Raphaël Porcher

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.

Influence of migration on characteristics of type 2 diabetes in sub-Saharan Africans

AIM This study compared the clinical and biochemical characteristics and microvascular complications found in three groups of type 2 diabetes (T2D) patients: Africans living in Africa; African immigrants living in France; and Caucasians living in France. METHODS Diagnosed T2D Africans living in Cameroon (n=100) were compared with 98 African migrants diagnosed with T2D after having moved to France, and a group of 199 T2D Caucasian patients living in France. All underwent clinical and biochemical evaluations, and all were assessed for microvascular complications. RESULTS The median duration of stay of the migrants in France was 15years before being diagnosed with diabetes. Despite similar durations of diagnosis, they were 8.9years younger at the time of diagnosis than Africans living in Cameroon (P<0.001). Caucasians and African immigrants in France had lower HbA1c values than Africans in Cameroon (P<0.001); they were also more aggressively treated for hypertension and dyslipidaemia and, therefore, had significantly lower blood pressure levels and better lipid profiles. Diabetic nephropathy and retinopathy rates were higher in Cameroon than in the two other groups. After adjusting for age, diabetes duration, HbA1c, hypertension and other covariates, only the prevalence of diabetic nephropathy (OR: 5.61, 95% CI: 2.32-13.53; P<0.0001) was higher in Cameroon compared with those living in France. CONCLUSION Our results suggest that Africans who emigrate to France may develop diabetes earlier than those staying in their home country. However, the latter may be a reflection of late diagnosis of diabetes. Also, the less adequate diabetes and hypertension control in the latter would explain their higher rates of nephropathy. Large-scale cohorts are now warranted to substantiate these observations.

Kidney Dysfunction in Adult Offspring Exposed In Utero to Type 1 Diabetes Is Associated with Alterations in Genome-Wide DNA Methylation

Background Fetal exposure to hyperglycemia impacts negatively kidney development and function. Objective Our objective was to determine whether fetal exposure to moderate hyperglycemia is associated with epigenetic alterations in DNA methylation in peripheral blood cells and whether those alterations are related to impaired kidney function in adult offspring. Design Twenty nine adult, non-diabetic offspring of mothers with type 1 diabetes (T1D) (case group) were matched with 28 offspring of T1D fathers (control group) for the study of their leukocyte genome-wide DNA methylation profile (27,578 CpG sites, Human Methylation 27 BeadChip, Illumina Infinium). In a subset of 19 cases and 18 controls, we assessed renal vascular development by measuring Glomerular Filtration Rate (GFR) and Effective Renal Plasma Flow (ERPF) at baseline and during vasodilatation produced by amino acid infusion. Results Globally, DNA was under-methylated in cases vs. controls. Among the 87 CpG sites differently methylated, 74 sites were less methylated and 13 sites more methylated in cases vs. controls. None of these CpG sites were located on a gene known to be directly involved in kidney development and/or function. However, the gene encoding DNA methyltransferase 1 (DNMT1)—a key enzyme involved in gene expression during early development–was under-methylated in cases. The average methylation of the 74 under-methylated sites differently correlated with GFR in cases and controls. Conclusion Alterations in methylation profile imprinted by the hyperglycemic milieu of T1D mothers during fetal development may impact kidney function in adult offspring. The involved pathways seem to be a nonspecific imprinting process rather than specific to kidney development or function.

Sex Difference In the Effect of Fetal Exposure to Maternal Diabetes on Insulin Secretion

Abstract We previously showed that fetal exposure to maternal type 1 diabetes (T1D) is associated with altered glucose-stimulated insulin secretion in adult offspring. Here, we investigated whether this β-cell defect displays a sex dimorphism. Twenty-nine adult nondiabetic offspring of T1D mothers (ODMs) were compared with 29 nondiabetic offspring of T1D fathers. We measured early insulin secretion in response to oral glucose and insulin secretion rate in response to intravenous glucose ramping. Insulin sensitivity and body composition were assessed by a euglycemic, hyperinsulinemic clamp and dual-energy X-ray absorptiometry, respectively. In response to oral glucose, male and female ODMs displayed a reduced insulin secretion. In contrast, in response to graded intravenous glucose infusion, only female ODMs (not males) exhibited decreased insulin secretion. There was no defect in response to combined intravenous arginine and glucose, suggesting that male and female ODMs exhibit a functional β-cell defect rather than a reduced β-cell mass. In conclusion, fetal exposure to maternal diabetes predisposes to β-cell dysfunction in adult male and female offspring. This β-cell defect is characterized by a sexual dimorphism following intravenous glucose stimulation.

Predicting the clinical outcome of ICSI by sperm head vacuole examination

ABSTRACT To assess whether high magnification sperm head vacuole examination (SHVE) and/or standard sperm morphology assessment can predict ICSI outcomes in terms of fertilization, embryo quality, and delivery rates, a prospective observational bicentric study was conducted in two publicly funded assisted reproductive technology (ART) units in France between January and July of 2012. A total of 111 ICSI cycles for exclusively male infertility factors were included. A Spearman’s correlation test was performed to validate SHVE reproducibility between the ART units. The normal morphology rate and SHVE performed on selected spermatozoa were respectively determined according to David’s and Vanderzwalmen’s classifications used for motile sperm organelle morphology examination (MSOME) on the day of the ICSI. Receiver Operating Characteristic (ROC) curve analysis was performed to determine thresholds associated with the occurrence of a delivery. There was an excellent correlation between the two operators (r=0.98), thus validating the study’s SHVE data. Percentages of normal morphology grade spermatozoa using the standard classification and first-best morphology grade spermatozoa determined by SHVE were not significantly associated with (i) delivery (p=0.58; 0.90 /area under curve (AUC) =0.532; 0.507), (ii) fertilization (p=0.88; 0.90), (iii) top-quality embryos (p=0.27; 0.98), and (iv) good quality embryo rates (p=0.73; 0.98), respectively. In conclusion, high magnification SHVE and standard sperm morphology assessment cannot predict clinical or biological ICSI outcomes. Abbreviations: ART: assisted reproductive technology; HBV: hepatitis B virus; HCV: hepatitis C virus; HIV: human immunodeficiency virus; ICSI: intra-cytoplasmic sperm injection; IVF: in vitro fertilization; LNVs: large nuclear vacuoles; MSOME: motile sperm organelle morphology examination; SHVE: sperm head vacuole examination; WHO: World Health Organization

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.