Submitted to: Diabetes
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/5/2005
Publication Date: 2/5/2005
Citation: Heptulla, R.A., Rodriguez, L.M., Bomgaars, L., Haymond, M. 2005. The role of amylin and glucagon in the dampening of glycemic excursions in children with type 1 diabetes. Diabetes. 54:1100-1107. Interpretive Summary: These investigations demonstrate that postprandial hyperglycemia contributes significantly to poor glycemic control in children with type 1 diabetes compared with control subjects. Despite the use of insulin pump therapy, immediate and prolonged hyperglycemia persists. Moreover, accurately counting carbohydrates and giving insulin before the meal does not effectively control blood glucose concentrations after a meal. Our results suggest that there is marked postprandial hyperglycemia even in well-controlled patients with type 1 diabetes and that insulin pump therapy alone does not correct postprandial hyperglycemia. Even increasing the insulin dose before a meal does not correct immediate postprandial hyperglycemia. Pramlintide is effective in decreasing immediate postprandial hyperglycemia in adolescents with type 1 diabetes. Minidose glucagon is effective in preventing late postprandial hypoglycemia. Therefore, we conclude that multiple hormones contribute to normal glucose homeostasis in type 1 diabetes. Further refinement in our understanding as to how to replace or correct the action of these hormones will result in decreased glycemic swings and will allow lowering of HbA1c into the true normal range without the increased risk of hypoglycemia.
Technical Abstract: Postprandial hyperglycemia and preprandial hypoglycemia contribute to poor glycemic control in type 1 diabetes. We hypothesized that postprandial glycemic excursions could be normalized in type 1 diabetes by suppressing glucagon with pramlintide acetate in the immediate postprandial period and supplementing glucagon in the late postprandial period. A total of 11 control subjects were compared with 8 type 1 diabetic subjects on insulin pump therapy, using the usual insulin bolus-to-carbohydrate ratio during a standard liquid meal. Type 1 diabetic subjects were then randomized to two open-labeled studies. On one occasion, type 1 diabetic subjects received a 60% increase in the insulin bolus-to-carbohydrate ratio with minidose glucagon rescue injections, and on the other occasion type 1 diabetic subjects received 30-45 microg pramlintide with their usual insulin bolus-to-carbohydrate ratio. Glucose, glucagon, amylin (pramlintide), and insulin concentrations were measured for 420 min. The plasma glucose area under the curve (AUC) for 0-420 min was lower in control versus type 1 diabetic subjects (316 +/- 5 vs. 929 +/- 18 mg x h(-1) x dl(-1), P < 0.0001). Pramlintide, but not an increase in insulin, reduced immediate postprandial hyperglycemia (AUC(0-180 min) 470 +/- 43 vs. 434 +/- 48 mg x h(-1) x dl(-1), P < 0.01). Pramlintide administration suppressed glucagon (P < 0.02), and glucagon injections prevented late hypoglycemia with increased insulin. In summary, in type 1 diabetes, glucagon modulation with pramlintide as an adjunct to insulin therapy may prove beneficial in controlling postmeal glycemic swings.