Philippe Vague

Correlation between blood fibrinolytic activity, plasminogen activator inhibitor level, plasma insulin level, and relative body weight in normal and obese subjects

This study was undertaken to obtain further information on the mechanism by which blood fibrinolytic activity, a balance between plasminogen activators and inhibitors, is lowered in obese subjects. Fasting blood samples were collected from 35 subjects, aged 15 to 45 years, with normal glucose tolerance and a Body Mass Index (BMI) varying widely between 16 and 45 (normal, 19 to 25). Euglobulin Fibrinolytic Activity (EFA) did not correlate with the level of tissue type plasminogen activator (t-PA) related antigen but exhibited a negative correlation with the level of PA inhibitor (r = -.609, P less than 0.01). EFA was negatively and PA inhibitor positively correlated with both BMI (r = -.381, P less than 0.02 and .664, P less than 0.01, respectively) and plasma insulin level (r = .410, P less than 0.02 and .521, P less than 0.01, respectively). Stepwise analysis showed that these correlations were independent. As expected, plasma insulin was correlated with BMI (r = .512, P less than 0.01) and triglyceride level (r = .38, P less than 0.02), total cholesterol with age (r = .379, P less than 0.02). Ten obese subjects were submitted to a 24-hour fast. While body weight did not change appreciably, plasma insulin decreased from 22.3 +/- 2.2 to 16.3 +/- 1.1 microU/ml, EFA increased from 3.6 +/- .8 to 4.9 +/- .67 mm, and PA inhibitor decreased from 4.52 +/- .76 to 3.44 +/- .63 IU/mL. All these differences were significant. T-PA-related antigen did not change.(ABSTRACT TRUNCATED AT 250 WORDS)

Plasma plasminogen activator inhibitor-1 in angina pectoris. Influence of plasma insulin and acute-phase response.

Plasminogen activator Inhibitor-1 (PAI-1) is an Important physiological Inhibitor of fibrlnolysls. It circulates in blood both In free active form and In Inactive form comptexed with tissue type plasminogen activator (t-PA). Control mechanisms for Its synthesis and release from hepatocytes and endothellal cells are important In the pathogenesis of thrombosis. Possible risk factors for myocardlal Infarction Include high insulin and PAH levels, which correlate with one another In healthy subjects, and fibrlnogen, which together with PAI-1, Is an acute-phase reactant We therefore studied the Interrelationships between PAI-1, plasma Insulin, and acute-phase proteins In 67 patients with angina pectoris. Plasma Insulin correlated strongly (r=0.59, p<0.001) with PAI activity, free PAI-1 antigen (r=0.60, p<0.001), and total PAI-1 antigen (r=0.58, p<0.001). The acute-phase proteins, fibrlnogen and C-reactive protein, correlated significantly with t-PA antigen, total PAI-1 antigen, and PAH/t-PA complexes but not with PAI activity or free PAI-1. The results suggest that Insulin stimulates synthesis and release of free PAI-1 (probably via hepatocytes as previously shown with cell culture) and that endothellal cell synthesis and release of t-PA, together with PAI-1, reflects a nonspecific acute-phase response to chronic vascular disease. Hyperlnsullnemia found In patients with angina pectoris could play a role In the development of myocardlal Infarction via the Induction of high plasma PAI-1 activity.

Insulin detemir used in basal-bolus therapy in people with type 1 diabetes is associated with a lower risk of nocturnal hypoglycaemia and less weight gain over 12 months in comparison to NPH insulin.

Aim:  The aim of this study was to compare the long‐term safety and efficacy of twice‐daily insulin detemir or NPH insulin as the basal component of basal‐bolus therapy in people with type 1 diabetes.

Thrombogenic and Fibrinolytic Factors and Cardiovascular Risk in Non-insulin-dependent Diabetes Mellitus

Disturbances of the haemostatic system may favour the development of vascular damage and the final occlusion events in the progress of coronary heart disease (CHD). It has been shown recently in epidemiological studies, that increased concentration of several factors, mainly fibrinogen, factor VII, von Willebrand factor (vWF), and the fibrinolytic variables plasminogen activator inhibitor 1 (PAI-1) and tissue plasminogen activator (t-PA), can be considered as risk factors for CHD. As morbidity and mortality through coronary atherosclerosis are higher in type 2 diabetic patients than in nondiabetic subjects and as insulin resistance represents a situation which favours the development of atherothrombosis, evaluation of the haemostatic factors which are recognized as risk factors may be interesting to consider in these situations. In fact, it has been shown that the fibrinolytic parameters PAI-1 and t-PA antigen are strongly related to the metabolic disorder of insulin resistance, whereas the link with fibrinogen, factor VII, and vWF remains weak. Many cross-sectional studies conducted in different populations have shown that PAI-1 and t-PA antigen (which represents t-PA/PAI-1 complexes) are strongly correlated with insulin, triglyceride, high-density lipoprotein (HDL) cholesterol, body mass index, walst-to-hip ratio and blood pressure, and that the improvement of insulin resistance improves in parallel the metabolic abnormalities and the concentration of the fibrinolytic parameters. Attempts at explaining the elevated PAI-1 and t-PA antigen levels in the insulin resistance syndrome have involved many clinical and in vitro studies, in which the role of insulin, insulin propeptides, very-low-density lipoprotein (VLDL) triglyceride, insulin resistance per se, glucose, and adipose tissue have successively been analysed and the main results of these studies are presented in this review. Due to recent experimental data from animal models of thrombosis, a pathogenic role of decreased fibrinolytic activity or increased PAI-1 levels can be proposed and could play a role in the development of vascular disease in subjects with Type 2 diabetes or insulin resistance.

Fat Distribution and Plasminogen Activator Inhibitor Activity in Nondiabetic Obese Women

Epidemiologic data strongly suggest that upper distribution of body fat and high plasminogen activator inhibitor (PAI) activity are risk factors for cardiovascular disease. Therefore, a link between these two parameters was evaluated by studying 51 menstrually active nondiabetic obese women. In this group positive correlations were observed between body mass index (BMI), waist to hip circumference ratio (W/H ratio, which estimates body fat distribution), plasma insulin, and PAI activity. In addition, plasma triglycerides were related to the W/H ratio and insulin and PAI activity. Partial correlations revealed that BMI was independently and solely related to W/H ratio, which was also independently related to plasma insulin, which in turn related to PAI activity. These results suggest that upper body fat distribution acts as a risk factor of cardiovascular disease through its association with high PAI activity.

Genetic polymorphisms and lipoprotein responses to diets.

While human diets have markedly evolved since their origin, the human genome has only marginally changed. Nevertheless, polymorphisms of common genes are widespread. It has been substantiated that most major diseases (including cardiovascular disease, diabetes, obesity and cancers) result from the interaction between genetic susceptibility and environmental factors, including diet. In the field of lipoprotein metabolism and cardiovascular disease several gene polymorphisms for key proteins, such as apoproteins (apo) E, B, A-IV and C-III, LDL receptor, microsomal transfer protein (MTP), fatty acid-binding protein (FABP), cholesteryl ester transfer protein (CETP), lipoprotein lipase and hepatic lipase, have been identified and linked to variable responses to diets. We are carrying out an intervention study (RIVAGE) in Marseille dedicated to investigating the interactions between diets (Mediterranean or low-fat types v. standard Western type), risk factors for cardiovascular disease and gene polymorphisms in about 300 patients randomized into two groups over periods of 3 and 12 months. Some data obtained in about 100 patients after 3 months of dietary change are available. Among single nucleotide polymorphisms (SNP) already studied (apoE (epsilon2, epsilon3, epsilon4), apoB (-516C/T), apoC-III (SstI), apoA-IV (Ser347Thr), MTP (-493G/T), intestinal FABP (Ala54Thr), CETP (TaqIB) and hepatic lipase (-480C/T)), some SNP showed interactions with diets in relation to changes in particular variables after 3 months on the dietary regimens. This was the case for apoE and LDL-cholesterol and triacylglycerols, apoA-IV and LDL-cholesterol, MTP and LDL-cholesterol, intestinal FABP and triacylglycerols. These data provide evidence of the interaction between some SNP and the metabolic response to diets.

Plasma C-peptide levels and clinical remissions in recent-onset type I diabetic patients treated with cyclosporin A and insulin.

Remission from insulin dependency in insulin-treated recent-onset type I (insulin-dependent) diabetic patients can result from a partial recovery of insulin secretion, an improvement in tissue sensitivity to insulin, or both. The same hypothesis must be analyzed when remission occurs in cyclosporin A (CsA)-treated patients. In this study, plasma C-peptide levels were serially measured in the basal state and after stimulation in 219 recent-onset type I diabetic patients; 129 received CsA, and all patients were similarly monitored and insulin treated. The results were analyzed in view of the occurrence of remission. Remission was defined as good metabolic control in the absence of hypoglycemic treatment for ≥1 mo. Remission occurred in 44% of the CsA-treated group and lasted for mean ± SE 10.0 ± 0.9 mo vs. 21.6% in the non-CsA-treated group with a duration of 4.4 ± 0.8 mo. Plasma C-peptide levels were initially dramatically lower than normal in both groups in the basal and stimulated states. C-peptide levels increased significantly later, at 3 and 6 mo, in both groups. C-peptide values were proportional to the rates of remission in both groups. In the non-CsA-treated group, C-peptide levels later decreased, and these patients inexorably relapsed to insulin dependency. In contrast, in the CsA-treated group, the initial recovery in insulin secretory capacity was maintained over the 18–24 mo of the study. Furthermore, higher remission rates and longer-lasting remission were obtained in patients who reached higher C-peptide levels at the 3rd mo of treatment. Conversely, a progressive decrease in C-peptide values followed interuption of CsA treatment in some patients who had previously maintained some C-peptide secretory capacity. Our results support the hypothesis of an efficient suspension by CsA of the progressive deterioration of islets. The maintenance of β-cell secretory capacity by CsA plus insulin was better than by insulin alone. However, C-peptide concentrations remained lower than normal in patients in remission. An improvement in sensitivity to insulin may have also contributed to the development of remission.

Effect of the aldose reductase inhibitor tolrestat on nerve conduction velocity, Na/K ATPase activity, and polyols in red blood cells, sciatic nerve, kidney cortex, and kidney medulla of diabetic rats.

Long-term prospective studies comparing the effects of conventional and intensive insulin therapy have linked diabetic hyperglycemia to the development of diabetic retinopathy, nephropathy, and neuropathy. The mechanisms through which glucose metabolism leads to the development of these secondary complications, however, are incompletely understood. In animal models of diabetic neuropathy, the loss of nerve function in myelinated nerve fibers has been related to a series of biochemical changes. Nerve glucose, which is in equilibrium with plasma glucose levels, rapidly increases during diabetic hyperglycemia because glucose entry is independent of insulin. This excess glucose is metabolized in large part by the polyol pathway. Increased flux through this pathway is accompanied by the depletion of myo-inositol, a loss of Na/K ATPase activity and the accumulation of sodium. Supportive evidence linking these biochemical changes to the loss of nerve function has come from studies in which aldose reductase inhibitors block polyol pathway activity, prevent the depletion of myo-inositol and the accumulation of sodium and preserve Na/K ATPase activity, as well as nerve function. The kidney and red blood cells (RBCs) are two additional sites of diabetic lesions that have been reported to develop biochemical changes similar to those in the nerve. We observed that polyol levels in the kidney cortex, medulla, and RBCs increased two- to ninefold in rats following 10 weeks of untreated diabetes. Polyol accumulation was accompanied by a 30% decrease in myo-inositol levels in the kidney cortex, but no change in RBCs or the kidney medulla. Na/K ATPase activity was decreased by 59% in RBCs but was unaffected in the kidney cortex or medulla. Aldose reductase inhibitor treatment that preserved myo-inositol levels, Na/K ATPase, and conduction velocity in the sciatic nerve also preserved Na/K ATPase activity in RBCs. Our results suggest that the pathophysiologic mechanisms underlying diabetic neuropathy are different from those of diabetic nephropathy. Our results also suggest that RBCs maybe a surrogate tissue for the assessment of diabetes-induced changes in nerve Na/K ATPase activity.

In vivo insulin effect on ATPase activities in erythrocyte membrane from insulin-dependent diabetics

Na+-K+-dependent ouabain-sensitive ATPase and Mg2+-ATPase have been assayed in the erythrocyte membranes of control subjects and in uncontrolled type I (insulin-dependent) diabetics. A decrease in Na+-K+-ATPase activity was observed in the patients that was significantly correlated with glycemia. The Mg2+-ATPase was increased moderately, and no correlation with glycemia was found. To study the in vivo effect of insulin, ATPase activities were measured in uncontrolled diabetics before and after a 24-h continuous insulin perfusion administered by means of an artificial pancreas. ATPase activities were corrected after normalization of glycemia. It therefore seems that glycemia and/or insulinemia are involved in the regulation of erythrocyte Na+-K + ouabain-sensitive ATPase and to a lesser extent in that of Mg2+-dependent ATPase.

Beneficial effects of gamma linolenic acid supplementation on nerve conduction velocity, Na+, K+ ATPase activity, and membrane fatty acid composition in sciatic nerve of diabetic rats.

Metabolic and vascular abnormalities are implicated in the pathogenesis of diabetic neuropathy. Two principal metabolic defects are altered lipid metabolism resulting from the impairment of delta-6-desaturase, which converts linoleic acid (LA) into gamma linolenic acid (GLA), and reduced nerve Na+, K+ ATPase activity. This reduction may be caused by a lack of incorporation of (n-6) fatty acids in membrane phospholipids. Because this ubiquitous enzyme maintains the membrane electrical potential and allows repolarization, disturbances in its activity can alter the process of nerve conduction velocity (NCV). We studied the effects of supplementation with GLA (260 mg per day) on NCV, fatty acid phospholipid composition, and Na+, K+ ATPase activity in streptozotocin-diabetic rats. Six groups of 10 rats were studied. Two groups served as controls supplemented with GLA or sunflower oil (GLA free). Two groups with different durations of diabetes were studied: 6 weeks with no supplementation and 12 weeks supplemented with sunflower oil. To test the ability of GLA to prevent or reverse the effects of diabetes, two groups of diabetic rats were supplemented with GLA, one group for 12 weeks and one group for 6 weeks, starting 6 weeks after diabetes induction. Diabetes resulted in a 25% decrease in NCV (P < 0.0001), a 45% decrease in Na+, K+ ATPase activity (P < 0.0001), and an abnormal phospholipid fatty acid composition. GLA restored NCV both in the prevention and reversal studies and partially restored Na+, K+ ATPase activity in the preventive treatment group (P < 0.0001). These effects were accompanied by a modification of phospholipid fatty acid composition in nerve membranes. Overall, the results suggest that membrane fatty acid composition plays a direct role in NCV and confirm the beneficial effect of GLA supplementation in diabetic neuropathy.