Grøndahl Magnus F G, Lund Asger, Bagger Jonatan I, Petersen Tonny S, Wewer Albrechtsen Nicolai J, Holst Jens J, Vilsbøll Tina, Christensen Mikkel B, Knop Filip K
Center for Clinical Metabolic Research, Copenhagen University Hospital - Herlev and Gentofte, Hellerup, Denmark.
Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Diabetes. 2021 Oct 21. doi: 10.2337/db21-0024.
Hyperglucagonemia is a common observation in both obesity and type 2 diabetes, and the etiology is primarily thought to be hypersecretion of glucagon. We investigated whether altered elimination kinetics of glucagon could contribute to the hyperglucagonemia in type 2 diabetes and obesity. Individuals with type 2 diabetes and preserved kidney function (8 with and 8 without obesity) and matched control individuals (8 with and 8 without obesity) were recruited. Each participant underwent a 1-hour glucagon infusion (4 ng/kg/min), achieving steady-state plasma glucagon concentrations, followed by a 1-hour wash-out period. Plasma levels, the metabolic clearance rate (MCR), half-life (T½) and volume of distribution of glucagon were evaluated and a pharmacokinetic model was constructed. Glucagon MCR and volume of distribution were significantly higher in the type 2 diabetes group compared to the control group, while no significant differences between the groups were found in glucagon T½. Individuals with obesity had neither a significantly decreased MCR, T½, nor volume of distribution of glucagon. In our pharmacokinetic model, glucagon MCR associated positively with fasting plasma glucose and negatively with body weight. In conclusion, our results suggest that impaired glucagon clearance is not a fundamental part of the hyperglucagonemia observed in obesity and type 2 diabetes.
高胰高血糖素血症在肥胖症和2型糖尿病中都很常见，其病因主要被认为是胰高血糖素分泌过多。我们研究了胰高血糖素消除动力学的改变是否会导致2型糖尿病和肥胖症中的高胰高血糖素血症。招募了具有保留肾功能的2型糖尿病患者（8例有肥胖症，8例无肥胖症）以及匹配的对照个体（8例有肥胖症，8例无肥胖症）。每位参与者接受1小时的胰高血糖素输注（4 ng/kg/分钟），以达到稳态血浆胰高血糖素浓度，随后是1小时的洗脱期。评估了血浆水平、代谢清除率（MCR）、半衰期（T½）和胰高血糖素的分布容积，并构建了药代动力学模型。与对照组相比，2型糖尿病组的胰高血糖素MCR和分布容积显著更高，而两组之间的胰高血糖素T½没有显著差异。肥胖个体的胰高血糖素MCR、T½和分布容积均无显著降低。在我们的药代动力学模型中，胰高血糖素MCR与空腹血糖呈正相关，与体重呈负相关。总之，我们的结果表明，胰高血糖素清除受损并非肥胖症和2型糖尿病中观察到的高胰高血糖素血症的基本组成部分。
