Advertisement

Journal of Biosciences

, 44:150 | Cite as

Type II diabetes mellitus and obesity: Common links, existing therapeutics and future developments

  • Subhadeep BanerjeeEmail author
  • Indrani Talukdar
  • Arnab Banerjee
  • Arnav Gupta
  • Advait Balaji
  • Raviprasad AduriEmail author
Review
  • 23 Downloads

Abstract

Type II diabetes mellitus (T2DM) and obesity are two common pathophysiological conditions of metabolic syndrome (MetS), a collection of similar metabolic dysfunctions due to sedentary lifestyle and overnutrition. Obesity arises from improper adipogenesis which otherwise has a crucial role in maintaining proper metabolic functions. Downstream events arising from obesity have been linked to T2DM. The nuclear receptor peroxisome proliferator activator gamma (PPAR-γ), responsible for maintaining lipid and glucose homeostasis, is down-regulated under obesity leading to a weakened insulin sensitivity of the human body. In course of our review we will outline details of the down-regulation mechanism, provide an overview of the current clinical therapeutics and their shortcomings. Toxicity studies on the seminal drug troglitazone, belonging to the most effective glitazone anti-diabetic category, is also discussed. This will lead to an overview about structural adaptations on the existing glitazones to alleviate their side effects and toxicity. Finally, we forward a concept of novel therapeutics mimicking the glitazone framework, based on some design concepts and preliminary in silico studies. These could be later developed into dual acting drugs towards alleviating the deleterious effects of obesity on normal glucose metabolism, and address obesity in itself.

Keywords

T2DM obesity PPAR-γ TNF-α SPPARγMs glitazones 

Abbreviations

GLUT

glucose transporter

NFκB

nuclear factor kappa B

JUNK

c-Jun N-terminal kinase

IKKβ

inhibitor of nuclear factor kappa-B kinase subunit beta

MAPK

mitogen activated protein kinase

FAS

fatty acid synthase

PEPCK

phosphoenolpyruvate carboxykinase

ACS

acetyl-CoA synthase

LPL

lipoprotein lipase

PKCθ

protein kinase C theta

ERK

extracellular signal-regulated kinase

Notes

References

  1. Agrawal R, Jain, P and Dikshit SN 2012 Balaglitazone: A second generation peroxisome proliferator-activated receptor (PPAR) gamma (γ) agonist. Mini-Rev. Med. Chem. 12 87–97PubMedCrossRefGoogle Scholar
  2. Aguirre V, Uchida T, et al. 2004 The c Jun NH2-terminal kinase promotes insulin resistance during association with insulin receptor substrate-1 and phosphorylation of Ser307. J. Biol. Chem. 275 9047–9054CrossRefGoogle Scholar
  3. Arner P 2005 Human fat cell lipolysis: biochemistry, regulation and clinical role. Best Pract. Res. Clin. Endocrinol. Metab. 19 471–482PubMedCrossRefGoogle Scholar
  4. Banerjee RR, Rangwala SM, Shapiro JS, et al. 2004 Regulation of fasted blood glucose by resistin. Science 303 1195–1198PubMedCrossRefGoogle Scholar
  5. Boden G 1997 Role of fatty acids in the pathogenesis of insulin resistance and NIDDM. Diabetes 46 3–10PubMedCrossRefGoogle Scholar
  6. Bolen S, Feldman L and Vassy J 2007 Systematic review: comparative effectiveness and safety of oral medications for type 2 diabetes mellitus. Ann. Internal Med. 147 386–399CrossRefGoogle Scholar
  7. Burgermeister E, Schnoebelen A, Flament A, et al. 2006 A novel partial agonist of peroxisome proliferator-activated receptor-γ (PPARγ) recruits PPARγ-coactivator-1α, prevents triglyceride accumulation, and potentiates insulin signaling in vitro. Mol. Endocrinol. 20 809–830PubMedCrossRefGoogle Scholar
  8. Capelli D, Cerchia C, et al. 2016 Structural basis for PPAR partial or full activation revealed by a novel ligand binding mode. Sci. Rep. 6.  https://doi.org/10.1038/srep34792
  9. Carter PH, Scherle PA, Muckelbauer JA, et al. 2001 Photochemically enhanced binding of small molecules to the tumor necrosis factor receptor-1 inhibits the binding of TNF-α. Proc. Nat. Acad. Sci. USA 98 11879–11884PubMedCrossRefGoogle Scholar
  10. Chen X, Yang L and Zhai SD 2012 Risk of cardiovascular disease and all-cause mortality among diabetic patients prescribed rosiglitazone or pioglitazone: a meta-analysis of retrospective cohort studies. Chinese Med. J. 125 4301–4306Google Scholar
  11. Dabhi AS, Bhatt NR and Shah MJ 2013 Voglibose: An alpha glucosidase inhibitor. J. Clin. Diagnostic Res. 7 3023–3027Google Scholar
  12. Davis SN 2004 The role of glimepiride in the effective management of type 2 diabetes. J. Diabetes Complications 18 367–376PubMedCrossRefGoogle Scholar
  13. Dixit VA, Rathi PC, Bhagat S, et al. 2016 Design and synthesis of novel Y-shaped barbituric acid derivatives as PPAR-γ activators. Eur. J. Med. Chem. 108 423–435PubMedCrossRefGoogle Scholar
  14. Dresner A, Laurent D, Marcucci M, et al. 1999 Effects of free fatty acids on glucose transport and IRS-1-associated phosphatidylinositol 3-kinase activity. J. Clin. Invest. 103 253–259PubMedPubMedCentralCrossRefGoogle Scholar
  15. Gale EAM 2006 Troglitazone: the lesson that nobody learned? Diabetologia 49 1–6PubMedCrossRefGoogle Scholar
  16. Gao Z, et al. 2002 Serine phosphorylation of insulin receptor substrate 1 by inhibitor κB kinase complex. J. Biol. Chem. 277 48115–48121PubMedCrossRefGoogle Scholar
  17. Gervois P, Torra IP, Fruchart JC and Staels B 2000 Regulation of lipid and lipoprotein metabolism by PPAR activators. Clin. Chem. Lab. Med. 38 3–11PubMedCrossRefGoogle Scholar
  18. Fernandez-Real, José-Manuel, et al. 2002 Shedding of TNF-α receptors, blood pressure, and insulin sensitivity in type 2 diabetes mellitus. Am. J. Physiol.-Endocrinol. Metab. 282 952–959CrossRefGoogle Scholar
  19. Griffin ME, et al. 1999 Free fatty acid-induced insulin resistance is associated with activation of protein kinase C theta and alterations in the insulin signaling cascade. Diabetes 48 1270–1274CrossRefGoogle Scholar
  20. Guilherme A, Virbasius JV, Puri V and Czech MP 2008 Adipocyte dysfunctions linking obesity to insulin resistance and type 2 diabetes. Nat. Rev. Mol. Cell Biol. 9 367–377PubMedPubMedCentralCrossRefGoogle Scholar
  21. Guirado A, Sánchez JLL, Ruiz-Alcaraz A, et al. 2012 Synthesis and biological evaluation of 4-alkoxy-6,9-dichloro[1,2,4]triazolo[4,3-a] quinoxalines as inhibitors of TNF-α and IL-6. Eur. J. Med. Chem. 54 87–94PubMedCrossRefGoogle Scholar
  22. Gururaja TL, Yung S, Ding R, et al. 2007 A class of small molecules that inhibit TNF-α-induced survival and death pathways via prevention of interactions between TNFaRI, TRADD, and RIP1. Chem. Biol. 14 1105–1118PubMedCrossRefGoogle Scholar
  23. Gustafson B, Gogg S, Hedjazifar S, et al. 2009 Inflammation and impaired adipogenesis in hypertrophic obesity in man. Am. J. Physiol. Endocrinol. Metab. 297 E999–E1003PubMedCrossRefGoogle Scholar
  24. He W, Barak Y, Hevener, A, et al. 2003 Genetics Adipose-specific peroxisome proliferator-activated receptor-γ knockout causes insulin resistance in fat and liver but not in muscle. Proc. Natl. Acad. Sci. USA 100 15712–15717PubMedCrossRefGoogle Scholar
  25. Herman G, Bergman A, Liu F, et al. 2006 Pharmacokinetics and pharmacodynamic effects of the oral DPP-4 inhibitor sitagliptin in middle-aged obese subjects. J. Clin. Pharmacol. 46 876–886PubMedCrossRefGoogle Scholar
  26. Hirosumi J, et al. 2002 A central role for JNK in obesity and insulin resistance. in Nature, 420 333–336PubMedCrossRefGoogle Scholar
  27. Hofmann C, Lorenz K, Braithwaite S, et al. 1994 Altered gene expression for tumor necrosis factor-α and its receptors during drug and dietary modulation of insulin resistance. Endocrinology 134 264–270PubMedCrossRefGoogle Scholar
  28. Hotamisligil GS, Arner P, Caro JF, Atkinson RL and Spiegelman BM 1995 Increased adipose tissue expression of tumor necrosis factor-α in human obesity and insulin resistance. J. Clin. Invest. 95 2409–2415PubMedPubMedCentralCrossRefGoogle Scholar
  29. Hube F and Hauner H 1999 The role of TNF-α in human adipose tissue: prevention of weight gain at the expense of insulin resistance. Hormone Metab. Res. 31 626–631CrossRefGoogle Scholar
  30. Jain VS, Vora DK and Ramaa CS 2013 Thiazolidine-2,4-diones: Progress towards multifarious applications. Bioorgan. Med. Chem. 21 1599–1620CrossRefGoogle Scholar
  31. Joshi SR and Parikh RM 2007. India – Diabetes capital of the world: Now heading towards hypertension. J. Assocn. Physicians India 55 323–324Google Scholar
  32. Kanda H et al. 2006 MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. J. Clin. Invest. 116 1494–1505PubMedPubMedCentralCrossRefGoogle Scholar
  33. Kim JK, et al. 2004 PKC-θ knockout mice are protected from fat-induced insulin resistance. J. Clin. Invest. 114 823–827PubMedPubMedCentralCrossRefGoogle Scholar
  34. Kraegen EW, Cooney GJ, Ye JM, Thompson AL and Furler SM 2001 The role of lipids in the pathogenesis of muscle insulin resistance and β cell failure in type II diabetes and obesity. Exp. Clin. Endocrinol. Diabetes 109 S189–S201PubMedCrossRefGoogle Scholar
  35. Kroker AJ, Bruning JB. 2015 Review of the structural and dynamic mechanisms of PPARγ partial agonism. PPAR Res. Article ID 816856Google Scholar
  36. Kwon H, Pessin JE, et al. 2013 Adipokines mediate inflammation and insulin resistance. Front. Endocrinol. 4 1–13CrossRefGoogle Scholar
  37. Leonardini A, Laviola L, Perrini S, et al. 2009 Cross-Talk between PPAR and insulin signaling and modulation of insulin sensitivity. PPAR Res. Article ID 818945Google Scholar
  38. Maeda K, et al. 1996 cDNA cloning and expression of a novel adipose specific collagen-like factor, apM1 (adipose most abundant gene transcript 1). Biochem. Biophys. Res. Commun. 221 286–289PubMedCrossRefGoogle Scholar
  39. Maruthur NM, Tseng E, Hutfless S, et al. 2016 Diabetes medications as monotherapy or metformin-based combination therapy for type 2 diabetes: a systematic review and meta-analysis. Ann. Internal Med. 164 740–751CrossRefGoogle Scholar
  40. Modak M, Dixit P and Londhe J 2007 Indian herbs and herbal drugs used for the treatment of diabetes. J. Clin. Biochem. Nutrit. 40 163–173CrossRefGoogle Scholar
  41. Morris GM, Huey R, Lindstrom W, et al. 2009 Autodock4 and AutoDockTools4 automated docking with selective receptor flexibility. J. Comput. Chem. 16 2785–2791CrossRefGoogle Scholar
  42. Nagy L, Tontonoz P, Alvarez JG, et al. 1998 Oxidized LDL regulates macrophage gene expression through ligand activation of PPAR-γ. Cell 93 229–240PubMedCrossRefGoogle Scholar
  43. Nakamura MT, Yudell BE and Loor JJ 2014 Regulation of energy metabolism by long-chain fatty acids. Progress Lipid Res. 53 124–144CrossRefGoogle Scholar
  44. Nawrocki AR, Rajala MW, Tomas, E, et al. 2006 Mice lacking adiponectin show decreased hepatic insulin sensitivity and reduced responsiveness to peroxisome proliferator-activated receptor γ agonists. J. Biol. Chem. 281 2654–2660PubMedCrossRefGoogle Scholar
  45. Nesto R, Bell W, Bonow D, et al. 2003 Thiazolidinedione use, fluid retention, and congestive heart failure: a consensus statement from the American Heart Association and American Diabetes Association. Circulation 108 2941–2948PubMedCrossRefGoogle Scholar
  46. Nolte RT, Wisely GB, Westin S, et al. 1998 Ligand binding and co-activator assembly of the peroxisome proliferator-activated receptor-gamma. Nature 395 137–143PubMedCrossRefGoogle Scholar
  47. Olansky L 2010a Do incretin-based therapies cause acute pancreatitis? J. Diabetes Sci. Technol. 4 228–229PubMedPubMedCentralCrossRefGoogle Scholar
  48. Olansky L 2010b DPP-4 inhibitors for type 2 diabetes: drug safety communication—may cause severe joint pain. FDA 2015–08–28 (https://www.fda.gov/drugs/drug-safety-and-availability/fdadrug-safety-communication-fda-warns-dpp-4-inhibitors-type-2-diabetes-may-cause-severe-joint-pain)
  49. Pandey M, Tuncman G, Hotamisligil GS, et al. 2003 Divergent Roles for p55 and p75 TNF-α receptors in the induction of plasminogen activator inhibitor-1. Am. J. Pathol. 162 933–941PubMedPubMedCentralCrossRefGoogle Scholar
  50. Pandit K, Goswami S, Ghosh S, et al. 2012. Metabolic syndrome in South Asians. Indian J. Endocrinol. Metab. 16 44–55PubMedPubMedCentralCrossRefGoogle Scholar
  51. Pascual G, Fong AL, Ogawa S, et al. 2005 A SUMOylation-dependent pathway mediates transrepression of inflammatory response genes by PPAR-γ . Nature 437 759–763PubMedPubMedCentralCrossRefGoogle Scholar
  52. Rosen ED, Hsu CH, Wang X, et al. 2002 C/EBPα induces adipogenesis through PPAR-γ: a unified pathway. Genes Dev. 16 22–26PubMedPubMedCentralCrossRefGoogle Scholar
  53. Rosen ED and Spiegelman BM 2006 Adipocytes as regulators of energy balance and glucose homeostasis. Nature 444 847–853PubMedPubMedCentralCrossRefGoogle Scholar
  54. Ruan H, Hacohen N, Golub TR, et al. 2002 Tumor necrosis factor-α suppresses adipocyte-specific genes and activates expression of preadipocyte genes in 3T3-L1 adipocytes: nuclear factor-κB activation by TNF-α is obligatory. Diabetes 51 1319–1336PubMedCrossRefGoogle Scholar
  55. Saha S, New LS, et al. 2010 Investigation of the role of the thiazolidinedione ring of troglitazone in inducing hepatotoxicity. Toxicol. Lett. 192 141–149PubMedCrossRefGoogle Scholar
  56. Saklayen GM 2018 The global epidemic of the metabolic syndrome. Curr. Hypertens. Rep. 20 12PubMedPubMedCentralCrossRefGoogle Scholar
  57. Scheen AJ 2014 Pharmacodynamics, Efficacy and safety of sodium–glucose co-transporter type 2 (SGLT2) inhibitors for the treatment of type 2 diabetes mellitus. Drugs 75 33–59CrossRefGoogle Scholar
  58. Shi et al. 2005 Design and synthesis of α-aryloxyphenylacetic acid derivatives:  a novel class of PPARα/γ dual agonists with potent antihyperglycemic and lipid modulating activity. J. Med. Chem. 48 4457PubMedCrossRefGoogle Scholar
  59. Sosale, A.; Saboo, B.; Sosale, B. 2015 Saroglitazar for the treatment of hypertriglyceridemia in patients with type 2 diabetes: current evidence. Diabetes, Metabolic Syndrome Obesity Targets Therapy 8 189–196PubMedCrossRefGoogle Scholar
  60. Sun L, Xu Y, Han W, et al. 2015 12/15-Lipoxygenase metabolites of arachidonic acid activate PPAR-γ: a possible neuroprotective effect in ischemic brain. J. Lipid Res.  https://doi.org/10.1194/jlr.m053058 CrossRefPubMedPubMedCentralGoogle Scholar
  61. Sundriyal S, Bharatam PV. 2009 Important pharmacophoric features of pan PPAR agonists: Common chemical feature analysis and virtual screening. Eur. J. Med. Chem. 44 3488–3495PubMedCrossRefGoogle Scholar
  62. Talukdar I, Szeszel-Fedorowicz W and Salati LM 2005 Arachidonic acid inhibits the insulin induction of glucose-6-phosphate dehydrogenase via p38 MAP kinase. J. Biol. Chem. 280 40660–40667PubMedCrossRefGoogle Scholar
  63. Taygerly JP, McGee LR, Rubenstein, et al. 2013 Discovery of INT131 A selective PPAR-γ modulator that enhances insulin sensitivity. Bioorgan. Med. Chem. 21 979–992CrossRefGoogle Scholar
  64. Tuccori M, Filion KB, Yin H, et al. 2016 Pioglitazone use and risk of bladder cancer: population based cohort study. BMJ 352 i1541PubMedPubMedCentralCrossRefGoogle Scholar
  65. Um SH, et al. 2004 Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity. Nature 431 200–205PubMedCrossRefGoogle Scholar
  66. Unnikrishnan AG, Kalra S and Garg MK 2012 Preventing obesity in India: Weighing the option. Indian J. Endocrinol. Metab. 16 4–6PubMedPubMedCentralGoogle Scholar
  67. van Marrewijk LM, Polyak SW, Hijnen M, et al. 2016 SR2067 Reveals a unique kinetic and structural signature for PPARγ partial agonism. ACS Chem. Biol. 11 273–283PubMedCrossRefGoogle Scholar
  68. Wu Z, Rosen ED, Brun R, et al. 1999 Cross-regulation of C/EBP alpha and PPAR gamma controls the transcriptional pathway of adipogenesis and insulin sensitivity. Mol. Cell. 3 51–58CrossRefGoogle Scholar
  69. Wu Z, Xie Y, et al. 1998 PPAR-γ Induces the insulin-dependent glucose transporter GLUT4 in the absence of C/ΕΒΠα during the conversion of 3T3 fibroblasts into adipocytes. J. Clin. Invest. 101 22–32PubMedPubMedCentralCrossRefGoogle Scholar
  70. Ye J 2008 Regulation of PPARγ function by TNF-α. Biochem. Biophys. Res. Commun. 374 405–408PubMedPubMedCentralCrossRefGoogle Scholar
  71. Yu C, Chen Y, Cline GW, et al. 2002 Mechanism by which fatty acids inhibit insulin activation of insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol 3-kinase activity in muscle. J. Biol. Chem. 52 50230–50236CrossRefGoogle Scholar
  72. Yuan M, et al. 2001 Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of Ikkβ. Science 293 1673–1677PubMedCrossRefGoogle Scholar
  73. Zhang F, Lavan BE and Gregoire FM 2007 selective modulators of ppar-γ activity: molecular aspects related to obesity and side-effects. PPAR Res. Article ID 32696Google Scholar
  74. Zhang HH, Halbleib M, Ahmad F, et al. 2002 Tumor necrosis factor-α stimulates lipolysis in differentiated human adipocytes through activation of extracellular signal-related kinase and elevation of intracellular cAMP. Diabetes 51 2929–2935PubMedCrossRefGoogle Scholar

Copyright information

© Indian Academy of Sciences 2019

Authors and Affiliations

  1. 1.Department of ChemistryBITS Pilani, K K Birla Goa CampusZuarinagarIndia
  2. 2.Department of Biological SciencesBITS Pilani, K K Birla Goa CampusZuarinagarIndia

Personalised recommendations