IRIS II study: intact proinsulin is confirmed as a highly specific indicator for insulin resistance in a large cross-sectional study design.

BACKGROUND: The cross-sectional IRIS-II study tried to assess the prevalence of insulin resistance and macrovascular disease in orally treated patients with Type 2 diabetes. METHODS: In total, 4,270 patients were enrolled into the study (2,146 male, 2,124 female; mean +/- SD age 63.9 +/- 11.1 years; body mass index 30.1 +/- 5.5 kg/m2; duration of disease 5.4 +/- 5.6 years; hemoglobin A1c 6.8 +/- 1.3%). The study consisted of a single morning visit with completion of a standardized questionnaire and collection of a fasting blood sample. RESULTS: The mean intact proinsulin value was 11.4 +/- 12.4 pmol/L (normal range < 10 pmol/L). Homeostasis model assessment resulted in 1,147 insulin-sensitive patients (26.9%) and 3,123 patients (73.1%) with insulin resistance. Of the latter patients 1,465 (34.3% of all patients) had also elevated intact proinsulin values, while 1,658 (38.8%) had no proinsulin elevation. In contrast, 1,042 (24.4%) of the insulin-sensitive patients had normal intact proinsulin, and only 105 (2.4%) had elevated intact proinsulin concentrations (chi2 test P < 0.0001). A specificity of 93.2% (sensitivity 46.9%) was calculated for elevated intact proinsulin as an indirect marker for insulin resistance. Of the 1,451 patients treated with sulfonylurea 52% had elevated intact proinsulin values and increased prevalence of cardiovascular complications (odds ratio 1.45). CONCLUSION: Type 2 patients with elevated fasting intact proinsulin values can be regarded as being insulin resistant. The results confirm that fasting intact proinsulin is a suitable measure for beta-cell dysfunction and insulin resistance in type 2 diabetes and may be used to support therapeutic decisions.

IRIS II Study: Sensitivity and specificity of intact proinsulin, adiponectin, and the proinsulin/adiponectin ratio as markers for insulin resistance.

OBJECTIVE: This study was performed to compare the specificity and sensitivity of intact proinsulin, adiponectin, and their ratio (proinsulin/adiponectin) in the prediction of insulin resistance as assessed by the homeostasis model assessment (HOMA) score (> or =2 = resistant). RESEARCH DESIGN AND METHODS: Using a cross-sectional approach, 500 orally treated patients with type 2 diabetes (272 women, 238 men; mean +/- SD age, 64.8 +/- 11.6 years; hemoglobin A1c, 7.0 +/- 1.5%; disease duration, 5.8 +/- 6.1 years) were investigated. Various cutoffs for body mass index-adjusted adiponectin and proinsulin/adiponectin were compared with the established cutoff value of 10 pmol/L for fasting proinsulin. RESULTS: Fasting proinsulin correlated more closely with the HOMA score (r = 0.560, P < 0.001) than fasting adiponectin (r = -0.204, P < 0.001) or proinsulin/adiponectin (r = 0.355, P < 0.001). For proinsulin, specificity and sensitivity for insulin resistance in correlation to the HOMA score results were 96% and 70%, respectively. At a comparable specificity level to proinsulin, adiponectin did not reach a comparable sensitivity (14%), while the proinsulin/adiponectin ratio almost reached the same sensitivity (65%). Overall, patients with elevated proinsulin had a higher prevalence of micro- and macrovascular disease [odds ratio 1.47 (adiponectin, 1.08; proinsulin/ adiponectin, 1.48) and 1.34 (adiponectin, 1.32; proinsulin/adiponectin, 1.27), respectively]. CONCLUSIONS: Elevation of fasting intact proinsulin seems to be the more specific marker for insulin resistance and increased cardiovascular risk than suppression of fasting adiponectin. Formation of the ratio does not lead to a further increase in the predictive value.

Nitric oxide does not mediate the vasodilation of early human pregnancy.

BACKGROUND: In early pregnancy, a substantial drop in arterial blood pressure occurs, that might be attributed to enhanced vascular nitric oxide synthesis. We investigated whether nitric oxide mediates the vasodilation that occurs in early human pregnancy. METHODS: Resting and stimulated forearm vascular resistance were measured (venous occlusion plethysmograph) in six women at 10 +/- 3 weeks of uncomplicated pregnancy and in the same women 7 +/- 5 weeks after elective termination of pregnancy. Forearm vascular resistance was also measured in six non-pregnant, healthy controls. RESULTS: Resting forearm vascular resistance was similar during pregnancy (33 +/- 16 arbitrary units (AU)), after pregnancy (31 +/- 10 AU) and in controls (41 +/- 13 AU, P > 0.05). The decreases in forearm vascular resistance to intrabrachial infusions of acetylcholine (2 and 20 microg/min), serotonin (10 and 100 ng/min) and sodium nitroprusside (1 and 2.5 microg/min) were similar in all groups. The nitric oxide synthase inhibitor NG-monomethyl-L-arginine (16 micromol/min) produced similar increases in vascular resistance in pregnant women (38 +/- 17 AU), after pregnancy (36 +/- 14 AU) and in control subjects (42 +/- 8 AU, P = NS). CONCLUSIONS: These results indicate that neither basal nor stimulated nitric oxide levels are altered in the forearm circulation during first trimester pregnancy.