Fasting Intact Proinsulin Is a Highly Specific Predictor of Insulin Resistance in Type 2 Diabetes

Abstract

OBJECTIVE -In later stages of type 2 diabetes, proinsulin and proinsulin-like molecules are secreted in increasing amounts with insulin. A recently introduced chemiluminescence assay is able to detect the uncleaved "intact" proinsulin and differentiate it from proinsulin-like molecules. This investigation explored the predictive value of intact proinsulin as an insulin resistance marker.RESEARCH DESIGN AND METHODS -In total, 48 patients with type 2 diabetes (20 women and 28 men, aged 60 Ϯ 9 years [means Ϯ SD], diabetes duration 5.1 Ϯ 3.8 years, BMI 31.2 Ϯ 4.8 kg/m 2 , and HbA 1c 6.9 Ϯ 1.2%) were studied by means of an intravenous glucose tolerance test and determination of fasting values of intact proinsulin, insulin, resistin, adiponectin, and glucose. Insulin resistance was determined by means of minimal model analysis (MMA) (as the gold standard) and homeostatis model assessment (HOMA).RESULTS -There was a significant correlation between intact proinsulin values and insulin resistance (MMA P Ͻ 0.05 and HOMA P Ͻ 0.01). Elevation of intact proinsulin values above the reference range (Ͼ10 pmmol/l) showed a very high specificity (MMA 100% and HOMA 92.9%) and a moderate sensitivity (MMA 48.6% and HOMA 47.1%) as marker for insulin resistance. Adiponectin values were slightly lower in the insulin resistant group, but no correlation to insulin resistance could be detected for resisitin in the cross-sectional design.CONCLUSIONS -Elevated intact proinsulin seems to indicate an advanced stage of ␤-cell exhaustion and is a highly specific marker for insulin resistance. It might be used as arbitrary marker for the therapeutic decision between secretagogue, sensitizer, or insulin therapy in type 2 diabetes. Diabetes Care 27:682-687, 2004I n the past decades, insulin resistance and cardiovascular disease in type 2 diabetic patients have been linked to hyperinsulinemia as an independent risk factor (1-3). However, many studies were not able to confirm the negative impact of insulin on cardiovascular risk (4 -6). One explanation for this overall confusing data may be found in the cross-reactivity between insulin and its precursor molecule, proinsulin, which was present in many assays for insulin measurement. Relatively few and contradicting data are available on the relation of proinsulin to insulin resistance, cardiovascular disease, and atherosclerosis (6 -8). Prospective studies have demonstrated that the determination of the proinsulin-to-insulin ratio may be used to predict deterioration in glucose tolerance (9,10). Des31,32 proinsulin is a commonly secreted by-product of ␤-cell secretion in later stages of type 2 diabetes and is involved in the development of macrovascular disease, whereas des64,65 is usually not present in the circulation (11,12).Assays that try to differentiate between intact proinsulin and the specific and unspecific proinsulin derivatives were used in cross-sectional and prospective follow-up studies to investigate the real relation of immunoreactive insulin with coronary risk and to explore and con...

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