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Molecular Targets in the Development of Antidiabetic Drugs



Adel S. Al- Zubairi and Eltayeb Elamin M. Eid
 
ABSTRACT
Type 2 diabetes mellitus (T2DM) is a worldwide public health problem. The fact that the existing treatments have limitations either because of their side effects as hypoglycaemia and weight gain or their other complications necessitate the need for development of new therapies for glycemic control. The therapeutic approachs represented by the incretin-based therapies, namely the dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon like peptide-1 (GLP-1) analogues/mimetics, offer a new therapeutic means for treatment of T2DM, in addition to other several even newer therapies in development. A great attention has been focused by many researchers on a number of potential molecular targets in fat cells or adipocytes, as the adipokines. In this article we will review the development of the possible molecular targets for the currently available antidiabetic agents with particular emphasis on incretin-based therapeutic targets as well as molecular targets in adipocytes and other future therapies.
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  How to cite this article:

Adel S. Al- Zubairi and Eltayeb Elamin M. Eid, 2010. Molecular Targets in the Development of Antidiabetic Drugs. International Journal of Pharmacology, 6: 784-795.

DOI: 10.3923/ijp.2010.784.795

URL: http://scialert.net/abstract/?doi=ijp.2010.784.795
 
Received: March 30, 2010; Accepted: May 23, 2010; Published: August 13, 2010

INTRODUCTION

In order to minimizing the adverse effects of many currently used drugs, researchers are continuously searching for new drug leads having more potency with less complications. In drug discovery and development, early-phase studies usually designed to evaluate safety, tolerability and pharmacokinetics of new drug leads (Abdul et al., 2008a, b, 2009; Abdel-Wahab et al., 2009; Al-Zubairi et al., 2010a, b) when the target of the drug lead is not well defined. Pharmaceutical agents generally exert their therapeutic effect by binding to and regulating the activity of a particular protein or nucleic acid target. Modern drug discovery has been primarily based on the search of leads directed against a preselected target and the subsequent testing of the derived drug candidates. Continuous efforts and interest have been directed at the discovery of new targets, as well as more-extensive exploration of the targets of successful drugs (Drews, 1997; Ohlstein et al., 2000). In general, the aim of targeted therapies is to increase the efficacy and reduce the toxicity of drugs.

Diabetes mellitus is a common, serious metabolic disorder characterized by a defect in insulin production and/or in insulin action on peripheral tissues leading to metabolic abnormalities and hyperglycemia (Shalam et al., 2006; American Diabetes Association, 2007; Kawahito et al., 2009). The disease can be divided into two major classes: insulin-dependent diabetes mellitus, also known as type 1 diabetes and non-insulin-dependent diabetes mellitus, also known as type-2 diabetes (World Health Organization, 1985). Type 1 results from insulin deficiency caused by cell-mediated autoimmune destruction of pancreatic β-cells and generally developed in young (Bach, 1995). Based on World Health Organization and American Diabetes Association data, studies in several countries have estimated that there will be 285 million people with diabetes worldwide in 2010 (Shaw et al., 2010). About 90% of diabetes cases are type 2 diabetes mellitus, which is characterized by peripheral insulin resistance and insulin deficiency and generally develops in adults (Yki-Jarvinen, 1994). However type 2 can also be developed at a younger age, as seen in the maturity onset diabetes of the young (MODY).Type 2 diabetes mellitus is currently though to be influenced by more than a single gene or environmental factors resulting in development of insulin resistance and β cell dysfunction (Taylor, 1999; Saltiel and Kahn, 2001; Ghosh and Schork, 1996; Stumvoll et al., 2005). The contribution of genetic and environmental factors to the development of type 2 diabetes differs among individuals. Patients generally have two common metabolic abnormalities: insulin resistance and defects in glucose-stimulated insulin secretion, which lead to the disease (Saad et al., 1991; DeFronzo et al., 1992; Lillioja et al., 1993). Genetic factors play an important role in the pathogenesis of type 2 diabetes mellitus. This is clear from the familial aggregation and the high concordance rate for the disease (60-100%) in identical twins (O'Rahilly et al., 1988; Jun et al., 1999). As well as the environmental factors such as obesity, physical activity and diet that play a strong role in the development of the disease (Helmrich et al., 1991). The adipose tissue seems to play an important role in the pathogenesis of type 2 diabetes. Hence the obesity is the key risk factor for type 2 diabetes at a young age (Kiess et al., 2001, 2003; Strauss and Pollack, 2001; Palmert et al., 2002; Jones et al., 2002). A genetic predisposition is generally believed to be required for the development of type 2 diabetes.

Pathophysiology of type 2 diabetes mellitus: The causes of type 2 diabetes are multifactorial including of both genetic (Gerich, 1998) and environmental factors that with the increasing prevalence of obesity, the prevalence of type 2 diabetes is reaching epidemic proportions (Scheen, 2001). Interactions of these factors affect beta-cell function and tissue insulin sensitivity. The progressive development of Type 2 diabetes mellitus start with the predisposing genetic factors starting with disturbance in glucose homeostasis in which initially individuals are at risk for type 2 diabetes because of genetic polymorphisms. Later on, as a result of a genetic predisposition and lifestyle, reduced insulin sensitivity probably emerges, which are initially compensated for by an increase in β cells function, so that glucose tolerance remains normal (Hales, 1994), but later both the β cells and insulin sensitivity, deteriorate leading to impaired glucose tolerance. Finally, as a result of further deterioration of β cells function, both fasting and postprandial blood glucose levels reach clearly diabetic levels and the patients become symptomatic. Thus, the development of new classes of drugs for treatment of diabetes mellitus needs to explore new targets to supplement older therapies, including lifestyle-directed interventions, insulin, sulfonylureas and metformin.

Antidiabetic drugs: Due to the absence of hormone synthesis, Type 1 diabetes mellitus requires insulin therapy from the beginning. While, type 2 diabetes can be managed by various means of treatments including insulin administration, stimulation of insulin release from the beta cells by sulfonylureas and metiglinides, increasing peripheral tissue utilization of glucose with receptor sensitizers such as the thiazolidnediones, decreasing hepatic glucose production (the biguanides) and decreasing utilization of ingested carbohydrates (α-glycosidase inhibitors such as acarbose and miglitol). The current anti-diabetic drugs lower blood glucose levels by one or more of the above listed mechanisms (Nathan, 2002; Chan and Abrahamson, 2003; Zangeneh et al., 2003). The classification of antidiabetic agents has been reviewed by Mehanna (2005) who categorized them into insulin pharmaceutical preparations and oral antidiabetic drugs. Insulin preparations were classified based on the onset and duration of action into rapid, intermediate and long-acting preparations. Meanwhile, oral antidiabetic agents were classified into five classes: sulfonylureas, non-sulfonylurea secretagogues (the thiazolidinediones), biguanides, insulin receptors sensitizers and a-glucosidase inhibitors (Tahrani et al., 2010).

Molecular targets: The main molecular targets for drugs are proteins (mainly enzymes, receptors and transport proteins) and nucleic acids (DNA and RNA). These molecular targets are undergoing a selective interaction with chemicals administered to treat or diagnose a disease. They are human genome-derived proteins, or belong to pathogenic organisms. A limited set of drugs act through physicochemical mechanisms, or have unknown mechanisms of action.

Analysis of the human genome in 2002 led to the estimation of 6000-8000 targets of pharmacological interest. Only a small part of these targets relates to approved drugs. In Drews and Ryser estimated the number of molecular targets by all marketed drug substances to be only 483 (Drews and Ryser, 1997). Hopkins and Groom estimated that drugs acted primarily through only 120 underlying molecular targets (Hopkins and Groom, 2002) while in 2003, Golden proposed that all the approved drugs acted through 273 proteins (Golden, 2003). Zheng et al. (2006) disclosed 268 successful targets in the current version of the therapeutic Targets Database, Zheng et al. (2006) and Imming et al. (2006) catalogued 218 molecular targets for approved drugs. A consensus number of 324 drug targets for all classes of approved therapeutic drugs were proposed by Overington et al. (2006). Of these, 266 are human genome-derived proteins and 58 are bacterial, viral, fungal or other pathogenic organism targets.

Generally, old therapies that target pancreatic beta cells and stimulate insulin secretion, targeting the three major defects associated with type 2 diabetes; defective insulin secretion, increased hepatic glucose output and insulin resistance. However, drugs used for these targets are almost had many problems in long term use. Thus scientists are looking for new approaches for management of diabetes mellitus. Recently, researchers plans include bridging the gap between understanding the role of lipids and exploring signal transduction pathways mainly in diabetes. They need to investigate how lipids, carbohydrates and kinases interact in normal and abnormal conditions as well as establishing relationships to diets, diseases and prevention. These specific interactions between proteins and lipids can be studied at several levels: at molecular level by investigating the possible structural interactions, biochemically by analyzing membrane microdomains in normal and abnormal conditions and finally genetically by exploring gene expression.

Recent drug targets for diabetes mellitus: The investigation of selective inhibition or activation of oncogenes by lipids through the analysis of gene expression modulation by specific nutrients, or via the molecular study of the occurrence of such interactions, may lead to the development of new areas of diabetes treatment, e.g. intestinal endocrine cells and adipocytes.

PTEN: PTEN is a dual-specificity protein phosphatase involved in signal transduction and tumour suppression. PTEN has phosphoinsositide 3-phosphotase activity and is therefore capable of suppressing PI3K signalling by dephosphorylating PIP3 (Maehama and Dixon, 1998; Lee et al., 1999). Because many of the metabolic effect of insulin are mediated through the activation of PI3K and the subsequent raise in intracellular PIP3 concentration, of this pathway, may enhance insulin signaling through the feedback inhibition as a pnegative regulator. PTEN inhibition lead to the translocation of GLUT4 to the plasma membrane where its exocytosis participates to increase glucose uptake (Nakashima et al., 2000; Thong et al., 2005), as well as overexpression in vitro inhibits glucose uptake and GLUT4 transport in 3T3LI cells. These results suggest that PTEN may modulate insulin signaling in vivo. Therefore, PTEN represent a good target for the reduction of blood glucose level by inhibiting its expression, as it play a role in glucose metabolism in vivo by negatively regulating insulin signalling. Therefore, depending on where the defect in the insulin signalling cascade occurs, PTEN targeting might help to overcome insulin resistance leading to reduction of blood glucose levels.

Adipocytes: Adipocytes have a considerable effect on glucose homeostasis mediated by endocrine and non-endocrine mechanisms. The endocrine participation of adipocytes is mainly through the synthesis and release of peptide hormones, the so-called adipokines (adipocyte-derived proteins with antidiabetic action include leptin, adiponectin, omentin and visfatin) (Berg et al., 2002; Fukuhara et al., 2005; Yang et al., 2005, 2006). In addition to its well characterized role in energy balance, leptin reverses hyperglycemia by improving insulin sensitivity in muscles and the liver. Intracellular lipids may contribute to insulin resistance, this occurs most likely by reducing intracellular lipid levels through a combination of direct activation of AMP-Activated Protein Kinase (AMPK) and indirect actions mediated through central neural pathways (Minokoshi et al., 2002). Other factors tend to raise blood glucose, including resistin, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and retinol-binding protein 4 (RBP4). TNF-α is produced in macrophages and reduces insulin action (Hotamisligil, 1999).

Adipocytes also release non-esterified fatty acids (NEFAs) into the circulation, which act as one of the adipocyte-derived secreted non-endocrine product. However, insulin resistance is also associated with lipolysis and NEFA release into the circulation due to reduced muscles and adipocytes glucose uptake and promoted hepatic release. Transiently elevated NEFAs (such as occur after a meal) tend to enhance insulin secretion, whereas chronic elevations in NEFAs (such as occur in insulin resistance) (Eldor and Raz, 2006) tend to reduce insulin secretion which may involve lipotoxicity induced apoptosis of islet cells (Lowell and Shulman, 2005). It has been suggested that insulin resistance in adipocytes is the first metabolic manifestation leading to type 2 diabetes mellitus (Bergman, 1997). Insulin resistance in adipocytes, paradoxically a condition in obesity in which insulin cannot promote a normal fat storage, resulting in excess circulating fatty acids that in turn, promote insulin resistance in muscle and consequently type 2 diabetes mellitus (Pilch and Bergenhem, 2006). Thus pharmacological targeting of fat cells to correct this abnormality seems to be a very promising strategy. Accordingly, there are three independent targets in adipocytes that may suitable for the treatment of diabetes; adipokines, modulator of hormonal sensitivity and enzymes involved in fat storage.

Adipokines: These are cytokines, (they are proteins, peptides or polypeptides act as signaling molecules use extensively in cells communication) secreted by adipose tissue, such as leptin, adopnectin and resistin and they considered as potential targets for the treatment of diabetes mellitus.

Leptin: Leptin is a protein hormone with important effects in regulating body weight and metabolism, expressed predominantly by adipocytes (Zhang et al., 1994) and the lack of functional leptin or leptin receptor causes massive obesity and diabetes in humans (Friedman, 1998). It has an important role in the regulation of food intake and energy expenditure and it is a major contributor to metabolic and neuroendocrine function both in animals and humans (Himms-Hagen, 1999). Its principal target is the central nervous system, although peripheral actions have been reported (Bjorbaek and Kahn, 2004). In humans and rodents that have molecular defects in leptin expression, its administration represent an effective therapy for their obesity (Farooqi et al., 2002) however, most obese patients have high levels of circulating leptin in their bodies and are resistant to the actions of this adipokine even when exogenously administered (Heymsfield et al., 1999). Increased plasma leptin levels act to increase peripheral insulin sensitivity. In vivo observations showed that both peripheral and central administration of leptin increased skeletal muscle glucose uptake (Kamohara et al., 1997; Wang et al., 1999) and oxidation (Ceddia et al., 1999).

Adiponectin: Adiponectin is an adipocyte-derived hormone discovered independently by four groups (Pilch and Bergenhem, 2006). It suppresses hepatic glucose production (Berg et al., 2001) and also stimulates oxidation of fatty acids primarily in skeletal muscle and the liver (Yamauchi et al., 2001), thereby preventing the accumulation of lipids in insulin target tissues. Adiponectin has become the most widely used name for this adipokine. Circulating adiponectin levels correlate with insulin sensitivity in humans; interestingly, injection of adiponectin in mice has been shown to induce weight loss (Berg et al., 2001). Serum adiponectin levels are reported to be decreased in obesity (Arita et al., 1999). Moreover, it has been demonstrated that the decreased expression levels of adiponectin coincided with insulin resistance in murine models of altered insulin sensitivity (Yamauchi et al., 2001).

PPARγ: Peroxisome Proliferator-Activated Receptor (PPAR) are a family of three (α, β/δ and γ) nuclear receptors that affect the transcription and expression level of numerous target genes in adipocytes and other tissue/cells (Feige et al., 2006). They have emerged as central regulators of lipid homeostasis and molecular targets for drugs to treat hyper-triglyceridaemia and type 2 diabetes mellitus and they have been implicated in variety of pathological states (Glass, 2006; Michalik and Wahli, 2006; Semple et al., 2006). PPARs are activated by a wide range of naturally occurring or metabolised FFA and eicosanoid-FFA derivatives and TZDs (thiazolidinediones). By lowering circulating lipids, PPARs oppose lipid-induced insulin resistance (Evans et al., 2005; Straus and Glass, 2007). PPARγ is an extensively studied member of PPAR family because its agonist has been used clinically and commercially for diabetes therapy for approximately 10 years. It was reported to play a critical role as metabolic regulator through stimulating insulin sensitivity, glucose-lowering and lipid uptake and storage in peripheral organs such as skeletal muscle, liver and adipose tissue (Lehrke and Lazar, 2005). The first insulin sensitizer and PPARγ agonist used was troglitazone (Rezulin), which was taken off from the market in 2000 because of liver toxicity, but now Rosiglitazone and Pioglitazone which are used for this purpose and considered to be the most potent and selective PPARγ agonists (Yki-Jarvinen, 2004; Henke, 2004). Increasing evidence suggests that natural and pharmacological PPARγ ligands induce rapid effects in different cell systems expressing high levels of PPARγ (Luconi et al., 2010).

Enzymes of fat metabolism: Storage of even modest caloric surplus in tissues other than white adipose tissues leads to insulin resistance and the development of diabetes (Unger, 2002). The precise identity of the lipid factor responsible development of insulin resistance is not known, although free fatty acids, long-chain fatty acyl-CoAs, 1,2 diacylglycerol and ceramide are probable suspects (McGarry, 2002). An ideal approach to treat obesity and diabetes would be to decrease fat storage and enhance its oxidation. A very promising approach is to use a classic type of drug such as enzyme inhibitors, like receptor agonists and antagonists. Thus, this approach will be promising in the treatment of type 2 diabetes mellitus.

SCD1: Stearoyl-CoA desaturase-1 (SCD1) is a central enzyme responsible for the synthesis of monounsaturated fatty acids-mainly oleate (C18:1) that is a major component of tissue lipids, triglyceride and membrane lipids synthesis and it is highly expressed in adipocytes as well as in liver (Ntambi et al., 1988). SCD1 has been shown to be an important control point of lipogenesis (Nitambi and Miyazaki, 2004; Dobrzyn and Ntambi, 2004). Furthermore, SCD1 has been found to be a major peripheral target gene of leptin-mediated signalling events (Cohen et al., 2002). One of the mechanisms of SCD1 is via increased activation of AMP-Activated Protein Kinase (AMPK) (Dobrzyn et al., 2004). SCD1 deficiency increases the rate of fatty acid β-oxidation through activation of the AMPK pathway and by upregulating genes of fatty acid oxidation in skeletal muscle (Dobrzyn et al., 2005). However, partial inhibition of SCD1 by appropriate small molecule might have beneficial metabolic actions (Cohen and Friedman, 2004). Therefore, SCD might be a potential therapeutic target in the treatment of the metabolic syndrome and diabetes and indication that the inhibition of this enzyme is both safe and efficacious.

DGAT1: Accumulation of triglycerides leads to the obesity and associated with insulin-resistance, so inhibition of triglycerides synthesis represents a potential therapeutic strategy for human obesity and type 2 diabetes.The microsomal enzyme, acyl-CoA:diacylglycerol acyltransfease 1 (DGAT1) catalyzes the final and committed step in the biosynthesis of triglycerides by covalently joining a long chain fatty acyl-CoA to diacylglycerol (Farese et al., 2000). Partial DGAT1deficiency in Knockout mice was observed to have an increase insulin sensitivity (Chen et al., 2002; Chen and Farese, 2005) that has been attributed to increased insulin-stimulated glucose transport in the skeletal muscle and White Adipose Tissue (WAT) (Chen et al., 2004). These observations very recently have been confirmed in Zucker fatty rat and the hyperlipidemic hamster (King et al., 2009). Therefore, partial inhibition of this enzyme might also have a promising target for the treatment of diabetes mellitus.

11β-HSD1: 11β-Hydroxysteroid dehydrogenase (Type 1) (11β-HSD1) catalyzes the conversion of inactive cortisone to active cortisol in the liver and adipose tissue. High levels of cortisol are well known to cause insulin resistance (Friedman et al., 1996) in fact, increase expression of 11β-HSD1 adipocytes has been reported in acquired obesity and diabetes. Pharmacological inhibition or transgenic disruption of 11β-HSD1 attenuates glucocorticoid action and increases insulin sensitivity (Walker et al., 1995). Mice lacking functional of 11β-HSD gene have been shown to be resistant to developing diabetes when put in a high fat-diet (Morton et al., 2004). 11β-HSD1 inhibition may also be beneficial in the pancreatic β-cells, where regeneration of glucocorticoid by 11β-HSD1 may inhibit insulin secretion (Davani et al., 2000) as these effects also have been predicted from in vitro studies (Handoko et al., 2000). Therefore, these findings have promoted interest in inhibition of 11β-HSD1 as a drug target for treatment of diabetes as currently being developed.

B3-adrenergic receptors: β3-adrenergic receptors (β3-AR) are expressed mostly in fat tissues (Krief et al., 1993; Arch and Kaumann, 1993; Berkowitz et al., 1995; Collins et al., 2004) and plays a significant role in controlling energy expenditure through the regulation of lipolysis and thermogenesis in brown adipose tissue (Umekawa et al., 1997). Their activation with selective agonists stimulates lipolysis and release of fatty acids in white adipose tissue and also activation of hermogenesis in brown adipose tissue (Arbeeny et al., 1995; Liu and Stock, 1995; Nagase et al., 1996; Grujic et al., 1997). Reduction of β3-AR number in adipose tissue of obese mice and Trp64Arg missense mutation of β3-AR in obese humans both indicate a possible role of β3-AR in obesity-related insulin resistance (Collins et al., 1994; Hoffstedt et al., 1999; Umekawa et al., 1999). In addition, obese rats treated with β3-AR agonists demonstrated an improvement of insulin sensitivity in adipose tissue as well as in skeletal muscle (Moreno-Aliaga et al., 2002). However, the actual physiological role of β3-AR in humans is not clear due to the lack of a highly selective β3-AR agonist despite continuous trials over the past 20 years. Chronic administration of β3-AR agonists has demonstrated antidiabetic and antiobesity effects in obese and diabetic rodent models (De Souza and Burkey, 2001; Arch, 2002). Possible antidiabetic effects of β3-AR agonists have been suggested by the observation of improved insulin-stimulated glucose disposal with enhanced insulin action in adipose tissues but with unchanged circulating glucose, insulin and lipid levels in normal Sprague-Dawley rats after chronic activation of β3-AR (Kiess et al., 2001).

Promising drugs targeting type 2 diabetes: These are drugs recently developed for management of type 2 diabetes mellitus, which were showed an excellent supplement for the old classes. GLP-1 and GIP are the prominent incretin hormones that exert well characterised insulin releasing effects (Green et al., 2004; Drucker and Nauck, 2006; Green and Flatt, 2007; Baggio and Drucker, 2007) and their inhibitor dipeptidyl peptidase 4 (DPP 4) which is largely responsible for their degradation and inactivation in vivo (Deacon et al., 2002). The increased understanding of biology and metabolism of incretins hastened the development and use of incretin analogues/mimetics/agonists (which exogeneously activate incretin receptors) and DPP 4 inhibitors (which enhance endogenous incretin activity) (Deacon, 2004; Green et al., 2006a; Flatt et al., 2008).

Glucose-Dependent Insulinotropic Peptide (GIP): GIP is secreted in a single bioactive form from the K-cells in the duodenum and jejunum in response to the ingestion of carbohydrates and/or lipids (Fehmann et al., 1995; Baggio and Drucker, 2007; Gautier et al., 2008). GIP reported to stimulates glucose-dependent insulin secretion in humans (Baggio and Drucker, 2007; Gautier et al., 2008). In addition, it plays a role in fat metabolism in the adipocytes and has a proliferative effect on the β-cells (Yip and Wolfe, 2000; Trumper et al., 2001; Gautier et al., 2008).

Glucagon-like peptide-1 analogues (GLP-1): GLP-1 is one of the incretin hormones, cleaved from pro-glucagon and secreted from the L-cells in the distal ileum and colon (Baggio and Drucker, 2007; Gautier et al., 2008). GLP-1 and GIP contribute and potentiate glucose-dependant insulin secretion in an additive manner but GLP-1 appears to be responsible for the majority of the incretin effects on the β-cell (Baggio and Drucker, 2007). These are new class of drugs for treatment of type 2 diabetes. One of their advantages is that they have a lower risk of causing hypoglycemia. With GLP-1, glucose stop going down when they reach a normal range, e.g., Exenatide. Administration of GLP-1 agonists inhibits glucagon secretion, lowers food intake and reduces body weight in diabetic animals and humans (Green et al., 2006b).

Dipeptidyl Peptidase 4 inhibitors (DPP 4 inhibitors): DPP 4 is responsible on the inactivation of incretin hormones GLP-1(glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic polypeptide) (Baggio and Drucker, 2007), which are normally released in the digestive tract in response to food and mediate glucose- dependent insulin secretion (Deacon et al., 2002). DPP-4 is widely expressed in human tissues including the brain, lungs, kidneys, adrenals, pancreas, intestine and lymphocytes (Gautier et al., 2008). GLP-1 stimulates glucose -dependent insulin release from the pancreatic islets. Insulin secretion can be enhanced indirectly with DPP 4 inhibitor drugs (gliptins) which minimise degradation of endogenous incretins and result in raised circulating concentrations of the biologically intact forms of GLP-1 and GIP, examples of these are Sitagliptin, Alogliptin and Saxagliptin.. Incretins have been suggested to be inactivated immediately following secretion into the blood and this is attributed to their short half life (Deacon et al., 1995; Mentlein, 1999; Baggio and Drucker, 2007; Gautier et al., 2008).

Sodium-dependent glucose cotransporters (SGLT-2): Sodium dependent glucose cotransporters (SGLT) are a family of glucose transporters found in the intestinal mucosa of the small intestine (SGLT1) and the proximal tubule of the nephron (SGLT2 and SGLT1) (Wright, 2001). They contribute to renal glucose reabsorption and responsible for about 90% of glucose reabsorption. SGLT2 inhibitors promote glycosuria by blocking the reabsorption of glucose in the proximal tubule of the kidney. Selective inhibition of SGLT2 in the proximal tubule increases urinary glucose excretion, but crucially these drugs only appear to have this effect in states of hyperglycaemia thereby reducing plasma glucose levels (Katsuno et al., 2007), which may present a novel therapeutic target for the control of hyperglycemia. Therefore, SGLT represent an excellent target for reduction of hyperglycemia preventing the adverse complications of glucose toxicity observed in diabetes. Sergliflozin (GlaxoSmithKline), Dapagliflozin (Bristol-Myers Squibb and Astra Zeneca) and some of the thioglycosides (Castaneda et al., 2007) are currently under development from this class of drugs.

Glucokinase activators: Glucokinase (GK) is a glucose-sensing enzyme found in the liver and pancreas (Leighton et al., 2005; Matschinsky et al., 2006; Matschinsky, 2009) known to phosphorylate D-glucose. Defects in this enzyme cause disease in humans, such as Maturity-Onset Diabetes of the Young type 2. Activation of this enzyme promotes hepatic glucose uptake and pancreatic insulin secretion and, therefore, is an ideal target for diabetic therapy (Leighton et al., 2005). Agents directed at selectively activating liver glucokinase are currently in development. These should produce only glucose-dependent effects and reduce the potential for hypoglycaemia (Fyfe et al., 2007). Several GKAs have been described during the past years. These compounds (GKA1, GKA2, RO-28-1675 and compound A) directly activate GK (Grimsby et al., 2003; Kamata et al., 2004). Activators of GK offer a potential therapeutic that could be a novel approach to decrease hyperglycaemia in people with diabetes.

CONCLUSION

The development in the understanding of type 2 diabetes mellitus pathophysiology at molecular level increases the number of antidiabetic drugs discovered. The demand to avoid the complications of the old therapeutic agents and to improve the recently discovered drugs enriched the area of antidiabeteic drug discovery with the most advanced and less adverse effects small molecular weight drugs. Among the recent antidiabetic therapies are the incretin-based therapies which are the latest marketed development in the field. Incretins are effective in improving glycemic control with low risk of hypoglycaemia. The impact of newer therapies associated with better concordance rates due to improved tolerability and lower toxicity compared with more traditional agents needs to be fully tested.

ACKNOWLEDGMENT

This study is the outcome of an in-house study and has not been supported financially.

REFERENCES
Abdel-Wahab, S.I., A.B. Abdul, A.S. Al-Zubairi, M.M. Elhassan and M. Syam, 2009. In vitro ultramorphological assessment of apoptosis induced by zerumbone on (Hela). J. Biomed. Biotechnol. 10.1155/2009/769568

Abdul, A.B., S.I. Abdel-Wahab, A.S. Al-Zubairi, M.M. El-Hassan and S.M. Murali, 2008. Anticancer and antimicrobial activities of zerumbone from the rhizomes of Zingiber zerumbut. Int. J. Pharmacol., 4: 301-304.
CrossRef  |  Direct Link  |  

Abdul, A.B., S.I. Abdel-Wahab, J.B. Jalinas, A.S. Al-Zubairi and M.M. Elhassan, 2009. Combination of zerumbone and cisplatin to treat cervical intraepithelial neoplasia in female balb/c mice. Int. J. Gyanacol., 19: 1004-1010.
CrossRef  |  PubMed  |  Direct Link  |  

Abdul, A.B.H., A.S. Al-Zubairi, N.D. Tailan, S.I. Abdel-Wahab, Z.N.M. Zain, S. Ruslay and M.M. Syam, 2008. Anticancer activity of natural compound (Zerumbone) extracted from Zingiber zerumbet in human hela cervical cancer cells. Int. J. Pharmacol., 4: 160-168.
CrossRef  |  Direct Link  |  

Al-Zubairi, A.S., A.B. Abdul and M.M. Syam, 2010. Evaluation of the genotoxicity of zerumbone in cultured human peripheral blood Lymphocytes. Toxicol In vitro, 24: 707-712.
CrossRef  |  PubMed  |  Direct Link  |  

Al-Zubairi, A.S., A.B. Abdul, M. Yousif, S.I. Abdelwahab, M.M. Elhassan and S. Mohan, 2010. In vivo and in vitro genotoxic effects of zerumbone. Caryologia, 63: 11-17.
CrossRef  |  Direct Link  |  

American Diabetes Association, 2007. Diagnosis and classification of diabetes mellitus. Diabetes Care, 30: S42-S47.
CrossRef  |  Direct Link  |  

Arbeeny, C.M., D.S. Meyers, D.E. Hillyer and K.E. Bergquist, 1995. Metabolic alterations associated with the antidiabetic effect of beta 3-adrenergic receptor agonists in obese mice. Am. J. Physiol. Endocrinol. Metab., 268: E678-E684.
PubMed  |  

Arch, J.R. and A.J. Kaumann, 1993. Beta 3 and atypical beta-adrenoceptors. Med. Res. Rev., 13: 663-729.

Arch, J.R., 2002. Beta(3)-adrenoceptor agonists: Potential, pitfalls and progress. Eur. J. Pharmacol., 440: 99-107.
PubMed  |  

Arita, Y., S. Kihara, N. Ouchi, M. Takahashi and K. Maeda et al., 1999. Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. Biochem. Biophys. Res. Commun., 257: 79-83.
CrossRef  |  PubMed  |  Direct Link  |  

Bach, J.F., 1995. Insulin-dependent diabetes mellitus as a β cell targeted disease of immunoregulation. J. Autoimmun., 8: 439-463.
PubMed  |  

Baggio, L.L. and D.J. Drucker, 2007. Biology of incretins: GLP-1 and GIP. Gastroenterology, 132: 2131-2157.
CrossRef  |  PubMed  |  Direct Link  |  

Berg, A.H., T.P. Combs and P.E. Scherer, 2002. ACRP30/adiponectin: An adipokine regulating glucose and lipid metabolism. Trends Endocrinol. Metab., 13: 84-89.
CrossRef  |  PubMed  |  

Berg, A.H., T.P. Combs, X. Du, M. Brownlee and P.E. Scherer, 2001. The adipocyte secreted protein Acrp30 enhances hepatic insulin action. Nat. Med., 7: 947-953.
Direct Link  |  

Bergman, R.N., 1997. New concepts in extracellular signaling for insulin action: The single gateway hypothesis. Recent. Prog. Horm. Res., 52: 359-385.
PubMed  |  

Berkowitz, D.E., N.A. Nardone, R.M. Smiley, D.T. Price, D.K. Kreutter, R.T. Fremeau and D.A. Schwinn, 1995. Distribution of beta 3-adrenoceptor mRNA in human tissues. Eur. J. Pharmacol., 289: 223-228.
PubMed  |  

Bjorbaek, C. and B.B. Kahn, 2004. Leptin signaling in the central nervous system and the periphery. Recent. Prog. Horm. Res., 59: 305-331.
PubMed  |  

Castaneda, F., A. Burse, W. Boland and R.K. Kinne, 2007. Thioglycosides as inhibitors of hSGLT1 and hSGLT2: Potential therapeutic agents for the control of hyperglycemia in diabetes. Int. J. Med. Sci., 4: 131-139.
PubMed  |  

Ceddia, R.B., W.N.Jr. William and R. Curi, 1999. Comparing effects of leptin and insulin on glucose metabolism in skeletal muscle: Evidence for an effect of leptin on glucose uptake and decarboxylation. Int. J. Obes. Relat. Metab. Disord., 23: 75-82.
PubMed  |  

Chan, J.L. and M.J. Abrahamson, 2003. Pharmacological management of type 2 diabetes mellitus: Rationale for rational use of insulin. Mayo. Clin. Proc., 78: 459-467.
PubMed  |  

Chen, H.C. and R.V. Farese, 2005. Inhibition of triglyceride synthesis as a treatment strategy for obesity: Lessons from DGAT1-deficient mice. Arterioscler. Thromb. Vasc. Biol., 25: 482-486.
PubMed  |  

Chen, H.C., D.R. Jensen, H.M. Myers, R.H. Eckel and R.V. Farese Jr., 2002. Increased insulin and leptin sensitivity in mice lacking acyl CoA: diacylglycerol acyltransferase1. J. Clin. Invest., 109: 1049-1055.
CrossRef  |  PubMed  |  

Chen, H.C., M. Rao, M.P. Sajan, M. Standaert and Y. Kanoh et al., 2004. Role of adipocyte-derived factors in enhancing insulin signaling in skeletal muscle and white adipose tissue of mice lacking acyl coenzyme A: Diacylglycerol acyltransferase 1. Diabetes, 53: 1445-1451.
PubMed  |  

Cohen, P. and J.M. Friedman, 2004. Leptin and the control of metabolism: Role for stearoyl-CoA desaturase-1 (SCD-1). J. Nutr., 134: 2455S-2463S.
Direct Link  |  

Cohen, P., M. Miyazaki, N.D. Socci, A.H. Greenberg and W. Liedtke et al., 2002. Role for stearoyl-CoA desaturase-1 in leptin-mediated weight loss. Science, 297: 240-243.
PubMed  |  Direct Link  |  

Collins, S., K.W. Daniel, E.M. Rohlfs, V. Ramkumar, I.L. Taylor and T.W. Gettys, 1994. Impaired expression and functional activity of the beta 3- and beta 1-adrenergic receptors in adipose tissue of congenitally obese (C57BL/6J ob/ob) mice. Mol. Endocrinol., 8: 518-527.
PubMed  |  

Collins, S., W. Cao and J. Robidoux, 2004. Learning new tricks from old dogs: Beta-adrenergic receptors teach new lessons on firing up adipose tissue metabolism. Mol. Endocrinol., 18: 2123-2131.
Direct Link  |  

Davani, B., A. Khan, M. Hult, E. Martensson and S. Okret et al., 2000. Type 1 11beta-hydroxysteroid dehydrogenase mediates glococorticoid activation and insulin release in pancreatic islets. J. Biol. Chem., 275: 34841-34844.
PubMed  |  

De Souza, C.J. and B.F. Burkey, 2001. Beta 3-adrenoceptor agonists as antidiabetic and anti-obesity drugs in humans. Curr. Pharm. Des., 7: 1433-1449.
PubMed  |  

DeFronzo, R.A., R.C. Bondonna and E. Ferranini, 1992. Pathogenesis of NIDDM. A balanced overview. Diabetes Care, 15: 318-368.
PubMed  |  

Deacon, C.F., 2004. Therapeutic strategies based on glucagon-like peptide 1. Diabetes, 53: 2181-2189.
Direct Link  |  

Deacon, C.F., A.H. Johnsen and J.J. Holst, 1995. Degradation of glucagon-like peptide-1 by human plasma in vitro yields an N-terminally truncated peptide that is a major endogenous metabolite in vivo. J. Clin. Endocrinol. Metab., 80: 952-957.
PubMed  |  

Deacon, C.F., S. Wamberg, P. Bie, T.E. Hughes and J.J. Holst, 2002. Preservation of active incretin hormones by inhibition of dipeptidyl peptidase IV suppresses meal-induced incretin secretion in dogs. J. Endocrinol., 172: 355-362.
PubMed  |  

Dobrzyn, A. and J.M. Ntambi, 2004. The role of stearoyl-CoA desaturase in body weight regulation. Trends Cardiovasc. Med., 14: 77-81.
PubMed  |  

Dobrzyn, A., P. Dobrzyn, S.H. Lee, M. Miyazaki and P. Cohen et al., 2005. Stearoyl-CoA desaturase-1 deficiency reduces ceramide synthesis by downregulating serine palmitoyltransferase and increasing beta-oxidation in skeletal muscle. Am. J. Physiol. Endocrinol. Metab., 288: E599-E607.
PubMed  |  

Dobrzyn, P., A. Dobrzyn, M. Miyazaki, P. Cohen and E. Asilmaz et al., 2004. Stearoyl-CoA desaturase 1 deficiency increases fatty acid oxidation by activating AMP-activated protein kinase in liver. Proc. Natl. Acad. Sci. USA, 101: 6409-6414.
PubMed  |  

Drews, J. and S. Ryser, 1997. Drug development: The role of innovation in drug development. Nature Biotechnol., 15: 1318-1319.
CrossRef  |  

Drews, J., 1997. Strategic choices facing the pharmaceutical industry: A case for innovation. Drug Discov. Today, 2: 72-78.
CrossRef  |  

Drucker, D.J. and M.A. Nauck, 2006. The incretin system: Glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet, 368: 1696-1705.
CrossRef  |  Direct Link  |  

Eldor, R. and I. Raz, 2006. Lipotoxicity versus adipotoxicity the deleterious effects of adipose tissue on β cells in the pathogenesis of type 2 diabetes. Diabetes Res. Clin. Pract., 74: S3-S8.
Direct Link  |  

Evans, J.L., J.J. Lin and I.D. Goldfine, 2005. Novel approach to treat insulin resistance, type 2 diabetes and the metabolic syndrome: Simultaneous activation of PPARα, PPARγ and PPARδ. Curr. Diabetes Rev., 1: 299-308.
Direct Link  |  

Farese, R.V.Jr., S. Cases and S.J. Smith, 2000. Triglyceride synthesis: Insights from the cloning of diacylglycerol acyltransferase. Curr. Opin. Lipidol., 11: 229-234.
PubMed  |  

Farooqi, I.S., G. Matarese, G.M. Lord, J.M. Keogh and E. Lawrence et al., 2002. Beneficial effects of leptin on obesity, T cell hyporesponsiveness and neuroendocrine/metabolic dysfunction of human congenital leptin deficiency. J. Clin. Invest., 110: 1093-1103.
PubMed  |  Direct Link  |  

Fehmann, H.C., R. Goke and B. Goke, 1995. Cell and molecular biology of the incretin hormones glucagon-like peptide-I and glucose-dependent insulin releasing polypeptide. Endocr. Rev., 16: 390-410.
Direct Link  |  

Feige, J.N., L. Gelman, L. Michalik, B. Desvergne and W. Wahli, 2006. From molecular action to physiological outputs: Peroxisome proliferator-activated receptors are nuclear receptors at the crossroads of key cellular functions. Prog. Lipid Res., 45: 120-159.
CrossRef  |  PubMed  |  Direct Link  |  

Flatt, P.R., C.J. Bailey and B.D. Green, 2008. Dipeptidyl peptidase IV (DPP IV) and related molecules in type 2 diabetes. Front. Biosci., 1: 3648-3660.
PubMed  |  

Friedman, J.M., 1998. Leptin, leptin receptors and the control of body weight. Nutr. Rev., 56: S38-S46.
Direct Link  |  

Friedman, T.C., G. Mastorakos, T.D. Newman, N.M. Mullen and E.G. Horton et al., 1996. Carbohydrate and lipid metabolism in endogenous hypercortisolism: Shared features with metabolic syndrome X and NIDDM. Endocr. J., 43: 645-655.
PubMed  |  

Fukuhara, A., M. Matsuda, M. Nishizawa, K. Segawa and M. Tanaka et al., 2005. Visfatin: A protein secreted by visceral fat that mimics the effects of insulin. Science, 307: 426-430.
CrossRef  |  Direct Link  |  

Fyfe, M.T.C., J. White, A. Taylor, R. Chatfield and E. Wargent et al., 2007. Glucokinase activator PSN-GK1 displays enhanced antihyperglycaemic and insulinotropic actions. Diabetologia, 50: 1277-1287.
Direct Link  |  

Gautier, J.F., S.P. Choukem and J. Girard, 2008. Physiology of incretins (GIP and GLP-1) and abnormalities in type 2 diabetes. Diabetes Metab., 34: S65-S72.
CrossRef  |  

Gerich, J.E., 1998. The genetic basis of type 2 diabetes mellitus: Impaired insulin secretion versus impaired insulin sensitivity. Endocr. Rev., 19: 491-503.
Direct Link  |  

Ghosh, S. and N. Schork, 1996. Genetic analysis of NIDDM. The study of quantitative traits. Diabetes, 45: 1-14.
Direct Link  |  

Glass, C.K., 2006. Going nuclear in metabolic and cardiovascular disease. J. Clin. Invest., 116: 556-560.
Direct Link  |  

Golden, J.B., 2003. Prioritizing the human genome knowledge management for drug discovery. Curr. Opin. Drug Discov. Dev., 6: 310-316.
PubMed  |  

Green, B.D. and P.R. Flatt, 2007. Incretin hormone mimetics and analogues in diabetes therapeutics. Best Pract. Res. Clin. Endocrinol. Metab., 21: 497-516.
PubMed  |  

Green, B.D., K.S. Lavery, N. Irwin, F.P. O'Harte and P. Harriott et al., 2006. Novel glucagon-like peptide-1 (GLP-1) analog (Val8) GLP-1 results in significant improvements of glucose tolerance and pancreatic beta-cell function after 3-week daily administration in obese diabetic (ob/ob) mice. J. Pharmacol. Exp. Ther., 318: 914-921.
PubMed  |  

Green, B.D., P.R. Flatt and C.J. Bailey, 2006. Dipeptidyl peptidase IV (DPP IV) inhibitors: A newly emerging drug class for the treatment of type 2 diabetes. Dia. Vasc. Dis. Res., 3: 159-165.
Direct Link  |  

Green, B.D., V.A. Gault, F.P. O'Harte and P.R. Flatt, 2004. Structurally modified analogues of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) as future antidiabetic agents. Curr. Pharm. Des., 10: 3651-3662.
PubMed  |  

Grimsby, J., R. Sarabu, W.L. Corbett, N.E. Haynes and F.T. Bizzarro et al., 2003. Allosteric activators of glucokinase: Potential role in diabetes therapy. Science, 301: 370-373.
CrossRef  |  Direct Link  |  

Grujic, D., V.S. Susulic, M.E. Harper, J. Himms-Hagen and B.A. Cunningham et al., 1997. Beta3-adrenergic receptors on white and brown adipocytes mediate beta3-selective agonist-induced effects on energy expenditure, insulin secretion and food intake. A study using transgenic and gene knockout mice. J. Biol. Chem., 272: 17686-17693.
PubMed  |  

Hales, C.N., 1994. The pathogenesis of NIDDM. Diabetologia, 3: S162-S168.
Direct Link  |  

Handoko, K., K. Yang, B. Strutt, W. Khalil and D. Killinger, 2000. Insulin attenuates the stimulatory effects of tumor necrosis factor α on 11β-hydroxysteroid dehydrogenase 1 in human adipose stromal cells. J. Ster. Biochem. Mol. Biol., 72: 163-168.
CrossRef  |  

Helmrich, S.P., D.R. Ragland, R.W. Leung and R.S. Paffenbarger, 1991. Physical activity and reduced occurrence of non-insulin-dependent diabetes mellitus. N. Engl. J. Med., 325: 147-152.
PubMed  |  

Henke, B.R., 2004. Peroxisome proliferator-activated receptor alpha/gamma dual agonists for the treatment of type 2 diabetes. J. Med. Chem., 47: 4118-4127.
Direct Link  |  

Heymsfield, S.B., A.S. Greenberg, K. Fujioka, R.M. Dixon and R. Kushner et al., 1999. Recombinant leptin for weight loss in obese and lean adults: A randomized, controlled, dose-escalation trial. JAMA., 282: 1568-1575.
PubMed  |  

Himms-Hagen, J., 1999. Physiological roles of the leptin endocrine system: Differences between mice and humans. Crit. Rev. Clin. Lab. Sci., 36: 575-655.
PubMed  |  

Hoffstedt, J., O. Poirier, A. Thorne, F. Lonnqvist, S.M. Herrmann, F. Cambien and P. Arner, 1999. Polymorphism of the human beta3-adrenoceptor gene forms a well-conserved haplotype that is associated with moderate obesity and altered receptor function. Diabetes, 48: 203-205.
PubMed  |  

Hopkins, A.L. and C.R. Groom, 2002. The druggable genome. Nat. Rev. Drug Discov., 1: 727-730.
PubMed  |  

Hotamisligil, G.S., 1999. The role of TNF-α and TNF receptors in obesity and insulin resistance. J. Intern. Med., 245: 621-625.
PubMed  |  

Imming, P., C. Sinning and A. Meyer, 2006. Drugs, their targets and the nature and number of drug targets. Nature Rev. Drug Discov., 5: 821-834.
Direct Link  |  

Jones, K.L., S. Arshanian, V.A. Peterova, J.S. Park and M.J. Tomlinson, 2002. Effect of metformin in pediatric patients with type 2 diabetes. Diabetes Care, 25: 89-94.
PubMed  |  

Jun, H.S., H.Y. Bae, B.R. Lee, K.S. Koh and Y.S. Kimc et al., 1999. Pathogenesis of non-insulin-dependent (type II) diabetes mellitus (NIDDM)-genetic predisposition and metabolic abnormalities. Adv. Drug Deliv. Rev., 35: 157-177.
PubMed  |  

Kamata, K., M. Mitsuya, T. Nishimura, J. Eiki and Y. Nagata, 2004. Structural basis for allosteric regulation of the monomeric allosteric enzyme human glucokinase. Structure, 12: 429-438.
CrossRef  |  

Kamohara, S., R. Burcelin, J.L. Halaas, J.M. Friedman and M.J. Charron, 1997. Acute stimulation of glucose metabolism in mice by leptin treatment. Nature, 389: 374-377.
Direct Link  |  

Katsuno, K., Y. Fujimori, Y. Takemura, M. Hiratochi and F. Itoh et al., 2007. Sergliflozin, a novel selective inhibitor of low-affinity sodium glucose cotransporter (SGLT2), validates the critical role of SGLT2 in renal glucose reabsorption and modulates plasma glucose level. J. Pharmacol. Exp. Ther., 320: 323-330.
Direct Link  |  

Kawahito, S., H. Kitahata and S. Oshita, 2009. Problems associated with glucose toxicity: Role of hyperglycemia-induced oxidative stress. World J. Gastroenterol., 15: 4137-4142.
Direct Link  |  

Kiess, W., A. Bottner, K. Raile, T. Kapellen and G. Muller et al., 2003. Type 2 diabetes mellitus in children and adolescents: A review from a European perspective. Horm. Res., 59: 77-84.
Direct Link  |  

Kiess, W., A. Galler, A. Reich, G. Muller and T. Kapellen, 2001. Clinical aspects of obesity in childhood and adolescence. Obesity Rev., 2: 29-36.
PubMed  |  

King, A.J., J.A. Segreti, K.J. Larson, A.J. Souers and P.R. Kym et al., 2009. Diacylglycerol acyltransferase 1 (DGAT-1) inhibition lowers serum triglycerides in the Zucker fatty rat and the hyperlipidemic hamster. J. Pharmacol. Exp. Therapeut., 330: 526-531.
Direct Link  |  

Krief, S., F. Lonnqvist, S. Raimbault, B. Baude and A. Van Spronsen et al., 1993. Tissue distribution of beta 3-adrenergic receptor mRNA in man. J. Clin. Invest., 91: 344-349.
Direct Link  |  

Lee, J.O., H. Yang, M.M. Georgescu, A. Di Cristofano and T. Maehama et al., 1999. Crystal structure of the PTEN tumor suppressor: Implications for its phosphoinositide phosphatase activity and membrane association. Cell, 99: 323-334.
PubMed  |  

Lehrke, M. and M.A. Lazar, 2005. The many faces of PPARγ. Cell, 123: 993-999.
CrossRef  |  PubMed  |  Direct Link  |  

Leighton, B., A. Atkinson and M.P. Coghlan, 2005. Small molecule glucokinase activators as novel anti-diabetic agents. Biochem. Soc. Trans., 33: 371-374.
PubMed  |  

Lillioja, S., D.M. Mott, M. Spraul, R. Ferraro and J.E. Foley et al., 1993. Insulin resistance and insulin secretory dysfunction as precursors of non-insulin-dependent diabetes mellitus: Prospective studies of Pima Indians. N. Engl. J. Med., 329: 1988-1992.
Direct Link  |  

Liu, Y.L. and M.J. Stock, 1995. Acute effects of the beta 3-adrenoceptor agonist, BRL 35135, on tissue glucose utilisation. Br. J. Pharmacol., 114: 888-894.
Direct Link  |  

Lowell, B.B. and G.I. Shulman, 2005. Mitochondrial dysfunction and type 2 diabetes. Science, 307: 384-387.
Direct Link  |  

Luconi, M., G. Cantini and M. Serio, 2010. Peroxisome proliferator-activated receptor gamma (PPARγ): Is the genomic activity the only answer?. Steroids, 75: 585-594.
CrossRef  |  

Maehama, T. and J.E. Dixon, 1998. The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. J. Biol. Chem., 273: 13375-13378.
PubMed  |  

Matschinsky, F.M., 2009. Assessing the potential of glucokinase activators in diabetes therapy. Nature Rev. Drug Discov., 8: 399-416.
Direct Link  |  

Matschinsky, F.M., M.A. Magnuson, D. Zelent, T.L. Jetton and N. Doliba et al., 2006. The network of glucokinase-expressing cells in glucose homeostasis and the potential of glucokinase activators for diabetes therapy. Diabetes, 55: 1-12.
CrossRef  |  PubMed  |  

McGarry, J.D., 2002. Banting lecture 2001: Dysregulation of fatty acid metabolism in the etiology of type 2 diabetes. Diabetes, 51: 7-18.
PubMed  |  

Mehanna, A.S., 2005. Insulin and oral antidiabetic agents. Am. J. Pharma. Educ., 69: 1-11.
Direct Link  |  

Mentlein, R., 1999. Dipeptidyl-peptidase IV (CD26)-role in the inactivation of regulatory peptides. Regul. Pept., 85: 9-24.
PubMed  |  

Michalik, L. and W. Wahli, 2006. Involvement of PPAR nuclear receptors in tissue injury and wound repair. J. Clin. Invest., 116: 598-606.
PubMed  |  Direct Link  |  

Minokoshi, Y., Y.B. Kim, O.D. Peroni, L.G. Fryer, C. Muller, D. Carling and B.B. Kahn, 2002. Leptin stimulates fatty-acid oxidation by activating AMP-activated protein kinase. Nature, 415: 339-343.
Direct Link  |  

Moreno-Aliaga, M.J., O. Lamas, A. Marti and J.A. Martinez, 2002. Effects of a beta3-adrenergic agonist on glucose uptake and leptin expression and secretion in cultured adipocytes from lean and overweight (cafeteria) rats. Biochem. Biophys. Res. Commun., 291: 1201-1207.
PubMed  |  

Morton, N.M., J.M. Paterson, H. Masuzaki, M.C. Holmes and B. Staels et al., 2004. Novel adipose tissue-mediated resistance to diet- induced visceral obesity in 11 beta-hydroxysteroid dehydrogenase type 1-deficient mice. Diabetes, 53: 931-938.
PubMed  |  

Nagase, I., T. Yoshida, K. Kumamoto, T. Umekawa and N. Sakane et al., 1996. Expression of uncoupling protein in skeletal muscle and white fat of obese mice treated with thermogenic beta 3-adrenergic agonist. J. Clin. Invest., 97: 2898-2904.
PubMed  |  

Nakashima, N., P.M. Sharma, T. Imamura, R. Bookstein and J.M. Olefsky, 2000. The tumor suppressor PTEN negatively regulates insulin signaling in 3T3-L1 adipocytes. J. Biol. Chem., 275: 12889-12895.
CrossRef  |  

Nathan, D.M., 2002. Initial management of glycemia in type 2 diabetic mellitus. N. Engl. J. Med., 347: 1342-1349.
Direct Link  |  

Nitambi, J. and M. Miyazaki, 2004. Regulation of stearoyl-CoA desaturases and role in metabolism. Prog. Lipid Res., 43: 91-104.
CrossRef  |  

Ntambi, J.M., S.A. Buhrow, K.H. Kaestner, R.J. Christy, E. Sibley, T.J. Kelly Jr. and M.D. Lane, 1988. Differentiation-induced gene expression in 3T3-L1 preadipocytes. Characterization of a differentially expressed gene encoding stearoyl-CoA desaturase. J. Biol. Chem., 263: 17291-17300.
PubMed  |  

O'Rahilly, S., J.S. Wainscoat and R.C. Turner, 1988. Type 2 (noninsulin dependent) diabetes mellitus. New genetics for old nightmares. Diabetologia, 31: 407-414.
Direct Link  |  

Ohlstein, E.H., R.R. Ruffolo and J.D. Elliott, 2000. Drug discovery in the next millennium. Annu. Rev. Pharmacol. Toxicol., 40: 177-191.
CrossRef  |  

Overington, J.P., B. Al-Lazikani and A.L. Hopkins, 2006. How many drug targets are there. Nature Rev. Drug Discov., 5: 993-996.
Direct Link  |  

Palmert, M.R., C.M. Gordon, A.I. Kartashowv, R.S. Legro, S.J. Emans and A. Dunaif, 2002. Screening for abnormal glucose tolerance in adolescents with polycystic ovary syndrome. J. Clin. Endocrinol. Metab., 87: 1017-1023.
PubMed  |  

Pilch, P.F. and N. Bergenhem, 2006. Pharmacological targeting of adipocytes/fat metabolism for treatment of obesity and diabetes. Mol. Pharmacol., 70: 779-785.
Direct Link  |  

Saad, M.F., W.C. Knowler, D.J. Pettitt, R.G. Nelson, M.A. Charles and P.H. Bennett, 1991. A two step model for development of non-insulin-dependent diabetes. Am. J. Med., 90: 229-235.
PubMed  |  

Saltiel, A.R. and C.R. Kahn, 2001. Insulin signalling and the regulation of glucose and lipid metabolism. Nature, 414: 799-806.
Direct Link  |  

Scheen, A.J., 2001. Obesity and Diabetes. In: The Management of Obesity and Related Disorders, Kopelman ,P.G. (Ed.). Martin Dunitz Ltd., London, UK., pp: 11-44.

Semple, R.K., V.K. Chatterjee and S. O'Rahilly, 2006. PPARgamma and human metabolic disease. J. Clin. Invest., 116: 581-589.
PubMed  |  

Shalam, M.D., M.S. Harish and S.A. Farhana, 2006. Prevention of dexamethasone- and fructose-induced insulin resistance in rats by SH-01D, a herbal preparation. Ind. J. Pharmacol., 38: 419-422.
CrossRef  |  Direct Link  |  

Shaw, J.E., R.A. Sicree and P.Z. Zimmet, 2010. Global estimates of the prevalence of diabetes for 2010 and 2030. Diabetes Res. Clin. Pract., 87: 4-14.
CrossRef  |  PubMed  |  Direct Link  |  

Straus, D.S. and C.K. Glass, 2007. Anti-inflammatory actions of PPAR ligands: New insights on cellular and molecular mechanisms. Trends Immunol., 28: 551-558.
PubMed  |  

Strauss, R.S. and H.A. Pollack, 2001. Epidemic increase in childhood overweight, 1986-1998. J. Am. Med. Assoc., 286: 2845-2848.
PubMed  |  

Stumvoll, M., B.J. Goldstein and T.W. Van Haeften, 2005. Type 2 diabetes: Principles of pathogenesis and therapy. Lancet, 365: 1333-1346.
CrossRef  |  PubMed  |  

Tahrani, A.A., M.K. Piya, A. Kennedy and A.H. Barnett, 2010. Glycaemic control in type 2 diabetes: Targets and new therapies. Pharmacol. Therapeut., 125: 328-361.
CrossRef  |  Direct Link  |  

Taylor, S.I., 1999. Deconstructing type 2 diabetes. Cell, 97: 9-12.
PubMed  |  

Thong, F.S., C.B. Dugani and A. Klip, 2005. Turning signals on and off: GLUT4 traffic in the insulin-signaling highway. Physiology, 20: 271-284.
PubMed  |  

Trumper, A., K. Trumper, H. Trusheim, R. Arnold, B. Goke and D. Horsch, 2001. Glucose-dependent insulinotropic polypeptide is a growth factor for beta (INS-1) cells by pleiotropic signaling. Mol. Endocrinol., 15: 1559-1570.
PubMed  |  

Umekawa, T., T. Yoshida, N. Sakane, A. Kogure, M. Kondo and H. Honjyo, 1999. Trp64Arg mutation of beta3-adrenoceptor gene deteriorates lipolysis induced by beta3-adrenoceptor agonist in human omental adipocytes. Diabetes, 48: 117-120.
Direct Link  |  

Umekawa, T., T. Yoshida, N. Sakane, M. Saito, K. Kumamoto and M. Kondo, 1997. Anti-obesity and anti-diabetic effects of CL316,243, a highly specific beta 3-adrenoceptor agonist, in Otsuka Long-Evans Tokushima Fatty rats: Induction of uncoupling protein and activation of glucose transporter 4 in white fat. Eur. J. Endocrinol., 136: 429-437.
PubMed  |  

Unger, R.H., 2002. Lipotoxic diseases. Annu. Rev. Med., 53: 319-336.
Direct Link  |  

Walker, B.R., A.A. Connacher, R.M. Lindsay, D.J. Webb and C.R.W. Edwards, 1995. Carbenoxolone increases hepatic insulin sensitivity in man: A novel role for 11- oxosteroid reductase in enhancing glucocorticoid receptor activation. J. Clin. Endocrinol. Metab., 80: 3155-3159.
PubMed  |  

Wang, J.L., N. Chinookoswong, S. Scully, M. Qi and Z.Q. Shi, 1999. Differential effects of leptin in regulation of tistissue glucose utilization in vivo. Endocrinology, 140: 2117-2124.
PubMed  |  

World Health Organization, 1985. Study group, diabetes mellitus. WHO Tech. Rep. Ser., 727: 1-113.

Wright, E.M., 2001. Renal Na(+)-glucose cotransporters. Am. J. Physiol. Renal. Physiol., 280: F10-F18.
PubMed  |  

Yamauchi, T., J. Kamon, H. Waki, Y. Terauchi and N. Kubota et al., 2001. The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat. Med., 7: 941-946.
Direct Link  |  

Yang, Q., T.E. Graham, N. Mody, F. Preitner and O.D. Peroni et al., 2005. Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes. Nature, 436: 356-362.
CrossRef  |  Direct Link  |  

Yang, R.Z., M.J. Lee, H. Hu, J. Pray and H.B. Wu et al., 2006. Identification of omentin as a novel depot specific adipokine in human adipose tissue: Possible role in modulating insulin action. Am. J. Physiol., 290: E1253-E1261.
PubMed  |  Direct Link  |  

Yip, R.G. and M.M. Wolfe, 2000. GIP biology and fat metabolism. Life Sci., 66: 91-103.
PubMed  |  

Yki-Jarvinen, H., 1994. Pathogenesis of non-insulin-dependent diabetes mellitus. Lancet, 343: 91-95.
PubMed  |  

Yki-Jarvinen, H., 2004. Thiazolidinediones. N. Engl. J. Med., 351: 1106-1118.
CrossRef  |  Direct Link  |  

Zangeneh, F., Y.C. Kudva and A. Basu, 2003. Insulin sensitizers. Mayo. Clin. Proc., 78: 471-479.
PubMed  |  

Zhang, Y., R. Proenca, M. Maffei, M. Barone, L. Leopold and J.M. Friedman, 1994. Positional cloning of the mouse obese gene and its human homologue. Nature, 372: 425-432.
CrossRef  |  Direct Link  |  

Zheng, C., L. Han, C.W. Yap, B. Xie and Y. Chen, 2006. Progress and problems in the exploration of therapeutic targets. Drug Discov. Today, 11: 412-420.
PubMed  |  

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