In our project « Nutrition, Diabetes and the Brain », we are interested in the role of the endogenous glucose production (EGP) in the control of normal and pathological glycæmia. Only three organs ensure this crucial physiological function: the liver, the kidneys and the intestine since they are the only organs to express the key enzyme: glucose 6-phosphatase (G6Pase).
Our research strategy is based on the comparison of two “mirror” pathologies associated with dysfunctions in the EGP: a rare disease – glycogen storage disease type 1, caused by G6Pase deficiency- characterized by the absence of the EGP and severe hypoglycæmia; an epidemic disease – diabetes, associated with an excessive EGP- characterized by chronic hyperglycæmia and adverse side effects, namely cardiovascular diseases or cancers.
In order to better understand the specific roles of each of the three organs in the EGP and/or in the specific pathologies associated with G6Pase deficiency, we base our approach on the study of worldwide unique transgenic mouse models: mice with either targeted deletion or overexpression of G6Pase in the three organs separately.
This strategy allowed us to highlight the paradoxically beneficial role of intestinal glucose production in diabetes and obesity. Indeed, intestinal glucose detection by the enteric nervous system initiates a gut-brain nervous circuit resulting in the induction of satiety and in an increase in resting energy expenditure and a better glycæmic control at a peripheral level.
A better understanding of the special features of the organs responsible for the EGP and their effects at the intra-tissular, central and peripheral levels should provide essential answers in the development of future treatments for pathologies associated with glucose control dysfunctions like glycogen storage disease type 1 and diabetes.