Type 2
diabetes has become the biggest public health challenge of the 21st century
with recent reports suggesting that we are eating ourselves into a diabetes
epidemic. Type 2 diabetes is characterized by two major metabolic
abnormalities: peripheral insulin résistance (liver, muscles and fat) and a
deficit in insulin secretion (beta cells). Although we do not understand
precisely interactions between these abnormalities, the final evolution towards
hyperglycemia results from the incapacity of beta-cells to produce enough
insulin to compensate peripheral insulin resistance.
Insulin
resistance, which characterizes type 2 diabetes and obesity, is the consequence
of the inhibition of insulin to act on its target tissues. It is clearly
established that an increase in lipid content within peripheral tissues is
responsible for the insulin resistance state by inducing the accumulation of
intracellular signaling molecules that interfere with the insulin signalling
pathway. Although lipotoxicity is often correlated with an increase in
intracellular lipids, it is now well documented that lipid-derived metabolites
are actually involved. In skeletal muscle, ceramide that is produced from
palmitate is a key factor responsible for the onset of insulin resistance
induced by lipid overload. Studies showed a positive correlation between the
increase in muscle ceramide and a loss in insulin sensitivity. The importance
of the deleterious action of ceramide was established in several recent studies
that showed that pharmacological or genetic inhibition of the ceramide
biosynthesis pathway restores insulin sensitivity in high-fat diet-fed animals.
Among the most original results, we highlighted (i) the role of the protein kinase Akt in transducing the insulin signal to glucose transporters in muscle cells, (ii) the harmful mechanisms of action of ceramides on the insulin signaling pathway in muscle and adipose cells (iii) a potential new target for the treatment of insulin resistance, the ceramide transporter CERT. These studies have been published in leading international journals in the field of metabolic regulation (Diabetes, Diabetologia, Journal of Biological Chemistry, Biochemical Journal).
In addition, wishing to extend our cellular studies in humans, we established collaborations with clinicians of the laboratory of the Pitié Salpêtrière hospital, but also with the Institute of Myology (Hôpital La Pitié Salpêtrière). These collaborations allowed to confirm in humans the data obtained in animals.
Among the most original results, we highlighted (i) the role of the protein kinase Akt in transducing the insulin signal to glucose transporters in muscle cells, (ii) the harmful mechanisms of action of ceramides on the insulin signaling pathway in muscle and adipose cells (iii) a potential new target for the treatment of insulin resistance, the ceramide transporter CERT. These studies have been published in leading international journals in the field of metabolic regulation (Diabetes, Diabetologia, Journal of Biological Chemistry, Biochemical Journal).
In addition, wishing to extend our cellular studies in humans, we established collaborations with clinicians of the laboratory of the Pitié Salpêtrière hospital, but also with the Institute of Myology (Hôpital La Pitié Salpêtrière). These collaborations allowed to confirm in humans the data obtained in animals.
At present, the
main interest of my group is to understand how sphingolipids interfere with
insulin signaling in skeletal muscle cells in
vivo and in vitro in animal
models and in humans.
Using both lipidomic and
cellular techniques, as well as experimental models (transgenic mice), the
objective of my current research projects will to counteract the deleterious
effects of ceramide by highlighting new targets in the sphingolipid
biosynthesis pathway.
