Anna Solini

Peripheral, rather than hepatic, insulin resistance and atherogenic lipoprotein phenotype predict cardiovascular complications in NIDDM

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.

Family history of hypertension, anthropometric parameters and markers of early atherosclerosis in young healthy individuals

The predisposition to thrombogenesis is increased in essential hypertension, and hypertensive patients are prone to develop more vulnerable atherosclerotic plaques. To evaluate the possible influence of family history of hypertension on some indicators of early atherosclerosis, we studied eighty-five healthy normotensive individuals with (FH+) or without (FH−) family history of essential hypertension by measuring metabolic profile and concentrations of P-selectin, interleukin 6 and matrix metalloproteinase (MMP)-2, MMP-9, and tissue inhibitor of metalloproteinase (TIMP)-1. In a subset of individuals, MMP-9 activity was assessed in monocytes by zymography, and TIMP-1 expression by western blot. As compared with FH− individuals, FH+ individuals had significantly higher P-selectin but similar interleukin-6 levels. Although no difference was observed in MMP-2 levels between the two groups, MMP-9 and TIMP-1 were higher in FH+ individuals, who also had higher intracellular MMP-9 levels and TIMP-1 protein expression. P-selectin (r=−0.32; P<0.01), MMP-9 (r=−0.37; P<0.001) and TIMP-1 (r=−0.23; P<0.05) levels were inversely related to high density lipoprotein (HDL) cholesterol. P-selectin was also directly related to serum triglycerides (r=0.30; P<0.01). We conclude that a positive family history of hypertension is associated with an initial increase in markers of inflammation and plaque instability in otherwise healthy young normotensive individuals, likely conveying a predisposition to develop early atherothrombosis.

Lipoprotein abnormalities in non-insulin-dependent diabetic patients with impaired extrahepatic insulin sensitivity, hypertension, and microalbuminuria.

We investigated whether specific lipoprotein abnormalities are present in non-insulin-dependent diabetes mellitus (NIDDM) patients with hypertension and/or microalbuminuria. Fifteen normotensive normoalbuminuric (H-M-), 32 hypertensive normoalbuminuric (H+M-), and 22 hypertensive microalbuminuric (H+M+) NIDDM patients and 20 sex-, age-, and weight-matched nondiabetic control subjects were studied. Lipoprotein size was measured by nondenaturing polyacrylamide gradient gel electrophoresis; insulin sensitivity was assessed by using a euglycemic hyperinsulinemic clamp and [6,6(2)H]glucose tracer infusion for simultaneous measurement of hepatic glucose output and whole-body glucose utilization. Total plasma and very-low-density lipoprotein cholesterol were higher in H+M+ than in control subjects (5.84 +/- 0.98 versus 4.97 +/- 0.98 and 0.57 +/- 0.54 versus 0.26 +/- 0.21 mmol/L, mean +/- SD, P < .05). Plasma triglycerides were higher in H+M+ than in either control or H-M- subjects (2.17 +/- 1.32 versus 1.18 +/- 0.67 and 1.30 +/- 0.59 mmol/L, respectively; P < .05). The mean low-density lipoprotein diameter was 27.2 +/- 0.8 in control, 26.7 +/- 0.8 in H-M-, 26.5 +/- 0.8 nm in H+M- (P < .05 versus control subjects), and 26.0 +/- 0.8 nm in H+M+ subjects (P < .05 versus control subjects). The mean cholesterol level of the large high-density lipoprotein particles was lower in H+M- and H+M+ (0.37 +/- 0.14 and 0.36 +/- 0.16 mmol/L) than in control and H-M- (0.54 +/- 0.41 and 0.54 +/- 0.27 mmol/L, P < .05) subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Insulin resistance, hypertension and cellular ion transport systems

Much epidemiological, physiological and biochemical evidence links insulin resistance and hyperinsulinaemia to the pathogenesis of hypertension in some metabolic diseases such as obesity and type 2 (non-insulin-depedent) diabetes mellitus. Insulin resistance per se, by altering the energy needs of the cell, by causing a shift from glucose to lipid metabolism, or by some other incompletely defined mechanisms, could be responsible for the development of hypertension. It is also possible that hyperinsulinaemia, by acting on the vascular tree, leads to an increase in blood pressure. Moreover, insulin has been shown to augment renal sodium reabsorption, to stimulate the sympathetic nervous system, to influence atrial natriuretic peptide release and the renin-angiotensin-aldosterone system and to activate a number of sodium pumps which are present in all cell membranes, including vascular smooth muscle cells. Insulin can also directly stimulate cell growth. All these mechanisms, in various combinations, with the concurrence of some genetic factors, could lead to the development of the association between hypertension and abnormalities in glucose metabolism.