PERIPHERAL, RATHER THAN HEPATIC, INSULIN-RESISTANCE AND ATHEROGENIC LIPOPROTEIN PHENOTYPE PREDICT CARDIOVASCULAR COMPLICATIONS IN NIDDM

Microalbuminuria, hypertension and hyperinsulinaemia are three indepen dent risk factors for cardiac disease in non insulin-dependent diabete s (NIDDM). However, it is unknown to what extent hyperinsulinaemia ref lects resistance to insulin action at hepatic, extrahepatic or at both sites. A cross-sectional study from our Department showed that periph eral insulin resistance, hypertension, microalbuminuria and lipid abno rmalities are associated in NIDDM. Non diabetic individuals with the s o-called 'atherogenic lipoprotein phenotype', characterized by small d ense low density lipoproteins (LDL subclass pattern B) have up to 3-fo ld higher risk of myocardial infarction. The aim of the present study was to investigate whether impaired peripheral insulin sensitivity, du ring euglycaemic-hyperinsulinaemic clamp, as well as abnormalities in lipid concentrations and LDL size, predict abnormalities in albumin ex cretion rate, blood pressure and cardiac function in 73 consecutive no rmotensive (< 85 mmHg diastolic level) and normoalbuminuric (< 15 mu g min(-1) daily albumin excretion rate) NIDDM patients. These patients showed a bimodal distribution of whole body glucose utilization rate, a parameter of peripheral insulin sensitivity. The cut-off point betwe en the two modes of distribution was located close to the mean value m inus one standard deviation in a population of 24 control subjects. Th erefore, this latter value was used to identify two subgroups inside t he overall population of NIDDM patients, i.e. 28 patients (group 1), w ith whole body glucose utilization rate, above, and 45 patients (group 2), below, the mean value minus 1 SD in the 24 controls. Both groups 1 and 2 had impaired insulin sensitivity at hepatic site, as assessed by the degree of inhibition of hepatic glucose output during insulin a dministration (controls vs, group 1 vs. group 2: 925 +/- 235 vs. 952 /- 166 vs. 506 +/- 121; P > 0.001). The two groups displayed similar p atterns of age, gender, body weight, diabetes duration, HbA(1c) and ca rdiac ischaemic events. During 6-year follow-up the rate of occurrence of microalbuminuria (> 20 mu g min(-1)) (7% vs. 15%, P < 0.01) and di astolic hypertension (> 90 mmHg) (l4 vs. 30%, P < 0.05) was significan tly higher in group 2 than in group 1 NIDDM patients. Events of cardia c ischaemic disease were more frequently found among group 2 rather th an group 1 patients, during the follow-up (angina pectoris: 3/28 subje cts in group 1 vs. 9/45 subjects in group 2, P < 0.05; positive restin g ECG: 3/28 subjects in group 1 vs. 9/45 subjects in group 2; positive exercise ECG 4/28 in group 1 vs. 11/45 in group 2). Group 2 patients were also characterized by higher triglyceride and lower high density lipoprotein cholesterol levels and by LDL subclass pattern B. Peripher al, rather than hepatic, resistance and atherogenic lipoprotein phenot ype are the clinical hallmark of NIDDM patients who are prone to devel op microalbuminuria, hypertension and cardiac ischaemic disease.