Peripheral, rather than hepatic, insulin resistance and atherogenic lipoprotein phenotype predict cardiovascular complications in NIDDM
Authors: NOSADINI R. , MANZATO E. , SOLINI A. , FIORETTO P. , BROCCO E. , ZAMBON S. , MOROCUTTI A. , SAMBATARO M. , VELUSSI M. , CIPOLLINA M. R. , CREPALDI G. 
Published: March 2008

Abstract Microalbuminuria, hypertension and hyper‐insulinaemia are three independent risk factors for cardiac disease in non insulin‐dependent diabetes (NIDDM). However, it is unknown to what extent hyperinsulinaemia reflects resistance to insulin action at hepatic, extrahepatic or at both sites. A cross‐sectional study from our Department showed that peripheral insulin resistance, hypertension, microalbuminuria and lipid abnormalities are associated in NIDDM. Non diabetic individuals with the so‐called ‘atherogenic lipoprotein phenotype’, characterized by small dense low density lipoproteins (LDL subclass pattern B) have up to 3‐fold higher risk of myocardial infarction. The aim of the present study was to investigate whether impaired peripheral insulin sensitivity, during euglycaemic‐hyperinsulinaemic clamp, as well as abnormalities in lipid concentrations and LDL size, predict abnormalities in albumin excretion rate, blood pressure and cardiac function in 73 consecutive normotensive (<85 mmHg diastolic level) and nor‐moalbuminuric (<15 μg 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 between the two modes of distribution was located close to the mean value minus one standard deviation in a population of 24 control subjects. Therefore, this latter value was used to identify two subgroups inside the overall population of NIDDM patients, i.e. 28 patients (group 1), with 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 administration (controls vs. group 1 vs. group 2: 925±235 vs. 952±166 vs. 506±121; P>0·001). The two groups displayed similar patterns of age, gender, body weight, diabetes duration, HbA1c and cardiac ischaemic events. During 6‐year follow‐up the rate of occurrence of microalbuminuria (>20 μg min‐1) (7% vs. 15%, P<0·01) and diastolic hypertension (>90 mmHg) (14 vs. 30%, P<0·05) was significantly higher in group 2 than in group 1 NIDDM patients. Events of cardiac ischaemic disease were more frequently found among group 2 rather than group 1 patients, during the follow‐up (angina pectoris: 3/28 subjects in group 1 vs. 9/45 subjects in group 2, P<0·05; positive resting 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. Peripheral, rather than hepatic, resistance and atherogenic lipoprotein phenotype are the clinical hallmark of NIDDM patients who are prone to develop microalbuminuria, hypertension and cardiac ischaemic disease.