Hypoglycaemia in Clinical Diabetes

124 COUNTERREGULATORY DEFICIENCIES IN DIABETESHypothalamusPituitary glandGrowth hormoneAutonomic Nervous SystemACTHPancreasAdrenalglandCortisolGlucagonNorepinephrineEpinephrineFigure 6.4The brain is the key regulatory organ involved in glucose counterregulationthe prevailing quality of glycaemic control. They do not appear, however, to be influencedby the rate of fall of blood glucose within the hyper- or euglycaemic range.The key organ in coordinating the hormonal and other responses to hypoglycaemia isthe brain. Although numerous neural areas have been proposed as the control centres forcounterregulation, it is likely that neurones located within the ventro-medial nuclei of thehypothalamus are essential for integrating the hormonal responses to a fall in peripheralblood glucose (Borg et al., 1994), possibly via ATP-sensitive K+ channels (McCrimmonet al., 2005), although other glucoreceptors outside the brain are involved in initiating thecounterregulatory responses, most notably within the liver (Smith et al., 2002). Althoughthe brain was once thought to be insensitive to insulin, there is clinical evidence to suggestthat insulin can act on the central nervous system (CNS) to influence the physiologicalresponses to hypoglycaemia (Kerr et al., 1991). Recently, in studies using brain/neuronalinsulin receptor knockout mice (i.e., mice with absent insulin receptor proteins in the brain),the induction of hypoglycaemia was associated with an attenuated epinephrine and an almostcompletely absent norepinephrine response, although glucagon release was unaffected whencompared to control animals. Therefore it appears that insulin has a role in protecting theCNS against hypoglycaemia (Fisher et al., 2005).