Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen , Copenhagen , Denmark.
Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen , Copenhagen , Denmark.
Am J Physiol Gastrointest Liver Physiol. 2018 Jan 1;314(1):G91-G96. doi: 10.1152/ajpgi.00216.2017. Epub 2017 Sep 28.
Patients with type 2 diabetes (T2D) and patients with nonalcoholic fatty liver disease (NAFLD) frequently exhibit elevated plasma concentrations of glucagon (hyperglucagonemia). Hyperglucagonemia and α-cell hyperplasia may result from elevated levels of plasma amino acids when glucagon's action on hepatic amino acid metabolism is disrupted. We therefore measured plasma levels of glucagon and individual amino acids in patients with and without biopsy-verified NAFLD and with and without type T2D. Fasting levels of amino acids and glucagon in plasma were measured, using validated ELISAs and high-performance liquid chromatography, in obese, middle-aged individuals with I) normal glucose tolerance (NGT) and NAFLD, II) T2D and NAFLD, III) T2D without liver disease, and IV) NGT and no liver disease. Elevated levels of total amino acids were observed in participants with NAFLD and NGT compared with NGT controls (1,310 ± 235 µM vs. 937 ± 281 µM, P = 0.03) and in T2D and NAFLD compared with T2D without liver disease (1,354 ± 329 µM vs. 511 ± 235 µM, P < 0.0001). Particularly amino acids with known glucagonotropic effects (e.g., glutamine) were increased. Plasma levels of total amino acids correlated to plasma levels of glucagon also when adjusting for body mass index (BMI), glycated hemoglobin (Hb), and cholesterol levels (β = 0.013 ± 0.007, P = 0.024). Elevated plasma levels of total amino acids associate with hyperglucagonemia in NAFLD patients independently of glycemic control, BMI or cholesterol - supporting the potential importance of a "liver-α-cell axis" in which glucagon regulates hepatic amino acid metabolism. Fasting hyperglucagonemia as seen in T2D may therefore represent impaired hepatic glucagon action with increasing amino acids levels. NEW & NOTEWORTHY Hypersecretion of glucagon (hyperglucagonemia) has been suggested to be linked to type 2 diabetes. Here, we show that levels of amino acids correlate with levels of glucagon. Hyperglucagonemia may depend on hepatic steatosis rather than type 2 diabetes.
患有 2 型糖尿病（T2D）和非酒精性脂肪性肝病（NAFLD）的患者常表现出升高的胰高血糖素（高胰高血糖素血症）血浆浓度。当胰高血糖素对肝氨基酸代谢的作用被破坏时，高胰高血糖素血症和α细胞增生可能是由于血浆氨基酸水平升高引起的。因此，我们测量了经活检证实的 NAFLD 患者和无 NAFLD 患者以及 T2D 患者和无 T2D 患者的血浆胰高血糖素和个别氨基酸水平。使用经过验证的 ELISA 和高效液相色谱法测量肥胖中年个体的空腹血浆氨基酸和胰高血糖素水平，这些个体具有 I）正常葡萄糖耐量（NGT）和 NAFLD，II）T2D 和 NAFLD，III）无肝脏疾病的 T2D，以及 IV）NGT 和无肝脏疾病。与 NGT 对照组相比，NAFLD 患者和 NGT 患者的总氨基酸水平升高（1,310 ± 235 μM 比 937 ± 281 μM，P = 0.03），与无肝脏疾病的 T2D 患者相比，NAFLD 患者和 NGT 患者的总氨基酸水平升高（1,354 ± 329 μM 比 511 ± 235 μM，P < 0.0001）。具有已知胰高血糖素作用的氨基酸（例如谷氨酰胺）增加尤其明显。当调整体重指数（BMI）、糖化血红蛋白（Hb）和胆固醇水平时，血浆总氨基酸水平与胰高血糖素水平相关（β=0.013±0.007，P=0.024）。在非酒精性脂肪性肝病患者中，总氨基酸的升高与高胰高血糖素血症相关，与血糖控制、BMI 或胆固醇无关-支持“肝-α细胞轴”在其中，胰高血糖素调节肝氨基酸代谢的潜在重要性。因此，在 2 型糖尿病中看到的空腹高胰高血糖素血症可能代表肝胰高血糖素作用受损，而氨基酸水平升高。新的和值得注意的是，胰高血糖素（高胰高血糖素血症）的过度分泌被认为与 2 型糖尿病有关。在这里，我们表明氨基酸水平与胰高血糖素水平相关。高胰高血糖素血症可能取决于肝脂肪变性而不是 2 型糖尿病。
