Glucagon Response to Prandial Insulin Administration in Persons With Type 1 Diabetes

Glucagon regulation and response in persons with T1D at the basal state and in response to various stimuli remains unclear. Dr. Philip Cryer has previously reported that, in T1D young adults with a course of the disease of 16+9 years, the absence of endogenous insulin secretion results in increased glucagon secretion after a mixed meal , concluding that endogenous insulin reciprocally regulates the alpha-cell glucagon secretion and also suggesting that glucagon dysregulation may play an important role in post-prandial hyperglycemia in T1D. Interestingly, recent research on human islets have shown that insulin inhibits counter-regulatory glucagon secretion by a paracrine effect mediated by SGLT2-dependent stimulation of somatostatin release. An important gap in our knowledge is whether the timing of prandial insulin doses affects the glucagon response to a hyperglycemic stimulus in patients with T1D who have undetectable C-peptide.

T1D course. In general, loss of 80% of beta cell function is needed to develop severe hyperglycemia. Endogenous insulin secretion is almost entirely lost within 3 to 5 years after the diagnosis . In children with new diagnosis of T1D, glucagon levels were highly associated with post prandial blood glucose, but not with HbA1c level. It has also been reported that postprandial hyperglucagonemia worsens significantly while C-peptide secretion declines during the first year of the disease. Also, in children with greater than five years of T1D, postprandial glucagon levels increased 160% from one to sixty months after diagnosis (8) and in those with disease duration of 6.9 + 4 years, glucagon levels were strongly correlated with post-prandial glucose and mildly correlated with HbA1C levels. A study in T1D adults performed in China showed that post-prandial glucagon levels were higher in T1D patients in the first year of the disease compared to those with longer course of the disease, and that hypoglycemic events were lower in newly diagnosed patients, suggesting that glucagon secretory function may become impaired with longer duration of the disease. These studies suggest that glucagon dysregulation could impact glucose control with exogenous insulin, and that this dysregulation may change with disease duration.

Post-prandial hyperglycemia adds to glucose variability, difficulty with insulin dosing and overall instability of glucose control. A recent analysis from the T1D Exchange study, that included 4768 participants younger than 26 years with a clinical diagnosis of T1D for at least 1 year showed that 21% of the participants reported administering insulin several minutes before, 44% immediately before, 10% during, and 24% after meal. Interestingly, participants who reported administering insulin during or after a meal were more likely to report missing ≥1 mealtime insulin dose per week compared with those who administered insulin before meals. In addition, a sub-analysis showed that participants who dose mealtime insulin in the postprandial period have poorer glycemic control and greater frequency of severe hypoglycemia. However, despite of these recent results, patients are often advised to give insulin after eating because caloric intake is uncertain. Understanding the mechanisms behind the higher post-prandial peak in glucose with delayed insulin administration may help clinicians guide appropriate timing of insulin administration for T1D patients with long course of the disease.

Glucagon Regulation:

Different models have been used to study glucagon regulation. Since both hyperglycemia and hypoglycemia stimulate alpha cells to produce glucagon, both the lack of intra-islet insulin and this U-shaped glucagon response contribute to glucose dysregulation in T1D . It has been reported that in T1D patients with a duration of the disease of 26.4+7.5 years, glucagon levels increased in response to the OGTT under euglycemic and hyperglycemic conditions, however the relative contribution of hyperglucagonemia to post-prandial glucose rise in the presence or absence of preprandial insulin has not been clearly elucidated. Whether appropriately timed exogenous insulin can modify the glucagon response to glucose fluctuations has not been studied. As such, this pilot study aims to characterize the glucagon response to meal-time hyperglycemia and to compare the difference in glucagon secretion when mealtime bolus insulin is given before the meal versus after the meal with the objective of understanding factors that contribute to the peak post-prandial blood glucose and AUC of blood glucose after a mixed meal in this target population.