Center for Integrative Genomics - UNIL
Glucose homeostasis critically depends on the balanced secretion of insulin and glucagon by pancreatic islet beta- and alpha-cells, respectively. Whereas insulin triggers glucose utilization by peripheral tissues in the absorptive phase, glucagon induces glucose release from the liver to prevent development of hypoglycemia in the fasted state. Type 2 diabetes is associated with insufficient insulin secretion and exaggerated glucagon secretion. Our goal is to uncover novel regulatory mechanisms that maintain glucose homeostasis through long-term control of islet cell mass and function. We are particularly focusing on molecular mechanisms controlling beta-cell adaptation to metabolic stress and response to the trophic actions of gluco-incretin hormones. We also investigate how central glucose sensing cells control islet cell mass and function through regulation of the autonomic nervous system and how they control feeding behavior.
Pancreatic beta-cells in health and type 2 diabetes
- Gluco-incretin hormones
The gluco-incretin hormones GLP-1 and GIP potentiate glucose-stimulated insulin secretion and increase beta-cell proliferation, enhance beta-cell secretion capacity, and protect these cells against apoptosis. We are exploring the molecular basis of these trophic effects as they may represent new targets to improve beta-cell function in diabetes. For instance we identified that GLP-1 controls beta-cell mass and function by activating an IGF-2/IGF-1R autocrine loop that operates in beta-cell by enhancing IGF-1R expression. On the other hand, we showed that nutrients, in particular glutamine, increase the biosynthesis and secretion of IGF-2. Using mice with beta-cell-specific knockout of IGF-2 (ßIGF2KO) we now show that IGF-2 secretion by beta-cells is required to preserve glucose-stimulated insulin secretion in aging, during pregnancy and in insulin resistance conditions.
- A Systems Biology approach to beta-cell functional architecture
As part of a European program (IMIDIA), we are performing a Systems Biology investigation of beta-cell plasticity in response to metabolic stress. This involves the careful phenotyping of different strains of mice, fed regular chow of a calorie-rich diet for different periods of time. Bioinformatic analysis (in collaboration with the Swiss Institute for Bioinformatics) of multiple phenotypic traits combined with islet transcriptomic and lipidomic data led to the identification of novel genes and gene modules associated with beta-cell adaptation (or failure) to the metabolic stress. Functional studies are now ongoing to identify novel regulatory mechanisms that control beta-cell mass and function.
Brain glucose sensing and the control of glucose homeostasis
The brain critically depends on glucose as a source of metabolic energy and several areas, in particular the hypothalamus and brainstem, contain glucose sensitive neurons that control glucose homeostasis through the regulation of autonomic nervous activity. Pancreatic islet are richly innervated by the autonomic nervous system and are thus under the indirect control of glucose sensing cells present in the brain. We are interested in identifying the brain cells involved in glucose sensing and the circuits they form to control islet cell mass and function.
In one line of investigation using mice with knockout of the glucose transporter Glut2 in the nervous system, we determined that nervous Glut2-dependent glucose sensing is required for the control by glucose of both the parasympathetic and sympathetic nervous system. This is required to control the proliferation rate of beta-cell during the weaning period, to achieve normal adult beta-cell mass, and for the control of first phase insulin secretion. Using mice that express a fluorescent protein in Glut2-cells, we demonstrated that Glut2-neurons from the nucleus tractus solitarius (a brainstem structure) are activated by hypoglycemia to increase vagal nerve firing to stimulate glucose secretion. This establishes a neuronal circuit that link detection of hypoglycemia to counterregulatory response.
These studies are now extended to study the role of additional brain glucose sensing systems involved in both homeostatic and hedonic control of feeding and glucose homeostasis. New glucose sensing systems are being identified by genetic screens in mice.
- Glucose metabolism
- glucose sensing
- pancreatic islets
- brain nutrient sensing
- integrative physiology
- interorgan communication
- type 2 diabetes