Erkki Voutilainen

Microalbuminuria predicts the development of serum lipoprotein abnormalities favouring atherogenesis in newly diagnosed type 2 (non-insulin-dependent) diabetic patients

SummaryWe studied the relationship of slight albuminuria (microalbuminuria) to serum lipid and lipoproteins in a representative group of middle-aged Type 2 (non-insulin-dependent) diabetic patients. A random sample of non-diabetic control subjects was also examined. Diabetic patients had both at diagnosis and after five years higher total, LDL- and VLDL-triglyceride levels and higher VLDL-cholesterol, but lower HDL-cholesterol levels than non-diabetic subjects. No consistent difference was found in LDL-cholesterol levels between diabetic and non-diabetic subjects. The prevalence of microalbuminuria (>35 mg/24 h) remained about the same in diabetic patients at both examinations (19–20%). The diabetic patients with persistent microalbuminuria were slightly hyperglycaemic and they tended to have lower creatinine clearance at the 5-year examination than those without persistent microalbuminuria. There were no differences in the blood pressure levels or the occurrence of hypertension between the diabetic groups with and without microalbuminuria. At the baseline examination, no differences were seen in serum lipids and lipoproteins between diabetic patients with and without microalbuminuria. In patients with persistent microalbuminuria. a statistically significant increase in VLDL-cholesterol (p<0.05) and VLDL- and LDL-triglyceride levels (p<0.05) and a decrease in HDL-cholesterol level (p<0.05) was seen at the 5-year follow-up. These changes could not be explained by age, sex, body mass index or HbA1. In conclusion, persistent microalbuminuria predicts and aggravates abnormalities in lipoprotein composition and a decrease in HDL-cholesterol in patients with Type 2 diabetes mellitus. The excess cardiovascular morbidity and mortality in diabetic patients with increased albuminuria may, in part, be explained by these lipoprotein abnormalities.

Serum lipids and lipoproteins in middle-aged non-insulin-dependent diabetics

Serum lipids and lipoproteins were measured in 277 non-insulin-dependent diabetics (NIDDs) and in 124 non-diabetic control subjects (65 males, 59 females), aged 45-64 years. Altogether 88 of the diabetics were treated with diet (48 males, 40 females), 134 with oral drugs (56 males and 49 females treated with sulphonylureas, 14 males and 15 females treated with a combination therapy of sulphonylurea drug and metformin) and 55 with insulin (17 males, 38 females). The postglucagon C-peptide concentration in insulin-treated diabetics exceeded 0.60 nmol/l. The diabetics had lower levels of HDL and HDL2 cholesterol and higher levels of total and VLDL triglycerides than non-diabetic control subjects irrespective of the mode of treatment. The HDL2 subfraction seemed to be alone responsible for the decrease of HDL cholesterol. In the whole group of diabetics body mass index had a significant negative correlation to HDL cholesterol and a positive correlation to total triglyceride concentration in both sexes but plasma glucose failed to show any consistent association to HDL cholesterol concentration. The difference in HDL cholesterol between diabetics and non-diabetics persisted after adjustment for age, physical activity, alcohol intake and body mass index. In conclusion, the dyslipoproteinaemia in non-insulin-dependent diabetes is principally characterized by decreased HDL and HDL2 cholesterol concentrations and by increased total and VLDL triglycerides. These manifestations of dyslipoproteinaemia are little influenced by the degree of glycaemia and obesity.

The relationship of cardiovascular risk factors to the prevalence of coronary heart disease in newly diagnosed Type 2 (non-insulin-dependent) diabetes

SummaryThe relationship of cardiovascular risk factors to the prevalence of coronary heart disease was examined in 133 newly diagnosed Type 2 (non-insulin-dependent) diabetic patients (70 men, 63 women) aged from 45 to 64 years and in 144 randomly selected non-diabetic control subjects (62 men, 82 women) of the same age. The prevalence of coronary heart disease in diabetic patients, defined by symptoms and ischaemic ECG abnormalities in resting or exercise ECG, was more than threefold that in non-diabetic subjects. In multiple logistic analyses (including age, history of smoking, hypertension (+/-), serum cholesterol, HDL-cholesterol, triglycerides, 2-h post-glucose serum insulin, body mass index and diabetes (+/-)) carried out separately for men and women, diabetes showed an independent, significant association to coronary heart disease in both sexes. In addition, age and hypertension had a borderline association to coronary heart disease in men, whereas smoking and high 2-h postglucose serum insulin level showed a significant association in women.

Association of low HDL and HDL2 cholesterol with coronary heart disease in noninsulin-dependent diabetics.

Lipids and lipoproteins were measured in 139 men and 145 women who were noninsulin-dependent diabetics (NIDDs) aged 45 to 64 years. Of these, 27 men and 16 women had had a previous definite myocardial infarction (Ml). The NIDDs with Ml (Ml+) showed lower values of HDL and HDL2 cholesterol concentrations than NIDDs without previous Ml (Ml−) or NIDDS without any symptoms or electrocardiographic signs of coronary heart disease (CHD-). The inverse relationship between HDL, HDL2, and CHD was evident in both sexes, but it was particularly strong among male NIDDs. The difference in HDL and HDL2 cholesterol concentrations between the MI + and Ml-groups or between the Ml + and CHD-groups persisted after adjustment by analysis of covariance for the effect of physical activity, alcohol intake, obesity, duration of diabetes, and glycemic control. It is concluded that in a cross-sectional study, even among NIDDs with generally low HDL and HDL2 cholesterol concentrations, the presence of CHD is associated with a further depression of HDL and HDL2 cholesterol levels. Prospective studies are needed, however, to confirm that the association is predictive and not a consequence of CHD.

Serum lipids and lipoproteins in newly diagnosed non-insulin-dependent (type II) diabetic patients, with special reference to factors influencing HDL-cholesterol and triglyceride levels.

Serum and lipoprotein lipids were examined in 133 newly diagnosed (type II) diabetic patients (70 men, 63 women), aged 45–64 yr, and in 144 randomly selected nondiabetic control subjects of similar age (62 men, 82 women). The serum total cholesterol levels in diabetic and nondiabetic subjects were similar, but the HDL-cholesterol levels were lower and the serum total triglyceride levels higher in the diabetic than in nondiabetic subjects. No significant differences were found in apoprotein A-I and A-II levels between the diabetic and nondiabetic subjects. After adjustment for age, alcohol intake, obesity, 2-h postglucose serum insulin, and serum triglycerides, male diabetic subjects still had lower HDL-cholesterol levels than corresponding nondiabetic subjects. On the other hand, female diabetic subjects had higher serum triglycerides than their nondiabetic counterparts, even after adjustment for age, alcohol intake, 2-h postglucose serum insulin, and obesity.

Lipid and lipoprotein abnormalities associated with coronary heart disease in patients with insulin-dependent diabetes mellitus.

We measured serum lipid and lipoprotein levels in 63 insulin-dependent diabetic (IDD) patients (32 men, 31 women) and in 63 nondiabetic control subjects (32 men, 31 women) without coronary heart disease (CHD) and in 19 IDD patients (11 men, 8 women) and in 18 nondiabetic subjects (8 men, 10 women) with CHD. All diabetic patients had postglucagon C-peptide levels of less than 0.60 mmol/liter and none had signs of renal failure. Male IDD patients with CHD had higher levels of total cholesterol, low density lipoprotein (LDL) cholesterol, total triglycerides, very low density lipoprotein (VLDL) triglycerides and lower level of high density lipoprotein (HDL) cholesterol than male IDD patients without CHD. In female IDD patients, similar lipid and lipoprotein abnormalities were observed between the groups of diabetics with and without CHD except for total cholesterol, which was the same in both groups. A comparison between IDD patients without CHD and nondiabetic control subjects without CHD showed no difference in lipid and lipoprotein levels in males; female IDD patients without CHD showed even higher levels of HDL and HDL2 cholesterol and lower levels of VLDL triglycerides than nondiabetic controls. Our results indicate that in IDD patients without nephropathy and CHD, the lipid and lipoprotein levels do not differ from nondiabetic controls, but in IDD patients with CHD the lipid and lipoprotein pattern is similar to that known to be characteristic for nondiabetic patients with CHD.

Insulin resistance in familial and nonfamilial hypercholesterolemia.

High levels of very low density lipoprotein triglycerides and low levels of high density lipoprotein cholesterol have been found to be associated with insulin resistance measured by the euglycemic clamp technique. In contrast, the association of isolated hypercholesterolemia with insulin resistance has not been systematically studied. Therefore, we performed two separate studies designed to investigate the degree of insulin resistance in familial hypercholesterolemia (FH) (study 1) and nonfamilial hypercholesterolemia (non-FH) (study 2). Study 1 included eight young adults with FH and 13 corresponding control subjects. Fasting blood glucose, insulin, and C-peptide levels were similar in FH patients and control subjects during an oral glucose tolerance test. During the euglycemic hyperinsulinemic (1,200-1,300 pmol/l) clamp studies, FH patients and control subjects had similar rates of whole-body glucose uptake (73 +/- 6 versus 70 +/- 3 mumol/kg per minute, respectively; p = NS). Glucose oxidation, glucose nonoxidation, lipid oxidation, suppression of free fatty acid levels, and potassium disposal were similar in both groups. Study 2 included 25 middle-aged non-FH patients and 18 corresponding control subjects. Glucose, insulin, and C-peptide responses in an oral glucose tolerance test were similar in both groups. During the euglycemic hyperglycemic clamp studies, non-FH patients and control subjects had similar rates of whole-body glucose uptake (61 +/- 3 versus 58 +/- 3 mumol/kg per minute, p = NS). In addition, glucose oxidation, glucose nonoxidation, lipid oxidation, and suppression of free fatty acid levels as well as potassium disposal were similar in non-FH patients and control subjects. We conclude that FH and non-FH are not insulin-resistant states.

Effects of bezafibrate on insulin sensitivity and glucose tolerance in subjects with combined hyperlipidemia

To investigate whether the lowering of triglyceride levels has beneficial effects on glucose metabolism, we studied 13 nondiabetic men with combined hyperlipidemia (phenotype IIB) before and after 2 months of treatment with a slow‐release formulation of bezafibrate (400 mg daily). The rates of whole body glucose disposal were quantitated by the euglycemic hyperinsulinemic clamp technique (insulin infusion rate of 80 mU/m2/min). In an oral glucose tolerance test, fasting glucose level decreased slightly (5.0 ± 0.2 versus 4.8 ± 0.2 mmol/L; p <0.05) during bezafibrate treatment. Glucose and insulin levels after an oral glucose load remained unchanged. Rates of whole body glucose disposal did not change during bezafibrate treatment (39.5 ± 3.3 µmol/kg/min before treatment versus 40.6 ± 2.7 µmol/kg/min after treatment; difference not significant). Basal hepatic glucose output also remained unchanged (8.2 ± 0.2 µmol/kg/min before treatment versus 8.3 ± 0.2 µmol/kg/min after treatment; difference not significant). Our findings show that bezafibrate has a triglyceride‐lowering effect without any significant influence on insulin sensitivity.

Cholesterol Lowering Effect of Metformin in Combined Hyperlipidemia: Placebo Controlled Double Blind Trial

Metformin, an antidiabetic biguanide derivative, prevents experimental atherosclerosis and induces structural changes in lipoproteins in experimental animals. In the present study we investigated the effect of metformin on serum lipoproteins and platelet function in 24 non-diabetic patients with type II B hyperlipidemia. The patients were randomly given metformin in two dosage levels (1.0 g/day and 2.0 g/day) and placebo for periods of nine weeks in a crossover trial. Metformin caused a dose dependent fall in the concentrations of total serum cholesterol and of LDL-cholesterol. The average concentration of total cholesterol was 8.54 +/- 0.22 (SE) mmol/l, 8.12 +/- 0.19 mmol/l and 7.79 +/- 0.15 mmol/l during placebo, metformin 1.0 g/day and 2.0 g/day treatments, respectively. Both metformin values differed significantly (P less than 0.05) from the placebo value. Thus there was an average fall of 8.1% in total cholesterol after the higher metformin dose. LDL-cholesterol was 5.25 +/- 0.23 mmol/l after placebo, falling by 3.1% and 9.6% after metformin doses of 1.0 g/day and 2.0 g/day, respectively. The concentrations of HDL-cholesterol and total serum triglycerides showed no significant changes. Body weight, blood glucose, plasma insulin, blood lactate, platelet function and urinary excretion of prostanoids remained unchanged during the study. The reduction of total- and LDL-cholesterol levels may be a welcome additional consequence of metformin during treatment of diabetic patients with hypercholesterolemia.

Relationship between postheparin plasma lipases and high-density lipoprotein cholesterol in different types of diabetes.

SummaryWe measured serum lipids, lipoproteins and postheparin plasma lipases, lipoprotein lipase and hepatic lipase, in 12 female patients with Type 1 (insulin-dependent) diabetes (postglucagon C-peptide undetectable), in 11 female insulin-treated patients with Type 2 (non-insulin-dependent) diabetes (postglucagon C-peptide >0.60 nmol/l) and in 16 non-diabetic female control subjects. These three groups of subjects were similar with respect to age and obesity. Insulin dose was similar in patients with Type 1 and with Type 2 diabetes. HDL and HDL2 cholesterol were lower in patients with Type 2 diabetes than in non-diabetic control subjects (p<0.05) but did not differ between patients with Type 1 diabetes and non-diabetic control subjects. No difference in lipoprotein lipase activity was seen between the groups. The highest levels of lipoprotein lipase and hepatic lipase activities were observed in patients with Type 2 diabetes. Lipoprotein lipase activity correlated significantly with HDL cholesterol in patients with Type 1 diabetes (p<0.01) and in patients with Type 2 diabetes (p<0.001) but not in control subjects. Hepatic lipase activity did not correlate significantly with HDL cholesterol in any of the groups. In conclusion, postheparin plasma lipoprotein lipase and hepatic lipase activities do not seem to explain the difference in HDL cholesterol concentration between patients with Type 1 and Type 2 diabetes.