metabolic diseases – Page 2 – Drug Discovery Opinion

MKP-1, Muscle Fibres and Obesity

The fibres that make up skeletal muscle broadly fall into two groups: Type I, ‘slow-twitch’ myofibres, and Type II, ‘fast-twitch’ myofibres. Slow-twitch fibres utilise oxidative metabolism for energy generation and are associated with endurance, whilst fast-twitch fibres use a mixture of oxidative and anaerobic metabolism but are quicker to fatigue. Sprinters have up to 80 per cent type II fibres while marathon runners have up to 90 per cent type I fibres. Those that have a more sedentary lifestyle have about the same percentage of both.

Obese individuals have relatively fewer Type I fibres compared to average-weight counterparts and Type I fibres are believed to confer resistance to obesity. Consistent with this, the numbers of Type I fibres decrease in response to inactivity and or a high-fat diet (HFD). Conversely, numbers of Type I fibres increase in response to exercise.

Researchers at Yale University School of Medicine have now identified MAPK phosphatase-1 (MKP-1) as a key player in the Type I/Type II shift in response to HFD. The group had previously shown that mice deficient in MKP-1 displayed increased energy expenditure and were resistant to diet-induced obesity. This new study, published in the Journal of Clinical Investigation, found that MKP-1 was overexpressed in skeletal muscle of mice in response to excess dietary fat.

MKP-1 dephosphorylates, and consequently deactivates, MAP kinases in the nucleus. In the study, MKP-1 overexpression reduced p38 MAPK-mediated phosphorylation of PPARγ coactivator 1α (PGC-1α), which plays a central role in maintaining levels of Type I myofibres. The phosphorylation of PGC-1α is believed to stabilise the protein and, consistent with this, MKP-1 deficient mice had higher levels of PGC-1α in skeletal muscle than did wild-type mice and were refractory to the loss of Type I myofibres when fed a high-fat diet.

Another Way to Control GLP-1

The incretin, glucagon-like peptide-1 (GLP-1), is an intestinal hormone that stimulates production and release of insulin from pancreatic beta cells. Consequently there has been considerable interest in mimicking the activity of GLP-1 for treatment of metabolic disorders such as Type-II diabetes and obesity. There are currently two approved classes of drug that modulate GLP-1 activity: analogues of GLP-1 and inhibitors of dipeptidyl peptidase IV (DPPIV). Analogues of GLP-1, such as the 39-residue synthetic peptide, exenatide, activate the GLP-1 receptor but are resistant to proteolytic cleavage by DPPIV. The gliptins, such as sitagliptin, inhibit DPPIV, extending the half-life of the natural hormone.

Researchers at Ecole Polytechnique Fédérale de Lausanne, in collaboration with the University of Perugia and Intercept Pharmaceuticals, have now published data showing that stimulation of TGR5, a G-protein coupled receptor, leads to release of GLP-1 in obese mice. The same group had previously demonstrated that activation of TGR5 in brown adipose tissue and muscle by endogenous bile acids boosted energy expenditure and reversed diet-induced obesity in mice.

INT-777 structure In the current work the researchers used a combination of genetic gain- and loss-of-function studies together with the TGR5 agonist, INT-777, to show the link between TGR5 signalling and GLP-1 secretion. In vitro experiments with INT-777 in enteroendocrine L-cells confirmed the induction of GLP-1 secretion and that this was linked to increased intracellular ATP/ADP ratio and a subsequent rise in intracellular calcium mobilization.

The study, published in the September 2^nd edition of Cell Metabolism, opens up a potential third route to modulation of GLP-1 activity and treatment of metabolic disorders.

New Insights into Adipogenesis

The nuclear receptor, PPARγ, has hitherto been regarded as the master regulator of adipogenesis, without which new adipose tissue cannot be formed. Adipogenesis plays a key role in obesity and associated metabolic diseases such as type II diabetes and the thiazolidines, which target PPARγ are widely used to treat type II diabetes. Researchers at the University of Central Florida have now discovered, however, that monocyte chemotactic protein-1 (MCP-1)-induced protein (MCPIP), can trigger adipogenesis without involvement of PPARγ. The authors had previously shown that binding of MCP-1 to its receptor, CCR2, leads to induction of the Zn-finger protein, MCPIP. In the present study, MCP-1 was found to be produced, and MCPIP to be induced, before induction of PPARγ or other transcription factors in fibroblasts undergoing differentiation into adipocytes. Knockdown of MCPIP using siRNA was found to inhibit both gene induction and adipogenesis whereas treatment with MCP-1 or forced expression of MCPIP induced adipogenesis. Forced expression of MCPIP was also shown to induce adipogenesis in PPARγ-/- mouse embryonic fibroblasts, further demonstrating that MCPIP can act independently of PPARγ.

Obesity is well known to increase MCP-1 levels and the finding that MCPIP is able to induce adipogenesis without involvement of PPARγ provides new mechanistic evidence for the role of MCP-1/CCR2 in obesity and type II diabetes. Since there is experimental evidence that MCPIP promotes angiogenesis, MCP-1/CCR2 interaction could promote the formation of new blood vessels to supply blood to growing adipose tissue as well as promoting development of the adipocytes. A drug that could block the function of MCPIP may thus have the potential to treat obesity and type II diabetes.

The study is published in the online edition of Journal of Biological Chemistry.

Put Vinegar on those Chips!

fish and chips Vinegar can be made from almost any carbohydrate source – the action of yeast first ferments the natural sugars to alcohol which is then converted into acetic acid by acetic acid bacteria. Vinegars typically contain around 5% acetic acid together with a variety of other components including polyphenols and organic acids.

Vinegars have been used for thousands of years as food preservatives and flavourings and, over the years, have also acquired a reputation for many health benefits. The human evidence for many of these claims remains equivocal although several studies have confirmed the anti-glycaemic properties of vinegar.

Largely anecdotal evidence has pointed to positive effects on weight loss and at a recent meeting of the Japan Society of Nutrition and Food Science, scientists at the Mizkan Central Research Institute have now described reductions in waist size, abdominal fat and blood neutral fat in overweight (BMI 25-30) men and women who drank 30mL of an apple vinegar-based drink (containing 1.5g acetic acid) each day for 12 weeks. Those who drank 15mL of the vinegar-based drink also saw reductions, whilst control subjects who did not take the drink saw no changes.

Writing in the Journal of Agricultural and Food Chemistry, researchers at Mizkan have also described studies in mice that highlight the mechanisms responsible for the changes in abdominal fat. Mice on a high-fat diet were divided into three groups and treated with 0.3% or 1.5% acetic acid solutions or water for 6 weeks. The groups treated with the acetic acid solutions consumed the same amount of food as the control group but showed reduced accumulation of body fat (about 10%) and hepatic lipids, with no changes in skeletal muscle weight. Significant increases in the expression of genes for peroxisome-proliferator-activated receptor-α (PPARα) and for fatty acid oxidation- and thermogenesis-related proteins were seen in the livers of the treatment groups. Similar up-regulation of gene expression was observed in vitro on addition of acetate to HepG2 cells. The effects were not observed in cells depleted of α2 5′-AMP-activated protein kinase (AMPK) by siRNA. The authors conclude that acetic acid suppresses accumulation of body fat and liver lipids by up-regulating genes for PPARα and fatty-acid-oxidation-related proteins in the liver via an α2 AMPK mediated process.

If larger clinical studies confirm fat reduction and positive effects on metabolism in overweight humans, vinegar could be set to take a share of a very large weight-loss market.

New Basis for Link Between Sleep and Weight

A number of human studies have linked lack of sleep to weight gain – decreased insulin sensitivity and glucose tolerance as well as disruption of the natural balance between the appetite hormones grehlin and leptin have been put forward to explain this link between disrupted sleep and weight gain. In studies in rodents, researchers at Merck have now shown that T-type calcium channels regulate both sleep and body weight maintenance. Mice lacking Ca_V3.1 T-type calcium channels were known to have altered sleep/wake patterns and the new study showed that these mice are also resistant to weight gain induced by a high fat diet.

Writing in the Journal of Clinical Investigation, the researchers report that the knock-out mice gained significantly less weight and had less body fat than their wild-type littermates when fed a high fat diet. The resistance to weight gain of the knock-out mice could not be fully explained by reduced food intake, an overall increase in activity or increased metabolic rate. TTA-A2 structure In further studies, a selective T-type channel antagonist, TTA-A2, was shown to prevent, and even reverse, weight gain induced by a high fat diet, and also to improve body composition to greater extent than the widely used appetite suppressant, fenfluramine. TTA-A2, when dosed either prior to the sleep phase or during the wake phase, was found to promote sleep – a result which was unexpected since the knock-out mice have increased wake time compared with wild type animals. Although the reasons for the observed differences between pharmacological antagonism and genetic knock-out remain to be fully explained, the study highlights the potential for antagonism of T-type calcium channels as a novel weight loss strategy.

The authors suggest that the benefits of T-type calcium channel antagonists may be the result of better alignment of feeding patterns and the circadian rhythm and that sleep or circadian treatments may be of particular benefit for people struggling to lose weight or maintain weight loss because of poor diet.

New DPP-4 Inhibitor Demonstrates Glucose Control in Type 2 Diabetes

Type-2 diabetes is a metabolic disorder that is increasing rapidly in the developed world. The disease is caused by reduced production of insulin by the pancreas and /or reduced responsiveness to insulin by cells in the body, particularly fat, muscle and liver cells. Reduced insulin activity causes higher blood glucose levels as well as other complex metabolic changes, leading eventually to organ damage with increased morbidity and mortality.

A number of medicines are used to treat type-2 diabetes; these include metformin, sulphonyl ureas, and thiazolidinediones. More recently, inhibitors of dipeptidyl peptidase-4 (DPP-4) have emerged as an alternative method of treatment. DPP-4 inhibitors act by increasing levels of the gastrointestinal hormones, incretins, which increase the amount of insulin released by the pancreas, inhibit glucagon release and also slow gastric emptying.

New data has been presented showing that Januvia™ (sitagliptin), in combination with metformin, provided significant glucose lowering over two years. In separate studies, addition of Januvia™ to regimens based on thiazolidinediones also led to improved blood sugar control. Januvia™ was the first DPP-4 inhibitor to be approved for the treatment of diabetes in the US and Europe although several other inhibitors are in varying stages of development.

More Benefits of ACE Inhibition and Angiotensin Receptor Blockade

Angiotensin Converting Enzyme (ACE) inhibitors and Angiotensin Receptor Blockers (ARBs) were developed primarily to treat hypertension, but several recent studies have shown that they could have additional benefits.

captopril In one study, mice in which the gene for ACE had been deleted were found to have lower body weight and a lower proportion of body fat than their wild type litter mates. The decreased body fat in the ACE knock-out mice was independent of food intake and appeared to be due to increased metabolism of fatty acids in the liver, with an additional effect of increased glucose tolerance.

Another study found that use of either ACE inhibitors or Angiotensin Receptor Blockers (ARBs) significantly reduced basal cell carcinoma and squamous cell carcinoma in patients at high risk of these keratinocyte cancers.

High levels of Angiotensin II have also been linked to the pro-angiogenic protein, vascular endothelial growth factor (VEGF) in pancreatic ductal adenocarcinoma (PDA).

losartan An ARB significantly inhibited the Angiotensin II induced increase in VEGF in PDA cell lines and, in an earlier study, an ACE inhibitor was shown to have a similar effect. These studies suggest that ACE inhibitors and ARBs may represent potential novel and promising strategies for controlling angiogenesis, prevention of metastasis, and prolongation of survival in patients with primary or metastatic PDA.

Non-peptide GLP-1 Agonist Shows Efficacy in Mouse Model of Diabetes

Boc5 Metabolic syndrome is a combination of medical disorders that increase the risk of developing cardiovascular disease, diabetes and obesity. A 39-residue synthetic peptide, Exenatide, which is approved for the treatment of type 2 diabetes, acts by mimicking the action of endogenous glucagon-like peptide-1 (GLP-1), a regulator of glucose metabolism and insulin secretion.

Researchers have now shown that chronic administration of a non-peptide molecule, Boc5, can induce weight loss and increase insulin sensitivity in a mouse model of diabetes and obesity by binding to the receptor for GLP-1. Boc5 is the only non-peptide molecule reported so far that behaves as a full GLP-1 mimetic in vitro and in vivo. Although Boc5 itself does not have the properties of a ‘drug-like’ molecule, it may represent a starting point for the discovery of orally bioavailable agents with the potential to treat metabolic disorders.

New Life for Old Drug

Ore Pharmaceuticals has recently announced that it has acquired from Roche the exclusive development rights for the clinical-stage compound romazarit. Ore Pharmaceuticals specialises in identifying potential new uses for drug candidates that have previously failed clinical development for reasons other than safety.

Romazarit was originally designed by scientists at Roche as a potential disease-modifying anti-rheumatic drug. The compound showed activity in an adjuvant arthritis model although the mechanism of action was not clearly defined. Romazarit was well tolerated in phase II clinical studies for rheumatoid arthritis, but did not make it to market.

Ore Pharmaceuticals has identified novel potential therapeutic uses for romazarit in prevalent metabolic diseases such as obesity, dyslipidemia and hypercholesterolaemia and has recently filed a patent application covering use of the compound for these indications. Romazarit has been shown to modulate a key pathway related to metabolic function, and lowered lipid levels, body weight, and plasma glucose levels in preclinical models. Ore Pharmaceuticals plans to select the most appropriate of the potential indications and prepare for Phase II clinical trials. The Company will engage in out-licensing efforts in parallel with internal development efforts.