| BACKGROUND:The increased prevalence of obesity and type 2 diabetes, with the attendant increase in morbidity and mortality, pose a substantial therapeutic challenge. Nevertheless, the rapid increase in the prevalence of obesity-associated disease conditions, including type 2 diabetes in worldwide populations suggests the contribution of environmental factors. A widely accepted explanation lays on the frequent consumption of processed foods with a high-calorie content and the reduction in physical exercise due to sedentary lifestyle in modern urban environment.Recent data collected in several laboratories indicate that AMP-activated protein kinase (AMPK)plays a key role in regulation of carbohydrate and fat metabolism, serving as a metabolic master switch in response to alterations in cellular energy charge. Stresses such as exercise, hypoxia,or prolonged starvation could activate AMPK via increasing intracellular AMP/ATP ratio. Once activated, its classical effect is to phosphorylate and inactivate acetyl-CoA carboxylase(ACC), resulting in a decrease in malonyl-CoA, thus relieving inhibition of CPT1 and facilitating FFA entry into mitochondria forβ-oxidation. Besides regulating fatty acid oxidation,AMPK has been proved recently as a regulator of insulin signaling. AMPK overexpression exhibited enhanced insulin sensitivity. Previous work and other studies have indicated that AMPK exist important roles in liver,skeletal muscle and adipocyte.Adipose tissue produces a variety of adipocytokines such as leptin, adiponectin, resistin,visfatin and omentin, which modulate insulin sensitivity and play a critical role in the regulation of lipid and glucose metabolism. In 2001, the gene affected by the fld mutation was identified using a positional cloning approach, revealing a null mutation in a novel gene (Lpinl Entrez GeneID 14245) encoding a 98 kDa protein that was named lipinl.Lipinl mRNA primarily expressed in adipose tissue,liver and skeletal muscle. The biological activity of lipinl is not well understood now.Lipinl has important roles in glycerolipid biosynthesis and gene regulation, and mutations in the corresponding genes cause lipodystrophy, myoglobinuria, and inflammatory disorders. Lipinl-deficient mice fail to develop subcutaneous and visceral white adipose tissue depots, as well as interscapular brown adipose tissue. In contrast, lipinl overexpression in adipose tissue of lipinl transgenic mice results in increased expression of lipogenic genes, increased lipid storage, and accelerated diet-induced obesity. Studies in mice showed that lipinl gene expression are negatively correlated with obesity and insulin resistance.It has been demonstrated that lipin-1 can localize to the nucleus in adipocytes and hepatocytes, and subcellular localization may be influenced by protein phosphorylation. The role of nuclear lipin-1 may be related to its function as a transcriptional coactivator. Finck and colleagues have shown that lipin-1 is required for the activation of hepatic fatty acid oxidation genes during fasting conditions. Lipin-1 directly interacts with the nuclear receptor PPAR and coactivator PGC-1 in a complex that modulates fatty acid oxidation gene expression. Lipin-1 coactivator activity requires an LxxIL sequence motif within the C-LIP domain.Many experients showed that adipocytokines were related with AMPK pahtyway.We want to know the relationship between Lipinl and AMPK in hepatic resistance.We designed animal experiment with wistar rat fed with high-fat diet, aimed to explore the changes of lipinl and AMPK in liver and analyze the impossible molecular mechanism of hepatic insulin resistance with high fat diet. Based on the animal tests, we select normal and newly diagnosed type 2 diabetes to observe the relationship of Lipinl and insulin resistance.Objective:1. Select normal and newly diagnosed type 2 diabetes patients to observe the relationship of lipinl and insulin resistance. 2. Explore the changes of Lipinl and AMPK in liver and analyze the impossible molecular mechanism of hepatic insulin resistance with high fat diet.Methods:1.Clinical research:From May 2009 to June 2010,One hundred and ninty-two participants were recruited from the outpatient endocrine and metabolic clinics and inpatient of endocrine department in the Second Hospital of ShanDong University; Patients and controls were age and sex matched. Subjects were classified into two groups:107 subjects with normal glucose tolerance (NGT), and 85 subjects with untreated newly diagnosed type 2 diabetes mellitus (T2DM). Diagnoses were based on the diagnostic criteria of World Health Organization (WHO) 2007. Based on BMI, subjects in each group were divided into two subgroups:normal weight (NW) subgroup (BMI...
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