Skip to main content


Log in

Type 2 diabetes mellitus: pathogenesis and genetic diagnosis

  • Review article
  • Published:
Journal of Diabetes & Metabolic Disorders Aims and scope Submit manuscript


Type 2 diabetes mellitus (T2DM) is a heterogeneous condition that is related to both defective insulin secretion and peripheral insulin resistance. Beta cells are the major organ for secreting insulin hence, it is important to maintain an adequate beta-cell mass in response to various changes. Insulin resistance is a major cause of T2DM leads to elevated free fatty acid (FFA) levels which increases beta-cell mass and insulin secretion to compensate for insulin insensitivity. Chronic increase of plasma FFA levels results in disturbances in lipid metabolism, which contributes to decreased beta-cell function and lipotoxicity thus promoting T2DM. In the present review, we have discussed the process of beta-cell destruction, the role of genes in contributing to the fast increase in the progression of T2DM in detail. More than 130 variants in various T2DM susceptibility and candidate genes have been discovered to be associated with T2DM. Still, these variants elucidate only a small amount of total heritability of T2DM. Further, there is also an inventory of presently used therapeutic tools and a review of novel therapeutic approaches like incretin-based therapies or sodium-glucose transporter-2 inhibitors. Additionally, providing a concise but comprehensive update, this review will be essential to every clinician involved in the treatment of diabetes mellitus.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2

Similar content being viewed by others


  1. Oh YS, Bae GD, Baek DJ, Park EY, Jun HS. Fatty acid-induced lipotoxicity in pancreatic beta-cells during development of type 2 diabetes. Front Endocrinol. 2018;9(07):1–10.

    Google Scholar 

  2. Prasad RB, Groop L. Genetics of type 2 diabetes—pitfalls and possibilities. Genes. 2015;6(1):87–123.

    Article  CAS  Google Scholar 

  3. Armstrong D. Advanced protocols in oxidative stress III. Advanced Protocols in Oxidative Stress III. 2014;1208:1–477.

    Google Scholar 

  4. Mohan V, Sandeep S, Deepa R, Shah B, Varghese C. Epidemiology of type 2 diabetes : Indian scenario. 2007;(03):217–30.

  5. Zatalia SR, Sanusi H. The role of antioxidants in the pathophysiology, complications, and management of diabetes mellitus. Acta medica Indonesiana. 2013;45(2):141–7.

    PubMed  Google Scholar 

  6. Tangvarasittichai S. Oxidative stress, insulin resistance, dyslipidemia and type 2 diabetes mellitus. World J Diabetes. 2015;6(3):456–80.

    Article  Google Scholar 

  7. Al-Goblan AS, Al-Alfi MA, Khan MZ. Mechanism linking diabetes mellitus and obesity. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy. 2014;7:587–91.

    Article  Google Scholar 

  8. Hardie DG. AMP-activated protein kinase — an energy sensor that regulates all aspects of cell function. 2011;1895–908.

  9. Yoon KH, Lee JH, Kim JW, Cho JH, Choi YH, Ko SH, et al. Epidemic obesity and type 2 diabetes in Asia. Lancet. 2006;368(9):1681–8.

    Article  Google Scholar 

  10. Abate N, Chandalia M, Satija P, Adams-huet B, Grundy SM, Sandeep S, et al. Susceptibility to type 2 diabetes. Diabetes. 2005;54(04):1207–13.

    Article  CAS  Google Scholar 

  11. Lyssenko V, Laakso M. Genetic Screening for the Risk of Type 2 Diabetes: Worthless or valuable? Diabetes Care. 2013;36(Supplement_2):S120–6.

  12. Jayashree S, Arindam M, Vijay K V. Genetic epidemiology of coronary artery disease : an Asian Indian perspective 2015;94(3):539–49.

  13. Asmat U, Abad K, Ismail K. Diabetes mellitus and oxidative stress—a concise review. Saudi Pharmaceutical Journal. 2016;24(5):547–53.

    Article  Google Scholar 

  14. Mccarthy M, Menzel S. The genetics of type 2 diabetes. 2010;195–9.

  15. Berumen J, Orozco L, Betancourt-cravioto M, Gallardo H, Zulueta M, Mendizabal L, et al. Influence of obesity , parental history of diabetes and genes in type 2 diabetes : A case-control study. 2019;(1):1–15.

  16. Meigs JB, Cupples LA, Wilson PWF. The Framingham Offspring Study. (23):2201–7.

  17. Moran Y, Labrador L, Camargo ME, Fernández D, Chiurillo MA. type 2 diabetes in Venezuelans. 2016;

  18. Wilding JPH, Bastien A., Norwood P, list JF, T’Joen C, Fiedorek FT. a study of Dapagliflozin in patients with type 2 diabetes receiving high doses of. Emerging Treatments and Technologies 2009;32(9):1656–62.

  19. Kaveeshwar SA, Cornwall J. The current state of diabetes mellitus in India. Australasian Medical Journal. 2014;7(1):45–8.

    Article  Google Scholar 

  20. McKeigue PM, Shah B, Marmot MG. Relation of central obesity and insulin resistance with high diabetes prevalence and cardiovascular risk in south Asians. Lancet. 1991;337(8):382–6.

    Article  CAS  Google Scholar 

  21. Raji A, Seely EW, Arky RA, Simonson DC. Body fat distribution and insulin resistance in healthy Asian Indians and Caucasians. J Clin Endocrinol Metab. 2001;86(11):5366–71.

    Article  CAS  Google Scholar 

  22. Introduction I. Monogenic Diabetes : What It Teaches Us on the Common Forms of Type 1 and Type 2 Diabetes. 2016;37(June):190–222.

  23. Hevener AL, Olefsky JM, Reichart D, Nguyen MTA, Bandyopadyhay G, Leung HY, et al. Macrophage PPARγ is required for normal skeletal muscle and hepatic insulin sensitivity and full antidiabetic effects of thiazolidinediones. J Clin Investig. 2007;117(6):1658–69.

    Article  CAS  Google Scholar 

  24. Wamique M, Ali W. Rizvi Fatima Nishat. Role of free fatty acid and elevated VLDL in type II diabetes mellitus - a review. EJPMR. 2015;2(7):115–9.

    Google Scholar 

  25. Iraj G. Clinical review 124: diabetic dyslipidemia : causes and consequences. J Clin Endocrinol Metab. 2001;86(3):965–71.

    Article  Google Scholar 

  26. Kitasato L, Tojo T, Hatakeyama Y, Kameda R, Hashikata T, Yamaoka-Tojo M, et al. Postprandial hyperglycemia and endothelial function in type 2 diabetes: focus on mitiglinide. Cardiovasc Diabetol. 2012;11:79.

    Article  CAS  Google Scholar 

  27. Cerf ME. Beta cell dysfunction and insulin resistance. Front Endocrinol. 2013;4(03):1–12.

    Google Scholar 

  28. Ripsin CM, Kang H, Urban RJ. Management of blood glucose in type 2 diabetes mellitus. Am Fam Physician. 2009;79(1):29–36.

    PubMed  Google Scholar 

  29. Besler C, Lüscher TF, Landmesser U. Molecular mechanisms of vascular effects of high-density lipoprotein: alterations in cardiovascular disease. EMBO Molecular Medicine. 2012;4(4):251–68.

    Article  CAS  Google Scholar 

  30. Saxena M, Agrawal CG, Srivastava N, Banerjee M. gene polymorphisms in type 2 diabetes. 2014;6(07):60–8.

  31. Han SJ, Boyko EJ. The evidence for an obesity paradox in type 2 diabetes mellitus. Diabetes Metab J. 2018;42(3):179–87.

    Article  Google Scholar 

  32. Plomin R, Haworth CMA, Davis OSP. Common disorders are quantitative traits. Nat Rev Genet. 2009;10(12):872–8.

    Article  CAS  Google Scholar 

  33. Avenue G. Heterogeneity in Healthy Women 2002;667–73.

  34. Kayıkcıoglu M. Polymorphisms of lipid metabolism enzyme-coding genes in patients with diabetic dyslipidemia. The Anatolian Journal of Cardiology. 2017;6:313–21.

    Google Scholar 

  35. Khodaeian M, Enayati S, Tabatabaei-malazy O, Amoli MM. Association between genetic variants and diabetes mellitus in Iranian populations : a systematic review of observational studies. 2015.

  36. Dasgupta S, Sirisha PVS, Neelaveni K, Anuradha K, Reddy BM. Association of CAPN10 SNPs and Haplotypes with Polycystic Ovary Syndrome among South Indian Women 2012;7(2):1–8.

  37. McClellan J, King MC. Genetic heterogeneity in human disease. Cell. 2010;141(2):210–7.

    Article  CAS  Google Scholar 

  38. Mitchell KJ. What is complex about complex disorders? Genome Biol. 2012;13(1):1–11.

    Article  Google Scholar 

  39. Spégel P, Bugliani M, Saxena R, Fex M, Pulizzi N. NIH Public Access. 2013;41(1):82–8.

    Google Scholar 

  40. Singh S. The genetics of type 2 diabetes mellitus : a review. JSR. 2011;55:35–48.

    Google Scholar 

  41. Wu Y, Ding Y, Tanaka Y, Zhang W. Risk Factors Contributing to Type 2 Diabetes and Recent Advances in the Treatment and Prevention. 2014;11.

  42. Ganza ML, Wintfeld N, Li Q, Alas V, Langer J, Hammer M. The association of body mass index with the risk of type 2 diabetes: a case-control study nested in an electronic health records system in the United States. Diabetol Metab Syndr. 2014;6(1):1–8.

    Article  Google Scholar 

  43. Tanaka H, Yoshida S, Oshima H, Minoura H, Negoro K, Yamazaki T, et al. Chronic Treatment with Novel GPR40 Agonists Improve Whole- Body Glucose Metabolism Based on the Glucose-Dependent Insulin Secretion. 2013;40(09):443–52.

    Google Scholar 

  44. Solun B, Marcoviciu D, Dicker D. Dipeptidyl peptidase-4 inhibitors and their effects on the cardiovascular system. Curr Cardiol Rep 2013;15(8).

  45. Feng ZC, Li J, Turco BA, Riopel M, Yee SP, Wang R. Critical role of c-kit in beta cell function: increased insulin secretion and protection against diabetes in a mouse model. Diabetologia. 2012;55(8):2214–25.

    Article  CAS  Google Scholar 

  46. Thornberry NA, Gallwitz B. Mechanism of action of inhibitors of dipeptidyl-peptidase-4 (DPP-4). Best Practice and Research: Clinical Endocrinology and Metabolism [Internet]. 2009;23(4):479–86.

    Article  CAS  Google Scholar 

  47. Hanefeld M, Forst T. Dapagliflozin, an SGLT2 inhibitor, for diabetes. Lancet. 2010;375(9):2196–8.

    Article  Google Scholar 

  48. Trevisan R. The role of Vildagliptin in the therapy of type 2 diabetic patients with renal dysfunction. Diabetes Therapy. 2017;8(6):1215–26.

    Article  CAS  Google Scholar 

  49. Wegrzyn P, Yarwood SJ, Fiegler N, Bzowska M, Koj A, Mizgalska D, et al. Mimitin - a novel cytokine-regulated mitochondrial protein. BMC Cell Biol. 2009;10:23.

    Article  Google Scholar 

  50. Park YJ, Ao Z, Kieffer TJ, Chen H, Safikhan N, Thompson DM, et al. The glucagon-like peptide-1 receptor agonist exenatide restores impaired pro-islet amyloid polypeptide processing in cultured human islets: implications in type 2 diabetes and islet transplantation. Diabetologia. 2013;56(3):508–19.

    Article  CAS  Google Scholar 

  51. Yu H, Spitz MR, Mistry J, Gu J, Hong WK, Wu X. Plasma levels of insulin-like growth factor-I and lung cancer risk: a case-control analysis. J Natl Cancer Inst. 1999;91(2):151–6.

    Article  CAS  Google Scholar 

  52. Zhang X, Zhang W, Saraf SL, Nouraie M, Han J, Gowhari M, et al. HHS Public Access. 2015;134(8):895–904.

    CAS  Google Scholar 

  53. Medicine S. Exercise and Type 2 Diabetes. 2010;33(12).

  54. Raveendran AV, Deshpandae A, Joshi SR. Therapeutic role of yoga in type 2 diabetes. Endocrinol Metab. 2018;33(3):307–17.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations


Corresponding author

Correspondence to Mohd Wamique.

Ethics declarations

Conflict of interest

No conflict of interest exists.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Himanshu, D., Ali, W. & Wamique, M. Type 2 diabetes mellitus: pathogenesis and genetic diagnosis. J Diabetes Metab Disord 19, 1959–1966 (2020).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: