Hypoglycaemia in Clinical Diabetes

AGE, OBESITY AND GLUCOSE COUNTERREGULATION 133GlucoseDeliveryUtilisationAdenosineCaffeineFigure 6.11 Caffeine may act by uncoupling brain glucose demand (increased) and substrate delivery(decreased) through its actions on adenosine receptors. Reproduced from Brain Research Reviews, 17,Nehlig et al., 139–169, Copyright (1992), with permission from Elsevierof the area with glucose suppresses these responses during systemic hypoglycaemia (Borget al., 1995; Borg et al., 1997). The mechanisms involved are unknown but may be a consequenceof increased glucokinase activity to enhance glucose metabolism in neurones in theregion (Gabriely and Shamoon, 2005). However, it is likely that brain metabolism in areasand other signalling mechanisms within the CNS are influenced by recurrent antecedenthypoglycaemia (Cryer, 2005).The brain glycogen supercompensation hypothesis suggests that after a single episodeof hypoglycaemia, there is a rebound increase in glycogen formation in brain astrocytes toprovide additional substrates (e.g. lactate) for brain metabolism (Choi et al., 2003). Alterationsof substrate delivery to the brain do appear to influence the magnitude of the hormonalcounterregulatory response to hypoglycaemia in healthy volunteers and in patients with type1 diabetes. Infusions of acetazolamide, a potent cerebral vasodilator, markedly attenuatesthese responses (Thomas et al., 1997) whereas ingestion of modest amounts of caffeine (toreduce substrate delivery) augments the responses (Debrah et al., 1996). The mechanismsof the latter is unknown but may involve antagonism of central adenosine receptors withuncoupling of brain blood flow (i.e., substrate delivery) and brain glucose metabolism (i.e.,brain glucose demand) resulting in relative cerebral neuroglycopenia (Figure 6.11). This isdiscussed in more detail in Chapter 5.AGE, OBESITY AND GLUCOSE COUNTERREGULATIONIn children with type 1 diabetes, the glucagon response to hypoglycaemia is markedly attenuatedcompared to non-diabetic individuals but compensated for by vigorous secretion of othercounterregulatory hormones, particularly epinephrine, with the peak epinephrine responsesbeing almost two-fold higher than in adults (Amiel et al., 1987). The total sympathoadrenalresponses to hypoglycaemia are also influenced by pubertal stage (Ross et al., 2005).