CNS mechanisms that regulate glucose homeostasis in health and disease


The primary focus of our Laboratory is to examine the CNS mechanisms involved in the maintenance of glucose homeostasis and how they are impacted on, or contribute to the development of disease states such as diabetes. Glucose homeostasis is abnormal in all forms of diabetes, reflecting abnormalities in both insulin secretion and insulin sensitivity. These leads to marked fluctuations in blood glucose levels as illustrated in the Figures below:

Glucose profile in Individual with Type 1 DiabetesGlucose Profile in Non-Diabetic Individual

A major research area for our laboratory is in those mechanisms underlying the detection of hypoglycaemia in diabetes and why they fail over time. In Type 1 Diabetes, severe hypoglycaemia is the major metabolic side-effect of insulin therapy and has emerged as the “…major limiting factor to optimal glycaemic management in Type 1 Diabetes” (Cryer PE, Banting Lecture to American Diabetes Association, 1994). Severe hypoglycaemia in T1DM results from two primary abnormalities. The first reflects the limitations of current insulin delivery systems that results in raised systemic insulin levels, because of the inability to deliver insulin directly to the portal system (insulin is ~50% metabolized in the liver), as well as the inability to switch-off insulin delivery during hypoglycaemia. The second is because of widespread defects in the normal hormonal counterregulatory response to hypoglycaemia, reducing an individual’s ability to respond to and counteract the glucose lowering action of insulin. The brain plays a major role in the detection of hypoglycaemia. Specialized glucose-sensing neurons can be found in a number of brain regions such as the ventromedial hypothalamus and medial amygdalar nucleus. Key components of this sensing mechanism include glucokinase, AMP-activated protein kinase, the ATP-sensitive potassium channel and the inhibitory neurotransmitter GABA. Our laboratory uses a number of techniques in order to examine the mechanisms and neural circuitry of hypoglycaemia. These include; (i) the study of hypothalamic glucose-sensing cell lines (ii) in vivo metabolic phenotyping and study of transgenic mice (iii) in vivo study of rats using pharmacological or viral vector-driven manipulation of discrete brain regions and neural tracing studies. In addition, we also have an interest in examining how these brain regions contribute to energy metabolism and to the development of type 2 diabetes through the regulation of hepatic glucose production and pancreatic beta-cell insulin secretion.






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