National Research Council (CNR) Institute of Clinical Physiology, Pisa, Italy
Diabetes. 2021 Feb;70(2):338-346. doi: 10.2337/dbi20-0028.
Insulin resistance and β-cell dysfunction are the core pathophysiological mechanisms of all hyperglycemic syndromes. Advances in in vivo investigative techniques have made it possible to quantify insulin resistance in multiple sites (skeletal and myocardial muscle, subcutaneous and visceral fat depots, liver, kidney, vascular tissues, brain and intestine), to clarify its consequences for tissue substrate selection, and to establish its relation to tissue perfusion. Physiological modeling of β-cell function has provided a uniform tool to measure β-cell glucose sensitivity and potentiation in response to a variety of secretory stimuli, thereby allowing us to establish feedbacks with insulin resistance, to delineate the biphasic time course of conversion to diabetes, to gauge incretin effects, and to identify primary insulin hypersecretion. As insulin resistance also characterizes several of the comorbidities of diabetes (e.g., obesity, hypertension, dyslipidemia), with shared genetic and acquired influences, the concept is put forward that diabetes is a systemic disease from the outset, actually from the prediabetic stage. In fact, early multifactorial therapy, particularly with newer antihyperglycemic agents, has shown that the burden of micro- and macrovascular complications can be favorably modified despite the rising pressure imposed by protracted obesity.
胰岛素抵抗和β细胞功能障碍是所有高血糖综合征的核心病理生理机制。体内研究技术的进步使得在多个部位（骨骼肌和心肌、皮下和内脏脂肪组织、肝脏、肾脏、血管组织、大脑和肠道）量化胰岛素抵抗成为可能，阐明了其对组织底物选择的影响，并确定了其与组织灌注的关系。β细胞功能的生理建模提供了一个统一的工具，用于测量β细胞对各种分泌刺激的葡萄糖敏感性和增强作用，从而使我们能够建立与胰岛素抵抗的反馈关系，描绘向糖尿病转化的双相时程，评估肠促胰岛素的作用，并确定原发性胰岛素分泌过多。由于胰岛素抵抗也存在于糖尿病的几种合并症中（如肥胖、高血压、血脂异常），具有共同的遗传和后天影响，因此提出了糖尿病从一开始就是一种全身性疾病的概念，实际上从糖尿病前期阶段就是全身性疾病。事实上，早期的多因素治疗，特别是使用新型抗高血糖药物，已经表明，尽管肥胖持续存在导致压力增加，但微血管和大血管并发症的负担可以得到有利的改善。
