Basic Research Team 4 « Aging and Diabetes »
Pr Emmanuel VAN OBBERGHEN, PU-PH, Team Leader
Diabetes and cardiovascular diseases afflict an increasing percentage of the ageing population. A tight link exists between these pathologies as diabetes predisposes to cardiac failure and conversely cardiovascular complications are the chief cause of increased mortality in diabetes. Both environmental/lifestyle factors and genetic factors participate in the defects of type 2 diabetes (T2D), which are insufficient insulin secretion and insulin resistance. An emerging paradigm is that the risk of chronic diseases in adult life is accounted for, at least in part, environmental influences, particularly those occurring in utero. Supporting this is the increased T2D risk in offspring of overfed mothers or exposed to deleterious uterine conditions. Our hypothesis is that under deleterious in utero conditions, the altered control exerted by miRNAs on gene regulation increases the risk of insulin resistance and T2D in adult life. We study offsprings of rat dams exposed during pregnancy to an inappropriate diet or to a deficient uterine environment, leading to increased insulin resistance and T2D risk, and identify miRNAs with modified expression in the liver and pancreas of the offspring. We also study the impact of the deleterious maternal environment on cardiac development.
The age-related increase in T2D involves beta cell failure due to insulin resistance. Therefore, we investigate whether age-related alterations in the dialogue between beta cells and endothelial cells participate in pancreatic insufficiency. Finally, as both ageing and diabetes have deleterious effects on kidney function we investigate the potential role of insulin resistance related factors on the kidney.
We believe that our multipronged approach using powerful cutting edge technologies will allow us to develop our proposal successfully, and significantly advance the understanding of the mechanisms leading to increased diabetes incidence during ageing. Our project will have important medical implications by fostering the development of prevention strategies for T2D and its cardiovascular complications, and may in the future harness the epidemic growth of the diseases. Hence the impact of our endeavour is likely to lead to health promotion.
Dumortier O, Van Obberghen E: MicroRNAs in pancreas development. Diabetes Obes Metab 14 Suppl 3:22-28, 2012
Fiory F, Lombardi A, Miele C, Giudicelli J, Beguinot F, Van Obberghen E: Methylglyoxal impairs insulin signalling and insulin action on glucose-induced insulin secretion in the pancreatic beta cell line INS-1E. Diabetologia 54:2941-2952, 2011
Arous C, Naimi M, Van Obberghen E: Oleate-mediated activation of phospholipase D and mammalian target of rapamycin (mTOR) regulates proliferation and rapamycin sensitivity of hepatocarcinoma cells. Diabetologia 54:954-964, 2011
Naimi M, Arous C, Van Obberghen E: Energetic cell sensors: a key to metabolic homeostasis. Trends Endocrinol Metab 21:75-82, 2010
Lebrun P, Cognard E, Gontard P, Bellon-Paul R, Filloux C, Berthault MF, Magnan C, Ruberte J, Luppo M, Pujol A, Pachera N, Herchuelz A, Bosch F, Van Obberghen E: The suppressor of cytokine signalling 2 (SOCS2) is a key repressor of insulin secretion. Diabetologia 53:1935-1946, 2010
Lebrun P, Cognard E, Bellon-Paul R, Gontard P, Filloux C, Jehl-Pietri C, Grimaldi P, Samson M, Penicaud L, Ruberte J, Ferre T, Pujol A, Bosch F, Van Obberghen E: Constitutive expression of suppressor of cytokine signalling-3 in skeletal muscle leads to reduced mobility and overweight in mice. Diabetologia 52:2201-2212, 2009
Hasseine LK, Hinault C, Lebrun P, Gautier N, Paul-Bellon R, Van Obberghen E: miR-139 impacts FoxO1 action by decreasing FoxO1 protein in mouse hepatocytes. Biochem Biophys Res Commun 390:1278-1282, 2009
Baroukh NN, Van Obberghen E: Function of microRNA-375 and microRNA-124a in pancreas and brain. Febs J 276:6509-6521, 2009
Segalen C, Longnus SL, Baetz D, Counillon L, Van Obberghen E: 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside reduces glucose uptake via the inhibition of Na+/H+ exchanger 1 in isolated rat ventricular cardiomyocytes. Endocrinology 149:1490-1498, 2008
El Ouaamari A, Baroukh N, Martens GA, Lebrun P, Pipeleers D, van Obberghen E: miR-375 targets 3'-phosphoinositide-dependent protein kinase-1 and regulates glucose-induced biological responses in pancreatic beta-cells. Diabetes 57:2708-2717, 2008
Demozay D, Mas JC, Rocchi S, Van Obberghen E: FALDH reverses the deleterious action of oxidative stress induced by lipid peroxidation product 4-hydroxynonenal on insulin signaling in 3T3-L1 adipocytes. Diabetes 57:1216-1226, 2008
Naimi M, Gautier N, Chaussade C, Valverde AM, Accili D, Van Obberghen E: Nuclear forkhead box O1 controls and integrates key signaling pathways in hepatocytes. Endocrinology 148:2424-2434, 2007
Baroukh N, Ravier MA, Loder MK, Hill EV, Bounacer A, Scharfmann R, Rutter GA, Van Obberghen E: MicroRNA-124a regulates Foxa2 expression and intracellular signaling in pancreatic beta-cell lines. J Biol Chem 282:19575-19588, 2007
Riboulet-Chavey A, Pierron A, Durand I, Murdaca J, Giudicelli J, Van Obberghen E: Methylglyoxal impairs the insulin signaling pathways independently of the formation of intracellular reactive oxygen species. Diabetes 55:1289-1299, 2006
Hinault C, Mothe-Satney I, Gautier N, Van Obberghen E: Amino acids require glucose to enhance, through phosphoinositide-dependent protein kinase 1, the insulin-activated protein kinase B cascade in insulin-resistant rat adipocytes. Diabetologia 49:1017-1026, 2006