Nonalcoholic Fatty liver disease, diabetes mellitus and cardiovascular disease: newer data.

Nonalcoholic fatty liver disease (NAFLD) is the most common, chronic liver disease worldwide. Within this spectrum, steatosis alone is apparently benign, while nonalcoholic steatohepatitis may progress to cirrhosis and hepatocellular carcinoma. NAFLD is strongly associated with obesity, dyslipidemia, type 2 diabetes mellitus, and cardiovascular disease. The pathogenesis of hepatic steatosis is not clearly known, but its main characteristics are considered insulin resistance, mitochondrial dysfunction, increased free fatty acids reflux from adipose tissue to the liver, hepatocyte lipotoxicity, stimulation of chronic necroinflammation, and fibrogenic response. With recent advances in technology, advanced imaging techniques provide important information for diagnosis. There is a significant research effort in developing noninvasive monitoring of disease progression to fibrosis and response to therapy with potential novel biomarkers, in order to facilitate diagnosis for the detection of advanced cirrhosis and to minimize the need of liver biopsy. The identification of NAFLD should be sought as part of the routine assessment of type 2 diabetics, as sought the microvascular complications and cardiovascular disease, because it is essential for the early diagnosis and proper intervention. Diet, exercise training, and weight loss provide significant clinical benefits and must be considered of first line for treating NAFLD.

Lipid peroxides in type 2 diabetic patients with neuropathy.

Diabetes and its metabolic changes in peripheral nerves contribute to cause a decrease of nitric oxide production and diminished nerve blood flow. Since lipid peroxides are thought to be formed by free radicals and may play an important role in the development of vascular disease, we have investigated the possible relationship between lipid peroxides (measured as thiobarbitouric acid reacting substances (TBARS) in diabetic patients with peripheral neuropathy. Seventy-seven patients with Type 2 diabetes (39 neuropathic and 38 non-neuropathic) and 38 control subjects were studied. The neuropathy study group had significantly lower levels of TBARS, 3.5micromol/l (2.2-5.6, 95% confidence limits) compared to controls 4.5microm/l (3.08-6.8), p < 0.001 and to diabetics without neuropathy 4.9micromol/l (3.09-8.05), p < 0.001. No differences were found in metabolic control between the two diabetic groups. In the neuropathy group there was a negative correlation between the score for nerve dysfunction with the TBARS levels (r = - 0.42, p < 0.01). In conclusion, in diabetic patients with neuropathy there are abnormalities of TBARS levels.

Hematological malignancies are associated with a lower interferon-a blocking activity than solid tumors.

UNLABELLED: Interferon (IFN) and especially IFN-alpha exhibit clinical anti-tumor activity against various types of malignant diseases. Natural inhibitors to various cytokines and IFNs have been documented in vitro as well as in vivo. IFN inhibitors have been implicated for the ineffectiveness of IFN treatment in malignant neoplasias. The aim of this study was to investigate the incidence of the IFN inhibiting activity in serum from patients with haematological malignancies versus patients with solid tumours, as an effort to explain, just in part, the different response of these patients to IFN treatment. PATIENTS AND METHODS: Ninety patients with a clinically evident solid tumour and forty-six patients with haematological malignancies were included in the study. Serum samples from all patients were collected before any treatment and stored at -70 degrees until use. Controls sera were selected from 50 apparently healthy blood donors. Interferon-inhibiting activity as well as endogenous IFN-like activity were determined in all serum samples in a cell line highly sensitive to IFN. RESULTS: There was no endogenous IFN-like activity in any of the patients' group or controls' group. Sera from patients with haematological malignancies exhibited IFN-blocking activity at a lower percentage (21.7%) in comparison to sera from patients with solid tumours (56.6%, P<0.001), but at a significantly higher percentage in comparison to sera from controls (P<0.01). CONCLUSIONS: The fact that IFN inhibitors were detected at a significantly lower percentage in sera from patients with haematological malignancies versus patients with solid tumours, could explain in part the better response of the haematological malignancies to IFN treatment.

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.

Effects of buflomedil on early carotid atherosclerosis in Type 2 diabetic patients.

BACKGROUND: An increased thickness of the carotid artery wall is thought to be a sign of early atherosclerosis. We have investigated the effect of early treatment with buflomedil on the prevention of the arterial wall thickening. METHODS: Eighty patients with Type 2 diabetes were studied. Oral buflomedil (600 mg once daily) was administered for 12 months in 42 patients randomly selected, while 38 received no treatment. The two groups were matched for age, sex, body mass index (BMI), duration of diabetes and glycaemic control. Arterial wall thickness was measured as the mean of the maximum intima media thickness (IMT) in 8 carotid segments measured by B-mode ultrasound. RESULTS: Blood pressure and lipid levels remained unchanged in the two studied groups while no difference was found in metabolic control between them. The IMT increase over 12 months was 0.04 mm in the buflomedil group whereas in that without buflomedil it was 0.10 mm. CONCLUSIONS: We conclude that buflomedil treatment may be useful in decreasing the progression rate of arterial wall thickness.

Ca(2+)-Mg(2+)-ATPase activity and ionized calcium in Type 2 diabetic patients with neuropathy.

Ca(2+)-Mg(2+)-ATPase is an important regulator of intracellular calcium concentration and therefore, of erythrocyte deformability. We have investigated the possible relationship between Ca(2+)-Mg(2+)-ATPase activity (ATPase) and ionized calcium (Ca(2+)), in diabetic patients with peripheral neuropathy. A total of 104 Type 2 diabetic patients (57 neuropathic and 47 non-neuropathic) and 25 non-diabetic subjects were studied. After an overnight fast, blood was taken for Ca(2+)-Mg(2+)-ATPase activity, Ca(2+), Mg(2+), PTH and HbA(1c). The neuropathy study group had significantly lower levels of ATPase, 6.6 (95% CI, 5.6-7.7) nmol/mg/min compared to controls 7. 1 (6.2-8.3) nmol/mg/min, P<0.001 and to diabetic patients without neuropathy 7.0 (6.0-8.1) nmol/mg/min, P<0.001. The study group had also lower levels of Ca(2+) (0.89+/-0.18 mmol/l vs. control 1.08+/-0. 24 mmol/l, P<0.01 and non-neuropathic 0.98+/-0.27 mmol/l, P<0.05) and Mg(2+) (0.73+/-0.13 mmol/l vs. control 0.81+/-0.14 mmol/l, P<0. 05), despite similar PTH levels. In diabetic subjects, no correlation was found between ATPase or Ca(2+) with glucose, HbA(1c), age or duration of diabetes. We conclude that in patients with diabetic neuropathy there are abnormalities of Ca(2+)-Mg(2+)-ATPase activity and Ca(2+). This provides further support for the role of microangiopathy in the pathogenesis of neuropathy.

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.

Effect of fosinopril sodium on early carotid atherosclerosis in diabetic patients with hypertension.

An increased thickness of the carotid artery wall is thought to be a sign of early atherosclerosis. We have investigated the effects of fosinopril sodium in asymptomatic diabetic hypertensive subjects on the 12-month progression of arterial wall thickness. Forty non-insulin-dependent diabetics with hypertension and without hyperlipidemia were studied. After a 4-week run-in-diet phase, oral fosinopril sodium was administered (20 mg once daily) to 20 patients randomly selected, while 20 subjects were treated only with diet. The two groups were matched for age, sex, body mass index (BMI), duration of diabetes and glycemic control. Arterial wall thickness was measured as the mean of the maximum intimal-media thickness (IMT) in 16 carotid segments by B-mode ultrasound. The IMT increase over 12 months was 4.3% in the fosinopril sodium group vs 15.1% in subjects with diet. We conclude that fosinopril sodium treatment may be useful in decreasing the progression rate.

Effect of gemfibrozil on early carotid atherosclerosis in diabetic patients with hyperlipidaemia.

BACKGROUND: An increased thickness of the carotid artery wall is thought to be a sign of early atherosclerosis. We have investigated the effects of gemfibrozil in asymptomatic diabetic hyperlipidaemic subjects on the 12-month progression of arterial wall thickness. METHODS: Forty non-insulin-dependent diabetics with hyperlipidaemia and without hypertension were studied. After a 4-week run-in-diet phase, oral gemfibrozil was administered (900 mg once daily) in 20 patients randomly selected, while 20 subjects were treated only with diet. The two groups were matched for age, sex, body mass index (BMI), duration of diabetes and glycaemic control. Arterial wall thickness was measured as the mean of the maximum intima of media thickness (IMT) in 16 carotid segments by B-mode ultrasound. RESULTS: Baseline size of IMT and lipid values were similar in both groups. The IMT increase over 12 months was 5% in the gemfibrozil group vs 15.2% in subjects treated by diet alone. CONCLUSIONS: We conclude that gemfibrozil treatment may be useful in decreasing the progression rate of arterial wall thickness.

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.

Ambulatory blood pressure measurement in type-II diabetic patients with autonomic neuropathy.

The aim of our study was to access the 24-hr ambulatory blood pressure (BP) in diabetic patients with autonomic neuropathy (AN). Twenty-two NIDDM patients without hypertension, being treated with sulfonylureas, were studied. The 24-hr ambulatory blood pressure recordings were performed using portable non-invasive automatic system. Autonomic neuropathy was assessed by standard cardiovascular reflex tests. There were ten patients with and 12 without AN, matched for age, body mass index, duration of diabetes and glycemic control. Mean BP increased at night in four of the subjects with AN and decreased in the remaining 18 patients. The group of subjects with nocturnal increases in BP had more severe autonomic nerve dysfunction compared with those with decreases in nocturnal BP. No significant difference between clinical and ambulatory day-time measurements was found. In three patients with AN after 5 weeks intensified therapy. 24-hr BP did not show any significant difference.

Diabetic retinopathy and urinary albumin excretion rate in type II (non-insulin-dependent) diabetic patients.

The aim of this study was to access the associations between urinary albumin excretion rate (AER) and diabetic retinopathy and its major risk factors in 105 type II non-insulin-dependent diabetic (NIDDM) patients. In 44.7% of the patients, there were no signs of retinopathy (NR), whereas 30.4% had background (BR) and 24.7% proliferative retinopathy (PR). Patients with retinopathy, both BR and PR, were older and the duration of diabetes was longer, than in the group consisting of patients with NR. Patients with retinopathy had elevated AER (BR: 9.4 +/- 2.8 micrograms/min, PR: 19.3 +/- 1.7 micrograms/min; vs. NR: 4.3 +/- 2.1 micrograms/min, p < 0.001). Patients with retinopathy had a higher systolic blood pressure and the metabolic control was worse than those without retifiopathy. In the diabetic group as a whole, raised AER was correlated with the duration of diabetes (rs = 0.287, p < 0.01) and systolic blood pressure (rs = 0.269; p < 0.01).

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.

The prevalence of peripheral vascular disease in type 2 diabetic patients with and without proteinuria.

It has been reported that albumin excretion rate may reflect not only an indication of renal disease but also a widespread vascular damage. We studied the relationship between overnight albumin excretion rate (AER) and peripheral vascular disease (PVD), using Doppler ultrasound, and its major risk factors in 80 Type 2 (non-insulin-dependent) diabetic patients. Thirty-eight of these patients had normoalbuminuria (AER < 30 micrograms/min), 22 had microalbuminuria (30-200 micrograms/min) and 20 had macroalbuminuria (> 200 micrograms/min). Patients with macroalbuminuria were older than those with normoalbuminuria (p < 0.01) and they also had a longer duration of diabetes (p < 0.05). Patients with elevated albumin excretion rates had elevated prevalence of PVD (macroalbuminuric 40%, p < 0.01; microalbuminuric 27.2%, p < 0.05; vs normoalbuminuric 7.8%). Among the risk factors analysed, hypertension and triglyceride concentrations were higher in the proteinuric diabetics (macroalbuminuric p < 0.001, p < 0.01; microalbuminuric p = NS, p < 0.01 respectively), while HDL-C levels were found to be significantly lower in this group (p < 0.05). In the diabetic group as a whole, raised AER was correlated with PVD (p < 0.05), duration of diabetes and systolic blood pressure (p < 0.01). We conclude that the prevalence of PVD was significantly higher in Type 2 diabetic patients with elevated albumin excretion rate. Furthermore, these patients had higher blood pressure and low HDL-C.

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.

Peripheral vascular disease in newly diagnosed non-insulin-dependent diabetic.

The aim of this study was to assess the prevalence of peripheral vascular disease (PVD) in newly diagnosed diabetic patients and the possible relationship to various risk factors. One hundred and twenty non-insulin-dependent diabetics (NIDDs) aged 50-70 years and 93 non-diabetic subjects, matched for age and sex, were studied using Doppler ultrasound. None had a history of alcoholic abuse, while 12 diabetic and 8 non-diabetic subjects were smokers. There were 6 male subjects with PVD (5 NIDDs, 1 control subject) and 2 female diabetic subjects with PVD (p: No SD). In group of male diabetics with PVD, HDL-C levels were found to be lower and triglyceride levels higher, than in those without diabetes, but the difference was not significant. Hypertension, body mass index and smoking were not associated with the presence of PVD in either female or male diabetic subjects. It is concluded that, although PVD tended to be more common in men with newly diagnosed diabetes, the overall findings support the view that macrovascular disease is related to duration of diabetes.