjects and in type 2 diabetic patients by measu ring intact proinsulin, total proinsulin immunoreactivity (PIM), intact ins ulin, and C-peptide (by radioimmunoassay) by specific enzyme-linked immunos orbent assays in the fasting state and during a 120-min glucagon (1 mg i.v) stimulation test. Lean (BMI 23.5 +/- 03 kg/m(2)) (LD) and obese (30.1 +/- 0.4 kg/m(2)) (OD) type 2 diabetic patients matched for fasting glucose (10. 2 +/- 0.6 vs. 10.3 +/- 0.4 mmol/l) were compared with age- and BMI-matched lean (22.4 +/- 0.6 kg/m(2)) (LC) and obese (30.8 +/- 0.9 kg/m(2)) (OC) norm al control subjects. RESULTS - Diabetic patients (LD vs. LC and OD vs. OC) had elevated fasting levels of intact proinsulin: 6.6 +/- 1.0 vs. 1.6 +/- 0.3 pmol/l and 7.7 +/- 2.0 vs. 1.2 +/- 0.2 pmol/l; PIM: 19.9 +/- 2.5 vs. 5.4 +/- 1.0 pmol/l and 2 9.6 +/- 6.1 vs. 6.1 +/- 0.9 pmol/l; and total PIM/intact insulin: 39 +/- 4 vs. 15 +/- 2% and 35 +/- 5 vs. 13 +/- 2%, all P < 0.01. After glucagon stim ulation, PIM levels were disproportionately elevated (PIM/intact insulin ba sed on area under the curve analysis) in diabetic patients (LD vs. LC and O D vs. OC): 32.6 +/- 6.7 vs. 9.2 +/- 1.1% and 22.7 +/- 5.2 vs. 9.1 +/- 1.1%, both P < 0.05. Intact insulin and C-peptide net responses were significant ly reduced in type 2 diabetic patients, most pronounced in the lean group. The ratio of intact proinsulin to PIM was higher in diabetic patients after stimulation in both LD versus LC: 32 +/- 3 vs. 23 +/- 2%, and OD versus OC : 28 +/- 4 vs. 16 +/- 2%, both P < 0.01. In obese normal subjects, intact p roinsulin/PIM was lower both in the fasting stare and after glucagon stimul ation: OC versus LC: 22 +/- 3 vs. 33 +/- 3% (fasting) and 16 +/- 2 vs. 23 /- 2% (stimulated), both P < 0.05. CONCLUSIONS - Increased secretory demand from obesity-associated insulin re sistance cannot explain elevated intact proinsulin and disproportionate hyp erproinsulinemia in type 2 diabetes. This abnormality may be an integrated part of pancreatic beta-cell dysfunction in this disease.