Hypoglycaemia in Clinical Diabetes

134 COUNTERREGULATORY DEFICIENCIES IN DIABETESFurthermore, it appears that the glycaemic thresholds for the secretion of epinephrine andgrowth hormone are set at a higher blood glucose level in non-diabetic children comparedto adults (Jones et al., 1991). In children with type 1 diabetes, the secretion of epinephrinein response to hypoglycaemia commences at an even higher level. In children who havemarkedly elevated HbA 1c values, there is a further shift of the blood glucose threshold to ahigher level for the release of counterregulatory hormones.Advanced age, in otherwise healthy people, does not appear to diminish or delay counterregulatoryresponses to hypoglycaemia (Brierley et al., 1995), although the magnitudeof responses of epinephrine and glucagon is lower at milder hypoglycaemic levels (around3.4 mmol/l ) compared to younger non-diabetic subjects, but is much more comparablewith a more profound hypoglycaemic stimulus (2.8 mmol/l) (Ortiz-Alonso et al., 1994) (SeeChapter 11). The magnitude of counterregulatory responses to low blood glucose levelsfollowing preceding hypoglycaemia also appears to depend on the gender of experimentalsubjects, with men having blunted responses compared to women (Davis et al., 2000b).Both the autonomic nervous system and the hypothalamic–pituitary–adrenal axis areactivated in excess in the morbidly obese. Before and after bariatric surgery (averageweight loss 40 kg over 12 months), severely obese non-diabetic subjects, underwenta hyperinsulinaemic hypoglycaemic clamp (blood glucose 3.4 mmol/l). Before weightreduction, patients demonstrated brisk peak responses in glucagon, epinephrine, pancreaticpolypeptide, and norepinephrine. After surgery and during hypoglycaemia, all theseresponses were attenuated and most markedly so for glucagon, which was totally abolishedin association with a marked improvement in insulin sensitivity. In contrast,the growth hormone response was increased after weight reduction (Guldstrand et al.,2003).HUMAN INSULIN AND COUNTERREGULATIONAt present there is no consistent evidence that the species of insulin is an important determinantof the counterregulatory response to hypoglycaemia. Over 25 clinical laboratory studieshave examined the effect of insulin species on the counterregulatory response to hypoglycaemiainduced by an intravenous bolus, intravenous infusion, or subcutaneous injection ofinsulin (Fisher and Frier, 1993; Jorgensson et al., 1994). Most of the studies showed nosignificant differences between the hormonal responses. Two studies showed a reduction inthe epinephrine response to hypoglycaemia, and both of these studies also reported diminishedautonomic symptoms to hypoglycaemia after human insulin (Schluter et al., 1982;Heine et al., 1989).A meta-analysis comparison of the effects of human and animal insulin as well as ofthe adverse reaction profiles did not show clinically relevant differences between speciesespecially in terms of risk and responses to hypoglycaemia (Richter and Neises, 2005).TREATMENT OF COUNTERREGULATORY FAILUREAt present no treatment is available that will reverse the glucagon deficit that developswithin a few years of the onset of type 1 diabetes (Figure 6.12). However, there are strategies