Archives of Pharmacal Research

, Volume 36, Issue 2, pp 145–153 | Cite as

Latest research and development trends in non-insulin anti-diabetics



Type 2 diabetes mellitus, also called non-insulin dependent diabetes mellitus, is a chronic endocrine disease characterized by insulin resistance in tissues such as fat, liver and skeletal muscle, and impaired insulin secretion in pancreatic β cells. The prevalence and incidence of type 2 diabetes exploded over last decades along with increased population obesity owing to western lifestyle factors such as lack of exercise and high calorie diets. As diabetes progresses without appropriate treatment, many micro- and macro-vascular complications occur, leading to increased risk of mortality. Although lifestyle modifications including a healthier diet and more frequent exercise are suggested as initial therapy for type 2 diabetes, pharmacotherapy is required in many cases. Currently, several anti-diabetic drugs with different mechanisms of action are available, but increased effectiveness and tolerability are a still unmet need for diabetes pharmacotherapy. Thus, the development of new anti-diabetic drugs is an active research area in both academia and the pharmaceutical industry. This review focuses on the targets in the latest developments of non-insulin anti-diabetics that attract the most interest in this disease area.


Type 2 diabetes mellitus Anti-diabetes Insulin resistance Insulin secretion 


  1. Ali, A.A., R.S. Weinstein, S.A. Stewart, A.M. Parfitt, S.C. Manolagas, and R.L. Jilka. 2005. Rosiglitazone causes bone loss in mice by suppressing osteoblast and bone formation. Endocrinology 146: 1226–1235.PubMedCrossRefGoogle Scholar
  2. Aliquier, T., and V. Poitout. 2009. GPR40: Good cop, or bad cop? Diabetes 58: 1035–1036.CrossRefGoogle Scholar
  3. Berger, J., and D.E. Moller. 2002. The mechanisms of action of PPARs. Annual Review of Medicine 53: 409–435.PubMedCrossRefGoogle Scholar
  4. Birch, A., L.K. Buckett, and A.V. Turnbull. 2010. DGAT1 inhibitors as anti-obesity and anti-diabetic agents. Current Opinion in Drug Discovery & Development 13: 489–496.Google Scholar
  5. Blonde, L. 2010. Current antihyperglycemic treatment guidelines and algorithms for patients with type 2 diabetes mellitus. The American Journal of Medicine 123(3A): S12–S18.PubMedCrossRefGoogle Scholar
  6. Brown, J.M., and L.L. Rudel. 2010. Stearoyl-coenzyme A desaturase 1 inhibition and the metabolic syndrome: considerations for future drug discovery. Current Opinion in Lipidology 21: 192–197.PubMedCrossRefGoogle Scholar
  7. Carpino, P.A., and B. Goodwin. 2010. Diabetes area participation analysis: A review of companies and targets described in the 2008–2010 patent literature. Expert Opinion on Therapeutic Patents 20: 1627–1651.PubMedCrossRefGoogle Scholar
  8. Cases, S., P. Zhou, J.M. Shillingford, B.S. Wiseman, J.D. Fish, C.S. Angle, L. Hennighausen, Z. Werb, and R.V. Farese Jr. 2004. Development of the mammary gland requires DGAT-1 expression in stromal and epithelial tissues. Development 131: 3047–3055.PubMedCrossRefGoogle Scholar
  9. Chen, H.C., S.J. Smith, Z. Ladha, D.R. Jensen, L.D. Ferreira, L.K. Pulawa, J.S. McGuire, R.E. Pitas, R.H. Eckel, and R.V. Farese Jr. 2002. Increased insulin and leptin sensitivity in mice lacking acyl CoA:diacylglycerol acyltransferase 1. The Journal of Clinical Investigation 109: 1049–1055.PubMedGoogle Scholar
  10. Christesen, H., B. Jacobsen, S. Odili, C. Buettger, A. Cuesta-Munoz, T. Hansen, K. Brusgaard, O. Massa, M.A. Magnuson, C. Shiota, F.M. Matschinsky, and F. Barbetti. 2002. The second activating glucokinase mutation (A456 V): Implications for glucose homeostasis and diabetes therapy. Diabetes 51: 1240–1246.PubMedCrossRefGoogle Scholar
  11. Chu, Z.L., C. Carroll, J. Alfonson, V. Gutierrez, H. He, A. Lucman, M. Pedraza, H. Mondala, H. Gao, D. Bagnol, R. Chen, R.M. Jones, D.P. Behan, and J. Leonard. 2008. A role for intestinal endocrine cell-expressed G protein-coupled receptor 119 in glycemic control by enhancing glucagon-like peptide-1 and glucose-dependent insulinotropic peptide release. Endocrinology 149: 2038–2047.PubMedCrossRefGoogle Scholar
  12. Cuesta-Munoz, A.L., H. Huopio, T. Otonkoski, J.M. Gomez-Zumaquero, K. Nanto-Salonen, J. Rahier, S. Lopez-Enriquez, M.A. Garcia-Gimeno, P. Sanz, F.C. Soriguer, and M. Laakso. 2004. Severe persistent hyperinsulinemic hypoglycemia due to a de novo glucokinase mutation. Diabetes 53: 2164–2168.PubMedCrossRefGoogle Scholar
  13. Deacon, C.F., M.A. Nauck, M. Toft-Nielsen, L. Pridal, B. Willms, and J.J. Holst. 1995. Both subcutaneously and intravenously administered glucagon-like peptide 1 are rapidly degraded from the NH2-terminus in type II diabetic patients and in healthy subjects. Diabetes 44: 1126–1131.PubMedCrossRefGoogle Scholar
  14. Doshi, L.S., M.K. Brahma, U.A. Bahirat, A.V. Dixit, and K.V.S. Nemmani. 2010. Discovery and development of selective PPARγ modulators as safe and effective antidiabetic agents. Expert Opinion on Investigational Drugs 19: 489–512.PubMedCrossRefGoogle Scholar
  15. Elchebly, M., P. Payette, E. Michaliszyn, W. Cromlish, S. Collins, A.L. Loy, D. Normandin, A. Cheng, J. Himms-Hagen, C.C. Chan, C. Ramachandran, M.J. Gresser, M.L. Tremblay, and B.P. Kennedy. 1999. Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphates-1B gene. Science 283: 1544–1548.PubMedCrossRefGoogle Scholar
  16. Enoch, H.G., and P. Strittmatter. 1978. Role of tyrosyl and arginyl residues in rat liver microsomal stearylcoenzyme A desaturase. Biochemistry 17: 4927–4932.PubMedCrossRefGoogle Scholar
  17. Goldfine, A.B., V. Fonseca, and S.E. Shoelson. 2011. Therapeutic approaches to target inflammation in type 2 diabetes. Clinical Chemistry 57: 162–167.PubMedCrossRefGoogle Scholar
  18. Guan, Y., C. Hao, D.R. Cha, R. Rao, W. Lu, D.E. Kohan, M.A. Magnuson, R. Redha, Y. Zhang, and M.D. Breyer. 2005. Thiazolidinediones expand body fluid volume through PPAR-gamma stimulation of ENaC-mediated renal salt absorption. Nature Medicine 11: 861–866.PubMedCrossRefGoogle Scholar
  19. Holst, J.J. 2007. The physiology of glucagon-like peptide 1. Physiological Reviews 87: 1409–1439.PubMedCrossRefGoogle Scholar
  20. Hotamisligil, G.S. 2006. Inflammation and metabolic disorders. Nature 444: 860–867.PubMedCrossRefGoogle Scholar
  21. Hotamisligil, G.S., P. Arner, J.F. Caro, R.L. Atkinson, and B.M. Spiegelman. 1995. Increased adipose tissue expression of tumor necrosis factor-α in human obesity and insulin resistance. The Journal of Clinical Investigation 95: 2409–2415.PubMedCrossRefGoogle Scholar
  22. Itoh, Y., Y. Kawamata, M. Harada, M. Kobayashi, R. Fujii, S. Fukusumi, K. Ogi, M. Hosoya, Y. Tanaka, H. Uejima, H. Tanaka, M. Maruyama, R. Satoh, S. Okubo, H. Kizawa, H. Komatsu, F. Matsumura, Y. Noguchi, T. Shinohara, S. Hinuma, Y. Fujisawa, and M. Fujino. 2003. Free fatty acids regulate insulin secretion from pancreatic beta cells through GPR40. Nature 422: 173–176.PubMedCrossRefGoogle Scholar
  23. Iversen, L.F., K.B. Moller, A.K. Pedersen, G.H. Peters, A.S. Petersen, H.S. Andersen, S. Branner, S.B. Mortensen, and N.P. Moller. 2002. Structure determination of T cell protein tyrosine phosphatase. Journal of Biological Chemistry 277: 19982–19990.PubMedCrossRefGoogle Scholar
  24. Kanai, Y., W.S. Lee, G. You, D. Brown, and M.A. Hediger. 1994. The human kidney low affinity Na +/glucose cotransporter SGLT-2. Delineation of the major renal reabsorptive mechanism for d-glucose. The Journal of Clinical Investigation 93: 397–404.PubMedCrossRefGoogle Scholar
  25. Kanda, H., S. Tateya, Y. Tamori, K. Kotani, K. Hiasa, R. Kitazawa, S. Kitazawa, H. Miyachi, S. Maeda, K. Egashira, and M. Kasuga. 2006. MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. The Journal of Clinical Investigation 116: 1494–1505.PubMedCrossRefGoogle Scholar
  26. Kaszubska, W., H.D. Falls, V.G. Schaefer, D. Haasch, L. Frost, P. Hessler, P.E. Kroeger, D.W. White, M.R. Jirousek, and J.M. Trevillyan. 2002. Protein tyrosine phosphatase 1B negatively regulates leptin signaling in a hypothalamic cell line. Molecular and Cellular Endocrinology 195: 109–118.PubMedCrossRefGoogle Scholar
  27. King, A.J., A.S. Judd, and A.J. Souers. 2010. Inhibitors of diacylglycerol acyltransferase: a review of 2008 patents. Expert Opinion on Therapeutic Patents 20: 19–29.PubMedCrossRefGoogle Scholar
  28. Koren, S., and I.G. Fantus. 2007. Inhibition of the protein tyrosine phosphatase PTP-1B: potential therapy for obesity, insulin resistance and type 2 diabetes mellitus. Best Practice & Research, Clinical Endocrinology & Metabolism 21: 621–640.CrossRefGoogle Scholar
  29. Kotelevtsev, Y., M.C. Holmes, A. Burchell, P.M. Houston, D. Schmoll, P. Jamieson, R. Best, R. Brown, C.R. Edwards, J.R. Seckl, and J.J. Mullins. 1997. 11beta-hydroxysteroid dehydrogenase type 2 knockout mice show attenuated glucocorticoid-inducible responses and resist hyperglycemia on obesity or stress. Proceedings of the National Academy of Sciences of the United States of America 94: 14924–14929.PubMedCrossRefGoogle Scholar
  30. Kusunoki, J., A. Kanatani, and D.E. Moller. 2006. Modulation of fatty acid metabolism as a potential approach to the treatment of obesity and the metabolic syndrome. Endocrine 29: 91–100.PubMedCrossRefGoogle Scholar
  31. Larsen, C.M., M. Faulenbach, A. Vaag, A. Volund, J.A. Eheses, B. Seifert, T. Mandrup-Poulsen, and M.Y. Donath. 2007. Interleukin-1 receptor antagonist in type 2 diabetes mellitus. New England Journal of Medicine 356: 1517–1526.PubMedCrossRefGoogle Scholar
  32. Leger, S., W.C. Black, D. Deschenes, S. Dolman, J.P. Falgueyret, M. Gagnon, S. Guiral, Z. Huang, J. Guay, Y. Leblanc, C.S. Li, F. Masse, R. Oballa, and L. Zhang. 2010. Synthesis and biological activity of a potent and orally bioavailable SCD inhibitor (MF-438). Bioorganic & Medicinal Chemistry Letters 20: 499–502.CrossRefGoogle Scholar
  33. Liu, G. 2009. Stearoyl-CoA desaturase inhibitors: update on patented compounds. Expert Opinion on Therapeutic Patents 19: 1169–1191.PubMedCrossRefGoogle Scholar
  34. Matschinsky, F.M., B. Zelent, N.M. Doliba, K.H. Kaestner, J.M. Vanderkooi, J. Grimsby, S.J. Berthel, and R. Sarabu. 2011. Research and development of glucokinase activators for diabetes therapy: theoretical and practical aspects. Handbook of Experimental Pharmacology 203: 357–401.PubMedCrossRefGoogle Scholar
  35. Matschinsky, F.M., M.A. Magnuson, D. Zelent, T.L. Jetton, N. Doliba, Y. Han, R. Taub, and J. Grimsby. 2006. The network of glucokinase-expressing cells in glucose homeostasis and the potential of glucokinase activators for diabetes therapy. Diabetes 55: 1–12.PubMedCrossRefGoogle Scholar
  36. Miyazaki, M., Y.C. Kim, M.P. Gray-Keller, A.D. Attie, and J.M. Ntambi. 2000. The biosynthesis of hepatic cholesterol esters and triglyceride is impaired in mice with a disruption of the gene for stearoyl-CoA desaturase 1. Journal of Biological Chemistry 275: 30132–30138.PubMedCrossRefGoogle Scholar
  37. Miyazaki, M., A. Dobrzyn, H. Sampath, S.H. Lee, W.C. Man, K. Chu, J.M. Peters, F.J. Gonzalez, and J.M. Ntambi. 2004. Reduced adiposity and liver steatosis by stearoyl-CoA desaturase deficiency are independent of peroxisome proliferator-activated receptor alpha. Journal of Biological Chemistry 279: 35017–35024.PubMedCrossRefGoogle Scholar
  38. Mudaliar, S., A.R. Chang, and R.R. Henry. 2003. Thiazolidinediones, peripheral edema, and type 2 diabetes: incidence, pathophysiology, and clinical implications. Endocrine Practice 9: 406–416.PubMedGoogle Scholar
  39. Ntambi, J.M., M. Miyazaki, J.P. Stoehr, H. Lan, C.M. Kendziorski, B.S. Yandell, Y. Song, P. Cohen, J.M. Friedman, and A.D. Attie. 2002. Loss of stearoyl-CoA desaturase-1 function protects mice against adiposity. Proceedings of the National Academy of Sciences of the United States of America 99: 11482–11486.PubMedCrossRefGoogle Scholar
  40. Page, R.I., W.S. Gozansky, and J.M. Ruscin. 2003. Possible exacerbation associated with rosiglitazone: case report and literature review. Pharmacotherapy 23: 945–954.PubMedCrossRefGoogle Scholar
  41. Rask, E., T. Olsson, S. Soderberg, R. Andrew, D.E. Livingstone, D. Johnson, and B.R. Walker. 2001. Tissue-specific dysregulation of cortisol metabolism in human obesity. Journal of Clinical Endocrinology and Metabolism 86: 1418–1421.PubMedCrossRefGoogle Scholar
  42. Ryden, L., E. Standl, M. Bartnik, G. Van den Berghe, J. Betteridge, M.J. de Boer, F. Cosentino, B. Jonsson, M. Laakso, K. Malmberg, S. Priori, J. Osergren, J. Tuomilehto, I. Thrainsdottir, I. Vanhorebeek, M. Stramba-Badiale, P. Lingren, Q. Qiao, S.G. Priori, and J.J. Blanc. 2007. Guidelines on diabetes, pre-diabetes, and cardiovascular diseases: executive summary. European Heart Journal 28: 88–126.PubMedCrossRefGoogle Scholar
  43. Semple, R.K., V.K.K. Chatterjee, and S. O’Rahilly. 2006. PPAR gamma and human metabolic disease. The Journal of Clinical Investigation 116: 581–589.PubMedCrossRefGoogle Scholar
  44. Soga, T., T. Ohishi, T. Matsui, T. Saito, M. Matsumoto, J. Takasaki, S. Matsumoto, M. Kamohara, H. Hiyama, S. Yoshida, K. Momose, Y. Ueda, H. Matsushime, M. Kobori, and K. Furuichi. 2005. Lysophosphatidylcholine enhances glucose-dependent insulin secretion via an orphan G-protein-coupled receptor. Biochemical and Biophysical Research Communications 326: 744–751.PubMedCrossRefGoogle Scholar
  45. Steneberg, P., N. Rubins, R. Bartoov-Shifman, M.D. Walker, and H. Edlund. 2005. The FFA receptor GPR40 links hyperinsulinemia, hepatic steatosis, and impaired glucose homeostasis in mouse. Cell Metabolism 1: 245–258.PubMedCrossRefGoogle Scholar
  46. Stone, S.J., H.M. Myers, S.M. Watkins, B.E. Brown, K.R. Feingold, P.M. Elias, and R.V. Farese Jr. 2004. Lipopenia and skin barrier abnormalities in DGAT2-deficient mice. Journal of Biological Chemistry 279: 11767–11776.PubMedCrossRefGoogle Scholar
  47. Tannin, G.M., A.K. Agarwal, C. Monder, M.I. New, and P.C. White. 1991. The human gene for 11 beta-hydroxysteroid dehydrogenase. Structure, tissue distribution, and chromosomal localization. Journal of Biological Chemistry 266: 16653–16658.PubMedGoogle Scholar
  48. Tilg, H., and A.R. Moschen. 2008. Inflammatory mechanisms in the regulation of insulin resistance. Molecular Medicine 14: 222–231.PubMedCrossRefGoogle Scholar
  49. Vilsbell, T., H. Tferso, T. Kraup, and J.J. Holst. 2003. Similar elimination rates of glucagon-like peptide-1 in obese type 2 diabetic patients and healthy subjects. The Journal of Clinical Endocrinology and Metabolism 88: 220–224.CrossRefGoogle Scholar
  50. Wild, S., G. Roglic, A. Green, R. Sicree, and H. King. 2004. Global prevalence of diabetes: Estimates for the year 2000 and projection for 2030. Diabetes Care 27: 1047–1053.PubMedCrossRefGoogle Scholar
  51. Weisberg, S.P., D. Hunter, R. Huber, J. Lemieux, S. Slaymaker, K. Vaddi, I. Charo, R.L. Leibel, and A.W. Ferrante Jr. 2006. CCR2 modulates inflammatory and metabolic effects of high-fat feeding. The Journal of Clinical Investigation 116: 115–124.PubMedCrossRefGoogle Scholar
  52. Yen, C.L., S.J. Stone, S. Koliwad, C. Harris, and R.V. Farese Jr. 2008. Thematic review series: Glycerolipids, DGAT enzymes and triacylglycerol biosynthesis. Journal of Lipid Research 49: 2283–2301.PubMedCrossRefGoogle Scholar
  53. Yu, X.X., S.F. Murray, S.K. Pandey, S.L. Booten, D. Bao, X.Z. Song, S. Kelly, S. Chen, R. Mckay, B.P. Monia, and S. Bhanot. 2005. Antisense oligonucleotide reduction of DGAT2 expression improves hepatic steatosis and hyperlipidemia in obese mice. Hepatology 42: 362–371.PubMedCrossRefGoogle Scholar

Copyright information

© The Pharmaceutical Society of Korea 2013

Authors and Affiliations

  1. 1.Department of Pharmacology and Pharmaceutical SciencesGachon UniversityIncheonKorea

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