Table of Contents  
REVIEW ARTICLE
Year : 2012  |  Volume : 3  |  Issue : 2  |  Page : 127-131  

Red carpeting the newer antidiabetics


Registrar, AMC, 3rd Floor, Medwin Hospital, Chirag Ali lane, Nampally, Hyderabad, Andhra Pradesh, India

Date of Web Publication2-May-2012

Correspondence Address:
Dilip Gude
Registrar, Internal Medicine, Medwin Hospital, Nampally, Hyderabad, Andhra Pradesh 500 001
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0976-500X.95507

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   Abstract 

The rapidly increasing prevalence of diabetes on a global scale beseeches an urgent need for newer and better treatment options. Our better understanding of the pathophysiology of diabetes has enabled a continual churn out of newer antidiabetic agents with varying modes of action. Sodium-Glucose Transport Proteins-2 inhibitors, dipeptidyl peptidase IV inhibitors, glucagon-like peptide analogues, glucokinase activators, dual peroxisome proliferator-activated receptor agonists, monoclonal antibodies, and dopamine-2 receptor agonists either as monotherapy or combination therapy with the existing oral hypoglycemic agents compound our fight against diabetes. A review of the newer drugs targeting various aspects in the management of diabetes is presented.

Keywords: Glucokinase activators, newer antidiabetics, Sodium-glucose transport proteins-2 inhibitors


How to cite this article:
Gude D. Red carpeting the newer antidiabetics. J Pharmacol Pharmacother 2012;3:127-31

How to cite this URL:
Gude D. Red carpeting the newer antidiabetics. J Pharmacol Pharmacother [serial online] 2012 [cited 2019 Aug 25];3:127-31. Available from: http://www.jpharmacol.com/text.asp?2012/3/2/127/95507


   Introduction Top


Diabetes mellitus is an entity of considerable morbidity comprising a spectrum of multisystem dysfunctions stemming from the combination of insulin resistance and inadequate insulin secretion. Management of diabetes, akin to a tightrope walk, requires a comprehensive understanding of various factors such as over-all clinical picture, adverse effect profile, the complex of inter-play of drugs, etc. More than two-thirds of people with type 2 diabetes will eventually require more than one oral agent, with or without insulin. There is a perpetually increasing newer range of antidiabetic drugs targeting novel aspects of diabetes which warrant adequate awareness by the treating clinicians. The newer antidiabetic drugs of different classes are discussed below.

Sodium-glucose transport proteins-2 (SGLT2) inhibitors

Sodium-dependent glucose co-transporters (SGLT) are found in the intestinal mucosa of the small intestine and the proximal tubules of the nephrons. Two types of SGLT are of considerable importance in diabetes-SGLT1 and SGLT2 (members of genes SLC5A1 and A2, respectively). [1] Intestines predominantly sport SGLT1 whereas the proximal tubules of the nephrons display both SGLT2 and SGLT1. A sodium-to-glucose co-transport ratio of SGLT1 is 2:1 and that of SGLT2 is 1:1 and while the former contributes 2% to glucose reabsorption, the latter contributes 98%. [2] Hence SGLT2 inhibition enables us to considerably reduce transcellular epithelial glucose reabsorption. SGLT2 inhibition is independent of glucose-dependent insulin secretion by the pancreatic β cells.

Dapagliflozin, the notable molecule in the class of SGLT2 inhibitors, reduces blood glucose levels in an insulin-independent manner by inhibition of SGLT2-mediated reabsorption of glucose in the kidney. Dapagliflozin sported a comparable 52-week glycemic efficacy with glipizide and in addition, unlike the latter, resulted in reduced weight and less hypoglycemia. [3] However, the FDA (Food and Drug Administration) presented an unfavorable review of the drug owing to increased incidence of breast and bladder cancers and hepatotoxicity. [4] Remogliflozin, another SGLT2 inhibitor, is found to be potent and highly selective. In experimental models, its prodrug remogliflozin etabonate increased urinary glucose excretion in a dose-dependent manner which in turn inhibited the increase in plasma glucose after glucose loading without stimulating insulin secretion. [5] Sergliflozin etabonate, in a study, showed superiority over gliclazide and showed reductions in glycated hemoglobin and improved glycemic control without resulting in insulin secretion, hypoglycemia, and body weight gain. [6] Canagliflozin and other similar molecules are being evaluated with encouraging results.

The adverse effects of SGLT2 inhibitors may include fatigue, hypoglycemia, increased urine output, increased hematocrit, and mycotic genital or urinary tract infections.

DPP IV inhibitors

Dipeptidyl peptidase IV (DPP IV) inhibitors act primarily by blocking incretin degradation [inhibit the breakdown of glucagon-like peptide (GLP-1) and glucose-dependent insulinotropic peptide (GIP) leading to an increase in plasma concentrations of the same]. This results in stimulation of insulin secretion, reduction in plasma glucose and glucagon levels, and inhibition of gastric emptying. Incretins also govern β:-cell differentiation, mitogenesis and survival which is how DPP IV inhibition can preserve β:-cell mass and improve their secretory function. [7] Treatment with the DPP IV inhibitors is shown to reduce the risk of myocardial infarction (an effect dependent on the blood glucose levels) probably mediated via the GLP-1 receptor pathway and the protein kinase-A (PKA) signaling pathway. [8]

Sitagliptin, the first DPP IV inhibitor, rises postprandial active GLP-1 concentrations without causing hypoglycemia in normoglycemic healthy male volunteers. In a 24-week study, on 741 patients, once-daily sitagliptin monotherapy improved glycemic control in the fasting and postprandial states, improved measures of β-cell function, and was well tolerated.[9] Another study on 2719 diabetics, lasting from 12 weeks to more than a year, showed that sitagliptin improved blood sugar control when used alone or in diabetes patients not satisfactorily managed with metformin or a peroxisome proliferator-activated receptor (PPAR) agonist. [10] Vildagliptin, apart from DPP IV inhibition, is also known to enhance α-cell responsiveness to both the suppressive effects of hyperglycemia and the stimulatory effects of hypoglycemia. These effects may mediate its efficacy to improve glycemic control as well as its low hypoglycemic potential. In an interim analysis of a large, randomized, double-blind, multicentre study, the addition of vildagliptin to metformin showed comparable efficacy to that of glimepiride after 52 weeks. [11] Saxagliptin, another DPP IV inhibitor, showed efficacy both as monotherapy and in combination. Once-daily saxagliptin monotherapy for 24 weeks demonstrated clinically meaningful reductions in HbA1c and FPG compared to placebo. [12] Even in drug naοve type 2 diabetics, saxagliptin showed beneficial glycemic effects. [13] Linagliptin, a new long-acting xanthine based DPP inhibitor with high selectivity to DPP-4 (vs. the related enzymes DPP-8 and DPP-9), is associated with minimal risk of hypoglycemia. In a study, linagliptin monotherapy produced a significant and sustained improvement in glycemic control (reduced fasting and postprandial glucose, improved proinsulin/insulin ratio, homeostasis model assessment), accompanied by enhanced parameters of β:-cell function. [14] A herbal supplement berberine is known for its antihyperglycemic effect with DPP IV inhibition and inhibition of the prodiabetic target human protein tyrosine phosphatase 1B being some of the mechanisms that may explain such effect. [15]

Adverse effects, including nasopharyngitis and upper respiratory infections (probably via immunomodulation), [16] headache, nausea, skin reactions and rarely hypersensitivity reactions, and pancreatitis (probably via ductal proliferation and metaplasia) [17] are reported with DPP IV inhibitors.

GLP-1 analogues

Glucagon-like peptide (GLP-1) analogues are synthesized by small intestinal L cells. They heighten glucose-dependent insulin secretion, reduce glucagon secretion, promote weight loss, slow gastric emptying, decrease appetite, and promote β:-cell regeneration. They do not cause hypoglycemia, in the absence of therapies that otherwise cause hypoglycemia. They also seem to play a role in halting the progression of more aggressive lesions from underlying steatosis in Nonalcoholic Fatty Liver Disease (NAFLD). [18]

Exenatide, a GLP-1 analogue and insulin secretagogue with glucoregulatory effects. It is recommended for use as adjunctive therapy to improve glycemic control in patients who are taking metformin, or a combination of metformin and a sulfonylurea, but have not achieved adequate glycemic control. Exenatide augments glucose-dependent insulin secretion by the pancreatic β:-cell. In a study, exenatide once weekly brought sustained improvements in glycemic control (HbA1C and FPG) and body weight through 52 weeks of treatment. [19] Weight-related quality of life, health utility, psychological well-being, and diabetes treatment satisfaction are all shown to be better when exenatide is used in combination with metformin. [20] The side effect profile of exenatide includes hypoglycemia (more upon combination therapy with sulfonylureas and thiazolidinediones), nausea, vomiting, diarrhea, heartburn, indigestion, dizziness, headache, and pancreatitis. Development of anti-exenatide antibodies may also be seen.

Lixisenatide, a once-daily injectable GLP-1 receptor agonist, demonstrates efficacy and safety in T2DM both as monotherapy and in combination with metformin. [21] In the GetGoal-1 Phase III trial, a GLP-1 receptor agonist, lixisenatide has significantly reduced HbA1c levels and reduced weight in T2D patients. [22] Liraglutide, a long acting GLP-1 receptor agonist, has shown evidence that it may benefit patients with inadequate diabetes control despite their use of another antidiabetic therapy. Liraglutide in type 1 diabetics is known to reduce insulin requirement with improved or unaltered glycemic control. In a study liraglutide induced similar glycemic control, reduced body weight, and lowered the occurrence of hypoglycemia compared to glimepiride, both used in combination with metformin. [23] Liraglutide is contraindicated in those with family history of medullary thyroid cancer. [24] Cases of acute pancreatitis have been reported in use of liraglutide use. Albiglutide is a recombinant human serum albumin (HSA)-GLP-1 hybrid protein with half life of about a week and is found to display resistance to DPP IV. [25] It has shown consistent efficacy in type 2 diabetics. Taspoglutide, another analogue, exerts insulinotropic action in vitro and in vivo, retains the glucoincretin property of human GLP-1, is fully resistant to DPP IV cleavage and has an extended in vitro plasma half-life. [26]

Glucokinase activators

Glucokinase (also called hexokinase IV or D) owing to its glucose sensor role in pancreatic β-cells and being the rate-controlling enzyme for hepatic glucose clearance and glycogen synthesis is known to have an exceptionally high impact on glucose homeostasis. Glucokinase activators (GKAs) stimulate insulin biosynthesis and secretion and augment glucose metabolism and related processes in other glucokinase-expressing cells via GKA-mediated increase in the affinity of glucokinase for glucose and its maximal catalytic rate. [27] GKAs mediate their antidiabetic effects via generalized enhancement of β-cell function and through fasting restricted changes in glucose turnover. Piragliatin, a GKA, has shown an acute glucose-lowering action in patients with mild type 2 diabetes. [28] An experimental GKA molecule ZYGK1 showed promising efficacy in controlling both fasting and non-fasting blood glucose. [29] The side effects although rare of GKAs are hypoglycemia, fatty liver, and hyperlipidemia.

Dual PPAR agonists

Inhibition of PPAR α:-agonists (Fibrates) lowers plasma triglycerides and VLDL particles and increases HDL cholesterol while PPAR γ:-agonists (thiazolidinediones) influence free fatty acid flux and reduce insulin resistance and blood glucose levels. The PPAR α:/γ: dual agonism addresses both insulin resistance (the inability of tissues to utilize insulin efficiently for the uptake of glucose) and key aspects of the dyslipidemia that contribute to the high risk of cardiovascular disease (CVD) in diabetics. They have documented heightened insulin sensitivity and are known to improve inflammation, vascular function, and vascular remodeling. [30]

Aleglitazar, a new balanced dual PPAR α/γ agonist, reduces hyperglycemia and improves the levels of HbA1C, HDL-C, LDL, and triglycerides with minimal PPAR-related adverse effects. [31],[32] In in vitro models, aleglitazar strongly decreased the multiple aspects of the inflamed phenotype of human adipocyte/macrophage co-culture system compared to pioglitazone and fenofibrate suggesting its contribution to prevent progression of adipose dysfunction and insulin resistance, and increased cardiovascular risk. [33] Although muraglitazar a similar molecule showed efficacy as an add-on therapy for poorly controlled diabetics, excess incidence of death, major adverse cardiovascular events (MI, stroke, TIA), and heart failure were noted with it and hence withdrawn. [34]

Monoclonal antibodies

To induce immune tolerance via monoclonal antibodies has been tried as a way to prevent and effectively treat diabetes. Otelixizumab, an anti-CD3 monoclonal antibody, is known to stimulate C-peptide levels and reduce insulin requirement in type 1 diabetes. [35] Similarly studies with teplizumab are also reassuring. [36] Other monoclonal antibodies such as anti-CD20, [37] anti-CTGF, [38] anti-IL-1β,[39] have shown promising results and are yet to be approved.

Dopamine-2 receptor agonist

Timed bromocriptine (centrally-acting dopamine D2 receptor agonist) is believed to act on circadian neuronal activities within the hypothalamus to reset abnormally elevated hypothalamic drive for increased plasma glucose, triglyceride, and free fatty acid levels in fasting and postprandial states in insulin-resistant patients. Its use as monotherapy and in combination with other OHAs is shown to reduce HbA1c, plasma triglyceride, and FFA concentrations in type 2 diabetic patients. [40] Side effects include nausea, fatigue, vomiting, headache, dizziness, orthostatic hypotension, and syncope, the latter two upon initiation or dose escalation.

Others

Chromium (Cr) may reduce myocellular lipids and enhance insulin sensitivity in subjects with type 2 diabetes mellitus independent of its effects on weight or hepatic glucose production. [41] Clinical response to Cr is more likely in insulin-resistant type 2 diabetics with elevated fasting glucose and A1C levels. It also has anti-inflammatory activity apparently mediated by elevated blood vitamin C and adiponectin and inhibition of NFκB, Akt, and Glut-2 and increased IRS-1 gene activation.[42] Sodium tungstate is known to preserve the pancreatic β-cell function in diabetics and normalize the activity of sucrase and SGLT1 in the brush-border membrane of enterocytes. [43] A combination of hyperglycemia-independent pathways are postulated to explain its antidiabetic effects. [44] Vanadium is known to mimic most effects of insulin on the main target tissues of the hormone in vitro and it is shown to induce a sustained fall in blood glucose levels in insulin-deficient diabetic rats, and improve glucose homeostasis in obese, insulin-resistant diabetic rodents (in vivo). It has shown antidiabetic effects in phase II trials [45] although another study showed no such benefits. [46] Proxyfan, a central histamine H3 receptor ligand, is shown to significantly improve glucose excursion by increasing plasma insulin levels via a glucose-independent mechanism. [47] Aspartame, guargum, and glucomannan have all displayed notable benefits in glycemic control either singly or as combinations.

Experimental research

A new molecule SR 1664 which is a potent binder to the nuclear receptor PPARγ shows that blockage of cyclin-dependent kinase 5 (Cdk5)'s action on PPARγ: is a viable therapeutic approach for development of antidiabetic agents. It also demonstrated fewer side effects, such as weight gain or increased plasma volume, compared to rosiglitazone. [48]

Systemic administration of toll-like receptor (TLR) ligands can suppress autoimmune responses (autoimmune diabetes) which reinforces the hypothesis that TLR stimulation can recapitulate the protective effect of infectious agents on autoimmunity. [49] Low-dose cyclosporine and methotrexate in subjects with new onset type 1 diabetes can safely induce remission of disease and decrease the insulin requirement. [50]

A new compound 5,8-diacetyloxy-2,3-dichloro-1,4-naphtho-quinone is known to selectively provoke insulin receptor activation by directly binding to the receptor kinase domain to trigger its kinase activity. It sensitizes insulin's action, elevates glucose uptake in adipocytes, and has oral hypoglycemic effects. [51]

β-Sitosterol has shown promising antidiabetic as well as antioxidant effects probably mediated via apoptosis induced by increased FAS levels and caspase 8 activity, phosphorylation of extracellular signal-regulated kinase and mitogen-activated protein kinase, with no cytotoxicity to normal cells. [52] S-Allylcysteine (a natural constituent of fresh garlic) is shown to have significant antihyperglycemic effects along with lowering of tissue glycoprotein components (such as hexose, hexosamine, fucose and sialic acid in plasma, liver and kidneys). [53] In a study cucurmin, (a natural ingredient of turmeric) via its antioxidant and anti-inflammatory effects, enhanced the ability of bone marrow transplantation to regenerate functional pancreatic islets. [54]


   Conclusion Top


There is rapid and accelerated progress in the antidiabetics drug-development front that runs parallel to our ever evolving comprehension of the pathophysiology of diabetes. Clinicians need to be abreast of this plethora of newer antidiabetic drugs coming up, their efficacy, adverse effect profile and stand in diabetes management that empowers them to better manage diabetes.


   Acknowledgment Top


I thank my colleagues and staff of Internal Medicine.

 
   References Top

1.Wright EM, Hirayama BA, Loo DF. Active sugar transport in health and disease. J Intern Med 2007;261:32-43.  Back to cited text no. 1
    
2.Sabino-Silva R, Mori RC, David-Silva A, Okamoto MM, Freitas HS, Machado UF. The Na(+)/glucose cotransporters: From genes to therapy. Braz J Med Biol Res 2010;43:1019-26.  Back to cited text no. 2
    
3.Nauck MA, Del Prato S, Meier JJ, Durán-García S, Rohwedder K, Elze M, et al. Dapagliflozin versus glipizide as add-on therapy in patients with type 2 diabetes who have inadequate glycemic control with metformin: A randomized, 52-week, double-blind, active-controlled noninferiority trial. Diabetes Care 2011;34:2015-22.  Back to cited text no. 3
    
4.FDA Briefing Document. NDA 202293. Dapagliflozin Tablets, 5 and 10 mg. Sponsor: Bristol-Myers Squibb. Advisory Committee Meeting, July 19, 2011. Available from: http://www.fda.gov/downloads/Advisory Committees/CommitteesMeetingMaterials/Drugs/Endocrinologic and Metabolic Drugs Advisory Committee/UCM262994.pdf [Last accessed on 2011 Oct 17].  Back to cited text no. 4
    
5.Fujimori Y, Katsuno K, Nakashima I, Ishikawa-Takemura Y, Fujikura H, Isaji M. Remogliflozin etabonate, in a novel category of selective low-affinity sodium glucose cotransporter (SGLT2) inhibitors, exhibits antidiabetic efficacy in rodent models. J Pharmacol Exp Ther 2008;327:268-76.  Back to cited text no. 5
    
6.Fujimori Y, Katsuno K, Ojima K, Nakashima I, Nakano S, Ishikawa-Takemura Y, et al. Sergliflozin etabonate, a selective SGLT2 inhibitor, improves glycemic control in streptozotocin-induced diabetic rats and Zucker fatty rats. Eur J Pharmacol 2009;609:148-54.  Back to cited text no. 6
    
7.McIntosh CH, Demuth HU, Pospisilik JA, Pederson R. Dipeptidyl peptidase IV inhibitors: How do they work as new antidiabetic agents? Regul Pept 2005;128:159-65.  Back to cited text no. 7
    
8.Hausenloy DJ, Wynne AM, Theodorou L, Mocanu MM, Yellon DM. FC1 Dipeptidyl peptidase IV inhibitors limit myocardial infarct size in a glucose-sensitive manner. Heart 2010;96:e11.  Back to cited text no. 8
    
9.Aschner P, Kipnes MS, Lunceford JK, Sanchez M, Mickel C, Williams-Herman DE, et al. Effect of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy on glycemic control in patients with type 2 diabetes. Diabetes Care 2006;29:2632-7.  Back to cited text no. 9
    
10.Sahelian R. Sitagliptin Phosphate a dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. Available from: http://www.raysahelian.com/sitagliptin.html [Last accessed on 2011 Sep 08].  Back to cited text no. 10
    
11.Ferrannini E, Fonseca V, Zinman B, Matthews D, Ahrén B, Byiers S, et al. Fifty-two-week efficacy and safety of vildagliptin vs. glimepiride in patients with type 2 diabetes mellitus inadequately controlled on metformin monotherapy. Diabetes Obes Metab 2009;11:157-66.  Back to cited text no. 11
    
12.Kulasa K, Edelman S. Saxagliptin: The evidence for its place in the treatment of type 2 diabetes mellitus. Core Evid 2010;5:23-37.  Back to cited text no. 12
    
13.Rosenstock J, Sankoh S, List JF. Glucose-lowering activity of the dipeptidyl peptidase-4 inhibitor saxagliptin in drug-naive patients with type 2 diabetes. Diabetes Obes Metab 2008;10:376-86.  Back to cited text no. 13
    
14.Del Prato S, Barnett AH, Huisman H, Neubacher D, Woerle HJ, Dugi KA. Effect of linagliptin monotherapy on glycaemic control and markers of β:-cell function in patients with inadequately controlled type 2 diabetes: A randomized controlled trial. Diabetes Obes Metab 2011;13:258-67.  Back to cited text no. 14
    
15.Al-masri IM, Mohammad MK, Tahaa MO. Inhibition of dipeptidyl peptidase IV (DPP IV) is one of the mechanisms explaining the hypoglycemic effect of berberine. J Enzyme Inhib Med Chem 2009;24:1061-6.  Back to cited text no. 15
    
16.Willemen MJ, Mantel-Teeuwisse AK, Straus SM, Meyboom RH, Egberts TC, Leufkens HG. Use of dipeptidyl peptidase-4 inhibitors and the reporting of infections: A disproportionality analysis in the World Health Organization VigiBase. Diabetes Care 2011;34:369-74.  Back to cited text no. 16
    
17.Matveyenko AV, Dry S, Cox HI, Moshtaghian A, Gurlo T, Galasso R, et al. Beneficial endocrine but adverse exocrine effects of sitagliptin in the human islet amyloid polypeptide transgenic rat model of type 2 diabetes: Interactions with metformin. Diabetes 2009;58:1604-15.  Back to cited text no. 17
    
18.Sharma S, Mells JE, Fu PP, Saxena NK, Anania FA. GLP-1 analogs reduce hepatocyte steatosis and improve survival by enhancing the unfolded protein response and promoting macroautophagy. PLoS One 2011;6:e25269.  Back to cited text no. 18
    
19.Buse JB, Drucker DJ, Taylor KL, Kim T, Walsh B, Hu H, et al. DURATION-1: Exenatide once weekly produces sustained glycemic control and weight loss over 52 weeks. Diabetes Care 2010;33:1255-61.  Back to cited text no. 19
    
20.Best JH, Rubin RR, Peyrot M, Li Y, Yan P, Malloy J, et al. Weight-related quality of life, health utility, psychological well-being, and satisfaction with exenatide once weekly compared with sitagliptin or pioglitazone after 26 weeks of treatment. Diabetes Care 2011;34:314-9.  Back to cited text no. 20
    
21.Christensen M, Knop FK, Vilsbøll T, Holst JJ. Lixisenatide for type 2 diabetes mellitus. Expert Opin Investig Drugs 2011;20:549-57.  Back to cited text no. 21
    
22.Sanofi. "Lyxumia® (lixisenatide) One-Step Regimen as Effective as Two-Step Regimen in Improving Glycemic Control in Type 2 Diabetes". Press release. Retrieved 2011-09-13. Available from: http://en.sanofi.com/press/_medias/20110912_EASD-Lyxumia_en.pdf [Last accessed on 2011 Sep 12].  Back to cited text no. 22
    
23.Yang W, Chen L, Ji Q, Liu X, Ma J, Tandon N, et al. Liraglutide provides similar glycaemic control as glimepiride (both in combination with metformin) and reduces body weight and systolic blood pressure in Asian population with type 2 diabetes from China, South Korea and India: A 16-week, randomized, double-blind, active control trial. Diabetes Obes Metab 2011;13:81-8.  Back to cited text no. 23
    
24.Goldenberg MM. Pharmaceutical Approval Update. P T 2010;35:216-8.  Back to cited text no. 24
    
25.Baggio LL, Huang Q, Brown TJ, Drucker DJ. A recombinant human glucagon-like peptide (GLP)-1-albumin protein (albugon) mimics peptidergic activation of GLP-1 receptor-dependent pathways coupled with satiety, gastrointestinal motility, and glucose homeostasis. Diabetes 2004;53:2492-500.  Back to cited text no. 25
    
26.Matschinsky FM, Zelent B, Doliba NM, Kaestner KH, Vanderkooi JM, Grimsby J, et al. Research and development of glucokinase activators for diabetes therapy: Theoretical and practical aspects. Handb Exp Pharmacol 2011;203:357-401.  Back to cited text no. 26
    
27.Sebokova E, Christ AD, Wang H, Sewing S, Dong JZ, Taylor J, et al. Taspoglutide, an analog of human glucagon-like Peptide-1 with enhanced stability and in vivo potency. Endocrinology 2010;151:2474-82.  Back to cited text no. 27
    
28.Bonadonna RC, Heise T, Arbet-Engels C, Kapitza C, Avogaro A, Grimsby J, et al. Piragliatin (RO4389620), a novel glucokinase activator, lowers plasma glucose both in the postabsorptive state and after a glucose challenge in patients with type 2 diabetes mellitus: A mechanistic study. J Clin Endocrinol Metab 2010;95:5028-36.  Back to cited text no. 28
    
29.Evaluate Pharma. Zydus' IND Application of ZYGK1 for Treating Diabetes Receives USFDA Approval. Press release. Retrieved 2011-09-13. Available from: http://www.evaluatepharma.com/Universal/View.aspx?type=Storyandid=244462 [Last accessed on 2011 July 04].  Back to cited text no. 29
    
30.Tenenbaum A, Motro M, Fisman EZ. Dual and pan-peroxisome proliferator-activated receptors (PPAR) co-agonism: The bezafibrate lessons. Cardiovasc Diabetol 2005;4:14.  Back to cited text no. 30
    
31.Hansen BC, Tigno XT, Bénardeau A, Meyer M, Sebokova E, Mizrahi J. Effects of aleglitazar, a balanced dual peroxisome proliferator-activated receptor α:/γ: agonist on glycemic and lipid parameters in a primate model of the metabolic syndrome. Cardiovasc Diabetol 2011;10:7.  Back to cited text no. 31
    
32.Henry RR, Lincoff AM, Mudaliar S, Rabbia M, Chognot C, Herz M. Effect of the dual peroxisome proliferator-activated receptor-alpha/gamma agonist aleglitazar on risk of cardiovascular disease in patients with type 2 diabetes (SYNCHRONY): A phase II, randomised, dose-ranging study. Lancet 2009;374:126.  Back to cited text no. 32
    
33.Dzyakanchuk A, Wright MB, Sebokova, E, Wabitsch M, Fischer-Posovszky P, Keuper M, et al. Abstract 10854: Aleglitazar, a balanced dual PPAR alpha/ gamma agonist, decreases lipolysis and cytokine production in a cellular model of inflamed human adipose tissue. Circulation 2010;122:A10854.  Back to cited text no. 33
    
34.Nissen SE, Wolski K, Topol EJ. Effect of muraglitazar on death and major adverse cardiovascular events in patients with type 2 diabetes mellitus. JAMA 2005;294:2581-6.  Back to cited text no. 34
    
35.Miller SA, St Onge E. Otelixizumab: A novel agent for the prevention of type 1 diabetes mellitus. Expert Opin Biol Ther 2011;11:1525-32.  Back to cited text no. 35
    
36.Masharani UB, Becker J. Teplizumab therapy for type 1 diabetes. Expert Opin Biol Ther 2010;10:459-65.  Back to cited text no. 36
    
37.Herold KC, Pescovitz MD, McGee P, Krause-Steinrauf H, Spain LM, Bourcier K, et al. Increased T cell proliferative responses to islet antigens identify clinical responders to anti-cd20 monoclonal antibody (Rituximab) therapy in type 1 diabetes. J Immunol 2011;187:1998-2005.  Back to cited text no. 37
    
38.Adler SG, Schwartz S, Williams ME, Arauz-Pacheco C, Bolton WK, Lee T, et al. Phase 1 study of anti-CTGF monoclonal antibody in patients with diabetes and microalbuminuria. Clin J Am Soc Nephrol 2010;5:1420-8.  Back to cited text no. 38
    
39.Owyang AM, Maedler K, Gross L, Yin J, Esposito L, Shu L, et al. XOMA 052, an anti-IL-1{beta} monoclonal antibody, improves glucose control and {beta}-cell function in the diet-induced obesity mouse model. Endocrinology 2010;151:2515-27.  Back to cited text no. 39
    
40.Keche Y. Bromocriptine mesylate: Food and Drug Administration approved new approach in therapy of non-insulin dependant diabetes mellitus with poor glycemic control. J Pharm Bioallied Sci 2010;2:148-50.  Back to cited text no. 40
    
41.Cefalu WT, Rood J, Pinsonat P, Qin J, Sereda O, Levitan L, et al. Characterization of the metabolic and physiologic response to chromium supplementation in subjects with type 2 diabetes mellitus. Metabolism 2010;59:755-62.  Back to cited text no. 41
    
42.Jain SK, Croad JL, Velusamy T, Rains JL, Bull R. Chromium dinicocysteinate supplementation can lower blood glucose, CRP, MCP-1, ICAM-1, creatinine, apparently mediated by elevated blood vitamin C and adiponectin and inhibition of NFkappaB, Akt, and Glut-2 in livers of zucker diabetic fatty rats. Mol Nutr Food Res 2010;54:1371-80.  Back to cited text no. 42
    
43.Fernández-Alvarez J, Barberà A, Nadal B, Barceló-Batllori S, Piquer S, Claret M, et al. Stable and functional regeneration of pancreatic beta-cell population in nSTZ-rats treated with tungstate. Diabetologia 2004;47:470-7.  Back to cited text no. 43
    
44.Altirriba J, Barbera A, Del Zotto H, Nadal B, Piquer S, Sánchez-Pla A, et al. Molecular mechanisms of tungstate-induced pancreatic plasticity: A transcriptomics approach. BMC Genomics 2009;10:406.  Back to cited text no. 44
    
45.Thompson KH, Lichter J, LeBel C, Scaife MC, McNeill JH, Orvig C. Vanadium treatment of type 2 diabetes: A view to the future. J Inorg Biochem 2009;103:554-8.  Back to cited text no. 45
    
46.Smith DM, Pickering RM, Lewith GT. A systematic review of vanadium oral supplements for glycaemic control in type 2 diabetes mellitis. QJM 2008;101:351-8.  Back to cited text no. 46
    
47.Henry MB, Zheng S, Duan C, Patel B, Vassileva G, Sondey C, et al. Antidiabetic properties of the histamine H3 receptor protean agonist proxyfan. Endocrinology 2011;152:828-35.  Back to cited text no. 47
    
48.Choi JH, Banks AS, Kamenecka TM, Busby SA, Chalmers MJ, Kumar N, et al. Antidiabetic actions of a non-agonist PPARγ: ligand blocking Cdk5-mediated phosphorylation. Nature 2011;477:477-81.  Back to cited text no. 48
    
49.Aumeunier A, Grela F, Ramadan A, Pham Van L, Bardel E, Gomez Alcala A, et al. Systemic Toll-like receptor stimulation suppresses experimental allergic asthma and autoimmune diabetes in NOD mice. PLoS One 2010;5:e11484.  Back to cited text no. 49
    
50.Sobel DO, Henzke A, Abbassi V. Cyclosporin and methotrexate therapy induces remission in type 1 diabetes mellitus. Acta Diabetol 2010;47:243-50.  Back to cited text no. 50
    
51.He K, Chan CB, Liu X, Jia Y, Luo HR, France SA, et al. Identification of a molecular activator for insulin receptor with potent anti-diabetic effects. J Biol Chem 2011 Sep 9. [Epub ahead of print]  Back to cited text no. 51
    
52.Gupta R, Sharma AK, Dobhal MP, Sharma MC, Gupta RS. Antidiabetic and antioxidant potential of β:-sitosterol in streptozotocin-induced experimental hyperglycemia. J Diabetes 2011;3:29-37.  Back to cited text no. 52
    
53.Saravanan G, Ponmurugan P, Senthil Kumar GP, Rajarajan T. Antidiabetic effect of S-allylcysteine: Effect on plasma and tissue glycoproteins in experimental diabetes. Phytomedicine 2010;17:1086-9.  Back to cited text no. 53
    
54.El-Azab MF, Attia FM, El-Mowafy AM. Novel role of curcumin combined with bone marrow transplantation in reversing experimental diabetes: Effects on pancreatic islet regeneration, oxidative stress, and inflammatory cytokines. Eur J Pharmacol 2011;658:41-8.  Back to cited text no. 54
    




 

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