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 multi-factorial 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.

Fig. (1)

Brain regions and afferent and efferent neural circuitry involved in the AR. Hypoglycaemia is first detected at the peripheral glucose sensors. Through the vagal afferents this information is relayed to the orexin neurons in the LH via the NTS. In turn, through Orexin-B receptors, orexin neurons excite the hippocampal- LH cholinergic (ChN) neuronal axis. Through muscarinic receptors, cholinergic excitation in the LH in turn activates (some as yet unknown type of) IIN which then activates a cascade in the PVH involving the eicosanoids (thromboxane-A2 and prostaglandin) and the CRF-1. Activation of this cascade excites descending catecholaminergic neurons in the RVLM (C1 group), which projects to the preganglionic neurons that stimulate the adrenal medullae to secrete epinephrine. (---) lines indicate peptide neurotransmitters. (Modified and reproduced with permission from Silveira et al. [90] and Barsh et al. [158]).

Fig. (2)

Model of the blunting of the AR. An axon terminal of an NA neuron from the hindbrain is shown. NA release from this terminal regulates 1) the expression of monocarboxylate transporters, MCT2, and mediates the glycogenolysis, glycogen-resynthesis and glucose entry into the astrocytes. This model suggests that during an episode of hypoglycaemia, low glucose levels increase the release of NO from GI neurons. Higher NO levels, via cholinergic (Ch) neurons, increase NA release from the axon terminals of the noradrenergic neurons (A2 group) in the VMH, which projects from the hindbrain. This NA release in the VMH up-regulates MCT2 expression (shown blue). Consequently, during a later episode of hypoglycaemia when, again, NA is released from these axon terminals, more lactate enters into the GABAergic neurons (which project to the LH). This leads to higher GABA synthesis and release, causing hyperpolarisation of orexin neurons, through GABA_A receptors, and thus blunts the AR. (Modified and reproduced with permission from Magistretti and Allaman [119], Iadecola [115], and Canabal et al. [117]).