Improvement of fibrinolysis and plasma lipoprotein levels induced by gemfibrozil in hypertriglyceridemia.

A randomized double-blind study was carried out with gemfibrozil (600 mg b.i.d.) vs placebo in 20 patients (twelve males and eight females, age 52 +/- 3 years, BMI 24.2 +/- 0.4) suffering from primary hypertriglyceridemia (Fredrickson's type IV). Each group was treated for a 12 week period with gemfibrozil (n = 10) or placebo (n = 10) patients) in a double-blind fashion. Total cholesterol, HDL-cholesterol (HDL-C) and its subfractions (HDL2-C and HDL3-C), blood glucose, Apolipoproteins A1 and B, fibrinogen, plasminogen, factor VII, t-PA:Ag and PAI activity pre- and post-venous occlusion (VO) were determined. In the gemfibrozil-treated group a significant decrease of total cholesterol and triglycerides and a significant increase of HDL-C and HDL2-C were found. During gemfibrozil treatment a significant reduction of factor VII, fibrinogen and plasminogen levels was also observed. After 12 weeks of treatment in the gemfibrozil group the release of t-PA:Ag in response to venous occlusion was significantly higher and plasma PAI activity was significantly lower than in placebo group. Moreover positive correlations between HDL cholesterol and t-PA:Ag post-VO (r = 0.56, P < 0.01) and between HDL2-C cholesterol and t-PA:Ag post-VO (r = 0.59, P < 0.01) and a negative correlation between triglycerides and t-PA:Ag post-VO (r = -0.65, P < 0.01) were found. The data obtained suggest that gemfibrozil, in addition to the well established lipid-regulating effect, appears to have a positive role in the regulation of reverse cholesterol transport and fibrinolytic system.

Blood coagulation and fibrinolysis in obese NIDDM patients.

Four group of age- and sex-matched patients were studied: 1. nondiabetic subjects (n = 20) with a body mass index (BMI) < 25 Kg/m2 (lean control subjects); 2. obese non diabetic subjects (n = 22) with a BMI > 30 Kg/m2 (obese control subjects); 3. lean NIDDM subjects (n = 22); and 4. obese NIDDM subjects (n = 24). We determined: total cholesterol, triglycerides, HDL-cholesterol, blood glucose, Apolipoproteins A1 and B, insulin, Lp(a), Factor VII, fibrinogen, plasminogen, t-PA(Ag) pre and post venous occlusion (VO) and PAI activity pre and post VO. In addition to metabolic abnormalities obese non diabetic subjects and lean and obese NIDDM patients displayed significantly higher levels of fibrinogen, Factor VII, plasminogen, PAI pre and post VO and tPA(Ag) pre VO and significantly lower levels of t-PA(Ag) post VO. Our findings demonstrate an impairment of the haemostatic and fibrinolytic mechanisms which may be a key role in the pathogenesis of atherosclerotic vascular complications in obesity and in NIDDM.

Fibrinolysis in hypertriglyceridaemic subjects in response to venous occlusion.

We have measured various fibrinolytic and coagulation parameters (t-PA antigen, PAI, fibrinogen, plasminogen and factor VII) before and after 10 min of venous occlusion in 20 hypertryglyceridaemic subjects (twelve males and eight females, age 38 +/- 4 years, body mass index 23 +/- 1.5) and 20 healthy normal subjects, matched for sex (twelve males and eight females), age (37 +/- 3.5 years) and body mass index (22.8 +/- 1.4). At rest, t-PA:Ag, PAI, fibrinogen, plasminogen and factor VII were significantly (P < 0.005) higher in hypertriglyceridaemic subjects than in normal controls. After venous occlusion, the increase in all parameters except t-PA:Ag was more marked in the patient group than in the controls. Only the percentage increase in t-PA:Ag was higher in normal controls (358.8%) than in hypertriglyceridaemic subjects (91.9%). There was a positive correlation between serum triglycerides levels and PAI at rest (r = 0.72, P < 0.01) and a negative correlation between serum triglycerides levels and t-PA antigen after venous occlusion (r = -0.45, P < 0.05) suggesting an impairment of fibrinolysis in hypertriglyceridaemia.

Insulin resistance and endogenous digoxin-like factor in obese hypertensive patients with glucose intolerance.

Hypertensive obese subjects with glucose intolerance have hyperinsulinaemia, insulin resistance and intracellular cation imbalance resulting in increased sodium content. The aim of our study was to assess in these patients plasma levels of endogenous digoxin-like factor (EDLF), an inhibitor of the sodium-pump mechanism. We studied 14 hypertensive and 12 normotensive subjects with obesity and glucose intolerance for fasting blood glucose, and plasma insulin, C-peptide and EDLF levels: the two groups were matched for age and BMI and were studied after a 2-week wash-out period from hypotensive drugs. Compared with normotensives, hypertensive subjects had higher plasma insulin levels, a greater immunoreactive insulin/C-peptide ratio, a lower glucose/insulin ratio and higher plasma EDLF levels. Our results confirm that among obese people with glucose intolerance, hypertensives are more hyperinsulinaemic and insulin-resistant than normotensives and indicate that the intracellular cation imbalance in these patients may be attributable, at least in part, to EDLF.

Detection of the terminal fluid-phase complement complex, SC5b-9, in the plasma of patients with insulin-dependent (type I) diabetes mellitus. Relation to increased urinary albumin excretion and plasma von Willebrand factor.

An ELISA was used to measure the fluid-phase complement complex in the plasma of 54 patients with insulin-dependent (type I) diabetes mellitus. Sixty-seven per cent of the diabetic patients had increased levels of SC5b-9. In individual diabetic patients, increased SC5b-9 was found to be significantly associated with the occurrence of anti-heparan sulphate cross-reactive anti-ssDNA antibodies and in some cases with circulating immune complexes. There was a significant correlation between levels of SC5b-9 and those of urinary albumin excretion rate (AER) (r = 0.39, P less than 0.01). Levels of AER were 8.4 +/- 2.26 micrograms/min and 2.04 +/- 0.35 micrograms/min in the SC5b-9 positive and negative patients, respectively (P less than 0.01). A relationship was also found between SC5b-9 and plasma von Willebrand Factor (r = 0.45, P less than 0.02), von Willebrand factor was 189.2 +/- 19.3% and 132.3 +/- 19.6% in SC5b-9 positive and negative patients, respectively (P less than 0.05). It may be that the abnormalities found in this study play a role in the pathogenesis of the late diabetic vascular complications.

[Plasma levels of beta-endorphin in obese subjects with normal glucose tolerance test and in diabetics]. / Livelli plasmatici di beta-endorfina in soggetti obesi normotolleranti e diabetici.

Forty obese subjects with normal glucose tolerance test (NGTT) thirteen diabetic obese subjects and sixteen normal subjects were studied to evaluate the possible interactions between beta-endorphin (B-Ep) and glucose homeostasis. On the basis of baseline B-Ep levels, two subgroups were selected: one group with normal mean values of B-Ep (7.02 +/- 0.59 pmol/l); another group with elevated mean values of B-Ep (18.95 +/- 1.52 pmol/l). No differences between these subgroups were found as regards body mass index (BMI), insulin and glucagon levels. Normal B-Ep values were found in diabetic obese subjects. No significant correlation was found between B-Ep and BMI, insulin or glucagon. Considering that B-Ep is involved in eating behavior and on the basis of our results, we suggest that elevated B-Ep levels can be found only in those obese NGTT subjects whose obesity is probably related to an abnormal modulation of food intake, such as hyperphagia.

Pravastatin vs gemfibrozil in the treatment of primary hypercholesterolemia. The Italian Multicenter Pravastatin Study I.

This study compared the efficacy and safety of pravastatin and gemfibrozil in the treatment of primary hypercholesterolemia. Three hundred eighty-five outpatients from 13 lipid clinics in Italy participated in this randomized double-blind study. Patients were assigned to receive either 40 mg once daily of pravastatin or 600 mg of gemfibrozil twice daily after an initial diet lead-in period. After 24 weeks, mean reductions from baseline values of plasma total and low-density lipoprotein cholesterol were, respectively, 23% and 30% with pravastatin and 14% and 17% with gemfibrozil. Significant lipid-lowering effects were noted within 4 weeks. Apolipoprotein B decrease was 21% with pravastatin and 13% with gemfibrozil. A statistically significant increase of high-density lipoprotein cholesterol of 5% was achieved with pravastatin compared with a 13% increase for gemfibrozil. Serum triglyceride values decreased 5% with pravastatin and 37% with gemfibrozil. Familial and polygenic hypercholesterolemic patients were also examined separately. Pravastatin effectiveness in reducing low-density lipoprotein cholesterol was greater by 6% in polygenic than in familial hypercholesterolemic patients. Treatment for 25 patients (eight treated with pravastatin and 17 treated with gemfibrozil) was discontinued during the study. The incidence of clinical symptoms and laboratory alterations was low for both treatment groups. Pravastatin and gemfibrozil were well tolerated, but pravastatin was significantly more effective in reducing total and low-density lipoprotein cholesterol levels in primary (either familial or polygenic) hypercholesterolemias than gemfibrozil.

Increase in red cell lactate concentration and its reduction by isologous plasma in NIDDM subjects.

We determined red blood cell (RBC) lactate concentrations in NIDDM subjects using an experimental protocol in which diabetic RBCs were incubated over 8 hours both with own plasma and with normal plasma. Furthermore, normal RBCs were incubated both with own plasma and with diabetic plasma. The results indicate that the increased lactate concentrations in RBCs from NIDDM subjects decreased significantly when the same RBCs were incubated in normal plasma. Conversely, lactate concentrations in normal RBCs increased significantly when RBCs were incubated in diabetic plasma. Thus, other than muscle and adipose tissue, RBCs may contribute to increase lactate release for hepatic gluconeogenesis in NIDDM and we suggest that there may be extrinsic plasmatic factor(s) capable of stimulatory effect on diabetic RBC glycolytic pathway.

Serum levels of type III procollagen peptide in diabetes mellitus.

Serum levels of type III procollagen peptide (P-III-P) were investigated in 19 patients with type 1 (insulin-dependent) and in 48 (25 orally treated, 23 insulinized) patients with type 2 (non insulin-dependent) diabetes mellitus. Among patients with type 2 diabetes, 16 orally treated and 14 insulin-treated subjects had macrovascular complications. P-III-P levels were not correlated with the duration of diabetes and with glucose control, nor were there any significant sex and age differences in the levels. P-III-P values were significantly higher in the sera of insulin-treated non insulin-dependent diabetic patients with macroangiopathy. These high values (18.5 +/- 10.8 ng/ml) were in contrast with normal values in healthy subjects (8.5 +/- 2.5, P less than 0.001), insulin-dependent diabetics (9.9 +/- 3.4 ng/ml, P less than 0.01), non insulin-dependent diabetics treated with oral agents (8.2 +/- 2.6 ng/ml, P less than 0.001) and insulin-treated non insulin-dependent patients without macroangiopathy (8.2 +/- 4.9 ng/ml, P less than 0.001). Although this study does not demonstrate that an increase in type III collagen synthesis is responsible for the pathogenesis of macroangiopathy, it suggests that insulin-dependent fibroblast sensitization may play a role in the acceleration and progression of macroangiopathy.

The relationship of insulin antibodies, platelet-fixing immune complexes and platelet-associated IgG to in vitro platelet aggregation and thromboxane B2 synthesis in childhood type 1 (insulin-dependent) diabetes mellitus.

The relationship of insulin antibodies, platelet-fixing soluble immune complexes and platelet associated IgG to in vitro platelet aggregation and thromboxane B2 synthesis was studied in a group of children with type 1 (insulin-dependent) diabetes mellitus. Insulin antibodies, through the formation of insulin anti-insulin platelet-fixing immune complexes, seem to increase the levels of platelet associated IgG and both insulin immunity and increased platelet associated IgG are associated with the highest degree of platelet aggregation and thromboxane synthesis. These data suggest a possible role of immune factors in the platelet disfunction of diabetic subjects. Both platelet abnormalities and immune factors have been thought to play a role in the pathogenesis of the late diabetic complications. In this paper data concerning a possible interaction between these two factors are presented.

Increased soluble interleukin-2 receptor levels in the sera of type 1 diabetic patients.

Recently, the presence of a soluble form of IL-2 receptor (IL-2RS) in human sera and in supernatants of PHA-stimulated lymphocytes has been demonstrated. It has been suggested that autoimmune diseases could be characterized by a defect in production of IL-2RS, unlike immunoproliferative disorders which are characterized by overproduction. Our aim was to investigate serum IL-2RS levels in 35 newly diagnosed Type 1 diabetic patients, in 25 age-matched healthy blood donors and in five patients with Hodgkin's disease. We found that newly diagnosed diabetic patients have higher IL-2RS levels (424.8 +/- 203 U/ml) than normal controls (252.4 +/- 38.4 U/ml) (p less than 0.005). In 22 out of 35 patients (62.8%) the IL-2RS values were above the higher 95% tolerance limit of controls. Furthermore, the persistence of high IL-2RS levels was observed in 18/35 diabetic patients six months after diagnosis (470 +/- 195.6 U/ml). The increased levels were not correlated with glycaemic and HbA1c levels and patients' age. Our findings suggest a potentially significant role for the released IL-2R in the regulation of IL-2 dependent lymphocyte functions in Type 1 diabetes. The study of IL-2RS in Type 1 diabetes may provide a new tool for the knowledge of cytokine involvement in the disease.

Collagen binding activity in sera of patients with insulin-dependent (type 1) and non insulin-dependent (type 2) diabetes mellitus.

An increase in the capacity of serum IgG to bind to native type IV collagen was observed in patients with both insulin-dependent and non insulin-dependent diabetes mellitus. This increased binding seems to be due to circulating immune complexes in the majority of the cases and to autoantibodies in some. The increased collagen binding activity was associated in postpubertal patients with the presence of diabetic microangiopathy, suggesting a pathogenetic role.

Effects of moderate low sodium/high potassium diet on essential hypertension: results of a comparative study.

It is generally accepted that a significant restriction in sodium intake can lower blood pressure in hypertensive patients and more recently it has also been suggested that a high potassium intake can exert an antihypertensive effect. We have therefore, conducted a double-blind, randomized, cross-over study to evaluate the antihypertensive efficacy of the combination of a modest dietary sodium restriction and a high potassium intake in hypertensive patients of mild and moderate degrees. During the modest sodium (100 mmol/day)/high potassium (130 mmol/day) diet the blood pressure was significantly reduced (-17/-6 mmHg) when compared to the normal diet (160 mmol Na/day and 80 mmol K/day). The blood pressure reduction did not interfere with hemodynamic and humoral responses to dynamic exercise. The modest reduction in sodium intake and increase in potassium content in the diet was well tolerated by the patients.

Effects of dynamic exercise and metabolic control on left ventricular performance in insulin-dependent diabetes mellitus.

In subclinical diabetic cardiomyopathy, previous reports did not positively correlate the altered cardiac performance with metabolic parameters. Fifteen insulin-dependent diabetic subjects, without any clinical or instrumental evidence of heart diseases, were studied. Signs of diabetic microangiopathy were absent. Systolic time intervals, metabolic and hormonal parameters (blood glucose, free fatty acids, blood lactate and plasma norepinephrine) were evaluated at rest and after dynamic exercise during poor (MAGE 6.36 +/- 0.72 mmol/l) and good (MAGE 3.46 +/- 0.66 mmol/l) metabolic control, obtained by means of insulin therapy. Rest values of systolic time intervals were normal during poor and good metabolic control. After exercise, pre-ejection period/left ventricular ejection time ratio increased mainly during poor control as a result of an increased pre-ejection period: conversely, a smaller increase in pre-ejection period/left ventricular ejection time ratio occurred during good metabolic control. The exercise induced free fatty acids utilization did not occur during poor control as it occurred during good control. The percentage of increments in blood lactate was virtually identical in ketotic and non-ketotic patients and in normal subjects. High norepinephrine plasma levels were observed both at rest and during dynamic exercise in poorly controlled diabetic patients. Conclusively, testing of systolic time intervals after exercise might be useful in the detection of preclinical diabetic cardiomyopathy. The decreased cardiac functional reserve observed during poor control might be related to an altered energetic fuel utilization.

Autoantibodies to albumin in the plasma of patients with diabetes mellitus. Relationship with circulating immune complexes.

Anti-albumin antibodies that recognize glutaraldehyde treated albumin have been detected in diabetes mellitus, belonging to all immunoglobulin classes. Anti-albumin antibodies have been found to be closely associated with circulating immune complexes, suggesting a role in their formation. It is suggested that such immune complexes may account for the positive immunofluorescence findings of albumin, immunoglobulin and complement in blood vessels previously reported in diabetes mellitus.

Optic pathway conduction in insulin-dependent diabetics.

Abnormal latency delay of pattern-reversal visual evoked cortical potentials (VECPs) has been demonstrated in insulin-dependent diabetics without retinopathy as a sign of subclinical damage. Pattern-reversal VECPs and onset-offset (on-off) VECPs probably originated at different cortical levels. On-off latencies of a group of 50 insulin-dependent diabetics without retinopathy or neuropathy and with normal oscillatory potentials have been studied in relation to various clinical and metabolic parameters. The results of our study showed that on-off VECPs have in diabetes the same latency alterations as pattern-reversal VECPs, if to a lesser extent. This finding can be a useful index in the evaluation of patients at risk.

[Comparison of intensified traditional insulin therapy and micropump therapy in pregnant women with type 1 diabetes mellitus]. / Confronto fra terapia insulinica tradizionale ottimizzata e con microinfusore in gravide affette da diabete mellito di tipo I.

Ten pregnant women, affected by type I diabetes mellitus, observed for the first time during the II-III month of pregnancy, were examined. These patients were divided in two groups at random: group A underwent continuous subcutaneous insulin infusion with micropump CPI 9100 Lilly; group B underwent intensified insulin therapy with three daily doses of MC rapid insulin, two of which associated with MC intermediate insulin. All the patients were able to monitor their own blood glucose levels at home by means of reactive strips and reflectometer. In both the groups the mean glycemic values during fast and two hours after meals, and the eventual presence of urinary keton bodies and hypoglycemic crisis were evaluated during the course of pregnancy: these parameters turned out to be identical in the two groups. The increased need of insulin, the maternal body weight gain, the week and mode of delivery, the neonatal weight and the maternal and fetal complications also turned out to be identical in the two groups. To conclude, a good maternal metabolic control can be obtained either with the intensified conventional insulin therapy of with micropumps, if the patients, being properly instructed, are responsible for the monitoring of their own blood glucose levels at home.