Reduced pancreatic B cell compensation to the insulin resistance of aging:Impact on proinsulin and insulin levels

Type 2 diabetes mellitus is associated with insulin resistance, reduced B c ell function, and an increase in the proinsulin (PI) to immunoreactive insu lin (IRI) ratio (PI/IRI); the latter is thought to be an indication of B ce ll dysfunction. Normal aging is associated with insulin resistance and redu ced B cell function, but it is not known whether changes in PI and the PI/I RI ratio are also a feature of the aging-associated B cell dysfunction. The refore, we tested whether the aging-associated changes in insulin sensitivi ty and B cell function result in changes in PI and IRI levels that are prop ortionate or whether they are disproportionate as in type 2 diabetes. Twenty-six healthy older (mean +/- SEM age, 67 +/- 1 yr) and 22 younger (28 +/- 1 yr) subjects with similar body mass indexes (27.9 +/- 0.6 vs. 26.3 /- 1.0 kg/m(2)) were studied. PI was measured by a RIA recognizing both int act PI and its conversion intermediates. The insulin sensitivity index (S-I ) was quantified using the minimal model, and B cell function was measured as fasting insulin levels, the acute insulin response to glucose (AIRglucos e), and as the acute insulin response to arginine at maximal glycemic poten tiation (AIRmax). B cell function was also adjusted for S-I based on the kn own hyperbolic relationship between these two variables. Older and younger subjects had similar fasting glucose (5.3 +/- 0.1 vs. 5.2 +/- 0.1 mmol/L), IRI (83 +/- 8 vs. 76 +/- 9 pmol/L), PI (8.9 +/- 0.8 vs. 1 0.6 +/- 2.0 pmol/L), and PI/IRI ratio (12.3 +/- 1.3% vs. 13.9 +/- 1.6%; all P = NS) despite a 50% reduction of insulin sensitivity (S-I, 1.94 +/- 0.21 vs. 3.88 +/- 0.38 x 10(-5) min(-1)/pmol.L; P < 0.001) and in B cell functi on [S-I x fasting IRI, 139 +/- 18 vs. 244 +/- 24 x 10(-5) (P < 0.001); S-I x AIRglucose, 0.75 +/- 0.13 vs. 1.70 +/- 0.15 x 10(-2) min(-1) (P < 0.001); S-I x AIRmax, 3.63 +/- 0.53 vs. 6.81 +/- 0.70 x 10(-2) min(-1) (P < 0.001) ] in the older subjects. These findings suggest that the B cell dysfunction in older subjects is not associated with disproportionate proinsulinemia. However, in older subject s the B cell response to the insulin resistance of aging is reduced whether measured as fasting levels of PI or IRI or as the acute response to secret agogues. Thus, when examined in terms of the degree of insulin sensitivity, the lower fasting IRI levels in older subjects suggest that the utility of fasting insulin levels as a surrogate measure of insulin resistance in old er individuals may be limited.