Severe hypoglycemia (SH) is the major limitation of intensive insulin treatment in type 1 diabetes (T1DM), and the near-term prospects for perfected insulin therapy without this risk are dim. Intensively treated T1DM patients suffer from impaired counterregulation of hypoglycemia (HYPO) ie, HYPO-Associated Autonomic Failure (HAAF) and HYPO unawareness (HU) which enhance their susceptibility to SH. The precise mechanisms of HAAF and HU, however, have not been clarified, though multiple redundant control systems are implicated. Experimental HYPO and exercise in normal and T1DM subjects reproduce HAAF and HU, providing a robust experimental paradigm of these disorders. We have shown that fructose, infused in a catalytic dose for modulating glucokinase activity, results in augmentation of the counterregulatory responses to HYPO in nondiabetic and in T1DM individuals. We hypothesize that an equivalent infusion of fructose will prevent HAAF in nondiabetic and in T1DM persons. Furthermore, since both HYPO and exercise are associated with endogenous opioid (EO) release, and blocking EO improves HYPO counterregulation, we hypothesize that repeated HYPO episodes induce alterations in the modulatory effects of EO on hormonal and glucose counterregulation, ultimately leading to HAAF. We also propose that HYPO autoregulation, and hepatic glycogen metabolism play important roles in the development of HAAF and HU.
The specific aims are: 1) to determine the effects of previous modulation of glucokinase activity on the counterregulatory hormonal and glucose recovery responses to subsequent HYPO in nondiabetic and T1DM subjects, 2) to examine the effects of blocking the inhibitory action of endorphins on the central neuroendocrine response system (with naloxone), during recurrent HYPO or exercise, on subsequent HYPO counterregulatory responses in nondiabetic and T1DM subjects, 3) to analyze the effects of recurrent mild HYPO (autoregulation), on subsequent HYPO counterregulation in nondiabetic and in T1DM subjects, and 4) to determine the effects of recurrent HYPO on hepatic glycogen content in nondiabetic and T1DM subjects, and the effects of normalization of liver glycogen content, by means of insulin and glucose administration, on experimental HAAF in T1DM subjects.Type 1 diabetes mellitus is a disease characterized by elevated blood sugar due to lack of insulin. Adequate treatment with insulin injections results in amelioration of blood sugar, but caries a risk of low blood sugar, which may be a fatal complication of this treatment. This proposal will analyze the mechanisms involved in the induction of low blood sugar and will develop methods to improve this risk.
|Carey, Michelle; Kehlenbrink, Sylvia; Hawkins, Meredith (2013) Evidence for central regulation of glucose metabolism. J Biol Chem 288:34981-8|
|Milman, Sofiya; Leu, James; Shamoon, Harry et al. (2012) Opioid receptor blockade prevents exercise-associated autonomic failure in humans. Diabetes 61:1609-15|
|Milman, Sofiya; Leu, James; Shamoon, Harry et al. (2012) Magnitude of exercise-induced ?-endorphin response is associated with subsequent development of altered hypoglycemia counterregulation. J Clin Endocrinol Metab 97:623-31|
|Vele, Septimiu; Milman, Sofiya; Shamoon, Harry et al. (2011) Opioid receptor blockade improves hypoglycemia-associated autonomic failure in type 1 diabetes mellitus. J Clin Endocrinol Metab 96:3424-31|
|Leu, James; Cui, Min-Hui; Shamoon, Harry et al. (2009) Hypoglycemia-associated autonomic failure is prevented by opioid receptor blockade. J Clin Endocrinol Metab 94:3372-80|