Antidiabetic Target Research Articles

The active conformation of human glucokinase is not altered by allosteric activators

Glucokinase (GK) catalyses the formation of glucose 6-phosphate from glucose and ATP. A specific feature of GK amongst hexokinases is that it can cycle between active and inactive conformations as a function of glucose concentration, resulting in a unique positive kinetic cooperativity with glucose, which turns GK into a unique key sensor of glucose metabolism, notably in the pancreas. GK is a target of antidiabetic drugs aimed at the activation of GK activity, leading to insulin secretion. Here, the first structures of a GK-glucose complex without activator, of GK-glucose-AMP-PNP and of GK-glucose-AMP-PNP with a bound activator are reported. All these structures are extremely similar, thus demonstrating that binding of GK activators does not result in conformational changes of the active protein but in stabilization of the active form of GK.

Revealing a steroid receptor ligand as a unique PPARγ agonist

Peroxisome proliferator-activated receptor gamma (PPARγ) regulates metabolic homeostasis and is a molecular target for anti-diabetic drugs. We report here the identification of a steroid receptor ligand, RU-486, as an unexpected PPARγ agonist, thereby uncovering a novel signaling route for this steroid drug. Similar to rosiglitazone, RU-486 modulates the expression of key PPARγ target genes and promotes adipocyte differentiation, but with a lower adipogenic activity. Structural and functional studies of receptor-ligand interactions reveal the molecular basis for a unique binding mode for RU-486 in the PPARγ ligand-binding pocket with distinctive properties and epitopes, providing the molecular mechanisms for the discrimination of RU-486 from thiazolidinediones (TZDs) drugs. Our findings together indicate that steroid compounds may represent an alternative approach for designing non-TZD PPARγ ligands in the treatment of insulin resistance.

Potential link between alpha 1 anti-trypsin and PAR-2 in the prevention of beta cell dysfunction

Objective Pancreatic islet beta cell death occurs in both type 1 (rapid onset) and type 2 (delayed onset) diabetes mellitus; the inflammatory mediators seem to play an important role in the beta cell failure/apoptosis in both cases. PAR-2 expression has been associated with inflammation. Therefore the objective of our study was to identify the new anti-diabetic drug target PAR-2’s expression on pancreatic islets and investigate the potential interaction between pro-inflammatory effects of PAR-2 and anti-inflammatory effect of alpha-1 antitrypsin on human pancreatic islets. Materials and methods PAR-2 expression was analyzed by confocal microscopy, western blot and qPCR in human pancreatic islets. Hormone secretion and cAMP content in islets were determined with RIA and apoptosis with the Annexin-V method. Results qPCR, western blots and confocal microscopy revealed that PAR-2 was expressed in pancreatic islets cultured with cytokines. Microarray data showed a higher expression of PAR-2 mRNA in the islets of diabetic vs. non-diabetic donors. PAR-2-transfected HeLa cells showed a further reduced rate of cell proliferation in the presence of SLIGKV or tryptase. Induction of apoptosis by a cocktail of cytokines (IL-1β100 ng/ml, TNFα and IFN125 ng/ml) was markedly inhibited by A1AT treatment. This effect of A1AT was associated with a concentration-dependent response on the glucose-stimulated (12 mmol/l) insulin release. Binding study showed that A1AT binds to PAR-2 in transfected HeLa cells with an IC 50 in a micromolar range. Conclusion In view of this novel finding we suggest that drugs e.g. A1AT, which can selectively inhibit the activity of PAR-2, represent a promising frontier in diabetes mellitus therapy.

Ligand-based modelling followed by synthetic exploration unveil novel glycogen phosphorylase inhibitory leads

Glycogen phosphorylase (GP) is a valid anti-diabetic target. Accordingly, we applied a drug discovery workflow to unveil novel inhibitory GP leads via combining pharmacophore modeling, QSAR analysis and in silico screening, followed by synthetic exploration of active hits. Virtual screening identified six low micromolar inhibitory leads from the National Cancer Institute (NCI) list of compounds. The most potent hits exhibited anti-GP IC50 values of 3.2 and 4.1μM. Synthetic exploration of hit 59 (IC50=4.1μM) yielded 25 lead inhibitors with the best illustrating IC50 of 3.0μM. Interestingly, we prepared several novel mixed oxalyl amide anti-GP leads employing new chemical reaction involving succinic acid-based adducts.

Targeting the AMP-regulated kinase family to treat diabetes: a research update

SUMMARY AMP-activated protein kinase (AMPK) has long been recognized as a master energy sensor. Activation of AMPK in response to metabolic stress preserves energy stores by switching on catabolic pathways, whilst its inhibition consumes the energy by switching on anabolic pathways. Over the past 10–15 years, much attention has been focused on the role of AMPK in mammalian metabolism, and particularly in diabetes. As a consequence, AMPK has emerged as much more than a simple energy regulator and is now recognized as a kinase involved in controlling numerous cellular processes, including cell growth, apoptosis, autophagy and polarity. Using different in vitro and in vivo tools, AMPK has also been found to play important roles in different glucose-sensing organs and to serve as a key regulator of glucose homeostasis in mammals. Perhaps most importantly, AMPK appears to be the major target for several antidiabetic drugs. Here, we review recent advances in the field and particularly those emerging from the ge...

A small molecule antagonist of ghrelin O-acyltransferase (GOAT)

Using our recently disclosed fluorescence-based assay to monitor acyltransferase activity, the first non-peptidic, small molecule antagonists of ghrelin O-acyltransferase (GOAT), a potential anti-obesity and anti-diabetes target, have been discovered. Each exhibits micromolar inhibition of the enzyme, and may be useful probes for future study of the ghrelin-GOAT system.

A Time‐Resolved Fluorescence Probe for Dipeptidyl Peptidase 4 and Its Application in Inhibitor Screening

The prevalence of type 2 diabetes is increasing dramatically throughout the world. Recently, dipeptidyl peptidase 4 (DPP4) was identified as a potential antidiabetes target. Many DPP4 inhibitors, such as sitagliptin and vildagliptin, have been developed and marketed, but superior therapeutic agents are still required. Therefore, we have developed new methodology for screening of DPP4 inhibitors. Absorption-based measurements with para-nitroaniline or fluorescence-based measurements with the coumarin derivative 7-amino-4-methylcoumarin are often used for the screening of protease inhibitors, including DPP4 inhibitors, but these strategies are not sufficiently sensitive because of interfering background absorption and fluorescence, thus giving rise to many false-positive and false-negative results. Therefore, we have designed and synthesised a novel DPP4 probe (Gly-Pro-BCD-Tb; Gly=glycine, Pro=proline, andBCD defines the backbone of the probe comprising an aniline derivative as on/off switch, a 7-amino-4-methyl-2(1H)-quinolinone (cs-124) as antenna moiety, and a diethylenetriamine-N,N,N',N'',N''-pentaacetic acid (DTPA) as chelator moiety, Tb=terbium) for time-resolved fluorescence (TRF) measurements. TRF measurements with Gly-Pro-BCD-Tb showed high sensitivity and reliability in the inhibitory assay relative to Gly-Pro-MCA (MCA=4-methylcoumarin-7-amide), a conventional fluorescence probe for DPP4. Further, we employed our probe for high-throughput DPP4 inhibitor screening with 3841 randomly selected compounds and found that epibestatin, an epimer of bestatin (a well-known anticancer drug and general aminopeptidase inhibitor), showed dose-dependent DPP4 inhibitory activity. Interestingly, bestatin did not exhibit DPP4 inhibitory activity. We believe that this screening system will be useful for the discovery of DPP4 inhibitors with novel structural scaffolds.

Ppm1E is an in cellulo AMP-activated protein kinase phosphatase

Activation of 5′-AMP-activated protein kinase (AMPK) is believed to be the mechanism by which the pharmaceuticals, metformin and phenformin, exert their beneficial effects for treatment of type 2 diabetes. These biguanide drugs elevate 5′-AMP, which allosterically activates AMPK and promotes phosphorylation on Thr172 of AMPK catalytic α subunits. Although kinases phosphorylating this site have been identified, phosphatases that dephosphorylate it are unknown. The aim of this study is to identify protein phosphatase(s) that dephosphorylate AMPKα-Thr172 within cells. Our initial data indicated that members of the protein phosphatase ce:sup>/ce:sup>/Mn 2+-dependent (PPM) family and not those of the PPP family of protein serine/threonine phosphatases may be directly or indirectly inhibited by phenformin. Using antibodies raised to individual Ppm phosphatases that facilitated the assessment of their activities, phenformin stimulation of cells was found to decrease the ce:sup>/ce:sup>/Mn 2+-dependent protein serine/threonine phosphatase activity of Ppm1E and Ppm1F, but not that attributable to other PPM family members, including Ppm1A/PP2Cα. Depletion of Ppm1E, but not Ppm1A, using lentiviral-mediated stable gene silencing, increased AMPKα-Thr172 phosphorylation approximately three fold in HEK293 cells. In addition, incubation of cells with low concentrations of phenformin and depletion of Ppm1E increased AMPK phosphorylation synergistically. Ppm1E and the closely related Ppm1F interact weakly with AMPK and assays with lysates of cells stably depleted of Ppm1F suggests that this phosphatase contributes to dephosphorylation of AMPK. The data indicate that Ppm1E and probably PpM1F are in cellulo AMPK phosphatases and that Ppm1E is a potential anti-diabetic drug target.

Antioxidant rich grape pomace extract suppresses postprandial hyperglycemia in diabetic mice by specifically inhibiting alpha-glucosidase

BackgroundPostprandial hyperglycemia is an early defect of type 2 diabetes and one of primary anti-diabetic targets. Treatment of postprandial hyperglycemia can be achieved by inhibiting intestinal α-glucosidase, the key enzyme for oligosaccharide digestion and further glucose absorption. Grape pomace is winemaking byproduct rich in bioactive food compounds such as phenolic antioxidants. This study evaluated the anti-diabetic potential of two specific grape pomace extracts by determining their antioxidant and anti-postprandial hyperglycemic activities in vitro and in vivo.MethodsThe extracts of red wine grape pomace (Cabernet Franc) and white wine grape pomace (Chardonnay) were prepared in 80% ethanol. An extract of red apple pomace was included as a comparison. The radical scavenging activities and phenolic profiles of the pomace extracts were determined through the measurement of oxygen radical absorbance capacity, DPPH radical scavenging activity, total phenolic content and flavonoids. The inhibitory effects of the pomace extracts on yeast and rat intestinal α-glucosidases were determined. Male 6-week old C57BLKS/6NCr mice were treated with streptozocin to induce diabetes. The diabetic mice were then treated with vehicle or the grape pomace extract to determine whether the oral intake of the extract can suppress postprandial hyperglycemia through the inhibition of intestinal α-glucosidases.ResultsThe red grape pomace extract contained significantly higher amounts of flavonoids and phenolic compounds and exerted stronger oxygen radical absorbance capacity than the red apple pomace extract. Both the grape pomace extracts but not the apple pomace extract exerted significant inhibition on intestinal α-glucosidases and the inhibition appears to be specific. In the animal study, the oral intake of the grape pomace extract (400 mg/kg body weight) significantly suppressed the postprandial hyperglycemia by 35% in streptozocin-induced diabetic mice following starch challenge.ConclusionThis is the first report that the grape pomace extracts selectively and significantly inhibits intestinal α-glucosidase and suppresses postprandial hyperglycemia in diabetic mice. The antioxidant and anti-postprandial hyperglycemic activities demonstrated on the tested grape pomace extract therefore suggest a potential for utilizing grape pomace-derived bioactive compounds in management of diabetes.

Cell-Specific Determinants of Peroxisome Proliferator-Activated Receptor γ Function in Adipocytes and Macrophages

The nuclear receptor peroxisome proliferator activator receptor gamma (PPARgamma) is the target of antidiabetic thiazolidinedione drugs, which improve insulin resistance but have side effects that limit widespread use. PPARgamma is required for adipocyte differentiation, but it is also expressed in other cell types, notably macrophages, where it influences atherosclerosis, insulin resistance, and inflammation. A central question is whether PPARgamma binding in macrophages occurs at genomic locations the same as or different from those in adipocytes. Here, utilizing chromatin immunoprecipitation and high-throughput sequencing (ChIP-seq), we demonstrate that PPARgamma cistromes in mouse adipocytes and macrophages are predominantly cell type specific. In thioglycolate-elicited macrophages, PPARgamma colocalizes with the hematopoietic transcription factor PU.1 in areas of open chromatin and histone acetylation, near a distinct set of immune genes in addition to a number of metabolic genes shared with adipocytes. In adipocytes, the macrophage-unique binding regions are marked with repressive histone modifications, typically associated with local chromatin compaction and gene silencing. PPARgamma, when introduced into preadipocytes, bound only to regions depleted of repressive histone modifications, where it increased DNA accessibility, enhanced histone acetylation, and induced gene expression. Thus, the cell specificity of PPARgamma function is regulated by cell-specific transcription factors, chromatin accessibility, and histone marks. Our data support the existence of an epigenomic hierarchy in which PPARgamma binding to cell-specific sites not marked by repressive marks opens chromatin and leads to local activation marks, including histone acetylation.

Regulation of ENaC-Mediated Sodium Reabsorption by Peroxisome Proliferator-Activated Receptors

Peroxisome proliferator-activated receptors (PPARs) are members of a steroid hormone receptor superfamily that responds to changes in lipid and glucose homeostasis. Peroxisomal proliferator-activated receptor subtype γ (PPARγ) has received much attention as the target for antidiabetic drugs, as well as its role in responding to endogenous compounds such as prostaglandin J2. However, thiazolidinediones (TZDs), the synthetic agonists of the PPARγ are tightly associated with fluid retention and edema, as potentially serious side effects. The epithelial sodium channel (ENaC) represents the rate limiting step for sodium absorption in the renal collecting duct. Consequently, ENaC is a central effector impacting systemic blood volume and pressure. The role of PPARγ agonists on ENaC activity remains controversial. While PPARγ agonists were shown to stimulate ENaC-mediated renal salt absorption, probably via Serum- and Glucocorticoid-Regulated Kinase 1 (SGK1), other studies reported that PPARγ agonist-induced fluid retention is independent of ENaC activity. The current paper provides new insights into the control and function of ENaC and ENaC-mediated sodium transport as well as several other epithelial channels/transporters by PPARs and particularly PPARγ. The potential contribution of arachidonic acid (AA) metabolites in PPAR-dependent mechanisms is also discussed.

Clinical effectiveness of telmisartan alone or in combination therapy for controlling blood pressure and vascular risk in the elderly.

Elderly patients (age ≥65 years) with hypertension are at high risk for vascular complications, especially when diabetes is present. Antihypertensive drugs that inhibit the renin-angiotensin system have been shown to be effective for controlling blood pressure in adult and elderly patients. Importantly, renin-angiotensin system inhibitors were shown to have benefits beyond their classic cardioprotective and vasculoprotective effects, including reducing the risk of new-onset diabetes and associated cardiovascular effects. The discovery that the renin-angiotensin system inhibitor and angiotensin II type 1 (AT1) receptor blocker (ARB), telmisartan, can selectively activate the peroxisome proliferator-activated receptor-γ (PPARγ, an established antidiabetic drug target) provides the unique opportunity to prevent and treat cardiovascular complications in high-risk elderly patients with hypertension and new-onset diabetes. Two large clinical trials, ONTARGET (Ongoing Telmisartan Alone in combination with Ramipril Global Endpoint Trial) and TRANSCEND (Telmisartan Randomized AssessmeNt Study in ACE-I iNtolerant subjects with cardiovascular disease) have assessed the cardioprotective and antidiabetic effects of telmisartan. The collective data suggest that telmisartan is a promising drug for controlling hypertension and reducing vascular risk in high-risk elderly patients with new-onset diabetes.

Insulin-releasing and metabolic effects of small molecule GLP-1 receptor agonist 6,7-dichloro-2-methylsulfonyl-3-N- tert-butylaminoquinoxaline

Much recent attention has focused on the GLP-1 receptor as a potential target for antidiabetic drugs. Enzyme resistant GLP-1 mimetics such as exenatide are now employed for the treatment of type 2 diabetes, but must be administered by injection. The present study has examined and compared the in vitro and in vivo metabolic actions of a small molecule GLP-1 receptor agonist 6,7-dichloro-2-methylsulfonyl-3-N- tert-butylaminoquinoxaline (DMB), with native GLP-1, exenatide and liraglutide. DMB significantly stimulated in vitro insulin secretion from BRIN-BD11 cells but with decreased molar potency compared to native GLP-1 or related mimetics. Administration of DMB in combination with glucose to mice significantly ( P < 0.05) decreased the overall glucose excursion compared to controls. Exenatide and liraglutide evoked similar ( P < 0.001) reductions of the overall glycaemic excursion, but were significantly ( P < 0.001 and P < 0.05; respectively) more effective than DMB. These observations were associated with prominently ( P < 0.05) enhanced glucose-mediated insulin release by exenatide and liraglutide, but not by DMB. Combined injection of DMB with either liraglutide or exenatide did not substantially improve glucose-lowering or insulin-releasing responses. However, administration of DMB in combination with exendin(9–39) did not impair its glucoregulatory actions. These results provide evidence to support the development and potential use of low molecular weight GLP-1 receptor agonists for the treatment of type 2 diabetes.

Effect of astragaloside IV on hepatic glucose‐regulating enzymes in diabetic mice induced by a high‐fat diet and streptozotocin

Hepatic glycogen phosphorylase (GP) and glucose-6-phosphatase (G6Pase) are important in control of blood glucose homeostasis, and are considered to be potential targets for antidiabetic drugs. Astragaloside IV has been reported to have a hypoglycemic effect. However, the biochemical mechanisms by which astragaloside IV regulates hepatic glucose-metabolizing enzymes remain unknown. The present study examines whether GP and G6Pase mediate the hypoglycemic effect of astragaloside IV. Type 2 diabetic mice were treated with astragaloside IV for 2 weeks. Blood glucose and insulin levels were measured by a glucometer and the ELISA method, respectively. Total cholesterol (TC) and triglyceride (TG) levels were determined using Labassay kits. Activities of hepatic GP and G6Pase were measured by the glucose-6-phosphate dehydrogenase-coupled reaction. The mRNA and protein levels of both enzymes were determined by real-time RT-PCR and Western blotting. Astragaloside IV at 25 and 50 mg/kg significally decreased the blood glucose, TG and insulin levels, and inhibited the mRNA and protein expression as well as enzyme activity of GP and G6Pase in diabetic mice. Astragaloside IV exhibited a hypoglycemic effect in diabetic mice. The hypoglycemic effect of this compound may be explained, in part, by its inhibition of hepatic GP and G6Pase activities.

Role of PPAR-gamma in inflammation. Prospects for therapeutic intervention by food components

Peroxisome proliferator activated receptor gamma (PPARγ) is a ligand-dependent transcription factor and a member of the nuclear receptor superfamily. Acting as sensors of hormones, vitamins, endogenous metabolites and xenobiotic compounds, the nuclear receptors control the expression of a very large number of genes. PPARγ has been known for some time to regulate adipocyte differentiation, fatty acid storage and glucose metabolism, and is a target of anti-diabetic drugs. More recently, PPARγ has been recognized as playing a fundamentally important role in the immune response through its ability to inhibit the expression of inflammatory cytokines and to direct the differentiation of immune cells towards anti-inflammatory phenotypes. A feature of PPARγ is the structural diversity of its ligands, which encompass endogenous metabolites, dietary compounds and synthetic drugs. The high and increasing incidence of inflammatory and allergic disease, coupled with encouraging results from recent clinical trials, suggest that natural PPARγ agonists found in foods may be beneficial to human health by acting as anti-inflammatory molecules. PPARγ is therefore not only a target of the pharmaceutical industry, but also of great potential interest to the food industry, since it is activated by several natural dietary constituents. The prospects for dietary intervention in inflammatory disease have improved somewhat over the last few years, and are reviewed here.

Resonance Raman Studies of the (His)(Cys)3 2Fe-2S Cluster of MitoNEET: Comparison to the (Cys)4 Mutant and Implications of the Effects of pH on the Labile Metal Center

MitoNEET is a 2Fe-2S outer mitochondrial membrane protein that was initially identified as a target for anti-diabetic drugs. It exhibits a novel protein fold, and in contrast to other 2Fe-2S proteins such as Rieske proteins and ferredoxins, the metal clusters in the mitoNEET homodimer are each coordinated by one histidine residue and three cysteine residues. The interaction of the ligating His87 residue with the 2Fe-2S moiety is especially significant because previous studies have shown that replacement with Cys in the H87C mutant stabilizes the cluster against release. Here, we report the resonance Raman spectra of this naturally occurring Fe(2)S(2)(His)(Cys)(3) protein to assess local structural changes associated with cluster lability. Comparison of mitoNEET to its ferredoxin-like H87C mutant indicates that Raman peaks in the approximately 250-300 cm(-1) region of mitoNEET are influenced by the Fe-His87 moiety. Systematic pH-dependent resonance Raman spectral changes were observed in this spectral region for native mitoNEET but not the H87C mutant. The approximately 250-300 cm(-1) region of native mitoNEET is also sensitive to phosphate buffer. Thus, conditions that influence cluster release are shown here to concomitantly affect the resonance Raman spectrum in the region with Fe-His contribution. These results support the hypothesis that the Fe-N(His87) interaction is modulated within the physiological pH range, and this modulation may be critical to the function of mitoNEET.

Disruption of the allosteric phosphorylase a regulation of the hepatic glycogen-targeted protein phosphatase 1 improves glucose tolerance in vivo

Type 2 diabetes is characterised by elevated blood glucose concentrations, which potentially could be normalised by stimulation of hepatic glycogen synthesis. Under glycogenolytic conditions, the interaction of hepatic glycogen-associated protein phosphatase-1 (PP1–G L) with glycogen phosphorylase a is believed to inhibit the dephosphorylation and activation of glycogen synthase (GS) by the PP1–G L complex, suppressing glycogen synthesis. Consequently, the interaction of G L with phosphorylase a has emerged as an attractive anti-diabetic target, pharmacological disruption of which could provide a novel mechanism to lower blood glucose levels by increasing hepatic glycogen synthesis. Here we report for the first time the in vivo consequences of disrupting the G L–phosphorylase a interaction, using a mouse model containing a Tyr284Phe substitution in the phosphorylase a-binding region of the G L protein. The resulting G L Y284F/Y284F mice display hepatic PP1–G L activity that is no longer sensitive to allosteric inhibition by phosphorylase a, resulting in increased GS activity under glycogenolytic conditions, demonstrating that regulation of G L by phosphorylase a operates in vivo. G L Y284F/Y284F and G L Y284F/+ mice display improved glucose tolerance compared with G L +/+ littermates, without significant accumulation of hepatic glycogen. The data provide the first in vivo evidence in support of targeting the G L–phosphorylase a interaction for treatment of hyperglycaemia. During prolonged fasting the G L Y284F/Y284F mice lose more body weight and display decreased blood glucose levels in comparison with their G L +/+ littermates. These results suggest that, during periods of food deprivation, the phosphorylase a regulation of G L may prevent futile glucose–glycogen cycling, preserving energy and thus providing a selective biological advantage that may explain the observed conservation of the allosteric regulation of PP1–G L by phosphorylase a in mammals.

Effect of geniposide, a hypoglycemic glucoside, on hepatic regulating enzymes in diabetic mice induced by a high-fat diet and streptozotocin

Hepatic glycogen phosphorylase (GP) and glucose-6-phosphatase (G6Pase) play an important role in the control of blood glucose homeostasis and are proposed to be potential targets for anti-diabetic drugs. Geniposide is an iridoid glucoside extracted from Gardenia jasminoides Ellis fruits and has been reported to have a hypoglycemic effect. However, little is known about the biochemical mechanisms by which geniposide regulates hepatic glucose-metabolizing enzymes. The present study investigates whether the hypoglycemic effect of geniposide is mediated by GP or G6Pase. Type 2 diabetic mice, induced by a high-fat diet and streptozotocin injection, were treated with or without geniposide for 2 weeks. Blood glucose levels were monitored by a glucometer. Insulin concentrations were analyzed by the ELISA method. Total cholesterol (TC) and triglyceride (TG) levels were measured using Labassay kits. Activities of hepatic GP and G6Pase were measured by glucose-6-phosphate dehydrogenase-coupled reaction. Real-time RT-PCR and Western blotting were used to determine the mRNA and protein levels of both enzymes. Geniposide (200 and 400 mg/kg) significantly decreased the blood glucose, insulin and TG levels in diabetic mice in a dose-dependent manner. This compound also decreased the expression of GP and G6Pase at mRNA and immunoreactive protein levels, as well as enzyme activity. Geniposide is an effective hypoglycemic agent in diabetic mice. The hypoglycemic effect of this compound may be mediated, at least in part, by inhibiting the GP and G6Pase activities.

Adenosine Monophosphate-Activated Protein Kinase (AMPK) as a New Target for Antidiabetic Drugs: A Review on Metabolic, Pharmacological and Chemical Considerations

In view of the epidemic nature of type 2 diabetes and the substantial rate of failure of current oral antidiabetic drugs the quest for new therapeutics is intensive. The adenosine monophosphate-activated protein kinase (AMPK) is an important regulatory protein for cellular energy balance and is considered a master switch of glucose and lipid metabolism in various organs, especially in skeletal muscle and liver. In skeletal muscles, AMPK stimulates glucose transport and fatty acid oxidation. In the liver, it augments fatty acid oxidation and decreases glucose output, cholesterol and triglyceride synthesis. These metabolic effects induced by AMPK are associated with lowering blood glucose levels in hyperglycemic individuals. Two classes of oral antihyperglycemic drugs (biguanidines and thiazolidinediones) have been shown to exert some of their therapeutic effects by directly or indirectly activating AMPK. However, side effects and an acquired resistance to these drugs emphasize the need for the development of novel and efficacious AMPK activators. We have recently discovered a new class of hydrophobic D-xylose derivatives that activates AMPK in skeletal muscles in a non insulin-dependent manner. One of these derivatives (2,4;3,5-dibenzylidene-D-xylose-diethyl-dithioacetal) stimulates the rate of hexose transport in skeletal muscle cells by increasing the abundance of glucose transporter-4 (GLUT-4) in the plasma membrane through activation of AMPK. This compound reduces blood glucose levels in diabetic mice and therefore offers a novel strategy of therapeutic intervention strategy in type 2 diabetes. The present review describes various classes of chemically-related compounds that activate AMPK by direct or indirect interactions and discusses their potential for candidate antihyperglycemic drug development.

Erratum to: Adenosine Monophosphate-Activated Protein Kinase (AMPK) as a New Target for Antidiabetic Drugs: A Review on Metabolic, Pharmacological and Chemical Considerations by Gruzman et al.

In the legends to Figures 2 and 3 of the article by Gruzman et al. in the spring issue 2009 of The Review of Diabetic Studies, pages 13-36, the copyright permission for the figures refer to reference [132], and not [135] as published. The references are published below. The correct text for the legend of Figure 2 on page 21 is: Figure 2. D-Xylose and Compounds 19, 21 and 24 activate AMPK. A: L6 rat myotube cultures were washed and received fresh medium supplemented with 2% (v/v) FCS, 23.0 mM D-glucose supplemented with 20 mM of D-xylose (D-xyl), 5 μM of Compound 19, 150 μM of Compound 21 or 50 μM of Compound 24. These compounds were present in the medium for 40 min, 12 h, 30 min and 2 h, respectively. Control myotubes received the vehicle (V) only. AICAR (4 mM), 100 nM of insulin (Ins) and 0.25 M of D-sorbitol (S) were present for 1h, 20 min and 30 min, respectively. Whole cell lysates were prepared and Western blot analyses were performed with antibodies against AMPKα and pThr172-AMPKα. B: Human myotubes were treated as described above and taken for Western blot analysis of AMPKα and pThr172-AMPKα. Representative blot and a summary of n = 3 (* p < 0.05) in comparison with the respective controls. Re-produced with permission from [132]. The correct text for the legend of Figure 3 on page 22 is: Figure 3. D-Xylose and Compounds 19, 21 and 24 activate AS160. Whole cell content of AS160 and pThr642-AS160 was determined by Western blot analysis in samples that were prepared from L6 myo-tubes, as described in the legend to Figure 1. Representative blot and a summary of n = 3 (* p < 0.05) in comparison the respective controls. Reproduced with permission from [132].