Differences in Postprandial and Counterregulatory Glucagon Excursions in Healthy Relatives to Type 1 Diabetes with Different Number of Islet Autoantibodies

Background and aims: Early changes in glucagon during the progression to type 1 diabetes (T1D) are not well understood. We investigate whether the glucagon responses to a mixed meal and hypoglycemia depend on the number of islet autoantibodies (Ab) in individuals at risk for T1D. Methods: Sixty healthy relatives of T1D with mean±SD age of 23.7±10.7 years, HbA1c of 5.3±0.3%, and BMI of 23.8±5.6 kg/m2 and zero (N=21), one (N=18), and ≥2 (N=21) Ab, were enrolled in an ancillary study from the NIH-funded TrialNet Pathway to Prevention study. Participants underwent a clinical test consisting of a mixed meal tolerance test (MMTT) followed by insulin-induced hypoglycemia. Glucagon was measured from -30 to 120 min around the MMTT and 0 to 40 min during hypoglycemia to estimate the Ab group differences in the meal and counter-regulatory glucagon responses assessed via the glucagon incremental area under the curve (iAUC). Results: There were significant differences in the net iAUC of the glucagon responses to the MMTT (p=0.024), while the group difference in the glucagon counter-regulation estimated via the total AUC approached significance (p=0.08). Conclusion: The study suggests that the glucagon responses to a meal and possibly, hypoglycemia, may be altered during the very early stages of the progression to T1D. Disclosure T. Igbe: None. E. Montaser: None. M. D. Breton: Consultant; Dexcom, Inc. Research Support; Dexcom, Inc. Consultant; Tandem Diabetes Care, Inc. Research Support; Tandem Diabetes Care, Inc., Novo Nordisk. Consultant; Roche Diabetes Care, Sanofi, Arecor. S. A. Brown: Research Support; Dexcom, Inc., Insulet Corporation, Tandem Diabetes Care, Inc. M. D. DeBoer: Research Support; Dexcom, Inc., Tandem Diabetes Care, Inc. A. L. McCall: None. B. Kovatchev: Speaker's Bureau; Tandem Diabetes Care, Inc. Research Support; Dexcom, Inc., Novo Nordisk, Tandem Diabetes Care, Inc. Other Relationship; Dexcom, Inc., Johnson & Johnson Medical Devices Companies, Novo Nordisk, Sanofi. L. Farhy: Research Support; Dexcom, Inc., Novo Nordisk. Funding National Institute of Diabetes and Digestive and Kidney Diseases (DP3DK106907); Commonwealth Research Commercialization Fund (MF20-007-LS); The Leona M. and Harry B. Helmsley Charitable Trust (2204-05134); JDRF (2-SRA-2022-1260-S-B)