Kushi Ryo, Hirota Yushi, Ogawa Wataru
Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017 Japan.
Diabetol Int. 2020 Jul 15;12(1):62-67. doi: 10.1007/s13340-020-00455-5. eCollection 2021 Jan.
Whereas the genetic basis of insulin sensitivity is determined by variation in multiple genes, mutations of single genes can give rise to profound changes in such sensitivity. Mutations of the insulin receptor gene ()-which trigger type A insulin resistance, Rabson-Mendenhall, or Donohue syndromes-and those of the gene for the p85α regulatory subunit of phosphoinositide 3-kinase (), which give rise to SHORT syndrome, are the most common and second most common causes, respectively, of single-gene insulin resistance. Loss-of-function mutations of the genes for the protein kinase Akt2 () or for TBC1 domain family member 4 () have been identified in families with severe insulin resistance. Gain-of-function mutations of the gene for protein tyrosine phosphatase nonreceptor type 11 (), which negatively regulates insulin receptor signaling, give rise to Noonan syndrome, and some individuals with this syndrome manifest insulin resistance. Gain-of-function mutations of the gene for the p110α catalytic subunit of phosphoinositide 3-kinase () have been identified in individuals with segmental overgrowth or megalencephaly, some of whom also manifest spontaneous hypoglycemia. A gain-of-function mutation of was also found in individuals with recurrent hypoglycemia. Loss-of-function mutations of the gene for phosphatase and tensin homolog (), another negative regulator of insulin signaling, give rise to Cowden syndrome in association with exaggerated metabolic actions of insulin. Clinical manifestations of individuals with such mutations of genes related to insulin signaling thus provide insight into the essential function of such genes in the human body.
胰岛素敏感性的遗传基础由多个基因的变异决定，而单基因的突变可导致这种敏感性发生深刻变化。胰岛素受体基因（引发A型胰岛素抵抗、拉布森 - 门登霍尔综合征或多诺霍综合征）的突变，以及磷脂酰肌醇3激酶p85α调节亚基基因（引发SHORT综合征）的突变，分别是单基因胰岛素抵抗最常见和第二常见的原因。在患有严重胰岛素抵抗的家族中，已鉴定出蛋白激酶Akt2基因（）或TBC1结构域家族成员4基因（）的功能丧失突变。蛋白酪氨酸磷酸酶非受体11型基因（负向调节胰岛素受体信号传导）的功能获得性突变会导致努南综合征，该综合征的一些患者表现出胰岛素抵抗。在患有节段性过度生长或巨脑症的个体中，已鉴定出磷脂酰肌醇3激酶p110α催化亚基基因（）的功能获得性突变，其中一些人还表现出自发性低血糖。在复发性低血糖患者中也发现了的功能获得性突变。磷酸酶和张力蛋白同源物基因（胰岛素信号的另一个负向调节因子）的功能丧失突变会导致考登综合征，并伴有胰岛素的过度代谢作用。因此，具有此类胰岛素信号相关基因突变的个体的临床表现有助于深入了解这些基因在人体中的基本功能。
