Studies on glucagon secretion in patients with type 1 diabetes : clinical and experimental studies

Abstract: Hypoglycaernia is the main limiting factor reaching normo-glycaemia in type I diabetic patients. The risk of hypoglycaemia increases usually with improvements in metabolic control. The annual prevalence of severe episodes of hypoglycaemia in intensively treated patients is reported to be in the range 20-80%. An estimation of such events, using a questionnaire, in type I diabetic patients attending the outpatient clinic at Danderyd hospital in 1984 and 1998, revealed a frequency of 20 and 21% respectively. During the same period of time a significant improvement in the HbA1c was registered, from 7,9 to 7,4%, p<0.001, along with an increased frequency of multiple injection therapy, homemonitoring of blood glucose and self-adjustments of insulin doses. A small group of patients are affected by repeated severe hypoglycaemia (RSH). In 1984 we identified 20 such patients, i.e. about 5% of the population, who were studied and followed for twelve years. In these patients severe hypoglycaemia remained a problem, although efforts were made to avoid such episodes. The annual incidence did however decline and multiple injection therapy seem to be beneficial compared to single and two dose regimens. These patients were found to have several risk factors, most notably hypoglycaemia unawareness. During the follow up no patient died due to hypoglycaemia. A standardised insulin infusion test is reproducible in patients with and without the problem of RSH. In the RSH group the standardised insulin infusion test resulted in a continues fall in blood glucose, until the test had to be omitted due to the presentation of neuroglucopenic symptoms. The test may therefore be helpful in identifying subjects with the problem of RSH. One important component for the enhanced risk of hypoglycaemia is the blunted counterregulatory response, most notably that of glucagon. Unfortunately, the reason for this blunted glucagon response, as well as means to restore its release during hypoglycaemia is poorly understood. In an acute experiment during insulin-induced hypoglycaemia exogenous C-peptide in a dose raising its concentration to a physiologic level did not interfere with the counterregulatory machinery and in particular, did not restore the glucagon response. However, it slightly enhanced the hypoglycaemic effect of insulin, an effect which is compatible with the known vasodilating effect of C-peptide. Prospective follow up of the glucagon response to hypoglycaemia in newly diagnosed type I diabetic patients, revealed that about 50% may have a preserved response at 12-15 months, in some instances in spite of an absent C-peptide response to a glucagon challenge. Therefore it seems that there is no obvious association between the blunting of the glucagon secretion seen and the disappearance of the endogenous insulin secretion. In the absence of a specific tool to restore the glucagon response to hypoglycaemia it seems that we are presently limited to only a few therapeutic options, one is to prevent as much as possible every single episode of hypoglycaemia and the other being to keep the plasma insulin level between meals within a low physiologic range, avoiding the postprandial hyperinsulinemia associated with conventional insulin treatment. The latter statement is based on the observation that hyperinsulinemia may suppress glucagon secretion. Thus, the L-arginine stimulated glucagon secretion is suppressed by hyperinsulinemia. Furthermore insulin treatment via the i.p. route with the use of an implantable pump enhanced the glucagon response to hypoglycaemia an effect possibly attributed to lower peripheral insulin levels after an insulin challenge. Such treatment also induced a more favourable effect on the glucagon secretion during physical exercise. However the hypoglycaemic effect during exercise was enhanced, underlining the need to reduce the circulating insulin level in connection with exercise.