Li Xiao C, Zhuo Jia L
Laboratory of Receptor and Signal Transduction, Division of Hypertension and Vascular Research, Henry Ford Hospital, Detroit, MI 48202, USA.
Clin Sci (Lond). 2007 Aug;113(4):183-93. doi: 10.1042/CS20070040.
Pancreatic bi-hormones insulin and glucagon are the Yin and Yang in the regulation of glucose metabolism and homoeostasis. Insulin is synthesized primarily by pancreatic beta-cells and is released in response to an increase in blood glucose levels (hyperglycaemia). By contrast, glucagon is synthesized by pancreatic alpha-cells and is released in response to a decrease in blood glucose (hypoglycaemia). The principal role of glucagon is to counter the actions of insulin on blood glucose homoeostasis, but it also has diverse non-hyperglycaemic actions. Although Type 1 diabetes is caused by insulin deficiency (insulin-dependent) and can be corrected by insulin replacement, Type 2 diabetes is a multifactorial disease and its treatment is not dependent on insulin therapy alone. Type 2 diabetes in humans is characterized by increased insulin resistance, increased fasting blood glucose, impaired glucose tolerance and the development of glomerular hyperfiltration and microalbuminuria, ultimately leading to diabetic nephropathy and end-stage renal disease. Clinical studies have suggested that an inappropriate increase in hyperglycaemic glucagon (hyperglucagonaemia) over hypoglycaemic insulin (not insulin deficiency until advanced stages) plays an important role in the pathogenesis of Type 2 diabetes. However, for decades, research efforts and resources have been devoted overwhelmingly to studying the role of insulin and insulin-replacement therapy. By contrast, the implication of glucagon and its receptor signalling in the development of Type 2 diabetic metabolic syndromes and end-organ injury has received little attention. The aim of this review is to examine the evidence as to whether glucagon and its receptor signalling play any role(s) in the pathogenesis of Type 2 diabetic renal injury, and to explore whether targeting glucagon receptor signalling remains only a theoretical antidiabetic strategy in Type 2 diabetes or may realize its promise in the future.
胰腺双激素胰岛素和胰高血糖素是调节葡萄糖代谢和体内平衡的阴阳两面。胰岛素主要由胰腺β细胞合成，并在血糖水平升高（高血糖症）时释放。相比之下，胰高血糖素由胰腺α细胞合成，并在血糖降低（低血糖症）时释放。胰高血糖素的主要作用是对抗胰岛素对血糖体内平衡的作用，但它也有多种非高血糖作用。虽然1型糖尿病是由胰岛素缺乏（胰岛素依赖型）引起的，并且可以通过胰岛素替代来纠正，但2型糖尿病是一种多因素疾病，其治疗并不仅依赖于胰岛素治疗。人类2型糖尿病的特征是胰岛素抵抗增加、空腹血糖升高、葡萄糖耐量受损以及肾小球高滤过和微量白蛋白尿的发展，最终导致糖尿病肾病和终末期肾病。临床研究表明，在2型糖尿病的发病机制中，高血糖的胰高血糖素（高胰高血糖素血症）相对于低血糖的胰岛素（直到晚期才出现胰岛素缺乏）不适当增加起着重要作用。然而，几十年来，研究工作和资源一直压倒性地致力于研究胰岛素的作用和胰岛素替代疗法。相比之下，胰高血糖素及其受体信号在2型糖尿病代谢综合征和终末器官损伤发展中的影响很少受到关注。本综述的目的是研究关于胰高血糖素及其受体信号在2型糖尿病肾损伤发病机制中是否起作用的证据，并探讨靶向胰高血糖素受体信号是否仍然只是2型糖尿病中一种理论上的抗糖尿病策略，还是可能在未来实现其前景。
