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P Vague

Publications and source records attributed to P Vague.

At least 91 records · Page 5Linked to original sources
PubMed1993

Autoimmune polyendocrine failure--type 1 (insulin-dependent) diabetes mellitus and hypothyroidism--after allogeneic bone marrow transplantation in a patient with lymphoblastic leukaemia.

In this report we describe a patient who, after allogeneic bone marrow transplantation from her HLA-identical sister, developed polyendocrine failure in the form of Type 1 (insulin-dependent) diabetes mellitus and hypothyroidism. This was the result of the transfer of donor lymphoid cells which were activated by allogeneic bone marrow transplantation. The full chimerism of the recipient was demonstrated by restriction fragment length polymorphism analysis from nucleated blood cells and fibroblast DNA. During the 9-year follow-up, the donor developed hypothyroidism and signs of pre-Type 1 diabetes. This clinical observation resembles the adoptive transfer of diabetes observed in non-obese-diabetic mice and BB rats and confirms the role of immune processes in the pathogenesis of this disease.

Adolescent↗
PubMed1993

Plasminogen activator inhibitor-1 synthesis in the human hepatoma cell line Hep G2. Metformin inhibits the stimulating effect of insulin.

High plasma plasminogen activator inhibitor-1 (PAI-1) activity is associated with insulin resistance and is correlated with hyperinsulinemia. The cellular origin of plasma PAI-1 in insulin resistance is not known. The hepatoma cell line Hep G2 has been shown to synthesize PAI-1 in response to insulin. The aim of this study was to analyze the insulin-mediated response of PAI-1 and lipid synthesis in Hep G2 cells after producing an insulin-resistant state by decreasing insulin receptor numbers. The effect of metformin, a dimethyl-substituted biguanide, known to lower plasma insulin and PAI-1 levels in vivo was concomitantly evaluated. Preincubation by an 18-h exposure of Hep G2 cells to 10(-7) M insulin aimed at reducing the number of insulin receptors, was followed by a subsequent 24-h stimulation with 10(-9) M insulin. The decrease in insulin receptors was accompanied as expected, by a reduction in [14C]acetate incorporation, an index of lipid synthesis, whereas PAI-1 secretion and PAI-1 mRNA expression were enhanced. The addition of metformin did not modify the effect of insulin on insulin receptors or [14C]acetate incorporation. In contrast, the drug (10(-4) M) inhibited insulin-mediated PAI-1 synthesis. The results indicate that PAI-1 synthesis in presence of insulin is markedly increased in down-regulated cells, and that metformin inhibits this effect by acting at the cellular level. These in vitro data are relevant with those found in vivo in insulin-resistant patients. Hep G2 cells may be a suitable model to study PAI-1 regulation in response to hyperinsulinemia.

Acetates↗
PubMed1993

Acute insulin response to glucose and glucagon in subjects at risk of developing type I diabetes.

OBJECTIVE: To determine if knowledge of characteristics of insulin response to various secretagogues during the preclinical phase of type I diabetes may facilitate the diagnosis of subjects at risk. RESEARCH DESIGN AND METHODS: A test consisting of sequential intravenous challenge with glucose (0.3 g/kg) and glucagon (1 mg, 10 min after the end of glucose injection) was performed on 171 ICA- relatives of type I diabetic patients, 18 ICA+ relatives of type I diabetic patients, and 5 transiently hyperglycemic subjects. Acute response to glucose was expressed as the sum of plasma insulin at 2 and 5 min and response to glucagon as the increase in plasma insulin after 10 min. RESULTS: Responses below the lower 95% confidence interval in the ICA- population (40 and 43 microU/ml for glucose and glucagon, respectively) were considered abnormal. The two values were correlated (r = 0.62). Abnormalities coexisted in 2.3% of the ICA- group, 11% of the ICA+ group, and 100% of the transiently hyperglycemic group. All the relatives who subsequently developed diabetes or hyperglycemic subjects who required insulin exhibited combined abnormalities. Some ICA- and ICA+ relatives were tested repeatedly over a follow-up period of 1.5-4 yr. Although the intraindividual coefficient of variation for the two responses was high (28 and 30%), values tended to run parallel in both ICA+ and ICA- relatives. In 2 patients monitored for 2 and 4 yr before diabetes developed, both responses declined at the same rate. In terms of prediction of diabetes, sensitivity of combined abnormalities was high (100%). But compared with the intravenous glucose tolerance test, improvement of specificity by the double challenge was not statistically significant. CONCLUSIONS: Both insulin responses to glucose and glucagon are related. They depend on the secretory capacity of beta-cells and simultaneously become abnormal in the prediabetic phase.

Adolescent↗
PubMed1992

Daytime fluctuations of plasminogen activator inhibitor 1 (PAI-1) in populations with high PAI-1 levels.

The mechanism underlying diurnal variations in PAI-1 as well as the cellular origin of PAI-1 in subjects with high PAI-1 levels are unknown. We evaluated diurnal changes (8:00 am vs 4:00 pm) in PAI-1 (functional and immunological assays), t-PA Ag and t-PA/PAI-1 complex levels in controls and subjects with high PAI-1 levels. Three test groups were recruited among obese hyperinsulinemic subjects, emergency care unit patients with inflammatory syndrome or infection and pregnant women. The classical afternoon decrease of PAI-1 level was observed in controls and obese subjects but its amplitude was greater in the latter. The decrease in t-PA Ag and t-PA/PAI-1 complex levels was the same in controls and in obese. As, in previous studies, elevated PAI-1 levels have been correlated with insulin resistance and a decrease in insulin sensibility has been described in the early morning, it is proposed that this "dawn phenomenon" could be implicated in the circadian variations of PAI-1 in controls and could be amplified in obese subjects. Great variability in PAI-1, t-PA Ag or t-PA/PAI-1 complex levels was observed in patients with acute inflammatory syndrome or infection for whom classical biorhythms are suppressed. No diurnal changes in PAI-1 and other fibrinolytic parameters were observed in patients with inflammatory syndrome or in pregnant women suggesting that other sources and/or other regulatory mechanisms of PAI-1 production are involved.

Adult↗
PubMed1992

Hemobiology, vascular disease, and diabetes with special reference to impaired fibrinolysis.

This brief review is intended to emphasize the multiple interactions between diabetes and the pathophysiological processes that lead to ischemic cardiovascular events. The main pathogenetic pathways of atherothrombosis and their relationship with diabetes are largely and frequently analyzed. In this review, we will focus on a particular aspect of this pathological process, namely, the impairment in fibrinolysis, the importance of which has been recently recognized in cardiovascular disease. Fibrinolysis is frequently impaired in diabetic patients.

Coronary Artery Disease↗
PubMed1992

The syndrome of insulin resistance.

It is well known that excessive weight is associated with resistance to insulin-mediated glucose uptake and predisposition to the development of type II diabetes. It has been shown more recently that excessive weight and insulin resistance tend to be associated to android fat distribution, arterial hypertension, elevated levels of triglycerides, low concentration of HDL cholesterol and defective fibrinolysis. The terms syndrome of insulin resistance, metabolic syndrome or syndrome X have been proposed to describe this cluster of abnormalities. The pathophysiological mechanisms which could explain the interrelations between these different parameters are still only partly understood. Epidemiological prospective studies have demonstrated that the metabolic syndrome is a risk factor for coronary heart disease and type II diabetes. The mechanisms involved in the development of diabetes are relatively well established, but those which are implicated in the atherothrombotic process are far from being clearly described. Anyway, sufficient presumption exists to attempt at decreasing insulin resistance when it exists. Physical training and, if indicated, weight reduction are the simplest means.

Arteriosclerosis↗
PubMed1991

Increased plasma plasminogen activator inhibitor 1 levels. A possible link between insulin resistance and atherothrombosis.

According to recent prospective studies, hypofibrinolysis due to elevated plasma plasminogen activator inhibitor 1 levels appears to be an independent risk factor for myocardial reinfarction in men, and hyperinsulinaemia, a major indicator of insulin resistance is considered as a risk factor for coronary disease. It has recently been shown that insulin resistance is accompanied by an increased plasma plasminogen activator inhibitor 1 concentration: A significant correlation coefficient was demonstrated between plasminogen activator inhibitor 1 and fasting plasma insulin in the normal population, in obese subjects, in Type 2 (non-insulin-dependent) diabetic patients and in angina pectoris. Attempts to decrease insulin resistance such as fasting, diet, or administration of an oral anti-diabetic drug such as Metformin induced a parallel decrease in plasma insulin and plasminogen activator inhibitor 1 levels. This inhibitor is produced by endothelial cells and by hepatocytes in culture. Plasminogen activator inhibitor 1 synthesis by hepatocytes in culture was stimulated by an increasing insulin concentration, or low density lipoproteins, whereas the endothelial cell synthesis was stimulated by very low density lipoproteins especially when they were obtained from hypertriglyceridaemic patients. Therefore, a direct effect of insulin or lipoprotein changes on the cells which synthesize plasminogen activator inhibitor 1 could be responsible for its increased plasma concentration in insulin resistance states. The increase in plasma plasminogen activator inhibitor 1 levels linked to hyperinsulinaemia is a tempting partial explanation for the association between insulin resistance and coronary disease.

Arteriosclerosis↗
PubMed1991

The soluble receptor of interleukin 2 is not a serum marker of the autoimmune activity in type I diabetes mellitus.

In order to determine if soluble interleukin 2 receptor (IL2R) was useful as a marker in screening for early Type 1 diabetes and in monitoring immunological treatment, we assayed serum IL2R levels in 67 controls, 43 patients with newly diagnosed diabetes and 28 first degree relatives of diabetic patients (5 subjects were islet cell antibody positive). In 23 diabetes, specimens were analysed at 3 and 6 months after diagnosis whether or not cyclosporin A was administered. Seven patients were in a clinical trial using anti IL2R monoclonal antibody and cyclosporin A. Since IL2R level in the normal population is elevated in the first 5 years of life then decreases until adulthood (age:IL2R correlation between 0 and 15 years: r = -0.42, P less than 0.05), subjects were carefully matched in age. In recent onset diabetes, this negative correlation disappeared and IL2R levels tended to decrease particularly in younger subjects. In Type 1 prediabetic subjects presenting persistent islet-cell antibody serum IL2R was not elevated. During immunological treatment of recent onset diabetes, serum IL2R remained stable and was not modified by cyclosporin A. As expected IL2R became undetectable during treatment with anti IL2R MC Ab. But it rebounded when treatment was stopped with no effect on remission. We concluded that IL2R levels in Type 1 diabetic patients is not useful in screening autoimmune activity or in evaluating the effectiveness of immunosuppressors.

Adolescent↗
PubMed1991

[Pancreatic conservation after autotransplantation in dogs. Value of histologic surface analysis].

A study of an artificial conservation fluid (hyperosmolar, pH = 8, rich in lactobionate and raffinose) was carried out by means of an experimental procedure involving segmental pancreatic autotransplants in dogs. The study covers 14 transplants, seven carried out without conservation and seven with 24-hour conservation at 4 degrees C. The caudal pancreas was removed after splenectomy and either transfused with 250 ml of 4 degrees C Euro-Collins before immediate transplant or with 250 ml of 4 degrees C conservation fluid for 24 hours before the transplant. The caudal pancreas was transplanted onto the right iliac vessels, while an arterio-venous fistula was created on the distal splenic vessels and the pancreatic duct was injected with modified tissucol. At the same time as the transplant, a cephalic pancreatectomy was performed. Laboratory tests included an intra venous glucose tolerance test monitored on days 0 and 28 and blood glucose and serum amylase measured every three days from days 1 to 28. The histological study of the pancreatic tissues 28 days after the transplants involved the light microscopic evaluation of the degree of fibrosis, inflammation of the pancreas, cystosteatonecrosis and peripancreatic inflammation. We used a computerized method to measure the surface area of the islets of Langerhans, as revealed by immunocytochemistry, and the surface area of fibrosis. The blood glucose and the serum amylase analyses from days 1 to 28, and the blood glucose variations during the intra venous glucose tolerance test, showed no differences between the two groups. Standard laboratory parameters were similar in the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Amylases↗
PubMed1991

Hypofibrinolysis and insulin-resistance.

A defect in the fibrinolytic system appears to be a risk factor for the development of cardiovascular disease. Such a defect is mainly characterized by increased plasma levels of an inhibitor of fibrinolysis the plasminogen activator inhibitor 1 (PAI-1). PAI-1 levels are elevated in the common syndrome of insulin resistance as it is encountered in obese non diabetic and in non insulin dependent diabetic subjects. These levels are closely related to insulinaemia in cross sectional studies as well as in intervention studies. Although in vitro insulin stimulates the PAI-1 synthesis in hepatocyte, but not in endothelial cells, acute elevation of insulinaemia in vivo in man does not result in an increase in PAI-1 levels. The mechanisms linking insulin-resistance, insulin and PAI-1 levels in man are still not understood.

Adolescent↗
PubMed1990

Paradoxical lessening of autoimmune processes in non-obese diabetic mice after infection with the diabetogenic variant of encephalomyocarditis virus.

In order to gain insight into the interaction between autoimmunity and viral infection in the onset of insulin-dependent diabetes, non-obese diabetic (NOD) mice which spontaneously develop autoimmune diabetes were inoculated with the diabetogenic variant of the encephalomyocarditis virus (EMCV-D) before the onset of the disease. The pre-diabetic period was divided into two phases: the early phase (days 88 to 116) during which development of spontaneous diabetes is rare and the late phase (day 123 to 200) during which the incidence of spontaneous diabetes is high. As controls ICR mice of common ancestry were also inoculated. During the early phase diabetes was observed in 4/10 inoculated, 0/13 control NOD and 7/13 inoculated ICR males vs. 6/12 inoculated, 1/11 control NOD and 0/15 inoculated ICR females. However, in NOD female, virus-induced diabetes prevalence was variable from one experiment to another. In parallel the flow cytometric analysis showed a high percentage of L3T4+ T lymphocytes in the pancreas of inoculated female NOD mice 10 days after the infection. At this time a large proportion of both L3T4+ and Ly-2+ cells expressed the interleukin 2 receptor. During the late phase no new case of diabetes occurred in inoculated NOD mice but one case was observed in control NOD males and five in control NOD females. This prevention of autoimmune diabetes was constantly found in other experiments. Insulitis was milder in inoculated NOD mice of both sexes than in control NOD. Adoptive transfer of diabetes into irradiated 8-week-old males by splenocytes from 28-week-old females was successful in five out seven attempts with control splenocytes and in zero out of six attempts with splenocytes from inoculated mice. This immunosuppression was specific as the ability of lymphocytes to respond to soluble or allogeneic antigens was preserved. In the early phase EMCV-D precipitated the onset of diabetes in females NOD mice by amplifying L3T4+ T lymphocyte-mediated immune mechanisms. During the late phase viral infection had lessened immune processes in animals which had resisted or recovered from virus-induced diabetes.

Animals↗
PubMed1990

Interrelations between carbohydrates, lipids, and the hemostatic system in relation to the risk of thrombotic and cardiovascular disease.

Metabolic diseases, such as obesity, impaired glucose tolerance, type I and type II diabetes, hypercholesterolemia, and hypertriglyceridemia, are among the main risk factors for the development of atherothrombosis. Various abnormalities of the hemostatic system (platelet hyperaggregability, hypercoagulability, and hypofibrinolysis) have been described in all these situations. The individual effect of each of these disease on the hemostatic system is difficult to evaluate because these states are often associated in the same patient and the treatment of one can benefit the others. Therefore it may be queried if a common abnormality of these pathologic states might explain their impact on the cardiovascular system. We have been interested by hyperinsulinemia, which is observed in obesity, impaired glucose tolerance, type II diabetes, and hypertriglyceridemia, and we have shown a very strong correlation between plasma insulin, body mass index, triglyceride levels, and one of the main inhibitors of the fibrinolytic system, plasminogen activator inhibitor-1. Partial correlation analysis showed that only the correlation between insulin and plasminogen activator inhibitor-1 was independent. Therefore a high plasma insulin level could be responsible for elevated levels of plasminogen activator inhibitor-1, which by inducing an hypofibrinolysis, could play a role in the deposition of fibrin and the development of atherothrombosis. The description of some interrelations between metabolic diseases and hemostasis is satisfactory but does not exclude specific effects of these diseases on hemostasis, such as glycation of the coagulation and fibrinolytic factors in diabetes or toxic action of lipoprotein on endothelial cells in hyperlipoproteinemia.

Carbohydrate Metabolism, Inborn Errors↗
PubMed1990

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 greater than or equal to 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.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1989

Increased plasminogen activator inhibitor activity in non insulin dependent diabetic patients--relationship with plasma insulin.

Type 2 diabetic patients are known to frequently have a high insulin level and were recently described as having high plasminogen activator inhibitor (PAI) activity, compared to normal controls. As we have shown in several clinical conditions (normal subjects, obese patients, angina pectoris patients) that plasma PAI activity was linked with plasma insulin, we have studied in 38 type 2 diabetic patients the relationship between PAI activity, insulin and other parameters. Patients showed higher level of PAI activity, as well as plasma glucose, insulin, triglyceride, cholesterol and Apolipoprotein B levels than normal controls; highest values were observed with diabetic patients also affected by coronary artery disease. A significant correlation was found between PAI activity and insulin (r = 0.60, p less than 0.001), body mass index (r = 0.32, p less than 0.05) and Apolipoprotein B (r = 0.33, p less than 0.05). The two latter correlations disappeared after adjustment for insulin. These results are in agreement with our previous report showing an in vitro effect of insulin on the synthesis of PAI by a hepatocellular cell line. Hyperinsulinemia presented by type 2 diabetic patients may increase the hepatic synthesis of PAI, inducing an hypofibrinolysis, which could play a role in the development of the vascular complications. Attempts to reduce hyperinsulinemia could have a favorable effect by lowering PAI activity.

Adult↗