The Role of Amylin and Glucagon in the Dampening of Glycemic Excursions in Children With Type 1 Diabetes

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 g 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 ⅐ h ؊1 ⅐ 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 ⅐ h ؊1 ⅐ 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.

IAPP and type 1 diabetes: implications for immunity, metabolism and islet transplants

“…Pramlintide injection has no influence on glycemia in the fasting state, nor during experimental hyperinsulinemic-euglycemic or hyperinsulinemichypoglycemic challenge (Kolterman et al 1996, Nyholm et al 1996, Amiel et al 2005. However, single-dose pramlintide injection in conjunction with insulin prior to a meal more effectively attenuates postprandial glycemia than insulin alone in T1D subjects , Heptulla et al 2005, Chase et al 2009, Hassan & Heptulla 2009, Weinzimer et al 2012. Pramlintide and insulin co-administration was also shown to be more effective relative to higher doses of insulin alone, pointing to distinct metabolic actions of IAPP and insulin (Heptulla et al 2005).…”

“…However, single-dose pramlintide injection in conjunction with insulin prior to a meal more effectively attenuates postprandial glycemia than insulin alone in T1D subjects , Heptulla et al 2005, Chase et al 2009, Hassan & Heptulla 2009, Weinzimer et al 2012. Pramlintide and insulin co-administration was also shown to be more effective relative to higher doses of insulin alone, pointing to distinct metabolic actions of IAPP and insulin (Heptulla et al 2005). Improved postprandial glycemia with single-dose pramlintide supplementation involves the inhibition of postprandial glucagon secretion and delayed gastric emptying.…”

“…IAPP levels are reduced in T1D subjects and negatively correlate with disease duration, as is the case for T2D subjects requiring exogenous insulin therapy (Hartter et al 1990, Koda et al 1992, Akimoto et al 1993, Heptulla et al 2005, Huml et al 2011. Thus, it has been postulated that IAPP deficiency may contribute to the metabolic dysregulation of established T1D.…”

Adjuvantes no tratamento da hiperglicemia do diabetes melito tipo 1

“…A associação do pramlintide nessa terapêutica reduz significativamente esse problema. Ao reduzir a secreção de glucagon, o pramlintide provoca diminuição imediata da glicemia (nadir ocorrendo após 45 a 60 minutos) e possibilita o uso de doses menores da insulina prandial, o que evita a hipoglicemia (35,36). Está demonstrado que esse efeito não é mediado pelo glucagon-like peptide 1 (GLP-1) (37).…”

Pharmacokinetics Modeling of Exogenous Glucagon in Type 1 Diabetes Mellitus Patients

“…As research interest and implementation of glucagon intervention in the treatment of T1DM patients grow, [3][4][5][6][7][8][9] especially in the field of modeling predictive AP systems, it becomes necessary to establish a robust and easily identifiable pharmacokinetic model of exogenous glucagon transport. In addition, such a model will provide the foundation for designing bihormonal strategies in AP systems, 10 leading to an easier regulatory pathway to clinical trials as well as accelerated system design and optimization.…”