Etiopathogenesis and pathophysiology of type 2 diabetes

peer reviewedEtiopathogenesis of type 2 diabetes is complex and still partially unknown. Its etiology is determined by the interaction of genetic and environmental factors. The genetic contribution is important, but has a polygenic origin. Obesity, especially when fat mass is preferably located in the abdomen, is the main predisposing factor for type 2 diabetes, and almost 80% of diabetic patients are overweight or obese. The diabetogenic effect of obesity is due to the capacity of excessive fat mass to induce or aggravate insulin resistance. Increasing lack of physical activity is also a contributing factor as it increases insulin resistance. As far as pathophysiology is concerned, the development of type 2 diabetes results from the coexistence of abnormalities of insulin secretion and insulin action. Insulin secretory dysfunction, whose underlying mechanism remains poorly understood, is characterized by a relative defect in circulating insulin levels of variable severity. Resistance to insulin action is located in the liver (increased hepatic glucose production), in the skeletal muscle (decreased muscular glucose uptake) and in the adipose tissue (exaggerated lipolysis with elevated plasma free fatty acids). Changes in life-style habits (weight reduction, regular physical activity) are able to prevent or delay the development of type 2 diabetes.L’étiopathogénie du diabète de type 2 est complexe et reste imparfaitement connue. Son étiologie est déterminée par l’interaction de facteurs génétiques et environnementaux. La contribution génétique est importante, de nature polygénique. L’obésité, surtout celle à répartition abdominale, est le plus puissant facteur prédisposant au diabète de type 2 et près de 80 % des sujets diabétiques présentent un excès pondéral. L’effet diabétogène de l’obésité est lié à sa capacité d’induire ou d’aggraver l’insulinorésistance de ces sujets. La sédentarité croissante des populations industrialisées représente également un facteur favorisant le diabète; car elle majore la résistance à l’insuline. Sur le plan physiopathologique, le développement du diabète de type 2 résulte de la coexistence d’anomalies de la sécrétion et de l’action de l’insuline. Le dysfonctionnement sécrétoire, dont la cause demeure mal comprise, se traduit toujours par une carence relative plus ou moins sévère en insuline. La résistance à l’action de l’insuline s’exerce au niveau du foie (augmentation de la production hépatique de glucose), du muscle squelettique (réduction de l’utilisation musculaire du glucose) et du tissu adipeux (lipolyse exagérée avec élévation des acides gras libres plasmatiques). Les mesures hygiéno-diététiques (réduction pondérale, activité physique régulière) permettent de prévenir ou de retarder l’apparition du diabète de type 2

Régulation du transport des corps cetoniques à l'exercice chez l'homme normal et diabétique

Doctorat en sciences médicalesinfo:eu-repo/semantics/nonPublishe

Régulation du transport des corps cetoniques à l'exercice chez l'homme normal et diabétique

Doctorat en sciences médicalesinfo:eu-repo/semantics/nonPublishe

Les nouveaux anti-diabétiques oraux

The therapeutic options for type 2 diabetes have grown considerably in recent years with the successive emergence on the market of glitazones, incretin mimetics, gliptins and very soon gliflozins. Meanwhile, physicians have been advised to take into account individual patient characteristics and preferences when setting glycemic targets and choosing the most appropriate molecule. Faced with an abundance of options, clinicians, even those specialized in diabetology, are left confused and are divided in their choices. To guide them in their practice, the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) jointly published a position statement in 2012. The guidelines posit that the main criteria to be considered are glucose-lowering efficacy, risk of hypoglycemia, effect on body weight, side effects and costs. Not surprisingly, they propose metformin as first line treatment but do not formulate a precise indication regarding the molecule to be introduced in case of metformin contra-indication, intolerance or monotherapy failure. In addition, there is no mention of gliflozins, which were still under evaluation at the time but are now approved and already marketed in some countries. Here we review the mechanisms of action, efficacy and side effects of the two most recent drug classes, namely incretin-based therapies and gliflozins, and try to position them in the therapeutic algorithm of type 2 diabetes.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Diabétologie et maladies du métabolisme et de la nutrition

MED4, PATO072info:eu-repo/semantics/published

Diabétologie et maladies du métabolisme et de la nutrition

MEDE4, MEDI-G-407info:eu-repo/semantics/published

Diabétologie et maladies du métabolisme et de la nutrition

8e édition 2000-2001/1MED4, PATO072info:eu-repo/semantics/published

Rôle du régime alimentaire dans le traitement du diabète.

Although diet has always been recognized as the cornerstone in the management of diabetes, dietary recommendations are evolving continuously. There is now some consensus that the goals of medical nutrition therapy should be to attain and/or maintain a reasonable body weight, to ensure the best possible glycemic control and to reduce cardiovascular risk factors but the means to achieve these goals are still under discussion. Apart from caloric restriction which is, without any doubt, highly efficient but hardly applied in obese diabetic patients, the clinical benefits of the traditional measures to alleviate postprandial hyperglycemia (increasing meal frequency, consumption of carbohydrates with a low glycemic index and/or rich in fibers) are not unanimously acknowledged. The hotly debated issue regarding the ideal proportions of carbohydrates and fat advisable for diabetic individuals has lapsed progressively into disuse, all the arguments having run out. At the present time, there remain many unanswered important questions related to nutrition and diabetes because of the lack of long-term randomized studies evaluating the impact of a diet modification on morbidity and mortality. Considering the difficulties of changing our usual feeding patterns on a long term basis, these uncertainties will not readily be solved.SCOPUS: re.jinfo:eu-repo/semantics/publishe

L'effet incrétine: Une nouvelle cible thérapeutique dans le diabète de type 2

The two incretin hormones GLP-1 (Glucagon-Like Peptide-1) and GIP (Glucose-dependent Insulinotropic Peptide) are released by the gut in response to nutrient ingestion. Both of them potentiate glucose-induced insulin response, enhance insulin biosynthesis and, at least in rodents, preserve β-cell mass through reduction of apoptosis and stimulation of β-cell proliferation. In addition to its insulinotropic action, GLP-1 (but not GIP) suppresses glucagon secretion, delays gastric emptying and promotes satiety. Since in type 2 diabetes, the secretion of GLP-1 is dramatically reduced whereas its effects are retained, a number of pharmacological strategies aiming at restoring the incretin activity of this peptide have been explored. Because GLP-1 is rapidly degraded by the ubiquitous enzyme, dipeptidyl peptidase-IV (DPP-IV) and has a very short-lived action, DPP-IV resistant mimetics have been designed. Several randomized placebo-controlled studies with DPP-IV resistant GLP-1 analogues confirmed their efficacy to improve glycemic control in type 2 diabetic patients. The first one, exenatide, has been approved by the Food and Drug Administration (FDA) in 2005 for the treatment of type 2 diabetes. Longer-acting mimetics requiring only one injection per day or even per week are currently assessed in phase 3 trials. Another successful approach has been the development of orally active DPP-IV inhibitors which reversibly and selectively block the enzymatic activity. Many small-molecule DPP-IV inhibitors, called gliptins, have been shown to be effective as antihyperglycemic agents and, up to now, devoid of major adverse events. The first drug of this new therapeutic class having received FDA approval, sitagliptin, is now available for the treatment of type 2 diabetes in U.S. However, the efficacy/safety profile of these compounds and their positioning in the therapeutic algorithm of type 2 diabetes remains to be defined.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Role of hepatic glucose production and glucose uptake in the pathogenesis of fasting hyperglycemia in type 2 diabetes: Normalization of glucose kinetics by short-term fasting

The relative impact of hepatic glucose production (HGP) and peripheral glucose uptake (GU) on plasma glucose concentration was assessed in 54 noninsulin-dependent diabetes mellitus (NIDDM) and 50 control subjects submitted to a variable period of fasting (14-108 h) with special focus on the normal and low hyperglycemic range. Within each population we found a highly significant (P < 0.001) positive correlation between plasma glucose concentration and HGP in the whole range of glycemia, but the slope of the regression line was steeper (P < 0.001) in the diabetic than in the control group. The two curves intersected at a glucose level of 4.0 mmol/L. Therefore, for a given HGP rate above the intersection point, diabetic patients had a higher plasma glucose concentration than nondiabetic individuals, owing to an approximately 15% reduction (P < 0.025) in the metabolic clearance rate, despite the fact that the plasma insulin level was 2-fold higher (P < 0.05) in the diabetic patients. When diabetic and nondiabetic subjects were compared at a similar low glucose level of 4.0 mmol/L brought about by short-term fasting, all parameters of glucose kinetics were identical in both groups. We thus conclude that 1) HGP is the major determinant of plasma glucose concentration in control as well as in diabetic subjects whatever the nutritional state; 2) the slight hyperglycemia prevailing in mild NIDDM results from the combination of an impaired insulin- induced inhibition of HGP and stimulation of GU because both parameters are inappropriately normal in the face of elevated plasma glucose and insulin levels: and 3) the normalization of GU and HGP after short-term fasting suggests that pathways of noninsulin-mediated GU operate in a normal way in NIDDM.SCOPUS: ar.jSCOPUS: ar.jinfo:eu-repo/semantics/publishe