Aging is associated with an increased risk of type 2 diabetes. To determine whether the insulin resistance of aging is associated with an increase in amylin release or whether amylin release parallels the reduction in insulin release, we studied 10 older (72 +/- 2 yr) and 9 young (25 +/- 1 yr) subjects. Insulin sensitivity was quantified as the insulin sensitivity index (SI) and B cell function as the acute insulin and amylin responses to iv glucose (AIRg and AARg, respectively) and iv arginine at a glucose level of >25 mM (AIRmax and AARmax). To account for the effect of SI to modulate B cell function, we calculated SI x B cell function. Older subjects were insulin resistant (SI: 4.6 +/- 0.8 vs. 8.6 +/- 1.4 x 10(-5) min-1/pM, P < 0.05). Acute responses to glucose [AIRg (older vs. young): 420 +/- 106 vs. 537 +/- 87 pM; AARg: 6.5 +/- 1.7 vs. 9.0 +/- 1.5 pM] and arginine (AIRmax: 1,096 +/- 203 vs. 1,572 +/- 307 pM; AARmax: 14.0 +/- 3.5 vs. 16.5 +/- 2.4 pM) did not differ despite the difference in SI. When adjusted for SI, insulin responses were reduced in older subjects (SI x AIRg: 1.54 +/- 0.29 vs. 4.10 +/- 0. 63 x 10(-2) min-1, P = 0.001; SI x AIRmax: 4.03 +/- 0.52 vs. 12.7 +/- 2.9 x 10(-2) min-1, P < 0.01), as was amylin release (SI x AARg: 2.46 +/- 0.59 vs. 6.85 +/- 0.95 x 10(-4) min-1, P < 0.001; SI x AARmax: 4.71 +/- 0.52 vs. 13.5 +/- 2.2 x 10(-4) min-1, P < 0.001). Amylin and insulin release was proportionate, with a molar ratio of 1.5% in older and 1.4% in young subjects. Thus aging is associated with parallel impairments in the adaptation of insulin and amylin release to insulin resistance. It is unlikely that an alteration in amylin release contributes to the increased risk of type 2 diabetes.