Røder M E, Schwartz R S, Prigeon R L, Kahn S E
Department of Medicine, Veterans Affairs Puget Sound Health Care System, Harborview Medical Center, University of Washington, Seattle 98108, USA.
J Clin Endocrinol Metab. 2000 Jun;85(6):2275-80. doi: 10.1210/jcem.85.6.6635.
Type 2 diabetes mellitus is associated with insulin resistance, reduced B cell function, and an increase in the proinsulin (PI) to immunoreactive insulin (IRI) ratio (PI/IRI); the latter is thought to be an indication of B cell dysfunction. Normal aging is associated with insulin resistance and reduced B cell function, but it is not known whether changes in PI and the PI/IRI ratio are also a feature of the aging-associated B cell dysfunction. Therefore, we tested whether the aging-associated changes in insulin sensitivity and B cell function result in changes in PI and IRI levels that are proportionate 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/m2) were studied. PI was measured by a RIA recognizing both intact PI and its conversion intermediates. The insulin sensitivity index (SI) was quantified using the minimal model, and B cell function was measured as fasting insulin levels, the acute insulin response to glucose (AIRglucose), and as the acute insulin response to arginine at maximal glycemic potentiation (AIRmax). B cell function was also adjusted for SI based on the known 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. 10.6 +/- 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 (SI, 1.94 +/- 0.21 vs. 3.88 +/- 0.38 x 10(-5) min(-1)/pmol x L; P < 0.001) and in B cell function [SI x fasting IRI, 139 +/- 18 vs. 244 +/- 24 x 10(-5)(P < 0.001); SI x AIRglucose, 0.75 +/- 0.13 vs. 1.70 +/- 0.15 x 10(-2) min(-1) (P < 0.001); SI 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 subjects 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 secretagogues. 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 older individuals may be limited.
2型糖尿病与胰岛素抵抗、B细胞功能减退以及胰岛素原（PI）与免疫反应性胰岛素（IRI）的比值（PI/IRI）升高有关；后者被认为是B细胞功能障碍的一个指标。正常衰老与胰岛素抵抗和B细胞功能减退有关，但尚不清楚PI和PI/IRI比值的变化是否也是衰老相关B细胞功能障碍的一个特征。因此，我们测试了与衰老相关的胰岛素敏感性和B细胞功能变化是否会导致PI和IRI水平的变化成比例，或者是否像2型糖尿病那样不成比例。研究了26名健康老年人（平均±标准误年龄，67±1岁）和22名年轻受试者（28±1岁），他们的体重指数相似（27.9±0.6对26.3±1.0kg/m2）。PI通过一种能识别完整PI及其转化中间体的放射免疫分析法进行测量。胰岛素敏感性指数（SI）使用最小模型进行量化，B细胞功能通过空腹胰岛素水平、对葡萄糖的急性胰岛素反应（AIR葡萄糖）以及在最大血糖增强作用下对精氨酸的急性胰岛素反应（AIRmax）来衡量。还根据这两个变量之间已知的双曲线关系对B细胞功能进行了SI校正。尽管老年受试者的胰岛素敏感性降低了50%（SI，1.94±0.21对3.88±0.38×10-5min-1/pmol×L；P<0.001），B细胞功能也降低了[SI×空腹IRI，139±18对244±24×10-5（P<0.001）；SI×AIR葡萄糖，0.75±0.13对1.70±0.15×10-2min-1（P<0.001）；SI×AIRmax，3.63±0.53对6.81±0.70×10-2min-1（P<0.001）]，但老年和年轻受试者的空腹血糖（5.3±0.1对5.2±0.1mmol/L）、IRI（83±8对76±9pmol/L）、PI（8.9±0.8对10.6±2.0pmol/L）和PI/IRI比值（12.3±1.3%对13.9±1.6%；所有P=无显著性差异）相似。这些发现表明，老年受试者的B细胞功能障碍与不成比例的胰岛素原血症无关。然而，在老年受试者中，无论以PI或IRI的空腹水平还是以对促分泌剂的急性反应来衡量，B细胞对衰老引起的胰岛素抵抗的反应都是降低的。因此，从胰岛素敏感性程度来看，老年受试者较低的空腹IRI水平表明，空腹胰岛素水平作为老年个体胰岛素抵抗替代指标的效用可能有限。
