Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390-8549, USA.
Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390-8549, USA; Medical Service, Veteran's Administration North Texas Health Care System, Dallas, TX 75216, USA.
Cell Rep. 2018 Feb 13;22(7):1760-1773. doi: 10.1016/j.celrep.2018.01.065.
The antidiabetic potential of glucagon receptor antagonism presents an opportunity for use in an insulin-centric clinical environment. To investigate the metabolic effects of glucagon receptor antagonism in type 2 diabetes, we treated Lepr and Lep mice with REMD 2.59, a human monoclonal antibody and competitive antagonist of the glucagon receptor. As expected, REMD 2.59 suppresses hepatic glucose production and improves glycemia. Surprisingly, it also enhances insulin action in both liver and skeletal muscle, coinciding with an increase in AMP-activated protein kinase (AMPK)-mediated lipid oxidation. Furthermore, weekly REMD 2.59 treatment over a period of months protects against diabetic cardiomyopathy. These functional improvements are not derived simply from correcting the systemic milieu; nondiabetic mice with cardiac-specific overexpression of lipoprotein lipase also show improvements in contractile function after REMD 2.59 treatment. These observations suggest that hyperglucagonemia enables lipotoxic conditions, allowing the development of insulin resistance and cardiac dysfunction during disease progression.
胰高血糖素受体拮抗作用的抗糖尿病潜力为在以胰岛素为中心的临床环境中提供了应用机会。为了研究胰高血糖素受体拮抗作用在 2 型糖尿病中的代谢效应，我们用 REMD 2.59 治疗 Lepr 和 Lep 小鼠，REMD 2.59 是胰高血糖素受体的人源单克隆抗体和竞争性拮抗剂。正如预期的那样，REMD 2.59 抑制肝葡萄糖产生并改善血糖。令人惊讶的是，它还增强了肝和骨骼肌中的胰岛素作用，同时伴随着 AMP 激活的蛋白激酶（AMPK）介导的脂质氧化增加。此外，数月来每周 REMD 2.59 治疗可预防糖尿病性心肌病。这些功能改善并非仅仅源于纠正全身环境；在心脏特异性过表达脂蛋白脂肪酶的非糖尿病小鼠中，REMD 2.59 治疗后收缩功能也得到改善。这些观察结果表明，高胰高血糖素血症使脂肪毒性条件成为可能，在疾病进展过程中导致胰岛素抵抗和心脏功能障碍的发生。
