Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus, Denmark.
Department of Internal Medicine, Gødstrup Regional Hospital, Herning, Denmark.
Am J Physiol Endocrinol Metab. 2024 Dec 1;327(6):E679-E685. doi: 10.1152/ajpendo.00187.2024. Epub 2024 Sep 18.
Hepatic amino acid (AA) metabolism and glucagon secretion are linked in a feedback cycle in which circulating AAs stimulate glucagon secretion and alpha-cell proliferation, whereas glucagon stimulates hepatic AA catabolism. It has been proposed that metabolic dysfunction-associated steatotic liver disease (MASLD) leads to hepatic glucagon resistance, which may result in hyperaminoacidemia and hyperglucagonemia. We tested the glucagon effect on AA metabolism in subjects with obesity; 11 with steatohepatitis (MASH), 10 with steatosis (MAS), and 7 subjects [control (CON)] without steatosis. We performed a somatostatin clamp with infusions of insulin and low dose followed by high-dose glucagon. We measured plasma levels of 17 AAs and assessed hepatic fat content (FF%) and body fat distribution (visceral and subcutaneous adipose tissue mass) by MRI. HighGlucagon suppressed plasma total AA equally in all groups; MASH 13% (SD 9%), MAS 14% (7%), and CON 11% (5%), respectively. In univariate regression analyses, visceral adipose tissue mass (β = 0.471, = 0.011) and AA concentration at LowGlucagon (β = -0.524, = 0.004), but not FF% (β = -0.243, = 0.213), were significant predictors of AA reduction. Using a stepwise backward multiple regression approach revealed similar results. Total and specific AA levels (glutamic acid and tyrosine) were higher in both MASLD groups during the study, and FF% was positively correlated to a number of individual AAs. Although finding elevated AA concentrations in subjects with MASLD, we conclude that in patients with MASLD that do not have elevated glucagon at baseline, glucagon suppresses circulating AA levels equally in subjects with and without MASLD. ClinicalTrials.gov: NCT04042142. The purpose of the study was to investigate the concept of "glucagon resistance" in metabolic dysfunction-associated steatotic liver disease (MASLD) pathogenesis. We asked if a disruption of the glucagon-mediated suppression of hepatic amino acid (AA) catabolism is present in individuals with MASLD compared with individuals with obesity but no MASLD. Contrary to expectations, we found no disruption of the glucagon-stimulated suppression of plasma AA concentration, which disputes the hypothesis that MASLD causes resistance to glucagon.
肝氨基酸（AA）代谢和胰高血糖素分泌在反馈循环中相关联，循环 AA 刺激胰高血糖素分泌和 α 细胞增殖，而胰高血糖素刺激肝 AA 分解代谢。有人提出，代谢功能障碍相关脂肪性肝病（MASLD）导致肝胰高血糖素抵抗，可能导致高氨基酸血症和高胰高血糖素血症。我们在肥胖患者中测试了胰高血糖素对 AA 代谢的影响；11 例脂肪性肝炎（MASH），10 例脂肪变性（MAS），和 7 例无脂肪变性的对照（CON）。我们进行了生长抑素钳夹，同时输注胰岛素和小剂量，然后输注高剂量胰高血糖素。我们测量了 17 种氨基酸的血浆水平，并通过 MRI 评估了肝脂肪含量（FF%）和体脂肪分布（内脏和皮下脂肪组织质量）。高胰高血糖素同样抑制了所有组的血浆总 AA；MASH 组减少 13%（SD 9%），MAS 组减少 14%（7%），CON 组减少 11%（5%）。在单变量回归分析中，内脏脂肪组织质量（β=0.471，=0.011）和低胰高血糖素时的 AA 浓度（β=-0.524，=0.004），但不是 FF%（β=-0.243，=0.213），是 AA 减少的显著预测因子。采用逐步向后多元回归方法得到了类似的结果。在研究过程中，两个 MASLD 组的总氨基酸和特定氨基酸（谷氨酸和酪氨酸）水平均升高，FF%与多种氨基酸呈正相关。尽管在 MASLD 患者中发现了升高的 AA 浓度，但我们得出结论，在基线时没有升高胰高血糖素的 MASLD 患者中，胰高血糖素同样抑制 MASLD 和非 MASLD 患者的循环 AA 水平。ClinicalTrials.gov：NCT04042142。本研究的目的是探讨代谢功能障碍相关脂肪性肝病（MASLD）发病机制中“胰高血糖素抵抗”的概念。我们询问在 MASLD 个体中是否存在破坏胰高血糖素介导的肝氨基酸（AA）分解代谢抑制的情况，与肥胖但无 MASLD 的个体相比。出乎意料的是，我们没有发现胰高血糖素刺激血浆 AA 浓度抑制的破坏，这驳斥了 MASLD 导致胰高血糖素抵抗的假说。
