Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Conjugated linoleic acid (CLA) is a naturally occurring fatty acid which has anti-carcinogenic and anti-atherogenic properties. CLA activates PPAR alpha in liver, and shares functional similarities to ligands of PPAR gamma, the thiazolidinediones, which are potent insulin sensitizers. We provide the first evidence that CLA is able to normalize impaired glucose tolerance and improve hyperinsulinemia in the pre-diabetic ZDF rat. Additionally, dietary CLA increased steady state levels of aP2 mRNA in adipose tissue of fatty ZDF rats compared to controls, consistent with activation of PPAR gamma. The insulin sensitizing effects of CLA are due, at least in part, to activation of PPAR gamma since increasing levels of CLA induced a dose-dependent transactivation of PPAR gamma in CV-1 cells cotransfected with PPAR gamma and PPRE X 3-luciferase reporter construct. CLA effects on glucose tolerance and glucose homeostasis indicate that dietary CLA may prove to be an important therapy for the prevention and treatment of NIDDM.
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PMID:Dietary conjugated linoleic acid normalizes impaired glucose tolerance in the Zucker diabetic fatty fa/fa rat. 953 24

Type 2 diabetes and associated cardiovascular disease have reached global epidemic proportions. Recent data from the World Health Organization Multinational Study of Vascular Disease in Diabetes indicate that cardiovascular disease is the leading cause of mortality (52% of deaths) in individuals with type 2 diabetes. Although insulin resistance plays a critical role in the pathogenesis of type 2 diabetes-related cardiovascular disease, other related risk factors often cluster in a single patient; the combination of insulin resistance and these risk factors is known as the metabolic syndrome. According to the World Health Organization definition, this constellation of risk factors includes hypertension, elevated plasma triacylglycerol, reduced HDL cholesterol, central obesity, and microalbuminuria. The Multiple Risk Factor Intervention Trial showed that, although diabetes or insulin resistance is an independent risk factor for cardiovascular disease mortality, these other components of the metabolic syndrome confer additive risk. Thus, to effectively address cardiovascular disease in persons with diabetes, intervention would ideally target all these factors. Conjugated linoleic acid could represent a candidate agent. The therapeutic potential of conjugated linoleic acid against insulin resistance-associated cardiovascular disease is discussed on the basis of the reported effects of conjugated linoleic acid on individual components of the metabolic syndrome.
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PMID:Insulin resistance-associated cardiovascular disease: potential benefits of conjugated linoleic acid. 1515 51

Several recent reports suggest that stearoyl-CoA desaturase 1 (SCD1), the rate-limiting enzyme in monounsaturated fatty acid synthesis, plays an important role in regulating lipid homeostasis and lipid oxidation in metabolically active tissues. As several manifestations of type 2 diabetes and related metabolic disorders are associated with alterations in intracellular lipid partitioning, pharmacological manipulation of SCD1 activity might be of benefit in the treatment of these disease states. In an effort to identify small molecule inhibitors of SCD1, we have developed a mass spectrometry based high-throughput screening (HTS) assay using deuterium labeled stearoyl-CoA substrate and induced rat liver microsomes. The methodology developed allows the use of a nonradioactive substrate which avoids interference by the endogenous SCD1 substrate and/or product that exist in the non-purified enzyme source. Throughput of the assay was up to twenty 384-well assay plates per day. The assay was linear with protein concentration and time, and was saturable for stearoyl-CoA substrate (K(m)=10.5 microM). The assay was highly reproducible with an average Z' value=0.6. Conjugated linoleic acid and sterculic acid, known inhibitors of SCD1, exhibited IC(50) values of 0.88 and 0.12 microM, respectively. High-throughput mass spectrometry screening of over 1.7 million compounds in compressed format demonstrated that the enzyme target is druggable. A total of 2515 hits were identified (0.1% hit rate), and 346 were confirmed active (>40% inhibition of total SCD activity at 20 microM--14% conformation rate). Of the confirmed hits 172 had IC(50) values of <10 microM, including 111 <1 microM and 48 <100 nM. A large number of potent drug-like (MW<450) hits representing six different chemical series were identified. The application of mass spectrometry to high-throughput screening permitted the development of a high-quality screening protocol for an otherwise intractable target, SCD1. Further medicinal chemistry and characterization of SCD inhibitors should lead to the development of reagents to treat metabolic disorders.
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PMID:Development of a high-throughput screening assay for stearoyl-CoA desaturase using rat liver microsomes, deuterium labeled stearoyl-CoA and mass spectrometry. 1879 Jan 33

Conjugated linoleic acid (CLA) is a group of positional and geometric isomers of conjugated dienoic derivatives of linoleic acid. CLA has been reported to be able to reduce body fat. In this study, we investigated the antidiabetic effect of fermented milk (FM) containing CLA on type II diabetes db/db mice. Mice were treated with 0.2% low FM, 0.6% high FM, or Glimepiride (GLM) for 6 wk. Our results revealed that the body weight and the levels of fasting blood glucose, serum insulin, and leptin were significantly decreased in FM fed mice compared to db/db mice. Oral glucose tolerance and insulin tolerance were significantly ameliorated in FM fed mice compared to db/db mice. Consistent with these results, the concentrations of serum total cholesterol, triglycerides, and LDL cholesterol were also significantly decreased in FM fed mice compared to db/db mice. However, the concentration of HDL cholesterol was significantly higher in FM fed mice compared to db/db mice. These results were similar to those of GLM, a commercial anti-diabetic drug. Therefore, our results suggest that FM has anti-diabetic effect as a functional food to treat type II diabetes mellitus.
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PMID:Anti-diabetic Effect of Fermented Milk Containing Conjugated Linoleic Acid on Type II Diabetes Mellitus. 2719 24

Obesity and its comorbidities, including type 2 diabetes and cardiovascular disease, are straining our healthcare system, necessitating the development of novel strategies for weight loss. Lifestyle modifications, such as exercise and caloric restriction, have proven effective against obesity in the short term, yet obesity persists because of the high predilection for weight regain. Therefore, alternative approaches to achieve long term sustainable weight loss are urgently needed. Conjugated linoleic acid (CLA), a fatty acid found naturally in ruminant animal food products, has been identified as a potential anti-obesogenic agent, with substantial efficacy in mice, and modest efficacy in obese human populations. Originally described as an anti-carcinogenic fatty acid, in addition to its anti-obesogenic effects, CLA has now been shown to possess anti-atherosclerotic properties. This review summarizes the pre-clinical and human studies conducted using CLA to date, which collectively suggest that CLA has efficacy against cancer, obesity, and atherosclerosis. In addition, the potential mechanisms for the many integrative physiological effects of CLA supplementation will be discussed in detail, including an introduction to the gut microbiota as a potential mediator of CLA effects on obesity and atherosclerosis.
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PMID:Conjugated Linoleic Acid Effects on Cancer, Obesity, and Atherosclerosis: A Review of Pre-Clinical and Human Trials with Current Perspectives. 3075 81