OBJECTIVEPrevious studies have demonstrated aberrant glucagon physiology in the setting of type 1 diabetes (T1D) but have not addressed the potential impact of ambient glycemia on this glucagon response. Thus, our objective was to evaluate the impact of euglycemia versus hyperglycemia on the glucagon response to an oral glucose challenge in T1D. RESEARCH DESIGN AND METHODSTen adults with T1D (mean age 56.6 6 9.0 years, duration of diabetes 26.4 6 7.5 years, HbA 1c 7.5% 6 0.77, and BMI 24.1 kg/m 2 [22.6-25.4]) underwent 3-h 50-g oral glucose tolerance tests (OGTTs) on two separate days at least 24 h apart in random order under conditions of pretest euglycemia (plasma glucose [PG] between 4 and 6 mmol/L) and hyperglycemia (PG between 9 and 11 mmol/L), respectively. RESULTSGlycemic excursion on the OGTT was similar between the euglycemic and hyperglycemic tests (P = 0.72 for interaction between time postchallenge and glycemic setting). Interestingly, glucagon levels increased in response to the OGTT under both glycemic conditions (P < 0.001) and there were no differences in glucagon response between the euglycemic and hyperglycemic days (P = 0.40 for interaction between time postchallenge and glycemic setting). In addition, the incretin responses to the OGTT (glucose-dependent insulinotropic polypeptide, glucagon-like peptide-1, glucagon-like peptide-2) were also not different between the euglycemic and hyperglycemic settings. CONCLUSIONSIn patients with T1D, there is a paradoxical increase in glucagon in response to oral glucose that is not reversed when euglycemia is achieved prior to the test. This abnormal glucagon response likely contributes to the postprandial hyperglycemia in T1D irrespective of ambient glycemia.