Journal of Biosciences

, Volume 26, Issue 3, pp 383–390 | Cite as

Orally active insulin mimics: where do we stand now?

  • M. Balasubramanyam
  • V. Mohan
Review

Abstract

The war against diabetes through the development of new drugs is an ongoing continuous process to counter the alarming global increase in the prevalence of diabetes and its complications, particularly in developing countries like India. Unfortunately, the speed with which our knowledge of diabetes and its effects is expanding is not matched by the availability of new drugs. Following the identification of the insulin receptor (IR), its intrinsic kinase activity and molecular cloning, many studies have looked at IR as an ideal drug target. This review summarizes in brief the latest advancements in this field with particular reference to the current situation in respect of the development of orally active insulin mimetics in the treatment of type 2 diabetes.

Keywords

Insulin mimetic insulin receptor tyrosine kinase PI 3-kinase vanadium 

Abbreviations used

EGFR

Epidermal growth factor receptor

GPI

glycosyl-phosphoinositol

IGF1R

insulin growth factor-1 receptor

IR

insulin receptor

IRS

insulin receptor substrate

IRTK

insulin receptor tyrosine kinase

OBA

2-(oxalylamino)-benzoic acid

pVs

peroxovanadiums

PI 3-kinase

phosphatidylinositol 3-kinase

PIG

phosphoinositolglycan

PTPases

phosphotyrosine phosphatase

PDGFR

platelet-derived growth factor receptor

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References

  1. Accili D, Drago J, Lee E J, Johnson M D, Cool M H, Salvatore P, Asico L D, Jose P A, Taylor S I and Westphal H 1996 Early neonatal death in mice homozygous for a null allele of the insulin receptor gene;Nat. Genet. 12 106–109CrossRefGoogle Scholar
  2. Alessi D R and Cohen P 1998 Mechanism of activation and function of protein kinase B;Curr. Opin. Genet. Dev. 8 55–62PubMedCrossRefGoogle Scholar
  3. Andersen H S, Iversen L F, Jeppesen C B, Branner S, Norris K, Rasmussen H B, Moller K B and Moller N P 2000 2-(oxalylamino)-benzoic acid is a general, competitive inhibitor of protein-tyrosine phosphatases;J. Biol. Chem. 275 7101–7108PubMedCrossRefGoogle Scholar
  4. Balasubramanyam M and Mohan V 1999 The need for high throughput screening of herbal medicine with special reference to diabetes mellitus;Brain storming colloquium on Biodiversity (sponsored by DST), Abstract p 31Google Scholar
  5. Bailey C J and Day C 1989 Traditional plant medicines as treatments for diabetes;Diabetes Care 12 553–564PubMedCrossRefGoogle Scholar
  6. Band C J, Posner B I, Dumas V and Contreres J O 1997 Early signaling events triggered by peroxovanadium [bpV(phen)] are insulin receptor kinase (IRK)-dependent: specificity of inhibition of IRK-associated protein tyrosine phosphatase(s) by bpV(phen);Mol. Endocrinol. 11 1899–1910PubMedCrossRefGoogle Scholar
  7. Bevan A P, Drake P G, Yale J F, Shaver A and Posner B I 1995 Peroxovanadium compounds: biological actions and mechanism of insulin-mimesis;Mol. Cell. Biochem. 153 49–58PubMedCrossRefGoogle Scholar
  8. Brand R M and Hamel F G 1999 Transdermally delivered peroxovanadium can lower blood glucose levels in diabetic rats;Int. J. Pharm. 183 117–123PubMedCrossRefGoogle Scholar
  9. Brichard S M, Ongemba L N and Henquin J C 1992 Oral vanadate decreases muscle insulin resistance in obese fa/fa rats;Diabetologia 35 522–527PubMedCrossRefGoogle Scholar
  10. Bulangu L N, Ossowski V M, Bogardus C and Mott D 1990 Insulin-sensitive tyrosine kinase: relationship within vivo insulin action in humans;Am. J. Physiol. 258 E964–974Google Scholar
  11. Cam M C, Brownsey R W and McNeill J H 2000 Mechanisms of vanadium action: insulin-mimetic or insulin-enhancing agent?;Can. J. Physiol. Pharmacol. 78 829–847PubMedCrossRefGoogle Scholar
  12. Carino G P and Mathiowitz E 1999 Oral insulin delivery;Adv. Drug. Deliv. Rev. 35 249–257PubMedCrossRefGoogle Scholar
  13. Caro J F, Ittoop O, Pories W J, Meelheim D, Flickinger E G, Thomas F, Jenquin M, Silverman J F, Khazanie P G and Sinha M K 1986 Studies on the mechanism of insulin resistance in the liver from humans with non-insulin-dependent diabetes;J. Clin. Invest. 78 249–258PubMedGoogle Scholar
  14. Caro J F, Sinha M, Raju S M, Itoop O, Pories W J., Flickinger E G, Meelheim D and Dohm G L 1987 Insulin receptor kinase in human skeletal muscle from obese subjects with and without non-insulin dependent diabetes;J. Clin. Invest. 79 1330–1337PubMedGoogle Scholar
  15. Chen H, Wertheimer S J, Lin C H, Katz S L, Amrein K E, Burn P and Quon M J 1997 Protein-tyrosine phosphatases PTP1B and syp are modulators of insulin-stimulated translocation of GLUT4 in transfected rat adipose cells;J. Biol. Chem. 272 8026–8031PubMedCrossRefGoogle Scholar
  16. Chen H, Cong L N, Li Y, Yao Z J, Wu L, Zhang Z Y, Burke T R and Quon M J 1999 A phosphotyrosyl mimetic peptide reverses impairment of insulin-stimulated translocation of GLUT4 caused by overexpression of PTP1B in rat adipose cells;Biochemistry 38 384–389PubMedCrossRefGoogle Scholar
  17. Clark S F, Martin S, Carozzi A J, Hill M M and James D E 1998 Intracellular localization of PI 3-kinase and insulin receptor substrate-1 in adipocytes: potential involvement of a membrane skeleton;J. Cell Biol. 140 1211–1225PubMedCrossRefGoogle Scholar
  18. Cohen N, Halberstam M, Shlimovich P, Chang C J, Shamoon H and Rossetti L 1995 Oral vanadyl sulfate improves hepatic and peripheral insulin sensitivity in patients with non-insulin-dependent diabetes mellitus;J. Clin. Invest. 95 2501–2509PubMedGoogle Scholar
  19. Crans D C 2000 Chemistry and insulin-like properties of vanadium (IV) and vanadium (V) compounds;J. Inorg. Biochem. 80 123–131PubMedCrossRefGoogle Scholar
  20. Denu J M, Kohse D L, Vijayalakshmi J, Saper M A and Dixon J E 1996 Visualization of intermediate and transition-state structures in protein-tyrosine phosphatase catalysis;Proc. Natl. Acad. Sci. USA 93 2493–2498CrossRefGoogle Scholar
  21. Egawa K, Sharma P M, Nakashima N, Huang Y, Huver E, Boss G R and Olefsky J M 1999 Membrane-targeted phosphatidylinositol 3-kinase mimics insulin actions and induces a state of cellular insulin resistance;J. Biol. Chem. 274 14306–14314PubMedCrossRefGoogle Scholar
  22. Elchebly M, Payette P, Michaliszyn E, Cromlish W, Collins S, Loy A L, Normandin D, Cheng A, Himms-Hagen J, Chan C, Ramachandran C, Gresser M J, Tremblay M L and Kennedy B P 1999 Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase-1B gene;Science 283 1544–1548PubMedCrossRefGoogle Scholar
  23. Ellis L, Morgan D O, Clauser E, Roth R A and Rutter W J 1987 A membrane-anchored cytoplasmic domain of the human insulin receptor mediates a constitutively elevated insulin-dependent uptake of 2-deoxyglucose;Mol. Endocrinol. 1 15–24PubMedCrossRefGoogle Scholar
  24. Flier J S 1992 Syndromes of insulin resistance. From patient to gene and back again;Diabetes 41 1207–1219PubMedCrossRefGoogle Scholar
  25. Freidenberg G R, Henry R R, Klein H H and Olefsky J M 1987 Decreased kinase activity of insulin receptors from adipocytes of non-insulin-dependent diabetes mellitus;J. Clin. Invest. 79 240–250PubMedGoogle Scholar
  26. Frick W, Bauer A, Bauer J, Wied S and Muller G 1998 Insulin-mimetic signaling of synthetic phosphoinositolglycans in isolated rat adipocytes;Biochem. J. 336 163–181PubMedGoogle Scholar
  27. Gray A M and Flatt P R 1998 Insulin-releasing and insulin-like activity ofAgaricus campestris (mushroom);J. Endocrinol. 157 259–266PubMedCrossRefGoogle Scholar
  28. Goodyear L J, Giorgino F, Sherman L A, Carey J, Smith R J and Dohm G L 1995 Insulin receptor phosphorylation, insulin receptor substrate-1 phosphorylation, and phosphatidylinositol 3-kinase activity are decreased in intact skeletal muscle strips from obese subjects;J. Clin. Invest. 95 2195–2204PubMedGoogle Scholar
  29. Gould G W, Merrall N W, Martin S, Jess T J, Campbell I W, Calderhead D M, Gibbs E M, Holman G D and Plevin R J 1994 Growth factor-induced stimulation of hexose transport in 3T3-L1 adipocytes: evidence that insulin-induced translocation of GLUT4 is independent of activation of MAP kinase;Cell Signal. 6 313–320PubMedCrossRefGoogle Scholar
  30. Grillo S, Gremeaux T, Casamayor A, Alessi D R, Le Marchand-Brustel Y and Tanti J F 2000 Peroxovanadate induces tyrosine phosphrorylation of phosphoinositide-dependent protein kinase-1 potential involvement of src kinase;Eur. J. Biochem. 267 6642–6649PubMedCrossRefGoogle Scholar
  31. Haring H U, Obermaier B, Ermel B, Su Z, Mushack J, Rattenhuber E, Holzl J, Kirsch D, Machicao F and Herberg L 1987 Insulin receptor kinase defects as a possible cause of cellular insulin resistance;Diabetes Metab. 13 284–293Google Scholar
  32. Heinmann L, Linkeschova R, Rave K, Hompesch B, Sedlak M and Heise T 2000 Time-action profile of the long-acting insulin analog insulin glargine (HOE 901) ion comparison with those of NPH insulin and placebo;Diabetes Care 23 644–649CrossRefGoogle Scholar
  33. Hubbard S R 1997 Crystal structure of the activated insulin receptor tyrosine kinase in complex with peptide substrate and ATP analog;EMBO J. 16 5572–5581PubMedCrossRefGoogle Scholar
  34. Hubbard S R, Wei L, Ellis L and Hendrickson W A 1994 Crystal structure of the tyrosine kinase domain of the human insulin receptor;Nature (London)372 746–754CrossRefGoogle Scholar
  35. Imparl-Radosevich J, Deas S, Polansky M M, Baedke D A, Ingebritsen T S, Andersen R A and Graves D J 1998 Regulation of PTP-1 and insulin receptor kinase by fractions from cinnamon: implications for cinnamon regulation of insulin signaling;Horm. Res. 50 177–182PubMedCrossRefGoogle Scholar
  36. Isakoff S J, Taha C, Rose E, Marcusohn J, Klip A and Skolnik E Y 1995 The inability of phosphatidylinositol 3-kinase activation to stimulate GLUT4 translocation indicates additional signaling pathways are required for insulin-stimulated glucose uptake;Proc. Natl. Acad. Sci. USA 92 10247–10251PubMedCrossRefGoogle Scholar
  37. Iversen L F, Andersen H S, Branner S, Mortensen S B, Peters G H, Norris K, Olsen O H, Jeppesen C B, Lundt B F, Ripka W, Moller K B and Moller N P 2000 Structure-based design of a low molecular weight, nonphosphorus, nonpeptide, and highly selective inhibitor of protein-tyrosine phosphatase 1B;J. Biol. Chem. 275 10300–10307PubMedCrossRefGoogle Scholar
  38. Jiang T, Sweeney G, Rudolf M T, Klip A, Traynor-Kaplan A and Tsien R Y 1998 Membrane-permeant esters of phosphatidylinositol 3,4,5-triphosphate;J. Biol. Chem. 273 11017–11024PubMedCrossRefGoogle Scholar
  39. Jiang Z Y, Lin Y W, Clemont A, Feener E P, Hein K D, Igarashi M, Yamauchi T, White M F and King G L 1999 Characterization of selective resistance to insulin signaling in the vasculature of obese zucker (fa/fa) rats;J. Clin. Invest. 104 447–457PubMedGoogle Scholar
  40. Joshi R L, Lamothe B, Gordonnier N, Mesbah K, Monthioux E, Jami J and Bucchini D 1996 Targeted disruption of the insulin receptor gene in the mouse results in neonatal lethality;EMBO J. 15 1542–1547Google Scholar
  41. Kasuga M, Karlsson F A and Kahn C R 1982 Insulin stimulates the phosphorylation of the 95,000-dalton subunit of its own receptor;Science 215 185–187PubMedCrossRefGoogle Scholar
  42. Kerouz N J, Horsh D, Pons D and Kahn C R 1997 Differential regulation of insulin receptor substrate-1 and -2 ((IRS-1 and IRS-2) and phosphatidylinositol 3-kinase isoforms in liver and muscle of the obese diabetic (ob/ob) mouse;J. Clin. Invest. 100 3164–3172PubMedCrossRefGoogle Scholar
  43. Kessler A, Muller G, Wied S, Crecelius A and Eckel J 1998 Signaling pathways of an insulin mimetic phosphoinositol-glycan-peptide in muscle and adipose tissue;Biochem. J. 330 277–286PubMedGoogle Scholar
  44. Kim Y B, Zhu J S, Zierath J R, Shen H Q, Baron A D and Kahn B B 1999 Glucosamine infusion in rats rapidly impairs insulin stimulation of PI 3-kinase but does not alter activation of Akt/protein kinase B in skeletal muscle;Diabetes 47 310–320CrossRefGoogle Scholar
  45. Kohn A D, Summers S A, Birnbaum M J and Roth R A 1996 Expression of a constitutively active Akt Ser/Thr kinase in 3T3-L1 adipocytes stimulates glucose uptake and glucose transporter 4 translocation;J. Biol. Chem. 272 31372–31378Google Scholar
  46. Krook A, Roth R A, Jiang X J, Zierath J R and Wallberg-Henriksson H 1998 Insulin-stimulated Akt kinase activity is reduced in skeletal muscle from NIDDM subjects;Diabetes 47 1281–1286PubMedCrossRefGoogle Scholar
  47. Liu K, Xu L, Szalkowski D, Li Z, Ding V, Kwei G, Huskey S, Moller D E, Heck J V, Zhang B B and Jones A B 2000 Discovery of a potent, highly selective, and orally efficacious small-molecule activator of the insulin receptor;J. Med. Chem. 43 3487–3494PubMedCrossRefGoogle Scholar
  48. Luo R Z, Beniac D R, Fernandes A, Yip C C and Ottensmeyer F P 1999 Quaternary structure of the insulin-insulin receptor complex;Science 285 1077–1080PubMedCrossRefGoogle Scholar
  49. Malalavidhane T S, Wickramasinghe S M and Jansz E R 2000 Oral hypoglycaemic activity ofipomoea aquatica;J. Ethnopharmacol. 72 293–298PubMedCrossRefGoogle Scholar
  50. Malamas M S, Sredy, J, Gunawan I, Mihan B, Sawicki D R, Seestaller L, Sullivan D and Flam B R 2000 New azolidine-diones as inhibitors of protein tyrosine phosphatase 1B with antihyperglycemic properties;J. Med. Chem. 43 995–1010PubMedCrossRefGoogle Scholar
  51. Marschurz M K and Bernkop-Schnurch A 2000 Oral peptide drug delivery: polymer-inhibitor conjugates protecting insulin from enzymatic degradation in vitro;Biomaterials 21 1499–1507CrossRefGoogle Scholar
  52. Marschutz M K, Caliceti P and Bernkop-Schnurch A 2000 Design andin vivo evaluation of an oral delivery system for insulin;Pharm. Res. 17 1468–1474PubMedCrossRefGoogle Scholar
  53. Meyerovitch J, Farfel Z, Sack Y and Shechter Y 1987 Oral administration of vanadate normalizes blood glucose levels in streptozotocin-treated rats;J. Biol. Chem. 263 6658–6662Google Scholar
  54. Moxham C M and Malbon C C 1996 Insulin action impaired by deficiency of the G-protein subunit Gialpha2;Nature (London) 379 840–844CrossRefGoogle Scholar
  55. Muller G, Satoh Y and Geisen K 1995 Extrapancreatic effects of sulfonylureas — a comparison between glimepiride and conventional sulfonylureas;Diab. Res. Clin. Pract. 28 S115–137CrossRefGoogle Scholar
  56. Muller G 2000 The molecular mechanisms of the insulin-mimetic/sensitizing activity of the antidiabetic sulfonylurea drug Amaryl;Mol. Med. 6 907–933PubMedGoogle Scholar
  57. Olefsky J M 1976 Decreased insulin binding to adipocytes and circulating monocytes from obese subjects;J. Clin. Invest. 57 1165–1172PubMedGoogle Scholar
  58. Posner B I, Faure R, Burgess J W, Bevan A P, Lachance D, Zhang-Sun G, Fantus I G, Ng J B, Hall D A, Lum B S 1994 Peroxovanadium compounds. A new class of potent phosphotyrosine phosphatase inhibitors which are insulin mimetics;J. Biol. Chem. 269 4596–4604PubMedGoogle Scholar
  59. Quon M J, Chen H, Ing B L, Liu M L, Zarnowski M J, Yonezawa K, Kasuga M, Cushman S W and Taylor S I 1995 Roles of 1-phosphatidylinositol 3-kinase and ras in regulating translocation of GLUT4 in transfected rat adipose cells;Mol. Cell. Biol. 15 5403–5411PubMedGoogle Scholar
  60. Qureshi S A, Ding V, Li Z, Szalkowski D, Biazzo-Ashnault D E, Xie D, Saperstein R, Brady E, Huskey S, Shen X, Liu K, Xu L, Salituro G M, Heck J V, Moller D E, Jones A B and Zhang B B 2000 Activation of insulin signal transduction pathway and anti-diabetic activity of small molecule insulin receptor activators;J. Biol. Chem. 275 36590–36595PubMedCrossRefGoogle Scholar
  61. Rosen O M, Herrera R, Olowe Y, Petruzzeli M and Cobb M H 1983 Phosphorylation activates the insulin receptor tyrosine protein kinase;Proc. Natl. Acad. Sci. USA 80 3237–3240PubMedCrossRefGoogle Scholar
  62. Sakurai H, Sano H, Takino T and Yasui H 2000 An orally active antidiabetic vanadyl complex, bis(1-oxy-2-pyridinethiolato)oxovanadium(IV), with VO(S2O2) coordination mode;in vitro andin vivo evaluations in rats;J. Inorg. Biochem. 80 99–105PubMedCrossRefGoogle Scholar
  63. Salmeen A, Andersen J N, Myers M P, Tonks N K and Barford D 2000 Molecular basis for the dephosphorylation of the activation segment of the insulin receptor by protein tyrosine phosphatase 1B;Mol. Cell. 6 1401–1412PubMedCrossRefGoogle Scholar
  64. Taylor S I 1992 Lilly Lecture: Molecular mechanisms of insulin resistance: Lessons from patients with mutations in the insulin receptor gene;Diabetes 41 1473–1490PubMedCrossRefGoogle Scholar
  65. Till J H, Ablooglu A J, Frankel M, Bishop S M, Kohanski R A and Hubbard S R 2001 Crystallographic and solution studies of an activation loop mutant of the insulin receptor tyrosine kinase: insights into kinase mechanism;J. Biol. Chem. 276 10049–10055PubMedCrossRefGoogle Scholar
  66. White M F 1998 The IRS-signaling system: a network of docking proteins that mediate insulin action;Mol. Cell. Biochem. 182 3–11PubMedCrossRefGoogle Scholar
  67. White M F and Yenush L 1998 The IRS-signaling system: a network of docking proteins that mediate insulin and cytokine action;Curr. Top. Microbiol. Immunol. 228 179–208PubMedGoogle Scholar
  68. Woo L C, Yuen V G, Thompson K H, McNeill J H and Orvig C 1999 Vanadyl-biguanide complexes as potential synergistic insulin mimics;J. Inorg. Biochem. 76 251–257PubMedCrossRefGoogle Scholar
  69. Yu K T and Czech M P 1984 Tyrosine phosphorylation of the insulin receptor beta subunit activates the receptor-associated tyrosine kinase activity;J. Biol. Chem. 259 5277–5286PubMedGoogle Scholar
  70. Zhang B, Salituro G, Szalkowski D, Li Z, Zhang Y, Royo I, Vilella D, Diez M T, Pelaez F, Ruby C, Kendall R L, Mao X, Griffin P, Calaycay J, Zierath J R, Heck J V, Smith R G and Moller D E 1999 Discovery of a small molecule insulin mimetic with antidiabetic activity in mice;Science 284 974–977PubMedCrossRefGoogle Scholar

Copyright information

© Indian Academy of Sciences 2001

Authors and Affiliations

  • M. Balasubramanyam
    • 1
  • V. Mohan
    • 1
  1. 1.Madras Diabetes Research Foundation (MDRF)Gopalapuram, ChennaiIndia

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