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ERC

INSIGHT Report Summary

Project ID: 268946
Funded under: FP7-IDEAS-ERC
Country: Switzerland

Final Report Summary - INSIGHT (An Integrated Network of Glucose Sensing Cells in Glucose Homeostasis)

Metabolic diseases such as obesity and diabetes are caused by defects in the control of feeding and energy expenditure, and of blood sugar levels. Among the many signals that control these different physiological functions, glucose itself is of major importance. Indeed fluctuations in its plasma level control the secretion of hormones regulating blood glucose concentrations (insulin and glucagon) and the activity of brain neurons that control the metabolic functions of liver, muscle and fat but also the endocrine cells that produce and secrete insulin and glucagon.
The role of glucose sensing cells of the central nervous system in physiological regulations is increasingly appreciated. However, their identity, how they sense glucose, in which neuronal circuits there are integrated, and the physiological function they control are still poorly understood. This prevents a real appreciation of their role in the development of obesity and diabetes.
The overall goal of INSIGHT was, 1) to get a new molecular description of the functional adaptability of insulin producing cells – the best described glucose-regulated cell type – in physiological and pathological conditions; 2) to identify brain glucose sensing cells and describe how they control glycemic levels in particular by their indirect (through the autonomic nervous system) control of insulin- and glucagon-producing cells and, 3) to identify by a genetic screen in mice novel hypothalamic regulators of glucagon secretion in response to hypoglycemia.
These three goals were successfully achieved. In beta-cells, we identified a signaling mechanisms that integrate food-related cues as well as changes in insulin sensitivity of peripheral tissues to increase insulin-producing beta-cell number as well as their secretion capacity. This mechanism depends on the production by beta-cells of a growth factor, IGF2, which binds to and activates the IGF1 receptor present at the surface of the same cells. The production of IGF2 is controlled by nutrients and the expression of IGF1R is controlled by hormones (GLP-1 and GIP) secreted by the gut in response to nutrient absorption. This mechanism is required for the normal adaptation of beta-cells to aging, pregnancy, and insulin resistance associated with the consumption of high fat, high energy containing food.
Related to the mechanisms of brain glucose sensing, we identified a small group of neurons located in the brainstem that are characterized by the expression of the glucose transporter Glut2 and which are activated by hypoglycemia. When activated, they increase the secretion of glucagon through a regulation of the parasympathetic nerve activity. They therefore control a neuronal circuit that link detection of hypoglycemia by the brain to the restoration of normoglycemia through the control of glucagon secretion.
Separately, we identified another group of Glut2 neurons, which are also activated by hypoglycemia. These are located in the paraventricular thalamic area and send projections to, and control the activity of neurons of the reward system that is involved in the control of motivated feeding. We found that when activated by hypoglycemia these Glut2 neurons increase the sucrose seeking behavior of mice. Their activity is suppressed by restoring normal glucose levels, but not by sweeteners nor by fructose. This indicates that sweeteners and fructose are not able to suppress the desire to seek sugar-containing food. This is a possible explanation for the continuous development of the current obesity epidemics despite the massive addition of sweeteners and fructose in industrial food and drinks.
Finally, a genetic screen performed with different recombinant inbred mouse lines has lead to the identification of a gene produced by a population of hypothalamic neurons, which modulates the capacity of the parasympathetic nerve to be activated by hypoglycemia. This finding paves the way for a new understanding of the complex brain mechanisms that control the restoration of normoglycemia following a fall in blood glucose concentrations.

Reported by

UNIVERSITE DE LAUSANNE
Switzerland
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