Development of therapeutic measures to reduce the risk of potentially fatal episodes of hypoglycaemia and thus to achieve the full benefits of intensive insulin therapy in diabetic patients requires a complete understanding of the multifactorial mechanisms for repeated hypoglycaemia-induced blunting of the sympatho-adrenal response (BSAR). After critical analysis of the hypotheses, this review paper suggests a heuristic theory. This theory suggests two mechanisms for the BSAR, each involving a critical role for the central brain noradrenergic system. Furthermore, this theory also suggests that the lateral hypothalamus (LH) plays an important role in this phenomenon. Within the framework of this theory, explanations for 1) sexual dimorphism in the adrenomedullary response (AR), 2) dissociation in the blunting of the AR and the sympathetic response (SR) and 3) antecedent exercise-induced blunting of the AR are provided. In addition, habituation of orexin-A neurons is suggested to cause defective awakening. Moreover, potential therapeutics measures have been also suggested that will reduce or prevent severe episodes of hypoglycaemia.
Keywords: Hypoglycaemia unawareness, Insulin therapy, Defective arousal, Glucose-sensing, Brain glycogen, Noradrenaline
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