Brain metabolism during hypoglycaemia

Hypoglycaemia is the major limiting factor in the glycaemic management of type 1 diabetes mellitus. Healthy humans are protected against low plasma glucose concentrations by several mechanisms making the occurrence of significant hypoglycaemia virtually impossible. In long-term type 1 diabetes the secretion of counterregulation hormones becomes progressively impaired leading to a high incidence of hypoglycaemic episodes. The central nervous system depends on a continuous supply of glucose since the energy stored in energy rich phosphates and glycogen can only provide fuel for ~80 seconds of normal energy consumption. There is increasing evidence that the brain is an important mediator of hypoglycaemia counterregulation. In animals, recurrent hypoglycaemia triggers the increased expression of the glucose transporters in the brain. A higher efficacy of glucose extraction could result in higher intracellular glucose concentrations thus increasing the threshold for central nervous responses to hypoglycaemia. However, both increased and decreased uptake of glucose has been reported in diabetic humans during hypoglycaemia. In a previous study we found a reduced phopsphocreatine/ATP ratio during both, euglycaemia and hypoglycaemia in type 1 diabetic humans. The reason for this finding remains unclear, but a similar reduction of the phosphocreatine/ATP ratio was found in the chronically failing myocardium and was attributed to a reduced velocity of the creatine kinase reaction. To further clarify the issue we will examine the metabolism of energy rich phosphates in the human brain by in vivo 31P MR spectroscopy with saturation transfer. This non invasive technique allows real time measurements of the creatine kinase activity in vivo and is potentially more sensitive than measuring concentrations of energy rich phosphates. Using this technique in type 1 diabetic patients and healthy subjects could enable us to find subtle differences in energy metabolism and help to clarify the issue of glucose uptake and energy metabolism in type 1 diabetes. This study is therefore designed to test the hypothesis that the velocity of the creatine kinase reaction is reduced during basal conditions and hypoglycaemia in the brain of type 1 diabetic patients.

Hypoglycaemia is the major limiting factor in the glycaemic management of type 1 diabetes mellitus. Healthy humans are protected against low plasma glucose concentrations by several mechanisms making the occurrence of significant hypoglycaemia virtually impossible. In long-term type 1 diabetes the secretion of counterregulation hormones becomes progressively impaired leading to a high incidence of hypoglycaemic episodes. The central nervous system depends on a continuous supply of glucose since the energy stored in energy rich phosphates and glycogen can only provide fuel for ~80 seconds of normal energy consumption. There is increasing evidence that the brain is an important mediator of hypoglycaemia counterregulation. In animals, recurrent hypoglycaemia triggers the increased expression of the glucose transporters in the brain. A higher efficacy of glucose extraction could result in higher intracellular glucose concentrations thus increasing the threshold for central nervous responses to hypoglycaemia. However, both increased and decreased uptake of glucose has been reported in diabetic humans during hypoglycaemia. In a previous study we found a reduced phopsphocreatine/ATP ratio during both, euglycaemia and hypoglycaemia in type 1 diabetic humans. The reason for this finding remains unclear, but a similar reduction of the phosphocreatine/ATP ratio was found in the chronically failing myocardium and was attributed to a reduced velocity of the creatine kinase reaction. To further clarify the issue we will examine the metabolism of energy rich phosphates in the human brain by in vivo 31P MR spectroscopy with saturation transfer. This non invasive technique allows real time measurements of the creatine kinase activity in vivo and is potentially more sensitive than measuring concentrations of energy rich phosphates. Using this technique in type 1 diabetic patients and healthy subjects could enable us to find subtle differences in energy metabolism and help to clarify the issue of glucose uptake and energy metabolism in type 1 diabetes. This study is therefore designed to test the hypothesis that the velocity of the creatine kinase reaction is reduced during basal conditions and hypoglycaemia in the brain of type 1 diabetic patients.