Gender and neurogenin3 influence the pathogenesis of ketosis-prone diabetes

Ketosis-prone diabetes (KPD) is a phenotypically defined form of diabetes characterized by male predominance and severe insulin deficiency. Neurogenin3 (NGN3) is a proendocrine gene, which is essential for the fate of pancreatic beta cells. Mice lacking ngn3 develop early insulin-deficient diabetes. Thus, we hypothesized that gender and variants in NGN3 could predispose to KPD. We have studied clinical and metabolic parameters according to gender in patients with KPD (n = 152) and common type 2 diabetes (T2DM) (n = 167). We have sequenced NGN3 in KPD patients and screened gene variants in T2DM and controls (n = 232). In KPD, male gender was associated with a more pronounced decrease in beta-cell insulin secretory reserve, assessed by fasting C-peptide [mean (ng/ml) +/- s.d., M: 1.1 +/- 0.6, F: 1.5 +/- 0.9; p = 0.02] and glucagon-stimulated C-peptide [mean (ng/ml) +/- s.d., M: 2.2 +/- 1.1, F: 3.1 +/- 1.7; p = 0.03]. The rare affected females were in an anovulatory state. We found two new variants in the promoter [-3812T/C (af: 2%) and -3642T/C (af: 1%)], two new coding variants [S171T (af: 1%) and A185S (af: 1%)] and the variant already described [S199F (af: 69%)]. These variants were not associated with diabetes. Clinical investigation revealed an association between 199F and hyperglycaemia assessed by glycated haemoglobin [HbA1c (%, +/-s.d.) S199: 12.6 +/- 1.6, S199F: 12.4 +/- 1.4 and 199F: 14.1 +/- 2.2; p = 0.01]. In vitro, the P171T, A185S and S199F variants did not reveal major functional alteration in the activation of NGN3 target genes. In conclusion, male gender, anovulatory state in females and NGN3 variations may influence the pathogenesis of KPD in West Africans. This has therapeutic implications for potential tailored pharmacological intervention in this population.     

Ketosis-prone type 2 diabetes in patients of sub-Saharan African origin: clinical pathophysiology and natural history of beta-cell dysfunction and insulin resistance

Nonautoimmune ketosis-prone diabetic syndromes are increasingly frequent in nonwhite populations. We have characterized a cohort of patients of sub-Saharan African origin who had ketosis-prone type 2 diabetes (n = 111), type 1 diabetes (n = 21), and type 2 diabetes (n = 88) and were admitted to a hospital for management of uncontrolled diabetes. We compared epidemiological, clinical, and metabolic features at diabetes onset and measured insulin secretion (glucagon-stimulated C-peptide) and insulin action (short intravenous insulin tolerance test) during a 10-year follow-up. Ketosis-prone type 2 diabetes shows a strong male predominance, stronger family history, higher age and BMI, and more severe metabolic decompensation than type 1 diabetes. In ketosis-prone type 2 diabetes, discontinuation of insulin therapy with development of remission of insulin dependence is achieved in 76% of patients (non-insulin dependent), whereas only 24% of patients remain insulin dependent. During evolution, ketosis-prone type 2 diabetes exhibit specific beta-cell dysfunction features that distinguish it from type 1 and type 2 diabetes. The clinical course of non-insulin-dependent ketosis-prone type 2 diabetes is characterized by ketotic relapses followed or not by a new remission. Progressive hyperglycemia precedes and is a strong risk factor for ketotic relapses (hazard ratio 38). The probability for non-insulin-dependent ketosis-prone type 2 diabetes to relapse is 90% within 10 years, of whom approximately 50% will become definitively insulin dependent. Insulin sensitivity is decreased in equal proportion in both ketosis-prone type 2 diabetes and type 2 diabetes, but improves significantly in non-insulin-dependent ketosis-prone type 2 diabetes, only after correction of hyperglycemia. In conclusion, ketosis-prone type 2 diabetes can be distinguished from type 1 diabetes and classical type 2 diabetes by specific features of clinical pathophysiology and also by the natural history of beta-cell dysfunction and insulin resistance reflecting a propensity to glucose toxicity.     

Value of genetic studies and immunologic markers in diabetes. Prediction of insulin dependence

A new classification based on physiopathological criteria distinguishes Type I diabetes, observed in patients with stigmata of anti-islet of Langerhans auto-immunity, from Type II diabetes without these autoimmune changes. Type I diabetes is sub-divided into Classes Ia and Ib, Class Ib comprising those cases associated with other auto-immune diseases. Serological analysis of 76 patients with clinical type Ia diabetes and 215 healthy, first degree relatives showed that the distinction between Classes Ia and Ib was not clear-cut and that patients classified clinically Ia were in fact infraclinical Ib subjects. Forty-one per cent of patients with Class Ia diabetes had anti-gastric, anti-adrenal or anti-thyroid antibodies, and 28 p. 100 of their healthy relatives also had the same types of antibodies. Several prospective studies of the families of patients with Type I diabetes have shown that anti-islet of Langerhans antibodies were associated with a high risk of diabetes. Similarly, the presence of these antibodies in patients apparently with Type II diabetes (non-insulin dependent) was associated with an increased risk of developing insulin dependence. These results illustrate the value of immunological investigations in diabetic patients. They may influence the choice of treatment in the future.     

Paradoxic improvement of glucose intolerance in 8 females using estrogen-progestagen contraceptives containing norgestrel and ethinyl-estradiol

Sixty females, aged 20 to 35, received an oral contraceptive pill (Norgestrel 0.5 mg and Ethinyloestradiol 50 micrograms/day) during one year. Group I was formed by 41 normal patients before and after 12 months. Group II was formed by 11 patients, normal before and with impaired oral glucose tolerance after 12 months. Group III was formed by 8 patients with impaired glucose tolerance before treatment and normal oral glucose tolerance after 12 months. All patients were submitted to 3 oral glucose tolerance tests, the first one at the 16th day of the control cycle, the second and the third at the 16th days of the 6th and 12th cycles during treatment. No significative modification of glycemia, insulinemia or weight was noted in group I. In group II the impaired oral glucose tolerance was associated with an increase of weight. In group III the improvement of glucose tolerance was marked by hyperinsulinemia.     

Effect of estroprogestative drugs on the secretion of corticoadrenal hormones

Estro-progestative drugs (EPD) have been used for many years and multiple secondary effects have been reported concerning mainly the glucidic and lipidic metabolisms. Effects of EPD on steroid metabolism have also been described and the authors present a review of the literature on this subject. Particularly it appears that EPD affect: the glucocorticoid metabolism, with augmentation of total cortisol although not in its free-form (augmentation of transcortine), the adrenal androgens metabolism, with diminution of their circulating rates, the aldosterone metabolism with augmentation of its secretion. These biological constatations could help explaining some clinical features occurring with administration of EPD: diminution of hirsutism and/or acne, augmentation of body weight, appearance of hypertension.     

Detection of islet cell antibodies by a microcytotoxicity method

A microcytotoxicity test for antibodies against islet cells (ICA) is described. Sera from patients with insulin-dependent diabetes, their healthy first degree relatives, and normal controls, genotyped for HLA-A, -B and -DR, were tested by 4 different methods. Cytoplasmic ICA and complement fixing ICA were detected by indirect immunofluorescence with human pancreas sections, and cytotoxic complement dependent ICA and surface ICA were tested against murine beta cell suspensions. Strong correlation was found between cytotoxic and surface antibodies (P less than 10(-7). The technique described is appropriate for use in the screening of large numbers of sera.     

Pattern of treatment among diabetic patients in France

Both the treatment pattern and the degree of metabolic control were estimated from a sample of 1172 French diabetic patients. The subjects were recruited from 80 medical-analysis laboratories scattered throughout the country, where they came for biologic blood sample tests. Patients had to be diagnosed as having diabetes, give consent for additional blood sampling, and fill out a short self-questionnaire. Glycosylated hemoglobin A1c (HbA1c) was centrally determined by liquid chromatography (normal range 3.5-6.3%). We found 135 patients (11.5%) who were not drug treated or treated with diet alone, 862 (73.5%) treated with oral agents, and 175 (15.0%) treated with insulin. Among the latter, 79 (6.7%) were defined as true insulin-dependent diabetes mellitus (IDDM) patients. Among patients receiving no drug or a slight dosage or oral agents, 47% were found to be in the normal range of HbA1c. On the other hand, among the patients intensively treated with oral agents or secondarily with insulin, less than half were under fair control (HbA1c less than 7.5%). These results are in agreement with previous estimates of treatment distribution derived from national drug sales data. They provide evidence regarding the particular features of diabetes in France, i.e., low prevalence of IDDM, low consumption of insulin, high consumption of oral agents. The finding of a large proportion of normal HbA1c values in non-insulin-dependent diabetic patients suggests a state of overdiagnosis linked to the use of nonspecific criteria of diagnosis in large-scale screening.     

Radioimmunoassay for 21-deoxycortisol: clinical applications

A radioimmunoassay for 21-deoxycortisol is described. The immunogen, 21-deoxycortisol-3-(0-carboxymethyl) oxime-bovine serum albumin, was prepared, the antisera raised against it were studied and the reliability of the assay was checked. The antiserum selected cross-reacted with 11-deoxycortisol (0.08%), corticosterone (0.25%), cortisol (0.6%) and 17-hydroxyprogesterone (1.6%). 21-deoxycortisol was separated by celite partition chromatography and eluted in the 70/30 (v/v) isooctane/ethyl acetate fraction together with 11-deoxycortisol and corticosterone. The radioimmunoassay was used to measure 21-deoxycortisol in the plasma of normal subjects and patients with androgen excess. In normal subjects, men (0.19 ng/ml +/- 0.08) and women (0.18 ng/ml +/- 0.09) had similar basal levels (mean +/- SD). One hour after ACTH stimulation, these levels were increased by a factor of 3.5. In 7 patients treated for classical congenital adrenal hyperplasia associated with 21-hydroxylase deficiency, basal values varied between 9.1 and 39.9 ng/ml (measured at 8 a.m.). In 7 untreated women with late-onset congenital adrenal hyperplasia (with 21-hydroxylase deficiency), ACTH-stimulated levels were increased to between 9 and 25.5 ng/ml. In 14 heterozygous carriers of 21-hydroxylase deficiency, diagnosed by HLA genotyping, all ACTH-stimulated levels were well above the highest corresponding levels in normal subjects, whereas 17-hydroxyprogesterone levels remained within the normal range in 9 of the cases.