Minimizing Morbidity of Hypoglycemia in Diabetes

Abstract

Type 1 diabetes is a common chronic disease of childhood and one of the most difficult conditions to manage. Advances in insulin formulations and insulin delivery devices have markedly improved the ability to achieve normal glucose homeostasis. However, hypoglycemia remains the primary limiting factor in achieving normoglycemia and is a frequent complication in children with acute gastroenteritis and/or poor oral intake. In situations of impaired carbohydrate intake or absorption, glucagon therapy is the only out-of-hospital treatment option available to families and caregivers. Glucagon is recommended for the treatment of severe hypoglycemia and rapidly increases blood glucose by increasing hepatic glucose production from glycogenolysis. Mini-dose glucagon is a widely utilized off-label treatment for managing mild or impending hypoglycemia and is administered as a small subcutaneous injection. It was initially described for use in children who were unable to tolerate or absorb oral carbohydrates but not in need of advanced medical care. Yet, mini-dose glucagon may be useful in any individual with relative insulin excess. The regimen aims to prevent severe hypoglycemic episodes and is safe, effective, and easily administered by patients and caregivers in the out-of-hospital setting. By empowering patients and their families, this important tool could help to alleviate the physical, psychosocial, and financial burden evolving from impending hypoglycemia.

Nonaqueous, Mini-Dose Glucagon for Treatment of Mild Hypoglycemia in Adults With Type 1 Diabetes: A Dose-Seeking Study

“…This is similar to the dose we have used in older adolescents using aqueous glucagon (4,5). The glycemic response after an overnight fast was greater than that after mild hypoglycemia, perhaps because of the known effects of insulin on glycogen metabolism (10,11).…”

“…Because most hypoglycemia occurs some hours after the last insulin bolus, we anticipate that the glycemic response to mini-dose glucagon would be similar to that observed after the overnight fast in this study. However, hypoglycemia occurring immediately after an insulin bolus could dramatically blunt the response to glucagon; therefore, rechecking blood glucose concentrations will always be recommended, and repeating the dose may be necessary (4,5). …”

“…Our previous findings of the utility of mini-dose glucagon in treating mild-to-moderate hypoglycemia in children and adolescents (4) has been confirmed at a diabetes summer camp and in the hospital setting, and is now widely recommended (5). Because rehydrated glucagon is unstable (6), Xeris Pharmaceuticals, Inc., has developed a ready-to-use, stable, nonaqueous liquid form of glucagon.…”

Comparative Pharmacokinetic/Pharmacodynamic Study of Liquid Stable Glucagon Versus Lyophilized Glucagon in Type 1 Diabetes Subjects

“…Other potential applications of stable glucagon include a mini-dose pen for administration of smaller doses in cases such as gastroenteritis 16,17 as well as delivery via a pump in the context of a closed-loop system. Xeris Pharmaceuticals' G-Pump glucagon is the first known native glucagon formulation to offer extended liquid stability at room or body temperature, and may ultimately enable such product applications.…”

Cross-Validation of a Glucose-Insulin-Glucagon Pharmacodynamics Model for Simulation Using Data From Patients With Type 1 Diabetes

“…Currently marketed glucagon is approved as a 1 mg rescuetreatment for severe hypoglycemia, although the interest in mini-dose glucagon is increasing [11,12]. Recent studies proved that the glycemic response to low-dose glucagon is dependent on ambient insulin levels [13], but neither on plasma glucose level [14,15] nor on prior glucagon dosing [16].…”