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The relationship between first-phase insulin secretion and glucose metabolism

A possible pathogenetic link between absence of first-phase insulin secretion and development of impaired glucose metabolism has been suggested by the results of several cross-sectional studies. First-phase insulin secretion measured during a + 7 mmol/l hyperglycemic glucose clamp correlated with total glucose disposal during the clamp (r = 0.65, p <0.001, N = 59). To examine whether restoration of first-phase insulin secretion improves peripheral glucose uptake in subjects with impaired glucose utilization, seven insulin-resistant subjects (age 54 (38–62) years; BMI 29.3 (21.7–35.8); fasting plasma glucose 5.5 (4.8–7.2) mmol/l; fasting insulin 57 (37–105) pmol/l with impaired first-phase (148 (29–587) vs controls 485 (326–1086) pmol/lx 10 min; p<0.05) and normal second-phase (1604 (777–4480) vs controls (1799 (763–2771) pmol/l x 110 min) insulin secretion were restudied. The impaired first-phase insulin secretion was restored by an iv insulin bolus at the start of the hyperglycemic clamp. Substrate oxidation rates and hepatic glucose production were determined by indirect calorimetry and [3-³H]glucose infusion. Total glucose uptake was impaired in the insulinresistant subjects with impaired first-phase insulin secretion compared to controls (18.8 (13.2–22.2) vs 34.8 (24.3–62.1) µmol·kg^–1·min^–1; p<0.01). Restoration of first-phase insulin secretion (1467 (746–2440) pmol/lx 10 min) did not affect glucose uptake (20.2 (9.9–23.8) µmol·kg^–1·min^–1), with no difference in oxidative and non-oxidative glucose metabolism between the experiments. Second-phase insulin secretion was similar during both experiments. We conclude that although first-phase insulin secretion correlates with total glucose uptake, replacement of impaired first-phase insulin secretion does not improve glucose uptake in subjects with impaired glucose disposal and normal second-phase insulin secretion. The data dispute a causal relationship between first-phase insulin secretion and impaired glucose uptake in these subjects.