Marie Laloi-Michelin

Abnormalities in insulin secretion in type 2 diabetes mellitus

Type 2 diabetes mellitus is a multifactorial disease, due to decreased glucose peripheral uptake, and increased hepatic glucose production, due to reduced both insulin secretion and insulin sensitivity. Multiple insulin secretory defects are present, including absence of pulsatility, loss of early phase of insulin secretion after glucose, decreased basal and stimulated plasma insulin concentrations, excess in prohormone secretion, and progressive decrease in insulin secretory capacity with time. beta-cell dysfunction is genetically determined and appears early in the course of the disease. The interplay between insulin secretory defect and insulin resistance is now better understood. In subjects with normal beta-cell function, increase in insulin is compensated by an increase in insulin secretion and plasma glucose levels remain normal. In subjects genetically predisposed to type 2 diabetes, failure of beta-cell to compensate leads to a progressive elevation in plasma glucose levels, then to overt diabetes. When permanent hyperglycaemia is present, progressive severe insulin secretory failure with time ensues, due to glucotoxicity and lipotoxicity, and oxidative stress. A marked reduction in beta-cell mass at post-mortem examination of pancreas of patients with type 2 diabetes has been reported, with an increase in beta-cell apoptosis non-compensated by neogenesis.

Kearns Sayre syndrome: an unusual form of mitochondrial diabetes

Kearns Sayre syndrome (KSS) is a mitochondrial disorder characterized by the emergence before age 20 of progressive external ophthalmoplegia, pigmentary retinopathy, together with other heterogeneous clinical manifestations, including cardiac conduction defects, muscle abnormalities and endocrinopathies. KSS is associated with large heteroplasmic deletions in mitochondrial DNA. We report the case of a 43-year-old woman, with diabetes mellitus as a first manifestation at age 19. Later, she exhibited bilateral ptosis and external ophthalmoplegia with progressive worsening. DNA analysis identified a large mitochondrial DNA (mtDNA) deletion, which confirmed the diagnosis of KSS. By reporting this case with diabetes mellitus as first manifestation, we aim at emphasizing problems of diagnosis in these subtypes of mitochondrial diabetes.

Traitement médicamenteux du diabète de type 2 (deuxième partie)

Drug treatment of 2 diabetes is intended to normalize glycosylated hemoglobin levels (HbA(1c)<6.5%) and thereby prevent the development of micro- and macrovascular complications. Oral antidiabetic agents target the metabolic abnormalities that cause diabetes. The two principal families of oral antidiabetic agents - insulin sensitizers and insulin secretagogues - can be taken together. Thiazolidinediones or glitazones (insulin sensitizers) improve peripheral tissue sensitivity to insulin. Metformin (an insulin sensitizer) reduces hepatic glucose production. Sulfonylureas and meglitinides (insulin secretagogues) stimulate insulin secretion and can cause hypoglycemia. GLP-1 (Glucagon-Like Peptide-1) analogs and DPP-IV (dipeptidyl-peptidase-IV) inhibitors are new drug classes currently under development.

The prevalence of IgG4-positive plasma cells in hypophysitis: a possible relationship to IgG4-related disease.

AIMS Hypophysitis is a rare chronic inflammation of the pituitary gland corresponding currently to six histopathological subtypes. Among them, immunoglobulin- G4-related hypophysitis was recently added in this classification. The aim of this study was to perform a retrospective histopathological and immunohistochemical analysis to evaluate the prevalence of IgG4-related hypophysitis and review reported cases. METHODS All samples of hypophysitis from Lariboisiere hospital were reviewed by two pathologists to assess their subtypes. An immunohistochemistry against IgG4 and IgG was performed. Slides were numerized, and IgG4-positive plasma cells and IgG plasma cells were counted in three high-power fields to evaluate the ratio. RESULTS Eight cases were included: 5 lymphocytic hypophysitis, 1 granulomatous subtype, and 2 IgG4-related hypophysitis, affecting two young women without other coaffected organ. CONCLUSION Our results show that IgG4-related hypophysitis is not an exceptional entity. Storiform fibrosis and obliterative phlebitis, histopathological characteristics of IgG4-related disease in other organs, are lacking in pituitary lesions. This study proves the interest of immunohistochemistry for diagnosis of IgG4-related hypophysitis. Due to the sensibility of IgG4-disease to steroids in other organs, this finding could be of clinical relevance.

Macular pattern dystrophy in MIDD: Long-term follow-up

A case of maternally inherited diabetes and deafness (MIDD)-associated macular pattern dystrophy with a 15-year follow-up is reported. On initial examination at age 37, visual acuity was normal, but chorioretinal atrophy at the posterior pole was already present in both eyes. At age 52, visual acuity remained normal in the right eye and was only slightly decreased in the left eye despite notable extension of the areas of chorioretinal atrophy in that eye. No evidence of diabetic retinopathy was present at any time. This case shows that visual acuity can remain stable in the long term despite extensive lesions of macular pattern dystrophy.

Diagnostic clinique et biologique du diabète mitochondrial et particularités de sa prise en charge

Mitochondrial diabetes affects up to 1% of patients with diabetes and is often unrecognised by the physicians. Maternally inherited diabetes and deafness (MIDD) resulting from the mutation 3243A>G of the mitochondrial DNA is the most frequent mutation associated with mitochondrial diabetes. This review summarizes the range of clinical phenotypes associated with MIDD and outlines the advances in genetic diagnosis, pathogenesis and management of these patients.

Drug treatment in type 2 diabetes (part 2)

Insulin secretagogues and insulin sensitizers can be combined with one another as well as with other treatments (described below). Alpha-glucosidase inhibitors delay intestinal absorption of carbohydrates and reduce postprandial glycemia. Orlistat and sibutramine improve insulin sensitivity by helping patients lose weight. Orlistat inhibits hydrolysis of dietary triglycerides. Sibutramine, a noradrenaline and serotonin reuptake inhibitor, reinforces feelings of satiety and increases energy expenditure. After approximately 10 years, insulin therapy is usually required together with oral antidiabetic agents (except glitazones) or alone if HbA(1c) (glycosylated hemoglobin) is>6.5%. New guidelines for management of type 2 diabetes were published in 2006.

Spécificités du diabète de type 2 chez le sujet âgé

La prevalence du diabete de type 2 (DT2) augmente fortement avec l’âge. Les donnees recentes montrent qu’un patient diabetique sur deux est âge de plus de 65 ans, et 25 % ont plus de 75 ans. Le vieillissement n’est pas equivalent d’une personne a l’autre ni d’un patient a un autre. On differencie 3 types de vieillissements : un vieillissement reussi, un vieillissement pathologique et la dependance physique. La fragilite est l’etat intermediaire. Le diabetique âge est un patient fragile car il cumule les complications vasculaires et atteintes fonctionnelles du diabete (neuropathie, deficit visuel, pathologies vasculaires…), les facteurs de risque vasculaires (hypertension, dyslipidemie), et les troubles mentaux (troubles cognitifs, demence, depression, et sequelles cerebrales). Il faut depister les criteres cliniques de fragilite chez les diabetiques âges car une intervention gerontologique a montre son efficacite sur la prevention de la perte d’autonomie et l’amelioration de la qualite de vie. La prise en charge therapeutique est difficile car elle doit tenir compte du risque/benefice. En effet, les effets iatrogenes medicamenteux, et surtout les hypoglycemies, peuvent etre parfaitement deleteres et dangereux chez le sujet âge. L’education therapeutique reste indispensable et doit etre specifiques. Les conseils dietetiques, l’activite physique et le traitement medical doivent etre personnalises et sont importants pour l’equilibre glycemique, nutritionnel et les chances d’un vieillissement reussi.

P61 Discordance entre HbA1c et fructosamine. Évaluer le ‘glycation gap’et sa corrélation avec les complications vasculaires du diabète

Objectif Des donnees recentes indiquent qu’il existe une correlation entre la vitesse de glycation, variable d’un individu a l’autre, et la presence de complications notamment microvasculaires. Le glycation gap, qui traduit cette variabilite, est defini par la difference entre l’HbA 1 c mesuree et l’HbA 1 c predite a partir de la fructosamine. L’objectif de l’etude etait de confirmer ces donnees et d’evaluer un lien avec les complications micro- et macrovasculaires chez des patients diabetiques. Patients et Methodes Ont ete evalues 108 patients consecutifs, diabetiques de type 1 ou 2, hospitalises en Hopital de jour de Septembre a Octobre 2009. 4 patients ont ete exclus pour hemoglobinopathie. L’HbA 1 c predite correspond a la formule deduite de la courbe de correlation entre l’HbA 1 c mesuree et la fructosamine [(R 2 = 0,57) (= 3,18 + (0,015 x fructosamine)]. Le coefficient de variation (CV) inter-essai de la fructosamine est de 2,5 % pour une valeur a 262 mg/l et 3,2 % pour une valeur a 520 mg/l, le CV % intra-essai etant de 0,5 %. Resultats Les caracteristiques des patients etaient : âge moyen 38,5 ± 16,1 ans, IMC 28,3 ± 5,2 kg/m 2 , 57 % d’hommes, duree du diabete 14,1 ± 10 ans, 93 % de DT2. Pour les complications, 28 % des patients presentaient une retinopathie, 38 % une nephropathie [28 % microalbuminurie (MA), 10 % proteinurie], 18 % une maladie coronaire et 34 % une maladie atheromateuse. L’HbA 1 c moyenne etait 7,5 ± 1,2 %, la fructosamine 291,7 ± 60,6 mg/L, et l’HbA 1 c predite 7,5 ± 0,9 %. La moyenne du glycation gap augmente significativement avec la presence d’une nephropathie (- 0,14 dans le groupe sans nephropathie, 0,32 dans le groupe MA et 0,20 dans le groupe proteinurique, p = 0,03). Il n’y pas de difference significative dans les valeurs du glycation gap pour la retinopathie et les complications macrovasculaires. Conclusion Le glycation gap est un bon facteur predictif de la nephropathie diabetique. Son lien avec les autres complications est moins clair. Toutefois, ces resultats vont etre consolides avec un effectif elargi.

Place respective de l’insulinorésistance et de l’insulinopénie dans l’histoire naturelle du diabète de type 2

Resume Le diabete de type 2, maladie multifactorielle, est lie a l’association d’un deficit de l’insulinosensibilite ou insulinoresistance liee aux habitudes de vie (acquise) et d’un deficit de l’insulinosecretion (inne). Aux stades de debut, hyperglycemie moderee a jeun (IFG) et intolerance au glucose (IGT), l’insulinoresistance devoile une dysfonction insulaire, ou incapacite des cellules β-insulaires a augmenter leur debit de secretion pour repondre a l’augmentation des besoins. Ce phenomene, appele compensation de l’insulinoresistance par la cellule β, est inoperant chez ces sujets, du fait d’une susceptibilite genetique a une moindre capacite potentielle d’insulinosecretion, ou d’une hypotrophie des cellules β acquise in utero . Ensuite, c’est la reduction progressive de l’insulinosecretion qui va conduire des premieres anomalies de la glycoregulation a un diabete patent, puis mener jusqu’a l’insulinorequerance, alors que le deficit de l’insulinosensibilite reste stable avec le temps.