Splanchnic and Leg Glucagon Metabolism in Healthy and Type 1 Diabetes:First in Human Study using [13C9, 15N1]-Glucagon
Circulating glucagon concentrations differ between nondiabetic (ND) and type 1 diabetes (T1D) individuals. We combined isotope dilution technique using stable tracers [6,22 13C9, 15N1]-Glucagon and [6,14,19,22 13C9, 15N1]-Glucagon with splanchnic and leg catheterization in ND (n=8; age 23.1±2.9 yrs, BMI 26.6±3.5 kg/m2, HbA1c 5.0±0.2% (31±2 mmol/mol) and T1D (n=6; 29.0±8.8 yrs, BMI 26.3±5.0 kg/m2, HbA1c 7.9±0.8% (63±8 mmol/mol) participants in the overnight fasted state. After baseline period, exogenous glucagon was infused at rates designed to achieve plasma glucagon concentrations spanning the physiological ranges, to determine the effects of rising glucagon concentrations on splanchnic and leg glucagon balance. At baseline, splanchnic glucagon extraction (SGE) was similar (30.7±2.7 vs. 29.1±2.9%), but leg glucagon extraction (LGE) lower (27.0±4.2 vs. 40.6±3.1%), in T1D than ND participants. However, with increasing plasma glucagon concentrations, while SGE remained unchanged within and between groups, LGE fell in ND (41 vs. 31 vs. 24%) but did not change in T1D participants. Despite a numerically lower net splanchnic glucagon production in T1D than ND participants, no changes were observed with increasing glucagon concentrations within the physiological range in both groups. This is the first human study, applying novel glucagon isotopes, that describes regional glucagon metabolism in ND and T1D participants. Our observations provide translational relevance for dual hormone closed loop systems as well as provide tools for probing the effects of GLP-1, dual and triple receptor agonists on pancreatic a-cell functions.
