HYPOGLYCEMIA AND AUTONOMIC NERVOUS SYSTEM FUNCTION
Principal Investigator: R Freeman
Abstract: The Diabetes Control and Complications Trial and the United Kingdom Prospective Diabetes Study have documented unequivocally that improved glycemic control decreases the incidence and progression of microvascular complicatons of diabetes. The implementation of regimens to rigorously control blood sugar in diabetic patients has led to an increased incidence of severe iatrogenic hypoglycemic events that have limited glycemic management of diabetes mellitus. Recent antecedent iatrogenic hypoglycemia impairs the neuroende:rine and autonomic response to subsequent hypoglycemia - a disorder known as hypoglycemia associated autonomic failure - thus increasing the predisposition to severe hypoglycemia. It is not known whether antecedent hypoglycemia has more general effects on autonomic nervous system function. Impaired autonomic function is associated with increased mortality and morbidity in individuals with diabetes mellitus. If hypoglycemia induces generalized autonomic dysfunction it may further increase the mortality and morbidity associated with diabetes mellitus. The goal of this research is to understand the mechanisms of hypoglycemia associated autonomic failure. The proposed studies test the hypothesis that antecedent hypoglycemia not only impairs the counterregulatory response to subsequent hypoglycemia but also impairs cardiovascular autonomic function in non-hypoglycemic individuals. These studies will examine those markers of cardiovascular autonomic function that, when impaired, are associated with increased morbidity and mortality in patients with diabetes. Furthermore, we hypothesize that antecedent hypoglycemia causes a rise in serum cortisol and that cortisol activation of glucocorticoid receptors mediates the development of hypoglycemia associated autonomic failure. The specific aims for the proposal are to assess autonomic control of cardiovascular function following antecedent euglycemia and hypoglycemia. In addition, we will determine whether administration of a glucocorticoid receptor antagonist, mifepristone, prior to antecedent hypoglycemia improves the autonomic and neuroendocrine response to subsequent hypoglycemia in healthy men and women. Thus, the broad long term objectives of the proposal are to fully understand the mechanisms and consequences of hypoglycemia associated autonomic failure with the ultimate goal of finding an efficacious treatment.
Funding Period: 2003-09-30 - 2009-07-31
more information: NIH RePORT
- Antecedent hypoglycemia impairs autonomic cardiovascular function: implications for rigorous glycemic controlGail K Adler
Division of Endocrinology, Diabetes, and Hypertension, Department of Medicine, Brigham and Women s Hospital, Boston, Massachusetts, USA
Diabetes 58:360-6. 2009..We tested the hypothesis that prior exposure to hypoglycemia leads to impaired cardiovascular autonomic function...
- Experimental hypoglycemia is a human model of stress-induced hyperalgesiaChristopher H Gibbons
Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
Pain 153:2204-9. 2012..This human model may provide a framework for hypothesis testing and targeted, mechanism-based pharmacological interventions to delineate the molecular basis of hyperalgesia and pain susceptibility...
- Treatment-induced diabetic neuropathy: a reversible painful autonomic neuropathyChristopher H Gibbons
Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
Ann Neurol 67:534-41. 2010..To describe the natural history, clinical, neurophysiological, and histological features, and outcomes of diabetic patients presenting with acute painful neuropathy associated with glycemic control, also referred to as insulin neuritis...
- Hypoglycaemia increases aldosterone in a dose-dependent fashionG K Adler
Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, Brigham and Women s Hospital, Harvard Medical School, Boston, MA, USA
Diabet Med 27:1250-5. 2010..Intensive glycaemic control increases the incidence of hypoglycaemia. We sought to define the effects of hypoglycaemia on aldosterone, a hormone involved in cardiovascular injury and baroreflex impairment...
- Pregabalin for painful HIV neuropathy: a randomized, double-blind, placebo-controlled trialD M Simpson
Mount Sinai School of Medicine, New York, NY, USA
Neurology 74:413-20. 2010..Pregabalin is effective in several neuropathic pain syndromes. This trial evaluated its efficacy, safety, and tolerability for treatment of painful HIV-associated neuropathy...