Type II diabetes mellitus

Insulin resistance is strongly associated with type II diabetes. "Diabetogenic" factors including FFA, TNFalpha and cellular stress induce insulin resistance through inhibition of IRS1 functions. Serine/threonine phosphorylation, interaction with SOCS, regulation of the expression, modification of the cellular localization, and degradation represent the molecular mechanisms stimulated by them. Various kinases (ERK, JNK, IKKbeta, PKCzeta, PKCtheta and mTOR) are involved in this process. The development of type II diabetes requires impaired beta-cell function. Chronic hyperglycemia has been shown to induce multiple defects in beta-cells. Hyperglycemia has been proposed to lead to large amounts of reactive oxygen species (ROS) in beta-cells, with subsequent damage to cellular components including PDX-1. Loss of PDX-1, a critical regulator of insulin promoter activity, has also been proposed as an important mechanism leading to beta-cell dysfunction. Although there is little doubt as to the importance of genetic factors in type II diabetes, genetic analysis is difficult due to complex interaction among multiple susceptibility genes and between genetic and environmental factors. Genetic studies have therefore given very diverse results. Kir6.2 and IRS are two of the candidate genes. It is known that Kir6.2 and IRS play central roles in insulin secretion and insulin signal transmission, respectively.

胰岛素抵抗与2型糖尿病的关联紧密。诸如自由脂肪酸（FFA）、肿瘤坏死因子α（TNFalpha）和细胞应激等“糖尿病原性”因素，通过抑制胰岛素受体底物1（IRS1）的功能，诱发胰岛素抵抗。由这些因素激发的分子机制包括丝氨酸/苏氨酸磷酸化、与SOCS的相互作用、表达调控、细胞定位的修饰以及降解。在胰岛素分泌和胰岛素信号传导中，各种激酶（如ERK、JNK、IKKbeta、PKCzeta、PKCtheta和mTOR）参与了这一过程。2型糖尿病的发展需要β细胞功能的障碍。慢性高血糖已被证实可诱导β细胞出现多种缺陷。高血糖被认为会在β细胞中产生大量的活性氧（ROS），从而对包括PDX-1在内的细胞成分造成损害。PDX-1的丧失，作为胰岛素启动子活性的关键调节因子，也被提出是导致β细胞功能障碍的重要机制之一。尽管在2型糖尿病中遗传因素的重要性无可置疑，但由于多个易感基因之间以及遗传与环境因素之间的复杂相互作用，遗传分析变得困难。因此，遗传研究的结果极为多样。Kir6.2和IRS是候选基因中的两个。已知Kir6.2和IRS分别在胰岛素分泌和胰岛素信号传导中扮演核心角色。