[Natural history and evolution of non-insulin-dependent diabetes].
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Biomedical subjects
Publications and source records attributed to B Vialettes.
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In order to investigate the endocrine pancreatic dysfunction resulting from iron overload, plasma pancreatic polypeptide (PP) response to a protein-rich meal was studied in 10 healthy controls and 30 insulin-dependent (type I) diabetic patients: ten with idiopathic haemochromatosis (IH), ten with chronic pancreatitis and ten with idiopathic type I diabetes. While fasting plasma PP levels were slightly higher in diabetic with IH (40,8 +/- 7 pmol/l) than those in controls (27,1 +/- 3) on in type I diabetics (31,3 +/- 3) they were similar after the meal (peak level 95 +/- 18, 139 +/- 23, 100 +/- 36 respectively). In contrast the mean PP level was low in diabetics with chronic pancreatitis in the fasting state (15.9 +/- 3.6 pmol/l) and did not rise following the meal. These findings suggest that there is no PP cell injury in diabetics with IH.
Type II, non insulin dependent diabetes mellitus is commonly diagnosed after the age of 45 years. For this reason it was previously called maturity onset diabetes. Type II diabetes occurring in young subjects has generally been described in selected pedigrees. The purpose of this work was to review data from all the unrelated type II diabetics (with fasting hyperglycemia) diagnosed before the age of 45 and observed in our department over the last four years. A total of 90 such patients including 44 men and 46 women were included in this study. Of 43 cases diagnosed before the age of 30, there were 30 women compared to only 16 women out of 47 cases diagnosed between 30 and 45 years (p less than 0.001). At the time of diagnosis 42 patients had a relative body weight lower than 120%. In 66,7% of the cases, one parent was a known diabetic. The rate of diabetes in the sibships was 50%. Differences in family history of diabetes were not observed in relation to age or weight at diagnosis. Comparison with a series of 150 conventional type II diabetics in whom diagnosis was made between 45 and 60 years of age showed a significantly greater frequency of obesity (86%) and fewer diabetic parent (36%). The mean apparent duration of diabetes was 14 years (range 5-42). Microangiopathy was not infrequent in these diabetic patients. Twenty-three patients had retinopathy, proliferative in 8 cases, and 3 were blind. Nine had renal insufficiency, severe in 3 cases.(ABSTRACT TRUNCATED AT 250 WORDS)
In a double-blind trial 122 patients aged 15-40 years with insulin-dependent diabetes of recent onset were randomly assigned to cyclosporin 7.5 mg/kg per day or placebo. At the sixth month 25.4% of the cyclosporin group and 18.6% of the placebo group were in complete remission (not a significant difference). Treatment was continued in those patients with complete or partial remission (insulin requirement less than 0.25 U/kg per day) and 106 patients were followed to nine months, at which stage 24.1% of the original cyclosporin group and 5.8% of the original placebo group were in complete remission (p less than 0.01). For those patients whose whole-blood trough cyclosporin levels in the first three months averaged 300 ng/ml or more, the rates of complete remission at six and nine months were 37.5% and 37%. The rates of partial remission were also higher in the cyclosporin group and at six months the rate of complete or partial remission was 46% in the whole cyclosporin group and 65.6% in those with an average blood level exceeding 300 ng/ml in the first three months, versus 28.8% in the placebo group. The principal side-effect of cyclosporin was a modest and reversible increase in plasma creatinine. These results indicate that cyclosporin promotes the remission of type I diabetes and suggest the need for new controlled protocols aimed at evaluating the length of the effect and selecting the best drug regimen.
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In order to elucidate the mechanism of the glucose intolerance frequently associated with myotonic dystrophy (MD), glucose metabolism of 10 patients and 10 controls was investigated using the following tests: successive intravenous stimulation of insulin secretion by glucose and tolbutamide, detection of serum islet cell antibodies, measure of the specific insulin binding on erythrocytes and evaluation in vivo of insulin sensitivity by the euglycaemic glucose clamp method. Glucose tolerance was decreased in MD patients (K value: 1.51 +/- 0.15 vs 2.4 +/- 0.2 X 10(-2)) in spite of a basal (26 +/- 4 vs 11 +/- 2 microU/ml) and post-stimulative hyperinsulinism (area of the plasma insulin curve after glucose IG: 642 +/- 120 vs 315 +/- 28 microU/ml/min and area after tolbutamide IT: 740 +/- 166 vs 335 +/- 35 microU/ml/min). No islet cell antibody was detected in the serum of MD patients. These results suggest that decrease of glucose tolerance is secondary to peripheral insulin resistance. Specific binding of insulin on erythrocytes was slightly but not significantly reduced in MD patients (specific binding: 8.21 +/- 0.9 vs 9.64 +/- 0.9%, receptor number: 23 +/- 2 receptors/cell, concentration of unlabelled insulin displacing 50% of the bound radioactivity: 7.2 +/- 0.56 vs 6.6 +/- 0.6 ng/ml). There was a loss of normal down regulation of insulin receptors in MD. The results of the euglycaemic glucose clamp confirmed the insulin resistance especially for the highest insulin infusion rates. These data show that the insulin resistance of MD is due to both receptor- and post receptor-defect but that the main abnormality is an unresponsiveness located after the insulin signal on the receptor.
The effect of cyclosporine was evaluated in a double blind placebo controlled trial in 122 recent onset insulin-dependent diabetics. A significantly higher incidence of complete remissions was observed in patients treated with cyclosporine than in those receiving placebo (respectively 24 and 5.8%). The effect was still more clear-cut in patients having presented the highest cyclosporine blood level (37%). These results which have been obtained with modest toxicity demonstrate that cyclosporine induces remission of insulin-dependent diabetes and prompt to set up new controlled trials to evaluate the duration of the effect obtained and the potential risks of the treatment.
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PROTIS is an expert system devised to help general practitioners in the treatment of diabetes. It provides weighted results in ranking order from the most indicated to the most contra-indicated treatment. The reliability of PROTIS was tested comparatively by asking the system and two diabetologists involved in its design to analyze 250 clinical cases. The therapeutic advice given by PROTIS was considered satisfactory in 91.2% of the cases and erroneous, though without vital consequences, in 4.4%. The system was unable to propose any treatment in 4.4% of the cases. Most errors or non-responses could be corrected. This evaluation showed that PROTIS faithfully reproduces the reasoning of diabetologists and could serve as an example of what an expert system could do for the general practitioner.
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We have studied the effect of insulin hypoglycemia on the secretion of pancreatic polypeptide (PP) in 14 obese subjects with normal glucose tolerance and in 6 normal controls. Infusion of insulin 0.1 U/kg/h in controls and 0.12 U/kg/h in the obese, for one hour, produced a progressive hypoglycemia, similar in both groups (nadir 2 mmol/l at 50 min). The secretion of PP was less in obese subjects than in controls (peak 116 mmol/l vs 184 pmol/l, P less than 0.01) (integrated secretion sigma delta PP 288 vs 472 pmol/l, P less than 0.01) and was also delayed in the obese subjects beginning at 50 min instead of 40 min. The secretion of glucagon and of C-peptide were not different in the two groups, but the integrated response of ACTH was higher in the obese (sigma delta ACTH 52 pmol/l vs 25 pmol/l, P less than 0.01). The secretory response of growth hormone (STH) was smaller in the obese group (peak 8.6 +/- 1.28 vs 21.4 +/- 6.4 ng/ml, P less than 0.01). The reduced secretion of PP in obese subjects could be due to impaired sensitivity to hypoglycemia of the central control mechanism for PP release. The similarity of the reductions in the secretion of both PP and STH support this hypothesis, although a reduction in the secretory capacity of pancreatic PP cells cannot be excluded.
HLA-A, B and DR antigens have been investigated in insulin-dependent diabetics and compared to controls in a population of Algerians. A decrease of A1 and DR2 and an increase of Aw 19.2; B8, B18 and especially DR3 were found in diabetics in comparison to controls. The strongest association was found for DR3, which is a good genetic marker of IDD (RR = 8.50) in this population. The frequency of some HLA antigen associations in IDD suggests that the diabetic gene(s) is linked to 2 main haplotypes: Aw 19.2; B18; DR3 and Aw 19.2; B8; DR3. Antigen DR4 was equally represented in IDD (21%) and controls (28.4%), but heterozygote DR3-DR4 was more frequent in diabetics. The relation between IDD and HLA antigens found in the Algerian population is very similar to that described in diabetic Caucasian populations of southern Europe, except for the lack of association with DR4.
Occurrence of a remission after initiation of insulin treatment in insulin dependent diabetes (type I) of recent onset is a well known phenomenon. It may be more or less complete up to insulin withdrawal. In newly diagnosed IDD requiring insulin for ketoacidosis or primary failure of oral agents and with a duration of symptoms of less than 6 months, initiation of optimized insulin therapy was followed by suppression of insulin (with or without the use of oral agents) in two thirds of cases for a mean period of 12 months while blood glucose and glycosylated haemoglobin remained normal. As therapeutic reversal of the etiopathological mechanism of IDD is foreseen it is relevant to define the characteristics of cases with remission induced by intensified insulin treatment, and the mechanisms by which they may be explained. Current knowledge on these questions will be analysed in this review. Furthermore it appears that withdrawing insulin for a mean period of 12 months does not hamper the subsequent control of diabetes.
A 60-year old male diabetic patient treated with insulin for 6 years developed ketosis whenever an attempt was made to replace porcine insulin by mixed bovine and porcine insulin. That this resistance was specific to bovine insulin and of immune origin was demonstrated by in vivo and in vitro studies. The in vivo study used a Biostator artificial pancreas: rapid decrease of plasma glucose concentrations was observed under insulin infusion at a constant rate of 200 mU/min with either porcine or semi-synthetic human insulin despite maximum glucose infusion rate (400 mg/min), but not with bovine insulin and a low glucose infusion rate (150 mg/min). In the in vitro study, high levels of anti-insulin antibodies (11.4 m U/ml, Christiansen method) were found in the plasma, and the curves of competitive binding of radiolabelled insulin to the patient's IgG in the presence of unlabelled porcine or bovine insulin showed a 50% decrease of total binding with 0.12 ng/ml of bovine insulin and 25 ng/ml of porcine insulin, suggesting that the affinity of these antibodies for the former was 200 times higher than for the latter.
Antibodies to tubulin, the fundamental protein of microtubules, were studied by radioimmunoassay in patients with Type 1 (insulin-dependent) diabetes of varying duration and in healthy control subjects. Elevated levels of anti-tubulin antibodies were found in 46% of 28 patients with Type 1 diabetes of recent onset (less than or equal to 6 months) and in only 6.2% of 64 patients with long-standing Type 1 diabetes (duration 6-43 years). None of 34 DR3-positive normal subjects and none of 20 Type 2 (non-insulin-dependent) diabetic patients were positive for anti-tubulin antibodies. Anti-tubulin antibody levels were elevated in two out of 26 first-degree relatives of Type 1 diabetic patients. The specificity of the detection of anti-tubulin antibodies was demonstrated by dilution of the sera, competitive binding experiments between labelled and unlabelled tubulin, immunoblotting. Antibodies to tubulin were elevated in 60% of patients with islet cell surface antibodies and there was a significant association between anti-tubulin antibodies and islet-cell surface antibodies. These antibodies, however, recognize different specificities, since adsorption of islet cell surface antibody by rat islets did not alter the anti-tubulin antibody activity. Elevated anti-actin antibody responses were found in two out of 17 and one out of 26 patients with recent onset and long-standing Type 1 diabetes, respectively. In conclusion, anti-tubulin antibodies are detected in a high proportion of patients with diabetes of recent onset, are associated with islet cell surface antibodies and like islet cell surface antibodies decrease or disappear during the course of the disease.(ABSTRACT TRUNCATED AT 250 WORDS)
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Three types of pancreatic islet cell antibodies (ICA) have been described in insulin-dependent diabetic patients: IgG-ICA directed against cytoplasmic antigens, complement-fixing antibodies (CF ICA) and islet cell surface antibodies (ICSA) directed against membrane antigens. They can be detected by indirect immunofluorescence methods using human pancreas sections for IgG-ICA and isolate rat live islet cells for ICSA. Distribution of these 3 types of antibodies and correlations within individual patients were investigated in non-diabetic controls, in patients with idiopathic diabetes of various duration and in patients whose diabetes was associated with autoimmune diseases, chronic pancreatitis or haemochromatosis. The respective incidences of IgG-ICA and ICSA were: 5.4% and 15.8% in controls, 67.3% and 64.3% in patients with recent onset diabetes, 22.6% and 21.5% in old-standing diabetes, 63% and 50% in auto-immune diabetes, 12.5% and 7.2% in diabetes from chronic pancreatitis, and 5.6% and 7.6% in diabetes from haemochromatosis. In contrast with these correlations within groups, individual concordances were only 67%. CF ICA were relatively rare and almost exclusively present in IgG-ICA positive patients (30% of all cases); they seem to constitute a sub-group of IgG-ICA. It is concluded that IgG-ICA and ICSA are equally frequent in each type or duration of insulin-dependent diabetes and that they are not associated with secondary diabetes. The lack of concordance in individual patients indicates that the anti-pancreatic immune response is not homogeneous.