To determine whether prolonged nicotinic acid (NA) administration produces insulin resistance and, if so, how the normal pancreatic islet adapts to prolonged insulin resistance, we administered incremental doses of NA to 11 normal men for 2 wk, ending at 2 g/day. Insulin sensitivity was measured with Bergman's minimal model. Islet function was evaluated by measurement of acute insulin (AIR) and glucagon (AGR) responses to arginine at three glucose levels. Insulin resistance was demonstrated and quantified by a marked drop in the insulin sensitivity index (S1) from 6.72 ± 0.77 to 2.47 ± 0.36 × 10−5 min−1/pM (P < .0001) and resulted in a doubling of basal immunoreactive insulin levels (from 75 ± 7 to 157 ± 21 pM, P < .001) with no change in fasting glucose (5.5 ± 0.1 vs. 5.7 ± 0.1 mM). Proinsulin levels also increased (from 9 ± 1 to 15 ± 2 pM, P < .005), but the ratio of proinsulin to immunoreactive insulin did not change (12.7 ± 1.9 vs. 10.3 ± 1.9%). β-Cell changes were characterized by increases in the AIR to glucose (from 548 ± 157 to 829 ± 157 pM, P < .005) and in the AIR to arginine at the fasting glucose level (from 431 ± 54 to 788 ± 164 pM, P < .05). At the maximal hyperglycemia level the AIR to arginine represents β-cell secretory capacity, and this increased with administration of NA (from 2062 ± 267 to 2630 ± 363 pM, P < .05). From the AIRs to arginine an estimate of the glucose level giving half-maximal AIR to arginine can be calculated. This measure did not increase (10.0 ± 0.5 vs. 9.6 ± 0.9 mM). The AGRs to argininewere reduced at all glucose levels during NA administration. Thus, the pancreatic islet adapts to the prolonged insulin resistance induced by NA. This adaptation comprises a combination of increased insulin secretion and reduced glucagon secretion. The changes in insulin secretion can be entirely explained by an increase in the secretory capacity of the β-cell.
Increased β-Cell Secretory Capacity as Mechanism for Islet Adaptation to Nicotinic Acid-Induced Insulin Resistance
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Steven E Kahn, James C Beard, Michael W Schwartz, W Kenneth Ward, Han Lun Ding, Richard N Bergman, Gerald J Taborsky, Daniel Porte; Increased β-Cell Secretory Capacity as Mechanism for Islet Adaptation to Nicotinic Acid-Induced Insulin Resistance. Diabetes 1 May 1989; 38 (5): 562–568. https://doi.org/10.2337/diab.38.5.562
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