Carotid atherosclerosis in type 2 diabetes mellitus: potential role of endothelin-1, lipoperoxides, and prostacyclin.

Factors were studied that may initiate macroangiopathy or enhance or aggravate its pathogenesis in patients with type 2 diabetes mellitus. A total of 151 diabetics were compared with healthy controls (n=50); all patients and subjects were normotensive and without renal failure. Plasma endothelin-1 and free radical levels were measured. In addition, plasma prostacyclin levels were assessed by assaying its stable, spontaneous, breakdown product 6-keto-prostaglandin-F1a. Diabetics were divided into three groups: those with clinically evident macroangiopathy and those with early or without atherosclerosis (as determined by the carotid intima-media thickness. Plasma endothelin-1 levels were increased in all diabetics with atherosclerosis. Plasma free radical levels were increased in diabetics with macroangiopathy when compared with control subjects. The plasma levels of 6-keto-prostaglandin-F1a were slightly, but significantly, decreased in the diabetics with macroangiopathy when compared with control subjects. The carotid intima-media thickness was significantly greater in diabetics without macroangiopathy when compared with the controls. Furthermore, the intima-media thickness increased significantly in this group of diabetics but not in the controls over a 30-month follow-up period. Several factors may contribute to atherogenesis in diabetics. These include increased plasma endothelin-1 and free radical levels as well as a deficiency of prostacyclin. These factors may become targets for intervention as well as markers of disease progression.

Plasma levels of endothelin, lipid peroxides and prostacyclin in diabetic patients with macroangiopathy.

The prevalence of macroangiopathy is increased in diabetes mellitus. Endothelial cell injury is thought to be an early event leading to atherosclerosis which may be initiated by several factors. We have investigated the relationship between plasma endothelin, lipid peroxide (measured as thiobarbituric acid reacting species (TBARS)) and 6-keto-prostaglandin-F1A (6-keto-PG-F1A) in Type 2 diabetic patients with macroangiopathy. Fifty-three diabetic subjects with macroangiopathy were investigated, together with 50 diabetic and 50 control subjects without evidence of vascular disease. Both the endothelin and TBARS levels were significantly higher in diabetic patients with macroangiopathy (10.8 (8.0-14.4) pmol/l and 5.6 (3.2-9.7) micromol/l, respectively) compared with control subjects (7.6 (5.0-11.0) pmol/l and 4.5 (3.0-6.4) micromol/l, P<0.001) and with diabetic subjects without macroangiopathy (7.4 (4.9-11.2) pmol/l (P<0.001) and 4.9 (3.0-8.0) micromol/l (P<0.05)). 6-Keto-PG-F1A levels were significantly decreased in diabetic subjects with macroangiopathy 209 (123-355) pg/ml than in normal subjects 241 (137-425) pg/ml, (P<0.05) and diabetic subjects without macroangiopathy 224 (162-309) pg/ml, (P<0.05). Comparison of levels of endothelin with those of TBARS in macroangiopathy group, showed that endothelin is a more consistent marker of the atherogenic process (P<0.01). In conclusion, we have shown that there are abnormalities of endothelium-derived factors in diabetic patients with macroangiopathy, mainly in endothelin. Furthermore, in this group there was a positive correlation between endothelin and fasting insulin levels.

Progression of carotid atherosclerosis and the role of endothelin in diabetic patients.

An increased thickness of the carotid artery wall is thought to be a sign of early atherosclerosis. Since vascular endothelium is the site of formation of several substances, we have investigated the rate of progression of carotid atherosclerosis and the contribution of endothelin (ET-1), lipid peroxides [measured as thiobarbituric acid reacting species (TBARS)] and 6-keto-Prostaglandin-F1A (6-keto-PG-F1A) at baseline and after 30-months. Fifty patients with Type 2 diabetes without evidence of macroangiopathy, hypertension, proteinuria or proliferative retinopathy, and 27 healthy, non-diabetic persons were studied. Arterial wall thickness was measured as the mean of the maximum intimal-medial thickness (IMT) in 16 carotid segments by b-mode ultrasound. The IMT values was significantly increased in diabetic subjects (at baseline: 1110 +/- 310 microm, after 30 months: 1260 +/- 280 microm, p < 0.01), but not in control subjects (1100 +/- 280 microm, 1200 +/- 290 microm, respectively). At baseline time both groups had similar levels of ET-1, TBARS and 6-keto-PG-F1A. In 30-months follow-up, the ET-1 level 8.0 pmol/l (5.8-10.7) was significantly elevated in diabetic subjects, compared with the level at baseline time 7.43 pmol/l (4.8-11.1) p < 0.01. No significant differences were found in the other examined parameters in the studied groups. Although insulin levels remained unchanged in the two studied groups, in 30 months follow-up, the insulin level in the diabetic subjects, 92.4 +/- 35.1 pmol/l was significantly elevated compared with those of control subjects 76.0 +/- 31.0 pmol/l, p < 0.05. In conclusion, endothelis is the main associate of the change of IMT value over 30 months in diabetic patients, in whom the extent of atherosclerosis was significantly greater than in control subjects.

Plasma levels of endothelin and early carotid atherosclerosis in diabetic patients.

An increased thickness of the carotid artery wall is thought to be a sign of early atherosclerosis. Since plasma endothelin concentrations were released from vascular endothelial cells, we have investigated the possible relationship between endothelin 1 (ET-1) and arterial wall thickness. Ninety-eight patients with Type 2 diabetes without evidence of macroangiopathy, hypertension, proteinuria or proliferative retinopathy, and 50 non-diabetic subjects were studied. After an overnight fast, blood was taken for ET-1, glucose, HbA1c, lipids, insulin and C-peptide. Arterial wall thickness was measured as the mean of the maximum intimal-medial thickness (IMT) in 16 carotid segments by B-mode ultrasound. ET-1 levels were significantly elevated in diabetic patients with IMT>1100 microm, 8.3 pmol/l (5.2-12.9) compared with control subjects, 7.6 pmol/l (5.0-11.0), p<0.01 and with diabetic subjects with IMT<500 microm, 7.43 pmol/l (4.8-11.1), p<0.01. The diabetic (IMT>1100 microm) study group had also significantly higher levels of insulin, 102.8 +/- 46.4 pmol/l vs control subjects, 77.5 +/- 32.4 pmol/l, p<0.01. In diabetic subjects, no correlation was found between ET-1 and IMT with glucose, HbA1c, lipids, age or duration of diabetes, respectively. We conclude that ET-1 levels are elevated in Type 2 diabetic patients with increased IMT. Thus providing further support for the role of endothelin in atherosclerosis.

Metabolic abnormalities in offspring of NIDDM patients with a family history of diabetes mellitus.

NIDDM appears to be an inherited condition. Our aim was to identify early metabolic abnormalities in non-diabetic offspring with one NIDDM parent and with a strongly positive (n = 58, age 27.8 +/- 7.0 years) or a negative family history (n = 38, age 27.4 +/- 6.7 years) of diabetes. These were compared with 31 offspring of non-diabetic parents (age 26.9 +/- 5.5 years). After an overnight fast, blood was taken for glucose, insulin, C-peptide, insulin receptors, and lipids. All the subjects underwent a 75 g oral glucose tolerance test. The positive family history group had significantly higher fasting levels of triglycerides (1.09 +/- 0.24 vs control subjects: CS: 0.93 +/- 0.16 mmol l-1, p < 0.001), insulin (102.8 +/- 46.4 vs CS: 77.5 +/- 32.4 pmol l-1, p < 0.01) and C-peptide (0.69 +/- 0.22 vs CS: 0.61 +/- 0.19 nmol l-1, p < 0.05) and lower numbers of insulin receptors per red cell (9.1 x 10(3) (4.5-18.1, 95% confidence intervals) vs CS: (11.2 x 10(3) (6.3-19.9)), p < 0.01, despite similar blood glucose levels. After a glucose challenge (120 min), the increases in both insulin and C-peptide concentrations were significantly greater in the positive family history group (289.2 +/- 214.1 pmol l-1, 2.23 +/- 1.48 nmol l-1), respectively, than in CS (192.4 +/- 170.3 pmol l-1, p < 0.05) (1.54 +/- 0.99 nmol l-1 p < 0.01), respectively. No significant differences were found in fasting and post-challenge glucose levels. The negative family history group had significantly lower numbers of insulin receptors 9.4 x 10(3) (4.1-15.2) compared with CS (p < 0.05). Insulin sensitivity was significantly reduced in the positive family history group (41.6%) compared with control subjects (51.9%), p < 0.01. The results strongly support the familial basis of the disease.

Insulin-like growth factor-I and IGF-I receptors in diabetic patients with neuropathy.

Since a number of animal studies have shown that insulin-like growth I (IGF-I) stimulates nerve regeneration, the aim of our study was to evaluate the possible relationship between IGF-I and IGF-I receptors in diabetic patients with peripheral neuropathy. One hundred and four patients with Type 2 diabetes (57 with peripheral neuropathy and 47 non-neuropathic) were studied. Controls were 17 non-diabetic persons. After an overnight fast, blood was taken for IGF-I, IGF-I receptors, glucose, HbA1, C-peptide, and insulin. The neuropathy study group had significantly lower levels of IGF-I:144.5 ng ml-1 (57.5-363.0, 95% confidence limits) compared to controls: 186.2 ng ml-1 (93.3-371.5), p < 0.01, and to diabetic patients without neuropathy: 173.7 ng ml-1 (83.1-363.0), p < 0.01. The study group also had a lower number of IGF-I receptors per red cell: 22.9 x 10(3) (13.08-38.01) vs control subjects: 28.1 x 10(3) (18.62-42.65), p < 0.01, and non-neuropathic diabetic patients: 26.3 x 10(3) (16.59-41.68), p < 0.01. In diabetic subjects there was a positive correlation (r = 0.20, p < 0.05) between IGF-I and HbA1, while in the neuropathy group there was a negative correlation between the score for nerve dysfunction with the IGF-I (r = -0.39, p < 0.01) and with IGF-I receptors (r = -0.34, p < 0.01). We conclude that in diabetic patients with peripheral neuropathy there are abnormalities of IGF-I and IGF-I receptors which may contribute to impaired neuronal regeneration.

Triiodothyronine administration in coronary artery bypass surgery: effect on hemodynamics.

OBJECTIVE: The purpose of this study was to investigate any potential hemodynamic effect of intravenously administered triiodothyronine in patients undergoing coronary artery bypass surgery. EXPERIMENTAL DESIGN: Thirty patients were randomized in this single-blind, placebo-controlled trial. Hemodynamic parameters including heart rate, stroke volume index, cardiac index, pulmonary wedge pressure, pulmonary vascular resistances, systemic vascular resistances, and mean blood pressure, were compared between the two groups preoperatively, before the initiation of cardiopulmonary bypass (CPB), 5 minutes after the end of CPB, and 2, 4, 10, 16, and 22 hours thereafter. INTERVENTION: Triiodothyronine was administered as a bolus infusion over a 1 min period after removal of the aortic cross-clamp, (0.15 microgram/kg), before the end of CPB (0.1 microgram/kg), 4 hours after the end of CPB (0.1 microgram/kg), 9 hours after CPB (0.1 microgram/kg), and 14 hours after CPB (0.1 microgram/kg). Patients received inotropes, vasodilators, and diuretics only if specifically indicated. RESULTS: Plasma FT3 levels were higher in the T3 group, but within the normal range. No significant differences were noted in the pre and post CPB hemodynamics between the two groups for the most part of the study except that heart rate was increased in T3 group. A greater number of patients in the control group received vasodilators. No adverse reactions were noted with triiodothyronine administration. CONCLUSION: Triiodothyronine administration in patients undergoing cardiopulmonary bypass surgery is safe, may lessen the need for pharmacological (vasodilator) therapy, but may increase heart rate.

Serum levels of type III procollagen peptide and peripheral vascular disease in diabetic patients.

The aim of this study was to assess the possible relationship between serum levels of Type III procollagen peptide (PIIINP) and peripheral vascular disease (PVD) in diabetic patients. Ninety Type 2 diabetic patients being treated with sulfonylureas, and 37 non-diabetic subjects were studied using Doppler ultrasound. After an overnight fast, blood was taken for PIIINP, glucose, glucosylated hemoglobin (HbA1), C-peptide, and lipids. Data were analysed according to the non-paired Student's t-test and the correlation coefficient, after log transformation. PIIINP levels were significantly elevated in diabetics with PVD (n = 44), 4.3 micrograms/l (2.4-7.6, 95% confidence limits) compared with controls 3.1 micrograms/l (1.9-4.9), P < 0.001, and with diabetics without PVD (n = 46), 3.1 micrograms/l (1.9-5.0), P < 0.001. No correlation was found between PIIINP and HbA1, glucose, C-peptide, age or duration of diabetes. We conclude that PIIINP levels are elevated in Type 2 diabetics with PVD. It may reflect an increase in collagen deposition in the large arteries that accompanies the development of macroangiopathy.

Size of the pancreas in non-insulin-dependent diabetic patients.

We investigated the relationship between the size of the pancreas in non-insulin-dependent diabetic patients (NIDDs) and normal subjects, and also the possible correlation between pancreatic size in diabetics and basal C-peptide concentrations. Eighty-four non-insulin-dependent diabetics and eighty control subjects matched for age, sex and body mass index (BMI) were studied, using a realtime sector system, with which we measured the head and body of the pancreas in cm2. Scans were performed twice in 50 subjects with no significant difference. Both the head and the body of the pancreas were significantly smaller in diabetics (4.60 +/- 1.10 cm2, 5.92 +/- 1.53 cm2, respectively) than in normal subjects (6.09 +/- 1.62 cm2, 7.43 +/- 2.14 cm2) (p less than 0.001). The mean total area of the pancreas for the diabetics was 10.53 +/- 2.45 cm2, and for the controls 13.53 +/- 3.60 cm2 (p less than 0.001). No correlation was found between the total area of the pancreas and the BMI in the two groups. In the diabetic group, there was a positive correlation between C-peptide and the total area of the pancreas (r = 0.30, p less than 0.01). We concluded that the size of the pancreas is smaller in NIDDs than in healthy controls, and there is a positive correlation with the basal C-peptide concentration.

Elevated serum levels of angiotensin-converting enzyme in patients with diabetic retinopathy.

Serum levels of angiotensin-converting enzyme (ACE) were measured in 53 patients with type II (non-insulin-dependent) diabetes (25 without ophthalmologic complications, 20 with background retinopathy, and eight with proliferative retinopathy) and in 33 healthy nondiabetic subjects. Diabetic subjects were excluded if they had hypertension, ischemic heart disease, peripheral vascular disease, or an elevated urine albumin level. After an overnight fast, blood was taken for determination of ACE, blood glucose, glycosylated hemoglobin (HbA1), and C peptide levels. Data were analyzed according to the nonpaired Student's t test and linear regression analysis. Levels of ACE were significantly elevated in the whole diabetic group as compared with control subjects (334.0 U/L +/- 97.0 vs 250.5 U/L +/- 85.5, P less than .001). This elevation was more marked in those diabetics with background retinopathy (344.6 U/L +/- 96.8, P less than .001) and proliferative retinopathy (357.3 U/L +/- 93.2, P less than .01); no significant difference was found between ACE levels of diabetics without complications and those of control subjects. No correlation was found between ACE levels and HbA1, blood glucose, or C peptide values. We conclude that ACE levels are elevated in type II diabetes, chiefly in patients with retinopathy. This finding may reflect microvascular damage caused by secretion of ACE by the vascular endothelial cells.

Correlation between high density lipoprotein cholesterol and C-peptide in sulfonylurea-treated diabetic patients.

The aim of this study was to assess the possible relationship between high density lipoprotein cholesterol (HDL-C) concentrations and endogenous insulin secretion, as measured by basal serum C-peptide secretion. Eighty-nine non-insulin-dependent diabetic patients (NIDDs) being treated with sulfonylureas were studied. There were 47 men and 42 women matched for age, body mass index (BMI), duration of diabetes and glycemic control. Blood samples were taken after an overnight fast. HDL-C concentrations were significantly lower in males (45.9 +/- 11.2 mg/dl) than in females (52.9 +/- 13.1 mg/dl) (p less than 0.01). There was a negative correlation between C-peptide and HDL-C (males r = -0.40, p less than 0.01; females r = -0.42, p less than 0.01), and a positive correlation between C-peptide and serum triglyceride (Tg) (males r = +0.36, p less than 0.05; females r = +0.31, p less than 0.05).