Mechanisms of the Blunting of the Sympatho-Adrenal Response: A Theory

Abstract

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.

Posttranscriptional regulation of adrenal TH gene expression contributes to the maladaptive responses triggered by insulin-induced recurrent hypoglycemia

“…Glucagon arises from pancreatic α ‐cells which are regulated in a paracrine fashion by insulin and somatostatin secreted from neighboring β ‐cell and delta‐cells, respectively, as well as by the firing of both sympathetic and parasympathetic nerve impulses (Ahren ; Ahren et al. ; Parekh ). Whether overlapping trans‐synaptic and humoral biosynthetic mechanisms are shared by both glucagon and epinephrine have yet to be specified.…”

Composite efficacy parameters and predictors of hypoglycaemia in basal‐plus insulin therapy—a combined analysis of 713 type 2 diabetic patients

“…The reasons are not completely understood however. Cryer and Paregh suggested that the magnitude of the neuroendocrine and metabolic responses to hypoglycaemia seems to be lower in women . It has been shown that, at least in type 1 diabetes, antecedent hypoglycaemia has less blunting effects on responses to subsequent hypoglycaemia in women compared with men .…”

Respiration and autonomic regulation and orexin

“…This postnatal development of orexin, and with it, of a presumed enhanced ability to manifest physiological responses to stress, e.g., increased CO 2 , fear, is of particular interest since it occurs at an age that is approximately that at which the peak incidence of the sudden infant death syndrome occurs (Kinney et al , 2009; Kinney and Thach, 2009). Recently, based on analysis of young type 1 diabetes patients who die suddenly while asleep, an orexin malfunction has been proposed, and hypothetically extended, to the sudden infant death syndrome (Parekh, 2009a, b). The postnatal maturation of orexin would certainly lend support to this conjecture.…”