P. Vexiau

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 of 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 <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.

β- and α-Cell Dysfunctions in Africans With Ketosis-Prone Atypical Diabetes During Near-Normoglycemic Remission

OBJECTIVE Ketosis-prone atypical diabetes (KPD) is a subtype of diabetes in which the pathophysiology is yet to be unraveled. The aim of this study was to characterize β- and α-cell functions in Africans with KPD during remission. RESEARCH DESIGN AND METHODS We characterized β- and α-cell functions in Africans with KPD during remission. The cohort comprised 15 sub-Saharan Africans who had been insulin-free for a median of 6 months. Patients in remission were in good glycemic control (near-normoglycemic) and compared with 15 nondiabetic control subjects matched for age, sex, ethnicity, and BMI. Plasma insulin, C-peptide, and glucagon concentrations were measured in response to oral and intravenous glucose and to combined intravenous arginine and glucose. Early insulin secretion was measured during a 75-g oral glucose tolerance test. Insulin secretion rate and glucagon were assessed in response to intravenous glucose ramping. RESULTS Early insulin secretion and maximal insulin secretion rate were lower in patients compared with control participants. In response to combined arginine and glucose stimulation, maximal insulin response was reduced. Glucagon suppression was also decreased in response to oral and intravenous glucose but not in response to arginine and insulin. CONCLUSIONS Patients with KPD in protracted near-normoglycemic remission have impaired insulin response to oral and intravenous glucose and to arginine, as well as impaired glucagon suppression. Our results suggest that β- and α-cell dysfunctions both contribute to the pathophysiology of KPD.

The polymorphism Arg585Gln in the gene of the sterol regulatory element binding protein-1 (SREBP-1) is not a determinant of ketosis prone type 2 diabetes (KPD) in Africans

AIMnKetosis prone type 2 diabetes (KPD) is an atypical form of diabetes described mainly in people of sub-Saharan African origin. Its pathogenesis is unknown, although we have previously described a high prevalence of glucose-6-phosphate-dehydrogenase (G6PD) deficiency in patients with KPD. However, 50% of these deficient patients lacked the G6PD gene mutation. The isoforms of the transcription factor sterol regulatory element binding protein 1 (SREBP-1) are known to stimulate G6PD gene expression, and some polymorphisms in the SREBP-1 gene (SREBF-1) have been described only in Africans. We investigated one of these, the Arg585Gln polymorphism, in a candidate gene approach for KPD.nnnMETHODSnWe examined the presence of the Arg585Gln polymorphism in SREBF-1 in 217 consecutive unrelated Africans [73 patients with KPD, 80 with classical type 2 diabetes (T2D) and 64 nondiabetic subjects]. Patients underwent clinical and biochemical evaluations, and were assessed for G6PD activity and insulin secretion (glucagon test).nnnRESULTSnThere were no differences in frequency of the Arg585Gln polymorphism and the 585Gln allele among the three groups (allele frequency: KPD: 0.089, T2D: 0.031, nondiabetic group: 0.070; P=0.1). When the 585Gln allele frequency was compared separately between patients with KPD and those with T2D, it was significantly higher in the former (P=0.032). There was no difference between carriers and noncarriers of the 585Gln allele regarding G6PD activity and insulin secretion.nnnCONCLUSIONnThe results of this exploratory study show that the polymorphism Arg585Gln in SREBF-1 is not associated with the KPD phenotype. Further studies in larger populations are needed to confirm our findings.

Organ-specific autoantibodies in HLA genotyped insulin-dependent diabetes mellitus families

The prevalence of cytoplasmic islet cell antibodies (ICA) and extrapancreatic antibodies (EPA), (stomach, adrenal and thyroid) was investigated in 132 juvenile onset diabetic patients, without personal or familial history of other autoimmune disease, and their 31 diabetic and 402 non-diabetic first degree relatives. The prevalence of ICA was 59% in index cases and 12% in the non-affected first degree relatives. The frequency of EPA was 23% and 16% respectively. There were no sex-related differences among the patients. However, among the non-affected relatives, an increased frequency of EPA was observed in females (23%) compared to males (8%) (P less than 10-4). There was a higher prevalence of ICA in healthy relatives bearing DR3 and/or DR4 antigen combinations compared to non-DR3 and non-DR4 individuals (14% versus 5%, P less than 0.05). Furthermore, ICA were more frequent in healthy siblings sharing two haplotypes compared with one or no haplotype (21% vs 10%, P less than 0.05). These results support the heterogeneity of the autoantibodies: ICA are related closely to diabetes, decline in frequency with the duration of the disease and show association with DR3 or DR4 and the number of HLA haplotypes shared with the proband; EPA are sex related, independent of the duration of diabetes, non-HLA linked, and clustered in families with parent-offspring overtransmission, reflecting an overlapping autoimmune background.

An unusual somatotropin and thyreotropin secreting pituitary adenoma efficiently controlled by Octreotide and Pegvisomant

We describe the first case of a 36 year-old male patient with a somatotropin and thyreotropin secreting pituitary adenoma, co-treated by a long-acting releasing somatostatin analog (Octreotide) and a GH receptor antagonist (Pegvisomant). The patient normalized his biological disease activity reflected by hormone levels but his tumor size remained unchanged as measured by MRI. The co-treatment was well tolerated and induced a synergic effect on IGF1 levels that allowed us to use low doses of both therapies.

Marital status and family size of type 1 diabetic patients in a French cohort

OBJECTIVEnTo compare the marital status, the number of offspring and the cumulative incidence of type 1 diabetes in offspring of type 1 diabetic men and women.nnnMETHODSnFrom the database of patients attending our department, we reviewed the files of all the 352 subjects aged >=40 years with type 1 diabetes and compared male and female patients for whom age, age at diagnosis of diabetes, marital status, socio-economic status, number and age of offspring, diagnosed type 1 diabetes in the offspring could be obtained from patients record and/or direct interview (86 males and 78 females).nnnRESULTSnIn this population, 73% of women and 81% of men were married or living a marital life (NS), and 35% of women versus 8% of men had no offspring (P<0.0001). The proportion of parents with 2 offspring or more was 43% in females and 61% in males (p=0.03) and was not related to the socio-economic status. The number of offspring with diagnosed type 1 diabetes was small (8/229) and did not show significant association with gender of the parent, with a cumulative incidence of 3.2 and 3.7% in offspring of type 1 diabetic mothers and fathers respectively.nnnCONCLUSIONnType 1 diabetic women born before 1960 had fewer children than men. In this cohort, there was no difference in the cumulative incidence of type 1 diabetes in offspring of type 1 diabetic men and women despite reduced family size in women.

P1003 L’exposition fœtale au diabète maternel de type 1 et le stress oxydant

Introduction L’exces de transmission maternelle du diabete de type 2 est en partie explique par l’exposition au diabete in utero. Nous avons montre precedemment que l’exposition fœtale au diabete maternel est associee chez le descendant adulte a un deficit de l’insulinosecretion. L’objectif de cette etude est d’evaluer si l’exposition au diabete de type 1 (DT1) in utero est associee a une augmentation du stress oxydant chez le descendant adulte non diabetique. Patients et methodes Nous avons explore 23 descendants de meres DT1 (groupe expose : âge 25,4xa0±xa06,2 (SD) ans) et 21 descendants de peres DT1 (groupe temoin : âge 26,7xa0±xa04,8 ans). Le stress oxydant a ete evalue par la mesure de la F2 isoprostane urinaire exprimee en pg a T0 et T50 minutes apres effort. La reponse precoce de l’insulinosecretion au glucose oral et la secretion d’insuline et de glucagon au cours d’une perfusion de glucose par paliers de 40xa0min de 4 a 16xa0mg/kg/min couplee a un test a l’arginine (bolus de 5xa0g) ont ete evaluees. La sensibilite a l’insuline a ete mesuree par un clamp euglycemique (80xa0mUI/m 2 /min). Resultats La F2 isoprostane urinaire etait similaire dans les 2 groupes (exposes T0 135xa0±xa088 T50 159xa0±xa080 vs temoins T0 76xa0±xa039 T50 145xa0±xa065 ; p > 0,05). Aucune correlation entre la sensibilite a l’insuline et le stress oxydant n’a ete retrouvee (groupe expose T0 r 2 xa0=xa00,0048 et T50 r 2 ;xa0=xa00,13 vs groupe temoin r 2 xa0=xa00,013 et T50 r 2 xa0=xa00,01 ; pxa0>xa00,05). La correlation entre la secretion d’insuline et la F2 isoprostane urinaire etait egalement negligeable (groupe expose T0 r 2 xa0=xa00,032 et T50 r 2 xa0=xa00,046 vs groupe temoin r 2 xa0=xa00,0045 et T50 r 2 xa0=xa00,047 ; pxa0>xa00,05). Conclusion L’exposition fœtale au diabete maternel de type 1 n’est pas associee a un exces du stress oxydant chez le descendant adulte.

O56 L’exposition fœtale au diabète maternel est associée à des différences de méthylation de l’ADN génomique (analyse pan-génomique)

Introduction : Nous avons montre precedemment que lexposition foetale au diabete maternel est associee chez le descendant adulte a un deficit de linsulinosecretion et a une diminution de la reserve fonctionnelle renale pouvant contribuer a un risque accru de diabete et de maladie cardiovasculaire. Lobjectif de ce travail est detudier lorigine epigenetique potentielle de ces anomalies. Patients et methodes : Nous avons evalue si lexposition au diabete de type 1 (DT1) in utero est associee a une alteration de la methylation dADN chez le descendant non diabetique et sans marqueurs dautoimmunite de DT1. Le profil de methylation de 27 578 sites CpG a ete analyse a partir de leucocytes circulants chez 29 descendants de meres DT1 (groupe expose) et 29 descendants de peres DT1 (groupe temoin) en utilisant la Human Methylation27 BeadChip de la plateforme Illumina Infinium ®. Resultats : Lâge, la proportion hommes/femmes, et le pourcentage de masse grasse etaient similaires chez les exposes et les temoins. Nous avons observe 214 sites differemment methyles entre les 2 groupes. La methylation globale de ces 214 sites etait moins importante dans le groupe expose (en moyenne de 5,3 % , IC95 % 3,8 – 6,9, p Conclusion : Ces premieres donnees de methylation du genome entier suggerent que des mecanismes epigenetiques pourraient contribuer a la programmation fœtale liee a un environnement hyperglycemique.

PO5 Diabète de type 2 chez les patients originaires d’Afrique Sub-saharienne : influence de la migration

Objectif La prevalence du diabete de type 2 est superieure dans les populations migrantes par rapport a celles observees dans le pays d’origine ou d’accueil. Le but de notre etude etait de comparer les caracteristiques du diabete de type 2 (DT2) chez des patients originaires d’Afrique sub-saharienne ayant migre en France a l’âge adulte a celles des patients africains vivant en Afrique sub-saharienne et a celles des patients caucasiens vivant en France. Patients et Methodes Nous avons realise de novembre 2005 a decembre 2006 une etude transversale multicentrique dans laquelle ont ete recrutes consecutivement des patients DT2 suivis dans les services de Diabetologie de l’hopital Central de Yaounde au Cameroun et de l’hopital St Louis a Paris. Les parametres releves etaient l’âge a l’inclusion dans l’etude et au diagnostic du diabete, l’IMC, l’HbA1c, et les complications microvasculaires. Les immigres africains devaient avoir developpe leur diabete au moins un an apres leur arrivee en France. Resultats Nous avons inclus 98 patients d’Afrique Sub-saharienne vivant a Paris (AP), 100 patients africains suivis a Yaounde (AY) et 199 patients caucasiens vivant a Paris (CP). L’âge moyen a l’inclusion [49 ± 11 (DS) (AP), 58 ± 10 (AY) et 61 ± 12 ans (CP)] et celui au diagnostic du diabete [43 ± 9 (AP), 52 ± 9 (AY) et 48 ± 11 ans (CP)] etaient significativement differents dans les 3 groupes (p Conclusion La migration d’Afrique Sub-saharienne est associee a un âge au diagnostic du diabete plus precoce, a un meilleur equilibre glycemique et a une plus faible prevalence des complications microangiopathiques. L’âge au diagnostic plus precoce chez les immigres que chez les caucasiens pourrait etre lie a des facteurs genetiques ou environnementaux en rapport avec la migration.

O62 Le diabète de type 2 cétonurique est associé à l’infection par l’herpès virus humain de type 8 (HHV-8) chez des patients originaires d’Afrique sub-Saharienne

Introduction Le diabete de type 2 cetonurique ( ketosis prone diabetes-KPD ) est une forme atypique de diabete de type 2 revele par une cetose voire une acidocetose, frequemment observe chez des personnes originaires d’Afrique subsaharienne et necessitant une insulinotherapie souvent transitoire. Son debut aigu suggere l’existence d’un facteur declenchant. Compte tenu de la distribution geographique du KPD, nous avons evalue l’implication possible de l’herpes virus humain de type 8 (HHV-8). Materiels et methodes Nous avons recherche par immunofluorescence des anticorps diriges contre les antigenes latents et lytiques du HHV-8 chez 187 patients consecutifs, originaires d’Afrique subsaharienne et ayant migre en France a l’âge adulte, comprenant 81 patients KPD et 106 patients diabetiques de type 2 (T2D). Un groupe de 90 temoins non diabetiques de memes origines geographiques et appariees aux patients pour l’âge et le sexe a ete evalue. La presence du HHV-8 dans l’ADN genomique a ete recherchee chez 22 patients a la phase aigue. Par ailleurs, nous avons evalue si le HHV-8 est capable d’infecter in vitro des cellules beta humaines provenant d’un donneur non diabetique. Resultats A l’inclusion, l’âge et l’IMC des patients etaient similaires : KPD 48xa0±xa011 (DS) ans et 27,7xa0±xa04,3 kg/m 2 ; T2D 50xa0±xa010 ans et 27,5xa0±xa04,8 kg/m 2 . Les anticorps anti HHV-8 ont ete retrouves chez 87,7 % des KPD versus 15,1 % des T2D, ORxa0=xa039,9 (17,1-93,4 ; p in vitro des proteines virales HHV-8 (LANA1) dans le cytoplasme des cellules beta humaines apres 4 jours de culture en presence de HHV-8. Conclusion Chez des patients KPD originaires d’Afrique subsaharienne, l’ADN du HHV-8 est retrouve chez presque la moitie des patients a la phase aigue et la prevalence de la seropositivite HHV-8 est tres elevee. Ces donnees et la capacite du HHV-8 d’infecter des cellules beta in vitro suggerent que l’infection par le HHV-8 est responsable du phenotype KPD chez des individus autrement predisposes au DT2.