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Lmptp Diabetes Reversal

Diabetes Reversal By Inhibition Of The Low-molecular-weight Tyrosine Phosphatase

Diabetes Reversal By Inhibition Of The Low-molecular-weight Tyrosine Phosphatase

Equine metabolic syndrome (EMS) is a cluster of metabolic disorders, such as obesity, hyperinsulinemia, and hyperleptinemia, as well as insulin resistance (IR). In accordance with the theory linking obesity and IR, excessive accumulation of lipids in insulin-sensitive tissues (lipotoxicity), like liver, alters several cellular functions, including insulin signaling. Therefore, the purpose of the study was to isolate equine hepatic progenitor-like cells (HPCs) and assess whether inhibition of low molecular weight protein tyrosine phosphatase (LMPTP) affects the expression of genes involved in macroautophagy, chaperone-mediated autophagy (CMA), endoplasmic reticulum stress, and mitochondrial dynamics in a palmitate-induced IR model. We demonstrated that LMPTP inhibition significantly enhanced expression of heat shock cognate 70 kDa protein (HSC70), lysosome-associated membrane protein 2 (LAMP2), and parkin (PRKN), all master regulators of selective autophagy. We also observed downregulation of C/EBP homologous protein (CHOP), activating transcription factor 6 (ATF6) and binding immunoglobulin protein encoded by the HSPA gene. Moreover, LMPTP inhibition increased alternative splicing of X-box binding protein 1 (XBP1), suggesting high endonuclease activity of inositol-requiring enzyme 1 alpha (IRE1). Taken together, our data provide convincing evidence that LMPTP inhibition reverses palmitate-induced insulin resistance and lipotoxicity. In conclusion, this study highlights the role of LMPTP in the regulation of CMA, mitophagy, and ER stress, and provides a new in vitro model for studying HPC lipotoxicity in pre-clinical research. Protein tyrosine phosphatases (PTPs), of the receptor and non-receptor classes, are key signaling molecules that play critical roles in cellular Continue reading >>

Is There Cure For Type 2 Yet

Is There Cure For Type 2 Yet

Diabetes Forum The Global Diabetes Community Find support, ask questions and share your experiences. Join the community Type 2 diabetes is estimated to affect more than one in sixteen people in the UK. Most of these are diagnosed, but there are still around half a million people who are unaware that the condition is affecting their body. When it is diagnosed, though, what can doctors do to stop it? Medication can regulate blood sugar levels, which counteracts the effects to some extent. But in a breakthrough study, scientists may have found a way to cure type 2 diabetes. According to the Medical Research Council, nearly four million people in the UK have diabetes. And the vast majority around 90 percent are suffering specifically from type 2 diabetes rather than type 1. Heres the difference: Type 1 diabetes: An autoimmune condition where the pancreas is damaged and cannot produce any insulin Type 2 diabetes: A condition which develops largely due to a persons diet and weight. The pancreas becomes unable to produce enough insulin, or the bodys cells fail to react to insulin Some people are genetically predisposed to type 2 diabetes, but it is generally brought on by long-term overweightness increasing in likelihood with age. And much like other weight-related diseases, doctors have so far only been able to recommend lifestyle changes to reduce its impact. While type 2 diabetes is a significant problem in the UK, over in the states its even worse. Around 1 in 11 Americans have type 2 diabetes. And a large amount of them are suffering specifically because of insulin resistance. Touched upon above, this is where the bodys cells cannot take in insulin as normal as opposed to insufficient insulin being produced. This prompted researchers at the University of California to se Continue reading >>

Diabetes Reversal By Inhibition Of The Low-molecular-weight Tyrosine Phosphatase.

Diabetes Reversal By Inhibition Of The Low-molecular-weight Tyrosine Phosphatase.

Nat Chem Biol. 2017 Jun;13(6):624-632. doi: 10.1038/nchembio.2344. Epub 2017 Mar 27. Diabetes reversal by inhibition of the low-molecular-weight tyrosine phosphatase. Division of Cellular Biology, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA. Department of Medicine, University of California, San Diego, La Jolla, California, USA. Infectious and Inflammatory Disease Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA. Conrad Prebys Center for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA. Center for Proteomics and Bioinformatics, Case Western Reserve University, Cleveland, Ohio, USA. Institute for Genetic Medicine, University of Southern California, Los Angeles, California, USA. Department of Respiratory, Inflammation and Autoimmunity, MedImmune LLC, Gaithersburg, Maryland, USA. Department of Orthopaedic Surgery and Department of Pediatrics, University of California, San Diego, La Jolla, California, USA. Obesity-associated insulin resistance plays a central role in type 2 diabetes. As such, tyrosine phosphatases that dephosphorylate the insulin receptor (IR) are potential therapeutic targets. The low-molecular-weight protein tyrosine phosphatase (LMPTP) is a proposed IR phosphatase, yet its role in insulin signaling in vivo has not been defined. Here we show that global and liver-specific LMPTP deletion protects mice from high-fat diet-induced diabetes without affecting body weight. To examine the role of the catalytic activity of LMPTP, we developed a small-molecule inhibitor with a novel uncompetitive mechanism, a unique binding site at the opening of the catalytic pocket, and an exquisite selectivity over other phosphatases. This inhibitor is orally bioavai Continue reading >>

A New Drug May Be Able To Completely Reverse Diabetes

A New Drug May Be Able To Completely Reverse Diabetes

Scientists have used a new drug to reverse diabetes in mice. The drug inhibits the enzyme LMPTP, which contributes to the development of Type 2 diabetes by weakening the body's sensitivity to the hormone. Defining Diabetes In the global community, the number of people with diabetes has been on the rise since 1980, with 422 million people diagnosed by 2014. The U.S. alone has experienced a substantial rise in the incidence of diabetes, with the number of Americans diagnosed increasing from 5.5 million in 1980, to 22 million in 2014—a more than 300 percent increase in less than 40 years. A team of researchers, led by Stephanie Stanford at the University of California, San Diego, is proposing a solution in the form of a single pill that aims to restore insulin sensitivity in diabetic patients. Type 2 diabetes develops when the body’s response to insulin, the hormone responsible for regulating sugar in our blood, weakens. A number of genetic and lifestyle factors will influence whether or not someone develops this type of diabetes in their lifetime. Up until now, drugs were unable to restore the insulin signaling function in diabetic patients — instead, they work by filtering out excess glucose in the blood that comes as a result of the dysfunction. The drug produced by Stanford’s team, on the other hand, hopes to restore function. Restoring Function The drug inhibits an enzyme called low molecular weight protein tyrosine phosphatase (LMPTP), which is suspected to contribute to the reduction in cell sensitivity to insulin. With reduced LMPTP activity, the drug reenables insulin receptors on the surface of cells — particularly those in the liver — which in turn restores the cell’s ability to regulate excess sugar. When the body can once again regulate blood sug Continue reading >>

Scientists Create A Pill That Can Stop Type 2 Diabetes In Its Tracks

Scientists Create A Pill That Can Stop Type 2 Diabetes In Its Tracks

Here’s a scary thought about one of America’s leading causes of death: in addition to the 29.1 million people who have diabetes, there are 86 million over the age of twenty who are prediabetic. This reality seems pretty daunting, but new research suggests a cure for type 2 diabetes which accounts for 90 percent of cases nationwide. With type 2 diabetes rising at an alarming rate because of obesity in America, this potential cure is not only timely but necessary.[1,2,3] A Very Brief History of Type 2 Diabetes The earliest record of diabetes that we know of is from the year 1552 BC. Physician Hesy-Ra recorded on 3rd Dynasty Egyptian papyrus that frequent urination is a symptom of the disease. Approximately one century later in the year 500 BC, people recorded descriptions of sugar in the urine and noted its occurrence in obese individuals. Because people believed that diabetic urine had a sweet taste, the Latin word for honey – Mellitus – was added to the term ‘diabetes’. In 1776, English physician Matthew Dobson observed diabetic urine. When he evaporated the urine, he found a brown sugar-like substance which both tasted and looked like brown sugar. Dobson noticed this flavor in diabetic blood as well. Upon further study, he observed that diabetes is fatal five weeks or less for some people while, for others, it’s a chronic condition. Dobson’s observations highlight the first time anyone ever made a distinction between type 1 and type 2 diabetes. American physician Frederick Allen believed that diabetics’ bodies couldn’t use food normally. So, in 1916, he promoted a diet that limited what and how much diabetics could eat. Those admitted to the hospital consumed whiskey mixed with black coffee six times a day, five days a week. After this, they’d fol Continue reading >>

New Research Claims To Find Breakthrough Cures For Diabetes

New Research Claims To Find Breakthrough Cures For Diabetes

New Research Claims To Find Breakthrough Cures For Diabetes The CDC recently shocked the public when they reported that40% of Americans walking around today would develop type 2 diabetes. Many people develop type 2 diabetes as they age because their bodys response to insulin the hormone that controls sugar levels gets weaker. Fortunately, scientists have discovered new treatments for the disease and have more in the pipeline. One such drug, ertugliflozin (brand name Steglatro) was released less than a week ago. Moreover, researchers at UCSD are developing a promising new therapy that attacks type 2 diabetes at its cellular roots. Furthermore, doctors have developed a medication maintenance program, which can help prevent type 2 diabetics from health-robbing complications such as blindness, heart and kidney disease, and peripheral vascular disease. There is also hope for type 1 diabetics, as scientists are working on improved insulin delivery devices, replacing damaged pancreases with stem cell-derived islet cells and the novel pancreas in a box that may restore normal insulin regulation. Diabetes has been a documented human disorder for millennia, but only in recent decades has it developed into an epidemic. Mentions of the condition in ancient medical texts are rare. The primary drivers of the worldwide epidemic are the increasing age of the population, and the obesity epidemic, fed by the growing global adoption of the Western diet. Obesity the most significant risk factor for type 2 diabetes is increasing rapidly as a global epidemic which threatens to offset the many medical advances that increase longevity. The Western diet high in fat, sugar, and calories is to blame for the so-called diabesity phenomenon, named for the rampant increase in obesity that is often a Continue reading >>

Diabetes Treatment New Developments: Type 2 Diabetes Reversal With New Drug

Diabetes Treatment New Developments: Type 2 Diabetes Reversal With New Drug

Diabetes Treatment New Developments: Type 2 Diabetes Reversal With New Drug Researchers from the University of California developed a drug that may do a reversal for Type 2 Diabetes. The diabetes treatment new developments make use of the inhibition of an enzyme called LMPTP to restore the insulin sensitivity of diabetics. The team led by Stephanie Stanford has offered a solution to Type 2 diabetes patients. In the form of one pill, they ambitiously aim to reverse diabetes, which is something that has never been done before with just medication. They studied mice that are fed a high-fat diet, which, due to obesity, developed high blood sugar levels. The rodent is then given a daily dosage of the drug that constrains the enzyme called low molecular weight protein tyrosine phosphatase (LMPTP). The presence of the LMPTP activity in the diabetes treatment new developments is found to cause the reduction of the sensitivity of the cell to insulin. When the insulin weakens, the body will have a hard time regulating blood sugar level that leads to the development of the Type 2 diabetes. With the drug, diabetes reversal can be achieved as the reduction of LMPTP can restore the cell's function. Moreover, the mice in the study showed no adverse side effects according to Nature.com . As of now, more studies should be made before the drug will be proven to be safe enough to move on to human clinical trials. Stanford, meanwhile, is confident on their drug to become the new therapeutic strategy for Type 2 Diabetes reversal. Over the years, being diagnosed with diabetes has continued to spiral upwards. From 1980 to 2014, over 422 million people are found to be diabetics. In the US alone, there has been a 40 percent increase in diabetes cases from 5.5 million in 1980 to 22 million in 2 Continue reading >>

Another Wonder Drug To Reverse Diabetes On The Horizon?

Another Wonder Drug To Reverse Diabetes On The Horizon?

Another Wonder Drug to reverse diabetes on the horizon? Helps to cancel insulin resistance , especially in Fat people Yet another promising drug for Type2 Diabetes on the horizon. The hypothesis is attractive We know that Type 2 diabetes occurs when the pancreas is either not able to produce enough insulin, or the cells of the body simply dont react to insulin. This is known as Insulin Resistance, which may in turn get blood glucose levels to rise.Insulin Resistance is therefore a major cause for Type 2 diabetes, especially in fat people. People with insulin resistance have high blood sugar despite normal or above normal levels of insulin in the blood. Seen in people with excessive body fat (especially in the tummy), insulin resistance is now believed to be mediated through an enzyme: Low Molecular-weight Protein Tyrosine Phosphatase (LMPTP). The hypothesis is that if we can inhibit LMPTP, we will reduce insulin resistance and can possibly cure Type 2 Diabetes at least in fat people. Presently there is no medical treatment available for this condition. The good news is that a new molecule has been developed by the University of California, and this may be the game-changer to this life threatening condition. Mice with insulin resistance were given a daily dose of the drug and this reversed the condition. The type 2 diabetes was effectively cured Scientists had an idea that insulin resistance was caused by a particular enzyme, known as Low molecular weight protein tyrosine phosphatase ( or LMPTP ). This enzyme is found in the liver and it causes the cells to become resistance to the presence of insulin. Hence, the scientists felt that LMPTP inhibitors would be a way to cure type 2 diabetes A study was done where laboratory mice were initially fed a very high fat diet , w Continue reading >>

Diabetes Wonder Drug: New Pill Can 'significantly' Improve Health Of Type 2 Sufferers

Diabetes Wonder Drug: New Pill Can 'significantly' Improve Health Of Type 2 Sufferers

British researchers have shown a simple pill has the power to lower blood sugar and promote weight loss in just three months. The development is significant as the once a day tablet could potentially end the need for painful daily insulin injections. And it comes as figures show the diabetes epidemic gripping the UK costs the NHS more than £10 billion a year with a new diagnosis made every two minutes. Trials showed up to 90 per cent of patients receiving semaglutide lowered their blood glucose levels and experienced “meaningful” weight loss. Study leader Melanie Davies, Professor of Diabetes Medicine at the University of Leicester, said: “These results demonstrating semaglutide’s ability to have a significant impact on lowering blood glucose and support weight loss when taken orally therefore are hugely promising. “Type 2 diabetes is a serious condition with potentially devastating complications which is posing a major challenge to health services across the world because of the increasing numbers of people developing it.” Although there are several treatments for Type 2 currently available many come with an increased risk of developing low blood sugar, a condition known as hypoglycaemia, and weight gain. The pill could be available in as little as two years. Type 2 diabetics either do not produce enough insulin, which controls blood sugar levels, or the insulin they produce does not work properly. The condition is largely lifestyle driven with nine in 10 sufferers overweight or obese. Fri, August 19, 2016 Diabetes is a common life-long health condition. There are 3.5 million people diagnosed with diabetes in the UK and an estimated 500,000 who are living undiagnosed with the condition. Meanwhile, about 12 million people in the UK are at increased risk of Continue reading >>

Drug Reverses Type 2 Diabetes In Mice

Drug Reverses Type 2 Diabetes In Mice

| Written by Jessica Moore Type 2 diabetes is a massive public health challenge. About eight percent of the worlds adult population has it, and the complications are seriousincreased risk of heart attack and stroke, kidney problems, hearing and vision loss and painful nerve damage. Managing blood sugar with diet, routine monitoring and insulin helps prevent these issues, but that takes more time and effort than many patients have. A new experimental drug developed with the help of scientists at Sanford Burnham Prebys Medical Discovery Institute (SBP) may spell the end of insulin reliance. A study published in Nature Chemical Biology shows that the compound, which can be given as a pill, restores blood sugar control in a mouse model of diet-induced diabetes. By targeting an enzyme that controls insulin receptor signaling, we found a way to recover cells ability to respond to insulin, says Anthony Pinkerton, Ph.D. , director of medicinal chemistry at SBPs Conrad Prebys Center for Chemical Genomics and a contributor to the research. This could lead to a new treatment approach for type 2 diabetes. The candidate drug blocks an enzyme called low molecular weight protein tyrosine phosphatase (LMPTP), which regulates the insulin receptor. Human genetic studies suggested that individuals with lower LMPTP activity were protected from type 2 diabetes, but the mechanism of protection remained unclear. The new investigation, led by Nunzio Bottini, M.D., Ph.D. , professor at UC San Diego, found that LMPTP has direct actions on the insulin receptor that reduce its signaling activity, making cells less sensitive to insulin. Turning off the LMPTP gene prevented mice from becoming diabetic when they were fed a high-fat diet, so the research team screened compounds to identify LMPTP inhi Continue reading >>

Diabetes Reversal By Inhibition Of The Low Molecular Weight Tyrosine Phosphatase

Diabetes Reversal By Inhibition Of The Low Molecular Weight Tyrosine Phosphatase

Diabetes reversal by inhibition of the low molecular weight tyrosine phosphatase 1Division of Cellular Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 2Department of Medicine, University of California, San Diego, La Jolla, CA 1Division of Cellular Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 2Department of Medicine, University of California, San Diego, La Jolla, CA 1Division of Cellular Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 2Department of Medicine, University of California, San Diego, La Jolla, CA 1Division of Cellular Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 2Department of Medicine, University of California, San Diego, La Jolla, CA 3Infectious and Inflammatory Disease Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 4Conrad Prebys Center for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 5Center for Proteomics and Bioinformatics, Case Western Reserve University, Cleveland, OH 6Institute for Genetic Medicine, University of Southern California, Los Angeles, CA 7Department of Respiratory, Inflammation and Autoimmunity, MedImmune LLC, Gaithersburg, MD 8Department of Orthopaedic Surgery and Department of Pediatrics, University of California, San Diego, La Jolla, CA *Address correspondence to: Nunzio Bottini, M.D., Ph.D., Department of Medicine, University of California, San Diego, 9500, Gilman Drive #0656, La Jolla, CA 92093-0656. Phone: 858-246-2398; [email protected] Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: The publisher's final edited version of this article is available at Continue reading >>

Rcsb Pdb - 5jns: Crystal Structure Of Human Low Molecular Weight Protein Tyrosine Phosphatase (lmptp) Type A Complexed With Phosphate

Rcsb Pdb - 5jns: Crystal Structure Of Human Low Molecular Weight Protein Tyrosine Phosphatase (lmptp) Type A Complexed With Phosphate

141415 Biological Macromolecular Structures Enabling Breakthroughs in Research and Education Funding Organization(s):National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Disease This is version 1.3 of the entry. See complete history . Diabetes reversal by inhibition of the low-molecular-weight tyrosine phosphatase. Obesity-associated insulin resistance plays a central role in type 2 diabetes. As such, tyrosine phosphatases that dephosphorylate the insulin receptor (IR) are potential therapeutic targets. The low-molecular-weight protein tyrosine phosphatase (LMP ... Obesity-associated insulin resistance plays a central role in type 2 diabetes. As such, tyrosine phosphatases that dephosphorylate the insulin receptor (IR) are potential therapeutic targets. The low-molecular-weight protein tyrosine phosphatase (LMPTP) is a proposed IR phosphatase, yet its role in insulin signaling in vivo has not been defined. Here we show that global and liver-specific LMPTP deletion protects mice from high-fat diet-induced diabetes without affecting body weight. To examine the role of the catalytic activity of LMPTP, we developed a small-molecule inhibitor with a novel uncompetitive mechanism, a unique binding site at the opening of the catalytic pocket, and an exquisite selectivity over other phosphatases. This inhibitor is orally bioavailable, and it increases liver IR phosphorylation in vivo and reverses high-fat diet-induced diabetes. Our findings suggest that LMPTP is a key promoter of insulin resistance and that LMPTP inhibitors would be beneficial for treating type 2 diabetes. Continue reading >>

Drug To Reverse Type 2 Diabetes Passes Critical Test In Mice

Drug To Reverse Type 2 Diabetes Passes Critical Test In Mice

In a groundbreaking study, researchers found that they were able to effectively reverse type 2 diabetes symptoms in mice by administering a daily oral drug with no adverse side effects. Millions of people worldwide suffer from diabetes, particularly type 2 diabetes—which accounts for nearly 90% of all documented cases. If the medication is successful in humans, it would revolutionize how diabetes is treated. Type 2 diabetes is common in older individuals whose bodies’ do not respond as they should to insulin, the key hormone that regulates blood sugar. Most diabetics opt for insulin injections to control their blood sugar levels, while others rely on restrictive diets to avoid sugar altogether. Though both of these techniques help manage the disease, they cannot cure it. They come with a number of potential of side effects including weight gain and diarrhea. What’s more, dependence on insulin injections may lead to insulin resistance. And if untreated, type 2 diabetes can lead to health problems like kidney disease, nerve damage, and vision problems. The proposed daily pill would restore the body’s sensitivity to insulin and increase the activity of the insulin receptor in the liver. Researchers believe this could introduce a new therapeutic strategy to treating type 2 diabetes and hopefully result in a lessened reliance on insulin injections by people with adult-onset diabetes. Here’s Andy Coghlan, reporting for New Scientist: The drug works by inhibiting an enzyme called low molecular weight protein tyrosine phosphatase (LMPTP), which seems to contribute to cells losing their sensitivity to insulin. By hindering LMPTP, the drug reawakens insulin receptors on the surface of cells – especially in the liver – which normally absorb excess sugar from the bloo Continue reading >>

Diabetes Reversal By Inhibition Of The Low-molecular-weight Tyrosine Phosphatase. | Diabetes Research Centers

Diabetes Reversal By Inhibition Of The Low-molecular-weight Tyrosine Phosphatase. | Diabetes Research Centers

Home Publications Center Diabetes reversal by inhibition of the low-molecular-weight tyrosine phosphatase. DIABETES REVERSAL BY INHIBITION OF THE LOW-MOLECULAR-WEIGHT TYROSINE PHOSPHATASE. Diabetes reversal by inhibition of the low-molecular-weight tyrosine phosphatase. Stanford, Stephanie M., Aleshin Alexander E., Zhang Vida, Ardecky Robert J., Hedrick Michael P., Zou Jiwen, Ganji Santhi R., Bliss Matthew R., Yamamoto Fusayo, Bobkov Andrey A., Kiselar Janna, Liu Yingge, Cadwell Gregory W., Khare Shilpi, Yu Jinghua, Barquilla Antonio, D Y Chung Thomas, Mustelin Tomas, Schenk Simon, Bankston Laurie A., Liddington Robert C., Pinkerton Anthony B., and Bottini Nunzio Animals, Binding Sites, Diabetes Mellitus, Type 2, Drug Evaluation, Preclinical, Enzyme Activation, Enzyme Inhibitors, Gene Deletion, Inhibitory Concentration 50, Mice, Mice, Knockout, Mice, Obese, Models, Biological, Molecular Structure, Molecular Weight, Protein Tyrosine Phosphatases, Small Molecule Libraries, Structure-Activity Relationship Obesity-associated insulin resistance plays a central role in type 2 diabetes. As such, tyrosine phosphatases that dephosphorylate the insulin receptor (IR) are potential therapeutic targets. The low-molecular-weight protein tyrosine phosphatase (LMPTP) is a proposed IR phosphatase, yet its role in insulin signaling in vivo has not been defined. Here we show that global and liver-specific LMPTP deletion protects mice from high-fat diet-induced diabetes without affecting body weight. To examine the role of the catalytic activity of LMPTP, we developed a small-molecule inhibitor with a novel uncompetitive mechanism, a unique binding site at the opening of the catalytic pocket, and an exquisite selectivity over other phosphatases. This inhibitor is orally bioavailable, and Continue reading >>

Small Molecule Inhibitors Of Lmptp: An Obesity Drug Target Bottini, Nunzio Pinkerton, Anthony Bruce La Jolla Institute, La Jolla, Ca, United States

Small Molecule Inhibitors Of Lmptp: An Obesity Drug Target Bottini, Nunzio Pinkerton, Anthony Bruce La Jolla Institute, La Jolla, Ca, United States

Small Molecule Inhibitors of LMPTP: An Obesity Drug Target Obesity-associated insulin resistance plays a central role in the pathogenesis of obesity-associated diabetes. Inhibiting protein tyrosine phosphatases that dephosphorylate and inactivate the insulin receptor is considered a promising approach to decrease insulin resistance in obesity. This grant focuses on a tyrosine phosphatase that directly associates with and dephosphorylates the insulin receptor, called the low molecular weight protein tyrosine phosphatase (LMPTP). LMPTP is highly expressed in insulin-target tissues. Human genetic studies and in vivo data obtained from mice carrying reduced expression of LMPTP suggest that LMPTP promotes diabetes and insulin resistance in obesity. Our goal is to validate LMPTP as a drug target for obesity-associated diabetes by demonstrating that chemical inhibitors of LMPTP ameliorate diabetes in mouse models of obesity. We screened the NIH chemical library for inhibitors of LMPTP, and identified a reasonably potent and selective compound -ML400- that selectively inhibits LMPTP in vitro and is active in cell-based assays of LMPTP activity. We have preliminary evidence that ML400 is active in vivo and ameliorates glucose tolerance in a model of diet-induced obesity. Importantly, inhibition of LMPTP by ML400 occurs through an uncompetitive mechanism of action, suggesting that ML400 targets a novel allosteric site of the phosphatase. The aims of this proposal are to optimize potency and selectivity of ML400 through chemistry (Aim 1), identify the allosteric site targeted by ML400 on LMPTP (Aim 2) and perform in vivo studies with the lead compounds to demonstrate that inhibition of LMPTP improves insulin resistance in obese mice (Aim 3). The proposed hit-to-lead work will yie Continue reading >>

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