Hypoglycaemia in Clinical Diabetes

DEFECTIVE HORMONAL GLUCOSE COUNTERREGULATION 127GlucagonIn non-diabetic individuals, glucagon is secreted by pancreatic -cells within 30 minutes ofthe blood glucose falling below normal. It is released directly as a consequence of local tissueglucopenia and indirectly by sympathetic neural inputs to the pancreas. It is unclear whetherlocal (pancreatic) tissue glucopenia or autonomic activation is the key process involved instimulating the release of glucagon during hypoglycaemia.In people with type 1 diabetes, the glucagon secretory response to hypoglycaemia isinitially diminished and is subsequently lost within a few years of the onset of diabetes(Gerich et al., 1973), although it can be released in response to other stimuli, such as exerciseor an intravenous infusion of arginine (Gerich and Bolli, 1993). This indicates that the failureof the glucagon response is most probably a signalling rather than a structural defect. Loss ofthe glucagon response to hypoglycaemia often coexists with clinical evidence of autonomicneuropathy but the latter is not invariably present (Bolli et al. 1983). Although recent studieshave suggested that an early sympathetic neuropathy limited to the pancreatic islets may bea potential mechanism, patients with pancreatic transplants (i.e., denervated islets) can stillproduce glucagon in response to hypoglycaemia (Diem et al., 1990). The cause of the defectin glucose counterregulation is not known but may include:• reduction in pancreatic -cell mass;• autonomic neuropathy;• local effect of insulin on normal -cell function;• generalised hyperinsulinaemia;• chronic hyperglycaemia;• increased pancreatic production of somatostatin;• accumulation of amylin within the islets;• local effect of insulin-like growth factor-1.An alternative hypothesis to explain the glucagon-counterregulatory defect suggests thatin healthy individuals a decrease in intra-islet insulin in association with a decrease in-cell glucose is the usual signal for release of glucagon as peripheral blood glucose levelsfall (Samols et al., 1972). Support for this comes from the observation that infusion ofthe -cell secretagogue, tolbutamide, prevents the glucagon response to hypoglycaemia innon-diabetic individuals (Banarer and Cryer, 2003). Similarly, supraphysiological levels ofinsulin have been shown to impair glucagon release in response to moderate hypoglycaemia(Kerr et al., 1991). Blunting of the normal glucagon response to hypoglycaemia can alsobe achieved in healthy volunteers by infusion of insulin-like growth factor-1 (IGF-1), theputative mediator of the somatotrophic action of growth hormone, at least in non-diabetichumans (Kerr et al., 1993) (Figure 6.7). Whether IGF-1 is involved in the pathogenesis ofglucagon counterregulatory failure in patients with type 1 diabetes is unclear.Alternatively, it is possible that chronic hyperglycaemia may directly impair pancreatic-cell function through the mechanism of glucose toxicity similar to the effect that this has on-cell function. Nevertheless, improvements in glycaemic control, following introduction of