Effect of Repeated Glucagon Doses on Hepatic Glycogen in Type 1 Diabetes: Implications for a Bihormonal Closed-Loop System

Abstract

OBJECTIVETo evaluate subjects with type 1 diabetes for hepatic glycogen depletion after repeated doses of glucagon, simulating delivery in a bihormonal closed-loop system.RESEARCH DESIGN AND METHODSEleven adult subjects with type 1 diabetes participated. Subjects underwent estimation of hepatic glycogen using 13C MRS. MRS was performed at the following four time points: fasting and after a meal at baseline, and fasting and after a meal after eight doses of subcutaneously administered glucagon at a dose of 2 µg/kg, for a total mean dose of 1,126 µg over 16 h. The primary and secondary end points were, respectively, estimated hepatic glycogen by MRS and incremental area under the glucose curve for a 90-min interval after glucagon administration.RESULTSIn the eight subjects with complete data sets, estimated glycogen stores were similar at baseline and after repeated glucagon doses. In the fasting state, glycogen averaged 21 ± 3 g/L before glucagon administration and 25 ± 4 g/L after glucagon administration (mean ± SEM) (P = NS). In the fed state, glycogen averaged 40 ± 2 g/L before glucagon administration and 34 ± 4 g/L after glucagon administration (P = NS). With the use of an insulin action model, the rise in glucose after the last dose of glucagon was comparable to the rise after the first dose, as measured by the 90-min incremental area under the glucose curve.CONCLUSIONSIn adult subjects with well-controlled type 1 diabetes (mean A1C 7.2%), glycogen stores and the hyperglycemic response to glucagon administration are maintained even after receiving multiple doses of glucagon. This finding supports the safety of repeated glucagon delivery in the setting of a bihormonal closed-loop system.

Incorporating an Exercise Detection, Grading, and Hormone Dosing Algorithm Into the Artificial Pancreas Using Accelerometry and Heart Rate

“…While each of the individual models used for insulin kinetics, insulin dynamics, carbohydrate absorption, and exercise have been validated independently, there has not yet been an extensive validation of these models together to form a virtual patient population. However, in a recent publication by our group, 28 we used a similar method of generating a virtual patient population by fitting physiologic data to the model, and in that article we included an appendix showing the residuals from the model fits to demonstrate that the model fit. A further limitation of our modeling is that we did not account for the time-varying nature of the model parameters.…”

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]. At high circulating insulin concentrations (50-60 mIU/l), the endogenous glucose production (EGP) is completely inhibited [17], and at insulin levels exceeding ~40 mIU/l the EGP cannot be stimulated by glucagon [13].…”

Relationship between Optimum Mini‐doses of Glucagon and Insulin Levels when Treating Mild Hypoglycaemia in Patients with Type 1 Diabetes – A Simulation Study

“…This priority of peak PG over the 2‐hr PG level was applied because patients will benefit from the acute rescue and still have time to avoid subsequent hypoglycaemia by suspending their insulin infusion and/or consuming carbohydrates. Alternatively, not reported here, a second bolus of glucagon could be given which has shown to give similar glucose response as the first glucagon bolus .…”