For more than 15 years, our team has been working on the pathophysiology of dyslipidemia in humans, mostly dyslipidemia associated with diabetes and insulin-resistance. Patients with diabetes and individuals with insulin-resistance (Metabolic Syndrome) show a very high cardiovascular risk that is largely promoted by the atherogenic dyslipidemia associated with diabetes and insulin resistance.
Our main goal is to get further insight into the pathophysiology of dyslipidemia associated with diabetes and with insulin-resistance in order to find new therapeutic targets and, thus, to reduce cardiovascular disease in these populations that represents a heavy burden in the world. For several years, our group has been able to develop transversal skills and a recognized experience in translational research. Interestingly, our research group includes several Medical Doctors, deeply involved in translational research, allowing easy access to patients and accomplishment of human studies. Our main research activities within the field of "pathophysiology of dyslipidemia in humans (PADYS)" are built in 3 axes:
1) Dysfunction of lipid metabolism in diabetes and insulin resistance (including in vivo human lipoprotein kinetic studies)
2) Study of HDL in diabetes and insulin resistance
3) Involvement of the endocannabinoid system in diabetes and insulin resistance
The major results obtained by the unit during the 2016-2021 period, for each axe, are listed below :
• Demonstration of a close relationship between HDL-apoA-II catabolism and VLDL1 catabolism in the metabolic syndrome (J Clin Endocrinol Metab 2016).
• Demonstration that the GLP-1 agonist, liraglutide, has a beneficial effect on postprandial lipid that is due to both a reduction of ApoB48 production and an increase in ApoB48 catabolism and that liraglutide has a direct effect by reducing the expression of genes involved in chylomicron production (Arteriosclerosis, Thrombosis, and Vascular Biology 2018).
• Demonstration that the GLP-1 agonist, liraglutide, increases the catabolism of apolipoprotein B100-containing lipoproteins, in patients with type 2 diabetes, and reduces Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) expression (Diabetes Care 2021).
• Evidence of altered de novo glutathione synthesis in subjects with high level of steatosis, in a collaborative multicenter study (Molecular Systems Biology 2017).
• In a study performed in Dijon, we showed that 6-month treatment with the GLP-1 agonist, liraglutide, induced a significant 33% reduction of liver fat content in patients with type 2 diabetes and that this effect was mainly driven by body weight reduction observed with that drug (J Clin Endocrinol Metab. 2017).
• Evidence that the risk of hepatocellular carcinoma in cirrhotic patients is associated with higher levels of saturated FAs, linoleic and eicosadienoic acids, and lower levels of stearic and arachidonic acids on the erythrocyte membranes (Alimentary Pharmacology & Therapeutics 2020).
• Significant modification of the sphingophospholipidome of HDL from non-diabetic obese patients with metabolic syndrome: depletion in sphingosine-1-phosphate, sphingomyelins and some plasmalogens (Atherosclerosis 2016).
• Evidence that sphingosine-1-phosphate depletion of HDL is responsible for decreased activation of endothelium NO synthase by HDL (Arteriosclerosis, Thrombosis, and Vascular Biology 2017).
• Evidence that glucocorticoids although increasing plasma HDL-cholesterol levels, impair HDL-mediated cholesterol efflux (European Journal of Endocrinology 2020).
• Exposure to n-3 FA at a young age decreases tissue endocannabinoid levels and prevent metabolic disorders induced by a later high-fat diet (HFD) challenge (Diabetes 2016).
• Evidence that peripheral ECS impairs the inhibitory function of insulin on the hormone sensitive lipase in the adipose tissue (American Journal of Physiology. Endocrinology and Metabolism 2017).
• Evidence that activation of CB1 R in podocytes contributes to both glomerular and tubular dysfunction in diabetic nephropathy (Diabetes, Obesity & Metabolism 2018).
• Evidence that inhibition of CB1R (endocannabinoid receptor 1) directly reduces hepatic VLDL production and that inhibition of nitric oxide synthase iNOS decreases the circulating levels of the proprotein convertase subtilisin/kexin type 9 (PCSK9) via a mTORC1-dependent mechanism (Diabetes 2020).
• Evidence that the endocannabinoids produced by white adipose tissue modulate lipolysis in lean but not in obese rodents and humans, in the fasting state (Frontiers in Endocrinology 2021).
• Development of a specific antagonist of the peripheral cannabinoid-1 receptors (CB1R) for which we obtained a patent in 2017 (FR3041641N° 1559067) which has been extended to Canada (2999617) and US in 2018 (US 20180265498 A1).
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Dysfunction of lipid metabolism in diabetes and insulin resistance