Mechanisms of Hypoglycemia-Associated Autonomic Failure and Its Component Syndromes in Diabetes

Abstract

Iatrogenic hypoglycemia is a problem for people with diabetes. It causes recurrent morbidity, and sometimes death, as well as a vicious cycle of recurrent hypoglycemia, precluding maintenance of euglycemia over a lifetime of diabetes. Improved therapeutic approaches that will minimize both hypo-and hyperglycemia will be based on insight into the pathophysiology of glucoregulation, specifically glucose counterregulation, in insulin-deficient (type 1 and advanced type 2) diabetes. In such patients, hypoglycemia is the result of the interplay of relative or absolute therapeutic insulin excess and compromised physiological (the syndrome of defective glucose counterregulation) and behavioral (the syndrome of hypoglycemia unawareness) defenses against falling plasma glucose concentrations. The concept of hypoglycemia-associated autonomic failure (HAAF) in diabetes posits that recent antecedent iatrogenic hypoglycemia causes both defective glucose counterregulation (by reducing epinephrine responses to a given level of subsequent hypoglycemia in the setting of absent decrements in insulin and absent increments in glucagon) and hypoglycemia unawareness (by reducing sympathoadrenal and the resulting neurogenic symptom responses to a given level of subsequent hypoglycemia) and thus a vicious cycle of recurrent hypoglycemia. The clinical impact of HAAF is well established in type 1 diabetes; it also affects those with advanced type 2 diabetes. It is now known to be largely reversible, by as little as 2-3 weeks of scrupulous avoidance of hypoglycemia, in most affected patients. However, the mechanisms of HAAF and its component syndromes are largely unknown. Loss of the glucagon secretory response, a key feature of defective glucose counterregulation, is plausibly explained by insulin deficiency, specifically loss of the decrement in intraislet insulin that normally signals glucagon secretion as glucose levels fall. Reduced neurogenic symptoms, a key feature of hypoglycemia unawareness, are largely the result of reduced sympathetic neural responses to falling glucose levels. The mechanism by which hypoglycemia shifts the glycemic thresholds for sympathoadrenal activation to lower plasma glucose concentrations, the key feature of both components of HAAF, is not known. It does not appear to be the result of the release of a systemic mediator (e.g., cortisol, epinephrine) during antecedent hypoglycemia or of increased blood-to-brain glucose transport (although increased transport of alternative fuels is conceivable). It is likely the result of alterations of brain metabolism. Although there is an array of clues, the specific alteration remains to be identified. While the research focus has been largely on the hypothalamus, hypoglycemia is now known to activate widespread brain regions, including the medial prefrontal cortex. The possibility that HAAF could be the result of posthypoglycemic brain glycogen supercompensation has also been raised. Finally, there appear to be diverse causes of HAAF. In addition to recent antecedent ...

The relationship between ACE genotype and risk of severe hypoglycaemia in a large population-based cohort of children and adolescents with type 1 diabetes

“…Recurrent episodes of hypoglycaemia may result in hypoglycaemia unawareness [5]. Large population-based studies have shown that despite efforts to improve treatment of type 1 diabetes, hypoglycaemia remains a problem [2,5] and there is need for strategies that will minimise episodes of severe hypoglycaemia. On the other hand, a majority of patients never experience a hypoglycaemic coma or convulsion [2].…”

Attenuation of Counterregulatory Responses to Recurrent Hypoglycemia by Active Thalamic Inhibition

“…While the fundamental alteration could be in the afferent or efferent components of the sympathoadrenal system, it is often assumed to reside within the central nervous system. Potential mechanisms, mostly focused on the hypothalamus, have been reviewed (11,12).…”

“…While the fundamental alteration could be in the afferent or efferent components of the sympathoadrenal system, it is often assumed to reside within the central nervous system. Potential mechanisms, mostly focused on the hypothalamus, have been reviewed (11,12).Measurements of the increase from baseline in regional cerebral blood flow with [15 O]water and positron emission tomography (PET) can be used to identify regions of increased brain synaptic activity and to determine which brain regions are involved with different physiological CBF, cerebral blood flow; HAAF, hypoglycemia-associated autonomic failure; PET, positron emission tomography; PVNT, paraventricular nucleus of the thalamus. …”

From Bedside to Bench and Back Again: Research Issues in Animal Models of Human Disease

“…Predictive validity, which is necessary for pharmacologic or interventional testing, can be the most difficult to achieve and has not yet been demonstrated for HAAF. Construct validity examines the theoretical rationale of the model for congruence to the clinical problem; both human studies and rodent HAAF models are being pursued in parallel to test several hypothesized mechanisms of HAAF (as reviewed in Cryer, 2005). Reliability of models is also important to establish but may be difficult to assess between laboratories if the model is relatively new, as with the HAAF models, or if any experimental practices vary widely.…”