Research Institute for Clinical Physiology, Kyoto Industrial Health Association, Kyoto 604-8472, Japan.
Department of Molecular Cell Physiology, Kyoto Prefectural University of Medicine Graduate School of Medical Science, Kyoto 602-8566, Japan.
Biochem Soc Trans. 2021 Apr 30;49(2):715-726. doi: 10.1042/BST20200667.
Type 2 diabetes mellitus (T2DM) is one of the most common lifestyle-related diseases (metabolic disorders) due to hyperphagia and/or hypokinesia. Hyperglycemia is the most well-known symptom occurring in T2DM patients. Insulin resistance is also one of the most important symptoms, however, it is still unclear how insulin resistance develops in T2DM. Detailed understanding of the pathogenesis primarily causing insulin resistance is essential for developing new therapies for T2DM. Insulin receptors are located at the plasma membrane of the insulin-targeted cells such as myocytes, adipocytes, etc., and insulin binds to the extracellular site of its receptor facing the interstitial fluid. Thus, changes in interstitial fluid microenvironments, specially pH, affect the insulin-binding affinity to its receptor. The most well-known clinical condition regarding pH is systemic acidosis (arterial blood pH < 7.35) frequently observed in severe T2DM associated with insulin resistance. Because the insulin-binding site of its receptor faces the interstitial fluid, we should recognize the interstitial fluid pH value, one of the most important factors influencing the insulin-binding affinity. It is notable that the interstitial fluid pH is unstable compared with the arterial blood pH even under conditions that the arterial blood pH stays within the normal range, 7.35-7.45. This review article introduces molecular mechanisms on unstable interstitial fluid pH value influencing the insulin action via changes in insulin-binding affinity and ameliorating actions of weak organic acids on insulin resistance via their characteristics as bases after absorption into the body even with sour taste at the tongue.
2 型糖尿病（T2DM）是由于过食和/或运动不足引起的最常见的生活方式相关疾病（代谢紊乱）之一。高血糖是 T2DM 患者最常见的症状。胰岛素抵抗也是最重要的症状之一，但胰岛素抵抗在 T2DM 中是如何发展的仍不清楚。详细了解主要导致胰岛素抵抗的发病机制对于开发 T2DM 的新疗法至关重要。胰岛素受体位于胰岛素靶向细胞（如肌细胞、脂肪细胞等）的质膜上，胰岛素与位于面向细胞间隙的细胞外受体部位结合。因此，细胞间隙微环境（特别是 pH 值）的变化会影响胰岛素与其受体的结合亲和力。关于 pH 值的最著名的临床情况是严重 T2DM 伴胰岛素抵抗时经常观察到的全身性酸中毒（动脉血 pH 值<7.35）。由于受体的胰岛素结合部位面向细胞间隙，我们应该认识到细胞间隙 pH 值是影响胰岛素结合亲和力的最重要因素之一。值得注意的是，即使在动脉血 pH 值保持在正常范围（7.35-7.45）的情况下，细胞间隙 pH 值也比动脉血 pH 值不稳定。这篇综述文章介绍了分子机制，即不稳定的细胞间隙 pH 值通过改变胰岛素结合亲和力影响胰岛素作用，以及通过吸收到体内后的碱基特性改善弱有机酸对胰岛素抵抗的作用，即使在舌头上有酸味。
