Targeting the AMPK pathway for the treatment of Type 2 diabetes.

International audienceType 2 diabetes is one of the fastest growing public health problems worldwide, resulting from both genetic factors and inadequate adaptation to environmental changes. It is characterized by abnormal glucose and lipid metabolism due in part to resistance to the actions of insulin in skeletal muscle, liver and fat. AMP-activated protein kinase (AMPK), a phylogenetically conserved serine/threonine protein kinase, acts as an integrator of regulatory signals monitoring systemic and cellular energy status. The growing realization that AMPK regulates the coordination of anabolic and catabolic metabolic processes represents an attractive concept for type 2 diabetes therapy. Recent findings showing that pharmacological activation of AMPK improves blood glucose homeostasis, lipid profile and blood pressure in insulin-resistant rodents suggest that this kinase could be a novel therapeutic target in the treatment of type 2 diabetes. Consistent with these results, physical exercise and major classes of antidiabetic drugs have recently been reported to activate AMPK. In the present review, we update these topics and discuss the concept of targeting the AMPK pathway for the treatment of type 2 diabetes

Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state.

pages 1-15International audienceMetformin is widely used to treat hyperglycemia in individuals with type 2 diabetes. Recently the LKB1/AMP-activated protein kinase (LKB1/AMPK) pathway was proposed to mediate the action of metformin on hepatic gluconeogenesis. However, the molecular mechanism by which this pathway operates had remained elusive. Surprisingly, here we have found that in mice lacking AMPK in the liver, blood glucose levels were comparable to those in wild-type mice, and the hypoglycemic effect of metformin was maintained. Hepatocytes lacking AMPK displayed normal glucose production and gluconeogenic gene expression compared with wild-type hepatocytes. In contrast, gluconeogenesis was upregulated in LKB1-deficient hepatocytes. Metformin decreased expression of the gene encoding the catalytic subunit of glucose-6-phosphatase (G6Pase), while cytosolic phosphoenolpyruvate carboxykinase (Pepck) gene expression was unaffected in wild-type, AMPK-deficient, and LKB1-deficient hepatocytes. Surprisingly, metformin-induced inhibition of glucose production was amplified in both AMPK- and LKB1-deficient compared with wild-type hepatocytes. This inhibition correlated in a dose-dependent manner with a reduction in intracellular ATP content, which is crucial for glucose production. Moreover, metformin-induced inhibition of glucose production was preserved under forced expression of gluconeogenic genes through PPARgamma coactivator 1alpha (PGC-1alpha) overexpression, indicating that metformin suppresses gluconeogenesis via a transcription-independent process. In conclusion, we demonstrate that metformin inhibits hepatic gluconeogenesis in an LKB1- and AMPK-independent manner via a decrease in hepatic energy state

La vaisselle en verre en usage à Toulouse à la fin du Moyen Age (XIVe siècle-XVe siècle)

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Macrophytic Communities Inhabiting the Huveaune (South-East France), a River Subject to Natural and Anthropic Disturbances

Few studies have dealt so far with the macrophytic communities inhabiting the small Mediterranean rivers in South-East France. In order to fill this gap, it was proposed to assess the effects of natural and anthropic disturbances on the biodiversity in the lowland River Huveaune (South-East France). The Mediterranean climate in this region results in strong seasonal variations in the hydrological regime: there is a long dry period and sudden episodes of flooding occur, which greatly affect the plant community dynamics. The River Huveaune is severely polluted by organic matter. Two stations were set up, one in an upstream reference sector and the other in a downstream polluted sector. The standard sampling area of 100 m2 was divided into plots 4 m2 in size, some of which included part of the river and part of a bank. In addition, plant inventories were drawn up over distances of 50 and 100 m. Seventeen sampling campaigns were carried out from April 2002 to October 2003, resulting in the first systematic list of macrophyte species occurring in small Mediterranean rivers in South-Eastern France. The great variability of the hydrological factors involved leads to considerable spatial and temporal variations in the biodiversity. The upstream station was found to be less severely disturbed and to show a wider range of macrophytes than the downstream station: bryophytes predominate upstream and phanerogams and macroalgae, downstream. The Macrophyte Biological Index for River (IBMR) was tested and found to be a valid means of water quality assessment in small Mediterranean rivers

Abnormal metabolism flexibility in response to high palmitate concentrations in myotubes derived from obese type 2 diabetic patients

International audienceInsulin resistance in type 2 diabetes (T2D) is associated with intramuscular lipid (IMCL) accumulation. To determine whether impaired lipid oxidation is involved in IMCL accumulation, we measured expression of genes involved in mitochondrial oxidative metabolism or biogenesis, mitochondrial content and palmitate beta-oxidation before and after palmitate overload (600 μM for 16h), in myotubes derived from healthy subjects and obese T2D patients. Mitochondrial gene expression, content and network were not different between groups. Basal palmitate beta-oxidation was not affected in T2D myotubes, whereas after 16h of palmitate pre-treatment, T2D myotubes in contrast to control myotubes, showed an inability to increase palmitate beta-oxidation (p<0.05). Interestingly, acetyl-CoA carboxylase (ACC) phosphorylation was increased with a tendency for statistical significance after palmitate pre-treatment in control myotubes (p=0.06) but not in T2D myotubes which can explain their inability to increase palmitate beta-oxidation after palmitate overload. To determine whether the activation of the AMP activated protein kinase (AMPK)-ACC pathway was able to decrease lipid content in T2D myotubes, cells were treated with AICAR and metformin. These AMPK activators had no effect on ACC and AMPK phosphorylation in T2D myotubes as well as on lipid content, whereas AICAR, but not metformin, increased AMPK phosphorylation in control myotubes. Interestingly, metformin treatment and mitochondrial inhibition by antimycin induced increased lipid content in control myotubes. We conclude that T2D myotubes display an impaired capacity to respond to metabolic stimuli

Les verreries à décor bleu rapporté de la seconde moitié du XIII e et du XIV e siècle : étude comparée de lots originaires de sites de consommation et d’ateliers de production du Sud et de l’Est de la France

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Fine mapping of RYMV3: a new resistance gene to Rice yellow mottle virus from Oryza glaberrima

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Rapid evolution of an RNA virus to escape recognition by a rice NLR immune receptor

Viral diseases are a major limitation for crop production and their control is crucial for sustainable food supply. We investigated by a combination of functional genetics and experimental evolution the resistance of rice to the rice yellow mottle virus which is among the most devastating rice pathogens in Africa and the mechanisms underlying the extremely fast adaptation of the virus to its host. We found that the RYMV3 gene that protects rice against the virus codes for a nucleotide-binding and leucine-rich repeat domain protein (NLRs) from the Mla-like clade of NLRs. RYMV3 detects the virus by forming a recognition complex with the viral coat protein (CP). The virus escapes efficiently from detection by mutations in its CP some of which interfere with the formation of the recognition complex.This study establishes that NLRs confer also in monocotyledonous plants immunity to viruses and reveals an unexpected functional diversity for NLRs of the Mla clade that were only known as fungal disease resistance proteins. In additions, it provides precise insight into the mechanisms by which viruses adapt to plant immunity and gives important knowledge for the development of sustainable resistance against viral diseases of cereals