Helena Sarlund

Insulin resistance is associated with lipid and lipoprotein abnormalities in subjects with varying degrees of glucose tolerance.

We tested the hypothesis that insulin resistance, rather than high insulin level, is associated with lipid and lipoprotein changes favoring atherosclerosis independently of the glucose tolerance status. To this aim, 50 subjects with normal glucose tolerance, 28 subjects with impaired glucose tolerance, and 54 subjects with noninsulin-dependent diabetes (NIDDM) were studied. Subjects with low glucose disposal rate (GDR) or a high degree of insulin resistance as measured by the euglycemic hyperinsulinemic clamp technique had lower high density lipoprotein (HDL) cholesterol and higher total and very low density lipoprotein (VLDL) triglycerides than did subjects with high GDR (highest GDR tertile). These associations were independent of fasting insulin level and other confounding factors. In stepwise multiple linear regression analysis, GDR was the most important single variable associated with HDL cholesterol and VLDL triglyceride level independently of age, obesity, distribution of obesity (waist/hip ratio), 2-hour glucose level, and free fatty acid concentration. We conclude: 1) insulin resistance measured by the euglycemic clamp technique is associated with adverse lipid and lipoprotein changes favoring atherosclerosis not only in nondiabetic subjects (as shown in previous studies) but also in impaired glucose tolerance and NIDDM subjects; 2) the association of high insulin level with adverse lipid and lipoprotein changes indirectly reflects the association of insulin resistance with lipid and lipoprotein levels; and 3) HDL cholesterol and VLDL triglycerides are independently associated with insulin-mediated glucose uptake, which may indicate that these lipoproteins have separate sites of interaction with insulin action.

Asymptomatic atherosclerosis and insulin resistance.

High plasma insulin has been shown to be associated with the risk of coronary heart disease in nondiabetic subjects in prospective population studies. Furthermore, insulin resistance measured by the euglycemic glucose clamp technique has been shown to be related to lipid and lipoprotein changes favoring atherosclerosis and to high blood pressure. No study, however, has demonstrated that insulin resistance per se is directly associated with atherosclerosis. With this aim, we studied 30 middle-aged nonobese subjects with asymptomatic atherosclerosis in the femoral or carotid arteries and 13 corresponding control subjects. Fasting blood glucose, insulin, and C-peptide levels were only slightly and nonsignificantly higher in subjects with atherosclerosis than in controls, and during the oral glucose tolerance test 1- and 2-hour glucose, insulin, and C-peptide levels were similar in both groups. During the euglycemic hyperinsulinemic (1,200 pmol/l) clamp studies, subjects with atherosclerosis had a 20% reduced whole-body glucose uptake (58 +/- 2 versus 71 +/- 4 mumol/kg/min, p = 0.004). Glucose oxidation, lipid oxidation, suppression of free fatty acid levels, and potassium disposal were similar in both groups. In contrast, nonoxidative glucose disposal was significantly reduced in patients compared with that in controls (37 +/- 2 versus 50 +/- 4 mumol/kg/min, p = 0.004). When glucose uptakes were matched during the hyperglycemic clamp studies, the rate of nonoxidative glucose uptake was normalized in the patients. These results provide the first direct evidence that asymptomatic atherosclerosis is associated with insulin resistance. This insulin resistance is characterized by reduced whole-body and nonoxidative glucose uptake. In contrast, glucose and lipid oxidation, potassium disposal, and suppression of free fatty acid levels during hyperinsulinemia did not differ between the subjects with and without atherosclerosis.

Chromium supplementation in impaired glucose tolerance of elderly: effects on blood glucose, plasma insulin, C-peptide and lipid levels

Altogether twenty-six elderly subjects (aged 65-74 years) with persistent impaired glucose tolerance (World Health Organization (1985) criteria) identified in a population-based study, were randomly treated either with chromium-rich yeast (160 micrograms Cr/d) or with placebo for 6 months. The 24 h urinary Cr increased from 0.13 (SE 0.03) to 0.40 (SE 0.06) micrograms/d in the Cr group (n 13) but no change was found in the placebo group (n 11) (0.13 (SE 0.02) v. 0.11 (SE 0.02) micrograms/d). No significant change was observed in the oral glucose tolerance test (glucose dose 75 g; 0, 1 and 2 h blood glucose respectively): 5.3 (SE 0.1), 9.3 (SE 0.3), 8.2 (SE 0.3) mmol/l v. 5.0 (SE 0.1), 8.5 (SE 0.4), 7.3(SE 0.5) mmol/l in the Cr group; 4.9 (SE 0.2), 9.2 (SE 0.6), 8.1 (SE 0.3) mmol/l v. 4.8 (SE 0.2), 8.5 (SE 0.5), 7.0 (SE 0.6) mmol/l in the placebo group (baseline v. 6 months). Glycosylated haemoglobin, plasma insulin, C-peptide and apolipoprotein A1 and B levels remained unchanged, and no improvement was seen in serum total cholesterol (6.2 (SE 0.3) v. 6.4 (SE 0.3) mmol/l for the Cr group, 6.2 (SE 0.4) v. 6.5 (SE 0.3) mmol/l for the placebo group), high-density-lipoprotein-cholesterol (1.1 (SE 0.1) v. 1.2 (SE 0.1) mmol/l for the Cr group, 1.0 (SE 0.1) v. 1.1 (SE 0.1) mmol/l for the placebo group) or triacylglycerols (2.5 (SE 0.4) v. 2.0 (SE 0.4) mmol/l for the Cr group, 2.4 (SE 0.2) v. 2.5 (SE 0.2) mmol/l for the placebo group). The present results indicate that Cr supplementation does not improve glucose tolerance or serum lipid levels in elderly subjects with stable impaired glucose tolerance.

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.

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.

Five-Year Follow-Up Study on Plasma Insulin Levels in Newly Diagnosed NIDDM Patients and Nondiabetic Subjects

A representative group of middle-aged (45- to 64-yr-old) patients with non-insulin-dependent diabetes mellitus (NIDDM) (n = 133; 70 men, 63 women) were examined at the time of diagnosis and 5 yr afterward for metabolic control and insulin response to oral glucose; 144 nondiabetic control subjects (62 men, 82 women) were similarly examined twice between 5-yr intervals. At the 5-yr examination, 56 of the diabetic patients (36 men, 20 women) were on diet therapy only, 60 (27 men, 33 women) received oral antidiabetic drugs, and 5 were treated with insulin. The metabolic control of diabetic patients was poor at the time of diagnosis and 5-yr examination. Fasting plasma insulin levels were higher in diabetic patients than in control subjects both at baseline (23 ± 2 vs. 14 ± 1 mU/L, P < 0.01, for men; 26 ± 2 vs. 15 ± 1 mU/L, NS, for women) and 5-yr examination (19 ± 1 vs. 16 ± 2 mU/L, NS, for men; 29 ± 5 vs. 15 ± 1 mU/L, P < 0.05, for women). The frequency of insulin deficiency in diabetic patients based on a postglucagon (1 mg i.v.) C-peptide level <0.60 nM was 3.3% at the 5-yr examination, indicating that true insulin deficiency was uncommon during the first years after diagnosis of diabetes in middle-aged subjects.

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.

Early abnormalities in coronary heart disease risk factors in relatives of subjects with non-insulin-dependent diabetes.

Coronary heart disease risk factor levels were studied in 184 first-degree relatives (sisters and brothers) of non-insulin-dependent diabetic subjects (124 relatives with normoglycemia, 34 relatives with impaired glucose tolerance [IGT], and 26 relatives with non-insulin-dependent diabetes mellitus [NIDDM]) and in 215 relatives of nondiabetic subjects (194 relatives with normoglycemia and 21 relatives with IGT). Subjects with IGT exhibited the highest insulin responses to an oral glucose load. Systolic blood pressure was significantly higher; serum high density lipoprotein cholesterol level was significantly lower; and total, low density lipoprotein, and very low density lipoprotein triglyceride levels were higher in the relatives with a family history of diabetes who had IGT or NIDDM than in the normoglycemic relatives without a family history of diabetes. These abnormal changes were not seen in normoglycemic relatives or relatives with IGT who had no family history of NIDDM. Thus, in relatives of diabetics, abnormal glucose tolerance seems to induce changes in cardiovascular heart disease risk factor levels that are similar to those observed in NIDDM. Therefore, a family history of diabetes adds substantially to the risk for atherosclerosis, particularly in subjects with IGT.

Inverse relationship of serum HDL and HDL2 cholesterol to C-peptide level in middle-aged insulin-treated diabetics

Serum lipids and lipoproteins were measured in 170 insulin-treated diabetics (90 females, 80 males) and in 124 nondiabetic control subjects (59 females, 65 males) aged 45 to 64 years. Plasma C-peptide response to intravenous (IV) glucagon was measured in order to classify the patients according to their capacity of endogenous insulin secretion. In both sexes, HDL and HDL2 cholesterol were higher in diabetics with no C-peptide response than in controls, whereas diabetics with high C-peptide response (postglucagon C-peptide level greater than 0.60 nmol/L) showed lower levels of HDL and HDL2 than nondiabetic controls. When adjustment for age, alcohol consumption, physical activity, body mass index, and insulin dose was made by analysis of covariance, the highly significant difference in HDL and HDL2 cholesterol level between diabetics with no C-peptide response and diabetics with high C-peptide response still remained in both sexes. This study gives support to the hypothesis that elevated HDL and HDL2 cholesterol levels in insulin-treated diabetics are not explained by effects of treatment with exogenous insulin, but rather are associated with the type of diabetes characterized by deficient endogenous insulin secretion.

Factors Associated With Fasting and Postglucagon Plasma C-Peptide Levels in Middle-Aged Insulin-Treated Diabetic Patient

We studied fasting and postglucagon plasma C-peptide levels and factors associated with them in two representative studies of middle-aged insulin-treated diabetic patients whose diabetes had been diagnosed after the age of 30 yr. Altogether, 75 men and 79 women from East Finland and 83 men and 62 women from West Finland aged 45–64 yr were studied. Of these patients, 44.4% had undetectable fasting and 38.5% undetectable postglucagon C-peptide concentrations. The φ coefficient expressing the concordance of fasting and postglucagon C-peptide concentrations in the classification of diabetic patients into nonresponders and responders was .75 in men and .91 in women. In multiple stepwise regression analyses, body mass index (BMI) and the period between diabetes diagnosis and the initiation of insulin treatment were positively and duration of diabetes inversely associated with fasting and postglucagon C-peptide levels in both sexes. We concluded that 7) insulin deficiency is not uncommon in middle-aged insulin-treated diabetic patients whose diabetes has been diagnosed after the age of 30 yr; 2) fasting C-peptide levels contain basically the same information as postglucagon C-peptide levels; and 3) a low BMI, a need for insulin treatment soon after the diagnosis of diabetes, and a long duration of diabetes are predictive of insulin deficiency.