Despite pharmacological and technical advances, risk of hypoglycemia remains the greatest impediment to optimal glycemia in type 1 diabetes (T1D) and there is increasing interest in how the opposing actions of insulin and glucagon (Gn) may be harnessed to optimize glycemic control. We studied T1D subjects (n=11; age 36±4y, gender M:F 5:6, BMI 25.0±0.7 kg/m2, disease duration 23±3y, A1C 7.0±0.3%, daily insulin dose 43±3u) on two occasions, under meal challenge conditions (liquid mixed meal, 100g carbohydrate) during a phased 6h IV regular insulin infusion with (+Gn) and without (-Gn) IV glucagon. On both occasions, subjects were treated overnight with low dose IV insulin prior to the morning meal to prevent antecedent nocturnal hypoglycemia and to attain near-normal fasting glycemia. Insulin dosing was designed to control the early rise in plasma glucose (PG) but also to elicit hypoglycemia in the later phase. During +Gn, glucagon was co-administered with insulin at a fixed molar ratio. At the two visits, fasting PG was similar (-Gn 121±5, +Gn 119±6 mg/dl) and the initial meal-induced PG elevation (0-3h) was indistinguishable whether glucagon was present or not (peak PG -Gn 224±18, +Gn 228±15 mg/dl; ΔPG 0-180AUC -Gn 10501±3014, +Gn 11537±1778 mg.min/dl). During the latter phase (3-6h), 7/11 -Gn subjects experienced an excessive fall in PG to <80mg/dl with 5/11 dropping to 50mg/dl requiring IV glucose rescue (by protocol). During +Gn, the fall in PG was attenuated in all cases with a significant difference observed in PG nadir (-Gn 51.1±4.0, +Gn100.5±11.0 mg/dl; p=0.007). Appropriate elevations in plasma insulin and glucagon were observed in keeping with study design. To conclude, it is feasible that insulin and glucagon can be co-administered under specific conditions allowing protection against insulin-induced hypoglycemia without impeding hyperglycemic control. This unique observation offers insight into novel approaches to glucose control in diabetes.
B.W. Bode: Advisory Panel; Self; Medtronic, Novo Nordisk A/S. Consultant; Self; Eli Lilly and Company, Medtronic, Novo Nordisk A/S. Research Support; Self; Abbott, Advance, Boehringer Ingelheim Pharmaceuticals, Inc., Dexcom, Inc., Diasome Pharmaceuticals, Inc., Eli Lilly and Company, Insulet Corporation, Janssen Pharmaceuticals, Inc., MannKind Corporation, Medtronic, National Institutes of Health, Nova Biomedical, Novo Nordisk A/S, Provention Bio, Inc., Sanofi, Senseonics. Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Janssen Pharmaceuticals, Inc., MannKind Corporation, Medtronic, Novo Nordisk A/S, Sanofi, Senseonics. Stock/Shareholder; Self; Aseko. J. Boyd: None. A. Shah: Consultant; Self; Abvance Therapeutics. Stock/Shareholder; Spouse/Partner; Fractyl Laboratories, Inc. D. Parkes: Consultant; Self; Abvance Therapeutics, Fractyl Laboratories, Inc., Prolynx, ProSciento. S. Ghosh: Consultant; Self; Abvance Therapeutics, Fractyl Laboratories, Inc., Takeda Pharmaceutical Company Limited. A.D. Cherrington: Advisory Panel; Self; Biocon, Fractyl Laboratories, Inc., Metavention, Sekkei Bio, Sensulin, LLC., vTv Therapeutics, Zafgen, Inc. Consultant; Self; Thetis Pharmaceuticals LLC. Research Support; Self; Diasome Pharmaceuticals, Inc. Other Relationship; Self; Abvance Therapeutics, Novo Nordisk Inc.