Tabagisme, obésité et diabète: une interaction cliniquement importante [Smoking, obesity and diabetes: a clinically important interaction].

Smoking, obesity and diabetes are among the leading cause of premature death worldwide. Smokers have globally a lower body weight compared with non smokers but they tend to accumulate more fat in the abdomen. Most smokers gain weight when they quit smoking, however this does not seem to diminish the health benefits associated with smoking cessation. Smoking increases the risk of developing type 2 diabetes. Among people with diabetes, smoking significantly increases the risks of complications and mortality. Interventions with pharmacologic help should be offered to all smokers, with or without diabetes, in order to increase smoking cessation rates and limit weight gain.

Hydrokolloid bei diabetischen Fussulzera: besser als herkömmliche Wundverbände

Sie betreuen einen 82-jährigen Typ-2-Diabetiker mit einer 1 cm grossen Wunde an der Grosszehe. Der Patient hat sich geschnitten, als er Hornhaut entfernte. Die Wunde vergrössert sich seither stetig und sondert Flüssigkeit ab. Die Wundumgebung ist hyperkeratotisch, aufgeweicht, leicht fibrinös und feucht. Weder ist Kontakt zum darunterliegenden Knochen vorhanden noch gibt es Infektionszeichen. Der Patient ist für eine Neuropathie und Veneninsuffizienz bekannt; die Fusspulse sind spürbar. Seine Blutzuckerwerte sind stabil, der HbA1c-Wert liegt bei 7,5%. Er möchte die Wunde selbst weiter versorgen und sich regelmässig duschen können.

Evolution of glucose induced thermogenesis in obese subjects with and without diabetes: a six-year follow-up study.

The thermogenic response to a 100 g oral glucose load was measured prospectively (by indirect calorimetry) in three groups of obese subjects: (1) normal glucose tolerance (n = 12, initial weight 86.4 +/- 3.9 kg, BMI 30.4 +/- 1.1 kg/m2; (2) impaired glucose tolerance (n = 8, initial weight 105.3 +/- 7.6 kg, body mass index (BMI) 37.6 +/- 2.9 kg/m2; (3) diabetes (n = 12), initial weight 102.1 +/- 5.3 kg, BMI 36.2 +/- 2.0 kg/m2). The thermogenic response to glucose averaged 6.8 +/- 1.1 and 7.0 +/- 1.0 per cent, in the two non-diabetic obese groups respectively, and was significantly lower in the obese diabetic group (3.1 +/- 0.8 per cent). With the evolution of obesity (i.e. 6 years later), the glucose-induced thermogenesis (GIT) was significantly reduced in the non-diabetic groups (P less than 0.05) to 4.1 +/- 0.8 and 3.0 +/- 1.1 per cent respectively, and was still blunted in the diabetic group (2.1 +/- 0.7 per cent). The decrease in GIT was accompanied by a reduction in glucose tolerance and insulin response with no change in fasting plasma insulin. These effects were observed despite the fact that the body weight of the subject did not change significantly over the 6-year period. It is concluded that the decrease in GIT which accompanies the worsening of glucose tolerance and the occurrence of diabetes is a mechanism which may contribute to maintain the obesity state by a reduction of energy expenditure.

Chirurgie du diabète: provocation ou réalité [Surgery for diabetes: challenge or reality?]

Bariatric surgery techniques can usually increase either sensitivity or insulin resistance, acting on three different levels: decrease of food intake, malabsorption and modifications of entero-insulaire axis activity. This latter is taken into account in order to develop a new protocol to obtain diabetes remission without important weight loss and nutritional deficiencies. Preliminary results are interesting but they come from very short time studies with few patients. Moreover, complications rate is at present very high. Knowing better gastrointestinal mechanisms of diabetes control and especially incretins role is absolutely necessary before identifying surgery as a true metabolic treatment.

Diabetes mellitus and vascular lesions.

Cardiovascular complications represent by far the most severe manifestations of diabetes mellitus. Treatment aimed at stopping progression of vascular lesions may fall short if initiated when the disease becomes clinically evident. Therefore, identification of the earliest vascular disfunctions may offer the best opportunity to interfere with pathogenic mechanisms and avoid progression of diabetic vasculopathy. In this report, we present a few mechanisms that alter hemodynamic and metabolic homeostasis in the course of diabetes mellitus. Endothelial function with special emphasis on nitric oxide and oxidative stress, advanced glycation end products, and the renin angiotensin system are briefly discussed. New pharmacological agents that may favorably influence these parameters are presently undergoing clinical trials. However, tight control of plasma glucose and cardiovascular risk factors represent the cornerstone of the treatment in diabetes to slow progression of vascular disease.

Differences in low-grade chronic inflammation and insulin resistance in women with previous gestational diabetes mellitus and women with polycystic ovary syndrome.

BACKGROUND: Polycystic ovary syndrome (PCOS) and gestational diabetes mellitus (GDM) are both characterized by an increase in insulin resistance. Our goal in the present study was to measure insulin resistance (as estimated by homeostasis model assessment, sex hormone-binding globulin (SHBG) and adiponectin concentrations) and parameters of low-grade inflammation in non-diabetic, non-hyperandrogenic ovulatory women with previous GDM (pGDM) and in non-diabetic women with classic PCOS, characterized by hyperandrogenism and oligo/anovulation. PATIENTS AND DESIGN: We evaluated 20 women with PCOS, 18 women with pGDM and 19 controls, all matched according to body mass index (BMI). Fasting blood samples were drawn in all women 3-6 days after spontaneous or dydrogesterone-induced withdrawal bleeding. Body fat distribution was assessed using dual-energy X-ray absorptiometry in all women. RESULTS: After adjusting for age and percent body fat, measures of insulin resistance such as SHBG and adiponectin concentrations were decreased and central obesity was increased in women with PCOS and pGDM compared with controls (all p < 0.05). Parameters of low-grade inflammation such as serum tumor necrosis factor-alpha and highly sensitive C-reactive protein concentrations, white blood cell and neutrophil count were increased only in women with PCOS compared with BMI-matched controls (all p < 0.05). CONCLUSIONS: Certain markers of insulin resistance are increased in both women with PCOS and women with pGDM, while low-grade inflammation is increased only in PCOS. PCOS and GDM might represent specific phenotypes of one disease entity with an increased risk of cardiovascular disease, whereby women with PCOS demonstrate an augmented cardiovascular risk profile.

Schizophrénie, diabète et nouveaux neuroleptiques [Schizophrenia, diabetes and new neuroleptics].

Diabetes mellitus occurs more frequently in schizophrenic patients. The use of a novel antipsychotic drug seems to be concomitant to a further increase in imbalance of blood glucose homeostasis. Such cases have already been reported in the literature indicating that diabetes mellitus might be a real side effect of this novel class of neuroleptics. In conclusion, it seems that schizophrenic patients under such treatment would greatly benefit from a closer clinical and biological follow up regarding glucose metabolism. Further randomised studies would be needed.

Enzyme polymorphism and clinical variability of diseases: a study of diabetes mellitus.

We investigated possible relations among four common neonatal manifestations of diabetic pregnancy (macrosomia, hypoglycemia, hypocalcemia, jaundice) and four enzyme polymorphisms (PGM1, ADA, AK1, ACP1 in a sample of infants born of diabetic mothers. The pattern of associations observed between the two sets of variables is consistent with known differences in enzymatic activity within phenotypes of each system, suggesting that low enzymatic activity may have unfavorable effects on fetal development and on adaptability of the neonate to the extrauterine environment, Some of the polymorphic enzymes studied influence fetal growth in normal pregnancy as well. Analysis of relations between genetic polymorphisms and the clinical pattern of common diseases may provide a better understanding of the genetic basis of the clinical variability of diseases within and between human populations.

Impaired glucose tolerance and diabetes in obesity: a 6-year follow-up study of glucose metabolism.

To investigate the time course of glucose metabolism in obesity 33 patients (21 to 69 years old; body mass index [BMI], 25.7 to 53.3 kg/m2) with different degrees of glucose intolerance or diabetes who had been studied initially and 6 years later were submitted to the same 100-g oral glucose tolerance test (OGTT) with indirect calorimetry. From a group of 13 obese subjects with normal glucose tolerance (NGT), four developed impaired glucose tolerance (IGT); from a group of nine patients with IGT, three developed non-insulin-dependent diabetes mellitus (NIDDM); five of six obese NIDDM subjects with high insulin response developed NIDDM with low insulin response. Five patients had diabetes with hypoinsulinemia initially. As previously seen in a cross-sectional study, the 3-hour glucose storage measured by continuous indirect calorimetry remained unaltered in patients with IGT, whereas it decreased in NIDDM patients. A further decrease in glucose storage was observed with the lowering of the insulin response in the previously hyperinsulinemic diabetics. These results confirm cross-sectional studies that suggest successive phases in the evolution of obesity to diabetes: A, NGT; B, IGT (the hyperglycemia normalizing the glucose storage over 3 hours); C, diabetes with increased insulin response, where hyperglycemia does not correct the resistance to glucose storage anymore; and D, diabetes with low insulin response, with a low glucose storage and an elevated fasting and postload glycemia.

Increased plasma levels of N-terminal brain natriuretic peptide (NT-proBNP) in type 2 diabetic patients with vascular complications.

AIMS: The plasma levels of either brain natriuretic peptide (BNP) or the N-terminal fragment of the prohormone (NT-proBNP) have recently gained extreme importance as markers of myocardial dysfunction. Patients with type 2 diabetes are at high risk of developing cardiovascular complications. This study was aimed to assess whether plasma NT-proBNP levels are at similar levels in type 2 diabetics with or without overt cardiovascular diseases. METHODS: We assayed plasma NT-proBNP in 54 type 2 diabetics, 27 of whom had no overt macro- and/or microvascular complications, while the remaining ones had either or both. The same assay was carried out in 38 healthy control subjects age and sex matched as a group with the diabetics. RESULTS: Plasma NT-proBNP was higher in diabetics (median 121 pg/ml, interquartile range 50-240 pg/ml, ) than in those without complications (37 pg/ml, 21-54 pg/ml, P<0.01). Compared with the controls (55 pg/ml, 40-79 pg/ml), only diabetics with vascular complications had significantly increased plasma NT-proBNP levels (P<0.001). In the diabetics, coronary heart disease and nephropathy (defined according to urinary excretion of albumin) were each independently associated with elevated values of plasma NT-proBNP. CONCLUSIONS: In type 2 diabetes mellitus, patients with macro- and/or micro-vascular complications exhibit an elevation of plasma NT-proBNP levels compared to corresponding patients with no evidence of vascular disease. The excessive secretion of this peptide is independently associated with coronary artery disease and overt nephropathy. The measurement of circulating NT-proBNP concentration may therefore be useful to screen for the presence of macro- and/or microvascular disease.

Phenotypic and molecular characterization of the onset of neuropathy in rodent models of diabetes mellitus

Abstract : The principal focus of this work was to study the molecular changes leading to the development of diabetic peripheral neuropathy (DPN). DPN is the most common complication associated with both type I and II diabetes mellitus (DM). This pathology is the leading cause of non-traumatic amputations. Even though the pathological and morphological changes underlying DPN are relatively well described, the implicated molecular mechanisms remain poorly understood. The following two approaches were developed to study the development of DPN in a rodent model of DM type I. As a first approach, we studied the implication of lipid metabolism in DPN phenotype, concentrating on Sterol Response Element Binding Protein (SREBP)-lc which is the key regulator of storage lipid metabolism. We showed that SREBP-1c was expressed in peripheral nerves and that its expression profile followed the expression of genes involved in storage lipid metabolism. In addition, the expression of SREBP-1c in the endoneurium of peripheral nerves was dependant upon nutritional status and this expression was also perturbed in type I diabetes. In line with this, we showed that insulin elevated the expression of SREBP-1c in primary cultured Schwann cells by activating the SREBP-1c promoter. Taken together, these findings reveal that SREBP-1c expression in Schwann cells responds to metabolic stimuli including insulin and that this response is affected in type I diabetes mellitus. This suggests that disturbed SREBP-1c regulated lipid metabolism may contribute to the pathophysiology of DPN. As a second approach, we performed a comprehensive analysis of the molecular changes associated with DPN in the Akital~1~+ mouse which is a model of spontaneous early-onset type I diabetes mellitus. This mouse expresses a mutated non-functional isoform of insulin, leading to hypoinsulinemia and hyperglycaemia. To determine the onset of DPN, weight, blood glucose and motor nerve conduction velocity (MNCV) were measured in Akital+/+ mice during the first three months of life. A decrease in MNCV was evident akeady one week after the onset of hyperglycemia. To explore the molecular changes associated with the development of DPN in these mice, we performed gene expression profiling using sciatic nerve endoneurium and dorsal root ganglia (DRG) isolated from early diabetic male Akita+/+ mice and sex-matched littermate controls. No major transcriptional changes were detected either in the DRG or in the sciatic nerve endoneurium. This experiment indicates that the phenotypic changes observed during the development of DPN are not correlated with major transcriptional alterations, but mainly with alterations at the protein level. Résumé Lors ce travail, nous nous sommes intéressés aux changements moléculaires aboutissant aux neuropathies périphériques dues au diabète (NPD). Les NPD sont la complication la plus commune du diabète de type I et de type II. Cette pathologie est une cause majeure d'amputations. Même si les changements pathologiques et morphologiques associés aux NPD sont relativement bien décrits, les mécanismes moléculaires provoquant cette pathologie sont mal connus. Deux approches ont principalement été utilisées pour étudier le développement des NPD dans des modèles murins du diabète de type I. Nous avons d'abord étudié l'impact du métabolisme des lipides sur le développement des NPD en nous concentrant sur Sterol Response Element Binding Protein (SREBP)-1 c qui est un régulateur clé des lipides de stockage. Nous avons montré que SREBP-1 c est exprimé dans les nerfs périphériques et que son profil d'expression suit celui de gènes impliqués dans le métabolisme des lipides de stockage. De plus, l'expression de SREBP-1c dans l'endoneurium des nerfs périphériques est dépendante du statut nutritionnel et est dérégulée lors de diabète de type I. Nous avons également pu montrer que l'insuline augmente l'expression de SREBP-1c dans des cultures primaires de cellules de Schwann en activant le promoteur de SREBP-1c. Ses résultats démontrent que l'expression de SREBP-1c dans les cellules de Schwann est contrôlée par des stimuli métaboliques comme l'insuline et que cette réponse est affectée dans le cas d'un diabète de type I. Ces données suggèrent que la dérégulation de l'expression de SREBP-1c lors du diabète pourrait affecter le métabolisme des lipides et ainsi contribuer à la pathophysiologie des NPD. Comme seconde approche, nous avons réalisé une analyse globale des changements moléculaires associés au développement des NPD chez les souris Akita+/+, un modèle de diabète de type I. Cette souris exprime une forme mutée et non fonctionnelle de l'insuline provoquant une hypoinsulinémie et une hyperglycémie. Afin de déterminer le début du développement de la NPD, le poids, le niveau de glucose sanguin et la vitesse de conduction nerveuse (VCN) ont été mesurés durant les 3 premiers mois de vie. Une diminution de la VCN a été détectée une semaine seulement après le développement de l'hyperglycémie. Pour explorer les changements moléculaires associés avec le développement des NPD, nous avons réalisé un profil d'expression de l'endoneurium du nerf sciatique et des ganglions spinaux isolés à partir de souris Akital+/+ et de souris contrôles Akita+/+. Aucune altération transcriptionnelle majeure n'a été détectée dans nos échantillons. Cette expérience suggère que les changements phénotypiques observés durant le développement des NPD ne sont pas corrélés avec des changements importants au niveau transcriptionnel, mais plutôt avec des altérations au niveau protéique. Résumé : Lors ce travail, nous nous sommes intéressés aux changements moléculaires aboutissant aux neuropathies périphériques dues au diabète (NPD). Les NPD sont la complication la plus commune du diabète de type I et de type II. Cette pathologie est une cause majeure d'amputations. Même si les changements pathologiques et morphologiques associés aux NPD sont relativement bien décrits, les mécanismes moléculaires provoquant cette pathologie sont mal connus. Deux approches ont principalement été utilisées pour étudier le développement des NPD dans des modèles murins du diabète de type I. Nous avons d'abord étudié l'impact du métabolisme des lipides sur le développement des NPD en nous concentrant sur Sterol Response Element Binding Protein (SREBP)-1c qui est un régulateur clé des lipides de stockage. Nous avons montré que SREBP-1 c est exprimé dans les nerfs périphériques et que son profil d'expression suit celui de gènes impliqués dans le métabolisme des lipides de stockage. De plus, l'expression de SREBP-1c dans l'endoneurium des nerfs périphériques est dépendante du statut nutritionnel et est dérégulée lors de diabète de type I. Nous avons également pu montrer que l'insuline augmente l'expression de SREBP-1c dans des cultures primaires de cellules de Schwann en activant le promoteur de SREBP-1c. Ses résultats démontrent que l'expression de SREBP-1c dans les cellules de Schwann est contrôlée par des stimuli métaboliques comme l'insuline et que cette réponse est affectée dans le cas d'un diabète de type I. Ces données suggèrent que la dérégulation de l'expression de SREBP-1c lors du diabète pourrait affecter le métabolisme des lipides et ainsi contribuer à la pathophysiologie des NPD. Comme seconde approche, nous avons réalisé une analyse globale des changements moléculaires associés au développement des NPD chez les souris Akita~~Z~+, un modèle de diabète de type I. Cette souris exprime une forme mutée et non fonctionnelle de l'insuline provoquant une hypoinsulinémie et une hyperglycémie. Afin de déterminer le début du développement de la NPD, le poids, le niveau de glucose sanguin et la vitesse de conduction nerveuse (VCN) ont été mesurés durant les 3 premiers mois de vie. Une diminution de la VCN a été détectée une semaine seulement après le développement de l'hyperglycémie. Pour explorer les changements moléculaires associés avec le développement des NPD, nous avons réalisé un profil d'expression de l'endoneurium du nerf sciatique et des ganglions spinaux isolés à partir de souris Akital+/+ et de souris contrôles Akita+/+. Aucune altération transcriptionnelle majeure n'a été détectée dans nos échantillons. Cette expérience suggère que les changements phénotypiques observés durant le développement des NPD ne sont pas corrélés avec des changements importants au niveau transcriptionnel, mais plutôt avec des altérations au niveau protéique.