Sam Haywood

INTRAHYPOTHALAMIC INSULIN INFUSION DOES NOT AUGMENT THE COUNTERREGULATORY RESPONSE TO GLUCOSE DEPRIVATION? Sam Haywood¹, Kent Ishihara², Simon Fisher², Biology Department, Washington University, St. Louis, MO¹, Division of Endocrinology, Metabolism, and Lipid Research, Washington University, St. Louis, MO².

The goal of insulin therapy in diabetes is to normalize glucose levels in the blood. The rate-limiting factor in achieving these goals is low blood sugar (hypoglycemia). The brain senses hypoglycemia and triggers a stress (counterregulatory) response that activates a number of neuro-hormonal signals in order to restore blood glucose levels. However, people with diabetes often develop an impaired counterregulatory response to hypoglycemia. Understanding how the brain senses and responds to hypoglycemia is essential to the development of therapies to restore a normal counterregulatory response. Previous studies have demonstrated that impaired brain insulin action reduces the counterregulatory response to hypoglycemia, whereas elevated insulin levels augment the counterregulatory response. The current study was undertaken to test the hypothesis that an infusion of insulin directly into the hypothalamic area of the brain (a postulated glucose sensing center) would augment the counterregulatory response to hypoglycemia.

Male Sprague-Dawley rats were surgically implanted with intrahypothalamic and intravascular cannulae. The rats were subjected to a simulated hypoglycemic episode with 2-deoxyglucose (2-DG), a non-metabolized glucose analog that induces a characteristic glucoprivic hypoglycemic response by competing with glucose for metabolism. Insulin or artificial cerebrospinal fluid (as a control) was continuously infused into the hypothalamus for three hours before the animals were given an intravenous bolus of 2-DG. Blood samples were taken at baseline and at 30 minute intervals during the experiment for measurement of glucose, corticosterone, epinephrine, norepinephrine, and glucagon.

Both the experimental and control groups experienced a marked increase in blood glucose levels throughout the experiment; however, there was no significant difference between the two treatment groups. Similarly, there was a dramatic rise in the levels of epinephrine and norepinephrine in response to 2-DG, but no significant differences between the two groups. Although glucagon levels were not statistically different overall, there was a trend toward higher levels of glucagon in the insulin group at 30 min.

Our data shows that intrahypothalamic insulin infusion does not augment the counterregulatory response to 2-DG in non-diabetic rats. Combining our data with results from our previous studies suggests the possibility of a saturable effect of insulin on brain insulin receptors, limiting the difference between control and treatment rats. However, based on previous studies suggesting that insulin does, in fact, augment the counterregulatory response to hypoglycemia, further research is needed to see if insulin can act in the brain to restore the counterregulatory response in rats with an impaired counterregulatory response.