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)

Life expectancy in the developed world is increasing, but this comes with a simultaneous explosion in 'age-related' as well as 'lifestyle-related' diseases, resulting in a decline in quality of life. Three such diseases are Type 2 diabetes mellitus (T2DM), Polycystic Ovarian Syndrome (PCOS) and non-alcoholic fatty liver disease (NAFLD), which all share a common reduced cellular response to the hormone insulin (termed insulin resistance). In T2DM, insulin resistance is clearly a contributing factor to disease progression, and is associated with obesity, the single greatest risk factor for all three conditions. Current research is focused on identifying the initial molecular lesion that results in reduced sensitivity to insulin, as improving insulin sensitivity would be beneficial to the prognosis of these conditions. However, the bulk of evidence suggests that more than one molecular defect in the insulin signalling pathway can lead to an insulin resistant phenotype. This raises the possibility that individuals with the same clinical phenotype may have distinct molecular reasons for the presence of the syndrome, and that the specific lesion influences the rate and direction of progression to the associated disease. Clearly the same insulin sensitiser could be of equal benefit in each disorder, if it reversed multiple signalling problems, however we suggest that appropriate molecular diagnosis of the defect may lead to a more targeted and effective therapeutic approach. This review discusses the molecular pathology of insulin resistance in relation to T2DM, PCOS and NASH. We highlight the shortcomings of current therapies, and suggest potential novel drug targets for each disorder.
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PMID:Dissecting insulin signaling pathways: individualised therapeutic targets for diagnosis and treatment of insulin resistant states. 1951 67

Metabolic syndrome (MS) is one of the most prevalent disease states in the so-called developed countries and is closely associated with the incidence of cardiovascular as well as other diseases. Predominant sign is the abdominal type of obesity with increased visceral fat mass and the associated insulin resistance. Glucose metabolism disorder, dyslipidemia and arterial hypertension are other important attributes. Metabolic syndrome is also closely associated with the liver steatosis, mostly benign and reversible liver disease. Nevertheless, uncomplicated steatosis may, under certain conditions, progress to inflammation and the disease may, through the stage of NASH (nonalcoholic steatohepatitis) and liver fibrosis, result in liver cirrhosis and hepatocellular carcinoma. Anglo-Saxon literature uses the term NAFLD (non-alcoholic fatty liver disease) to refer to these various stages ofthe liver disease (uncomplicated liver steatosis, steatohepatitis, fibrosis and cirrhosis). While simple steatosis is not dangerous for the patient, NASH is the sign of developing cirrhosis. Etiopathogenesis of NASH features identical characteristics as etiopathogenesis of insulin resistance and metabolic syndrome. Even though liver biopsy remains the gold standard in the diagnosis, new diagnostic approaches are emerging that could be useful in distinguishing simple steatosis from NASH. Therapy includes lifestyle changes, insulin resistance-reducing medication (also useful in the treatment of type 2 diabetes) with a range of other agents under development. In the meantime, randomized double-blind placebo-controlled studies with histological proof of the results are still lacking. A range of unresolved issues remains with regards to etiopathogenesis as well as diagnosis and treatment of NAFLD and NASH.
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PMID:[Metabolic syndrome and the liver (NAFLD/NASH)]. 1973 69

Excess lipid accumulation in nonadipose tissues may occur in the setting of high levels of plasma free fatty acids or triglycerides (TGs) in a process called "lipotoxicity". Evidence from human studies and animal models suggests that lipid accumulation in the heart, skeletal muscle, pancreas, and liver play an important role in the pathogenesis of heart failure, obesity, metabolic syndrome, and type 2 diabetes mellitus (T2DM). During the past few years, several studies have shown that n-3 polyunsaturated fatty acids (PUFA) have potentially cardioprotective effects, especially in high-risk patients with dyslipidemia, and might therefore be expected to be of benefit in T2DM. Moreover, new information has demonstrated the beneficial effects of consuming n-3 PUFA in preventing the complications of lipotoxicity. n-3 PUFA dietary intake thus had positive effects on fatty liver in patients with non-alcoholic fatty liver disease (NAFLD), with an improvement in liver echotexture and a significant regression of hepatic brightness, associated with improved liver hemodynamics. The n-3 PUFA also had beneficial effects on ectopic fat accumulation inside the heart, with stabilization of cardiac myocytes and antiarrhythmic effects. On the other hand, recent data from animal models suggest that oral dosing of eicosapentaenoic acid (EPA) could contribute to protect against beta-cell lipotoxicity. This review discusses the latest hypotheses regarding lipotoxicity, concentrating on the impact of the n-3 PUFA that contribute to ectopic lipid storage, affecting organ function. Further human studies are needed to test the evidence and elucidate the mechanisms involved in this process.
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PMID:n-3 PUFA and lipotoxicity. 1978 63

Fifty years of the Gastroenterological Society of Australia have witnessed the changing appearance of Australians. Asian immigration has transformed the dominant urban culture from European to Eurasian, with some unique Australian attributes. Meanwhile, global conditions have altered body shape, and our sports-proud country is now fat! Thus, as in North America, Europe, China, and affluent Asia-Pacific countries, prosperity and lifestyle, cheap processed foods coupled with reduced physical activity have created an epidemic of over-nutrition resulting in overweight/obesity. Additional genetic factors are at the core of the apple shape (central obesity) that typifies over-nourished persons with metabolic syndrome. Indigenous Australians, once the leanest and fittest humans, now have exceedingly high rates of obesity and type 2 diabetes, contributing to shorter life expectancy; Asian Australians are also at higher risk. Like non-steroidal anti-inflammatory drugs (NSAIDs) and cigarette smoking, obesity now contributes much to gastrointestinal morbidity and mortality (gastroesophageal reflux disease, cancers, gallstones, endoscopy complications). This review focuses on Australian research about fatty liver, particularly roles of central obesity/insulin resistance in non-alcoholic fatty liver disease/steatohepatitis (NAFLD/NASH). The outputs include many highly cited original articles and reviews and the first book on NAFLD. Studies have identified community prevalence, clinical outcomes, association with insulin resistance, metabolic syndrome and hypoadiponectinemia, developed and explored animal models for mechanisms of inflammation and fibrosis, conceptualized etiopathogenesis, and demonstrated that NASH can be reversed by lowering body weight and increasing physical activity. The findings have led to development of regional guidelines on NAFLD, the first internationally, and should now inform daily practice of gastroenterologists.
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PMID:The liver and the waistline: Fifty years of growth. 1979 88

Metabolic consequences of obesity including insulin resistance, type 2 diabetes mellitus, hyperlipidemia, hypertension, polycystic ovarian syndrome, and non-alcoholic fatty liver infiltration are rapidly emerging in the pediatric population. Identifying effective strategies for identifying and treating these obesity related comorbidities in children are crucial to the prevention of future cardiovascular disease and poor health outcomes.This review discusses the pathophysiologic connections between obesity, metabolic disease and cardiovascular risk. Current evidence and recommendations for screening and treatment for the metabolic consequences of pediatric obesity are reviewed.
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PMID:Identification and treatment of metabolic complications in pediatric obesity. 1980 79

The metabolic syndrome (MetS) represents a combination of cardiometabolic risk determinants including obesity (central adiposity), insulin resistance, glucose intolerance, dyslipidaemia, non-alcoholic fatty liver disease and hypertension. MetS is rapidly increasing in prevalence worldwide as a consequence of the continued obesity "epidemic", and as a result will have a considerable impact on the global incidence of cardiovascular disease and type 2 diabetes. Currently, there is debate concerning whether the risk of cardiovascular disease is greater in patients diagnosed with MetS than that of the sum of the individual risk factors. At present, no unifying origin that can explain the pathogenesis of MetS has been identified and therefore no unique pharmacological treatment is available. This review summarises and critically evaluates the current clinical and scientific evidence supporting the existence of MetS as a multifactorial endocrine disease, for which maternal nutrition may be a common pathogenic mechanism. In addition, we suggest that ectopic fat accumulation (such as visceral and hepatic fat accumulation) and the proinflammatory state are central to the development of the MetS.
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PMID:The metabolic syndrome: common origins of a multifactorial disorder. 1989 97

Lipid biosynthesis is essential for the maintenance of cellular homeostasis. The lipids produced by cells (glycerolipids, fatty acids, phospholipids, cholesterol, and sphingolipids) are used as an energy source/reserve, as building blocks for membrane biosynthesis, as precursor molecules for the synthesis of various cellular products, and as signaling molecules. Defects in lipid synthesis or processing contribute to the development of many diseases, including obesity, insulin resistance, type 2 diabetes, non-alcoholic fatty liver disease, and cancer. Studies published over the last few years have shown that the target of rapamycin (TOR), a conserved serine/threonine kinase with an important role in regulating cell growth, controls lipid biosynthesis through various mechanisms. Here, we review these findings and briefly discuss their potential relevance for human health and disease.
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PMID:An emerging role of mTOR in lipid biosynthesis. 1994 45

The excessive supply of fatty acids to the liver contributes to hepatic insulin resistance and endoplasmic reticulum (ER) stress associated with obesity or type 2 diabetes mellitus. Furthermore, excess and/or prolonged ER stress contributes to hepatic cell death deteriorating nonalcoholic fatty liver disease to steatohepatitis. The aim of this study was to investigate the effects of metformin on palmitate-induced ER stress and hepatic insulin resistance in HepG2 cells. Metformin significantly inhibited palmitate-induced cell death and apoptosis via caspase-3 activation. Metformin also blocked the induction of ER stress proteins (GRP78, Chop, Cleaved ATF-6, p-eIF2 alpha and XBP-1) and regulated serine phosphorylation of IRS-1. Metformin may therefore protect hepatocytes from death induced by saturated fatty acids. These data may also provide a further rationale for exploring the use of metformin in the treatment of non-alcoholic fatty liver disease, revealing its blocking effect for hepatic insulin resistance evoked by saturated fatty acids.
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PMID:Metformin regulates palmitate-induced apoptosis and ER stress response in HepG2 liver cells. 2003 65

Polyunsaturated fatty acids (PUFAs) form an important constituent of all the cell membranes in the body. PUFAs such as arachidonic acid (AA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) form precursors to both pro-inflammatory and anti-inflammatory compounds. Low-grade systemic inflammation occurs in clinical conditions such as insulin resistance, hypertension, type 2 diabetes mellitus, atherosclerosis, coronary heart disease, lupus, schizophrenia, Alzheimer's disease, and other dementias, cancer and non-alcoholic fatty liver disease (NAFLD) that are also characterized by an alteration in the metabolism of essential fatty acids in the form of excess production of pro-inflammatory eicosanoids and possibly, decreased synthesis and release of anti-inflammatory lipoxins, resolvins, protectins and maresins. We propose that low-grade systemic inflammation observed in these clinical conditions is due to an imbalance in the metabolism of essential fatty acids that is more in favour of pro-inflammatory molecules. In this context, transgenic fat-1 mouse that is designed to convert n-6 to n-3 fatty acids could form an ideal model to study the altered metabolism of essential fatty acids in the above mentioned conditions. It is envisaged that low-grade systemic inflammatory conditions are much less likely in the fat-1 mouse and/or these diseases will run a relatively mild course. Identifying the anti-inflammatory compounds from n-3 fatty acids that suppress low-grade systemic inflammatory conditions and understanding their mechanism(s) of action may lead to newer therapeutic strategies.
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PMID:Transgenic fat-1 mouse as a model to study the pathophysiology of cardiovascular, neurological and psychiatric disorders. 2004 3

Bariatric surgery is known to be the most effective and long lasting treatment for morbid obesity and many related conditions, but now mounting evidence suggests it may be among the most effective forms of treatment for metabolic diseases and conditions including type 2 diabetes, hypertension, high cholesterol levels, non-alcoholic fatty liver disease and obstructive sleep apnea. Surgery for severe obesity goes way beyond weight loss. This surgery results in the complete remission or significant improvement of type 2 diabetes and other life-threatening diseases in most patients. The new name metabolic surgery was created and reflects this expanded and evolving view of surgery. Therefore, metabolic surgery is expected to play an ever increasing role in managing these diseases. New research results indicate that metabolic surgery may improve insulin resistance and secretion by mechanisms independent of weight loss, most likely involving changes in gastrointestinal hormones. Many patients with type 2 diabetes experience complete remission within days of metabolic surgery, long before significant weight is lost. This has led to a new concept that metabolic surgery may also be appropriate for diabetic individuals who are of normal weight or only slightly overweight.
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PMID:[Indications and principles of metabolic surgery]. 2036 70


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