Étude dans la cellule bêta pancréatique de voies inhibitrices de la sécrétion d'insuline liées au métabolisme des lipides

Type 2 diabetes (T2D) is a complex metabolic disease caused by genetic as well as environmental factors, such as sedentarity and obesity. Pancreatic β cell dysfunction is now recognized as the key factor in T2D development. Our laboratory is studying the mechanisms of regulation of insulin secretion by the pancreatic β cell in response to nutrients. While the knowledge of the mechanisms responsible for initiation of insulin secretion in response to glucose and fatty acids is quite advanced, the inhibitory processes of insulin secretion in normal or pathological situations are still poorly understood. This doctoral thesis has focused on the identification of some of the mechanisms responsible for negative regulation of insulin secretion in pancreatic β cell. We have addressed this issue under normal situation or pathological conditions related to T2D.  We first tested the hypothesis by which a mitochondrial enzyme, short-chain hydroxyacyl-CoA dehydrogenase (SCHAD), negatively regulates glucose-induced insulin secretion (GIIS) by limiting the concentrations of some fatty acids and their derivatives such as acyl-CoA or acyl-carnitine molecules in the β cell. For this purpose, the downregulation of SCHAD by RNA interference (RNAi) was used in the pancreatic β cell line INS832/13. Then, we tested wether a prolonged administration of high-fat diet to mice (diet-induced obesity mouse model, DIO) would modulate intracellular metabolic and molecular pathways responsible for inhibition of insulin secretion. C57BL/6 mice were therefore fed a high-fat diet for 8 weeks followed by insulin secretion, intracellular lipid metabolism, mitochondrial function and intracellular signaling measurements on isolated pancreatic islets of Langerhans of those mice.  Our results suggest that SCHAD negatively regulates GIIS and amino acid-induced insulin secretion. We propose that fatty acid oxidation by SCHAD would prevent the accumulation of short-chain acyl-CoAs or acyl-carnitines capable of potentiating insulin secretion. In addition, SCHAD regulates glutamate metabolism by the allosteric inhibition of glutamate dehydrogenase (GDH) preventing the hyperinsulinemia caused by excessive GDH activity.  The study of β cell dysfunction in the DIO mouse model stratified LDR and HDR highlighted various fatty acid metabolism pathways involved in the reduction of GIIS. A decrease in the triglycerides/free fatty acid (TG/FFA) cycling associated with an increase in fatty acid oxidation and intracellular accumulation of cholesterol was shown to contribute to the decreased GIIS in DIO-HDR mice. Furthermore, alteration of AMP-activated kinase (AMPK) and protein kinase C epsilon (PKC epsilon) signaling pathways would be responsible for those alterations in metabolic pathways observed in DIO islets and cause decreased insulin secretion. In summary, we have shed light on important pathways negatively regulating insulin secretion in pancreatic β cell. These pathways could either limit the amplitude or duration of insulin secretion after a meal, or help to preserve β-cell function by delaying exhaustion. Some of those signaling pathways could explain the altered insulin secretion observed in T2D obese patients. In light of our research, the development of therapies targeting pathways that negatively regulate insulin secretion may be beneficial for treating diabetic patients.

Keyphrases: Short-chain hydroxyacyl-CoA deshydrogénase, Acyl-CoA, Acyl-carnitine, Diet-induced obesity, Negative regulation, Insulin secretion, Type 2 diabetes, Islets of Langerhans, Lipid metabolism, Fatty acids, Protein kinase C epsilon, Cholesterol, Mitochondrial dysfunction