Activation of Atypical PKC by Insulin and Other Agonists

胰岛素和其他激动剂对非典型 PKC 的激活

• 批准号: 8103734
• 负责人: ROBERT V FARESE
• 金额: $ 38.88万
• 依托单位: ROSKAMP INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8103734
• 关键词: 1-Phosphatidylinositol 3-Kinase; Accounting; Acute; Adipocytes; Adult; Agonist; Alleles; Binding Proteins; Biochemical; Blood Circulation; Blood Glucose; Carbohydrates; Cardiovascular Diseases; Central obesity; Defect; Development; Disease; Elements; Enzymes; Fatty acid glycerol esters; Gluconeogenesis; Glucose; Glucose Intolerance; Health; Heart; Hepatic; Hepatocyte; High Density Lipoprotein Cholesterol; Human; Hyperglycemia; Hyperinsulinism; Hyperlipidemia; Hypertension; Hypertriglyceridemia; Insulin; Insulin Resistance; Knock-out; Knockout Mice; LDL Cholesterol Lipoproteins; Lipids; Liver; Mediating; Metabolic; Metabolic syndrome; Methods; Modeling; Molecular; Multiple Abnormalities; Mus; Muscle; Mutagenesis; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Phosphoenolpyruvate Carboxylase; Population; Production; Protein Kinase C Inhibitor; Reporting; Rodent; Rodent Model; Serum; Signal Transduction; Site; Skeletal Muscle; Sterols; Therapeutic Agents; Tissues; Triglycerides; Up-Regulation; adenoviral-mediated; atypical protein kinase C; cytokine; effective therapy; glucose disposal; glucose tolerance; glucose transport; glucose-6-phosphatase; hypercholesterolemia; improved; inhibitor/antagonist; insulin signaling; mouse model; novel; novel strategies; novel therapeutics; receptor; restoration

DESCRIPTION (provided by applicant): We have (a) defined upstream activators of atypical protein kinase C (aPKC) and Akt during insulin action in muscle, adipocytes and liver and (b) showed that aPKC is required for insulin-stimulated increases in glucose transport in muscle and adipocytes and activation of lopogenic enzymes in liver. Also, in multiple rodent models of obesity (O) and type 2 diabetes mellitus (T2DM), we defined the following tissue-specific defects in insulin signaling factors: (a) aPKC activation is impaired in muscle and adipocytes in all O and T2DM models via diminished IRS-1-dependent phosphatidylinositol 3-kinase (PI3K) activation, but, in contrast, fully conserved in liver via IRS-2-dependent PI3K; and (b) Akt activation is impaired via diminished IRS-1/PI3K activation in muscle in most O and T2DM models, and in liver in all T2DM models. Selective conservation of hepatic IRS-2/aPKC activation in O and T2DM is problematic, as hyperinsulinemia therein causes excessive activation of sterol receptor element binding protein-1c (SREBP-1c), which increases expression of multiple enzymes that control hepatic lipid synthesis, and this upregulation provokes many "metabolic syndrome" (MS) abnormalities. Indeed, using adenoviral-mediated expression methods, selective inhibition of hepatic aPKC in multiple O/MS and T2DM models elicits rapid and dramatic improvements in hepatosteatosis, hyperlipidemia, glucose intolerance, hyperinsulinemia, and insulin signaling in muscle and liver; also, as an added benefit, inhibition of hepatic aPKC surprisingly diminishes expression of glucogenic enzymes, phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase). In other words, hepatic aPKC inhibition has insulin-like effects on these hepatic enzymes that regulate blood glucose levels. Similarly, in preliminary studies, two newly discovered highly specific aPKC inhibitors preferentially inhibited hepatic aPKC and thereby diminished expression of hepatic enzymes that promote both lipid and glucose synthesis/release in both human hepatocytes and intact rodent liver; furthermore, in an mouse model of O/MS/T2DM, these biochemical agents selectively inhibited hepatic aPKC and this was attended by (a) a rapid and complete or nearly complete reversal of O/MS features, viz., abdominal obesity, hepatosteatosis, and hypertriglyceridemia and (b) restoration of insulin signaling in muscle, fat and liver, and normalization of serum glucose-lowering effects of insulin. Clearly, we need to further develop agents that selectively diminish aPKC activation in liver and thereby effectively control O/MS and T2DM. Accordingly, there is an urgent need to: Specific Aim 1, define insulin signaling mechanisms and consequences of aPKC inhibition in human hepatocytes; Specific Aim 2, elucidate molecular mechanisms for aPKC activation; and Specific Aim 3, further develop our novel biochemical inhibitors of hepatic aPKC and define their metabolic effects in mouse O/MS/T2DM models. We are confident that the proposed studies will provide a new approach for effective treatment of O/MS and T2DM. PUBLIC HEALTH RELEVANCE: These findings will provide new avenues for finding treatments for the metabolic syndrome and type 2 diabetes, which together are estimated to cause at least 50% of the cardiovascular disorders seen in the US population, and which are exceedingly costly health issues.

描述（由申请人提供）：我们（a）在胰岛素，脂肪细胞和肝脏中胰岛素作用过程中，非典型蛋白激酶C（APKC）和AKT定义上游激活剂，（b）表明，APKC是胰岛素刺激的肌肉和脂肪细胞中胰岛素刺激性增加的胰岛素刺激增加所必需的。同样，在多种肥胖（O）和2型糖尿病（T2DM）的啮齿动物模型中，我们在胰岛素信号传导因素中定义了以下组织特异性缺陷：（a）APKC激活在所有O和T2DM模型中通过IRS-1依赖性磷酸3-依赖性磷酸3-依赖性磷酸3-依赖性的肌肉和T2DM模型中的肌肉和脂肪细胞受损相反，通过IRS-2依赖性PI3K在肝脏中完全保守； （b）在大多数O和T2DM模型中的肌肉中的IRS-1/PI3K激活以及所有T2DM模型中的肝脏中的IRS-1/PI3K激活降低，AKT激活受到损害。 Selective conservation of hepatic IRS-2/aPKC activation in O and T2DM is problematic, as hyperinsulinemia therein causes excessive activation of sterol receptor element binding protein-1c (SREBP-1c), which increases expression of multiple enzymes that control hepatic lipid synthesis, and this upregulation provokes many "metabolic syndrome" (MS) abnormalities.实际上，使用腺病毒介导的表达方法，在多个O/MS和T2DM模型中对肝APKC的选择性抑制引起了肝抑制病，高脂血症，葡萄糖不耐症，高胰岛素高胰岛素血症以及肌肉和肝脏中的胰岛素信号的快速和急剧改善；同样，作为额外的好处，肝APKC的抑制作用令人惊讶地降低了糖原酶，磷酸烯醇丙酮酸羧基酶（PEPCK）和葡萄糖-6-磷酸酶（G6Pase）的表达。换句话说，肝APKC抑制作用对调节血糖水平的这些肝酶具有类似胰岛素样的作用。同样，在初步研究中，两种新发现的高度特异性APKC抑制剂优先抑制肝APKC，从而减少肝酶的表达，这些肝酶在人肝细胞和完整的啮齿动物植物肝脏中均促进脂质和葡萄糖的合成/释放。 furthermore, in an mouse model of O/MS/T2DM, these biochemical agents selectively inhibited hepatic aPKC and this was attended by (a) a rapid and complete or nearly complete reversal of O/MS features, viz., abdominal obesity, hepatosteatosis, and hypertriglyceridemia and (b) restoration of insulin signaling in muscle, fat and liver, and normalization of serum胰岛素降低葡萄糖作用。显然，我们需要进一步开发有效地减少肝脏中APKC激活的剂，从而有效控制O/MS和T2DM。因此，迫切需要：特定目标1，定义胰岛素信号传导机制和APKC抑制作用在人肝细胞中的后果；特定的目标2，阐明分子机制以激活APKC；和特定的目标3，进一步开发了我们新型的肝APKC生化抑制剂，并定义了它们在小鼠O/MS/T2DM模型中的代谢作用。我们相信拟议的研究将为O/MS和T2DM有效治疗提供一种新的方法。 公共卫生相关性：这些发现将为寻找代谢综合征和2型糖尿病的治疗方法提供新的途径，据估计，这些糖尿病至少会引起至少50％的心血管疾病，这些心血管疾病在美国人群中至少会引起其成本高昂的健康问题。