Skip to main content
SpringerLink
Log in

Gene Expression Analysis in T2DM and Its Associated Microvascular Diabetic Complications: Focus on Risk Factor and RAAS Pathway

  • Research
  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Prolonged hyperglycemic conditions in type 2 diabetes mellitus (T2DM) cause pathological and functional damage to many organs and tissues, including the kidneys, retina, skin, and neuronal tissues, resulting in the development of microvascular diabetic complications. The altered renin angiotensin aldosterone system (RAAS) pathway has been reported to play an important role in the development of insulin resistance in T2DM and associated complications. The current study was carried out to evaluate the association of risk factors and altered expression of RAAS genes in T2DM patients without complications and T2DM patients with complications (retinopathy, nephropathy, and neuropathy). Four hundred and twenty subjects including 140 healthy controls, 140 T2DM patients with diabetic complications, and 140 T2DM patients without diabetic complications were included in the study. Risk factors associated with the development of T2DM and diabetic complications were evaluated. Further, expression analysis of RAAS genes (AGT, ACE, ACE2, and AGT1R) was carried out using qRTPCR in healthy controls, T2DM patients with complications, and T2DM patients without complications. Various risk factors like urban background, higher BMI, alcoholism, smoking, and family history of diabetes among others were found to be associated with the development of T2DM as well as diabetic complications. The expression level of AGT, ACE, and AGT1R was found to be upregulated whereas ACE2 was found to be downregulated in T2DM patients with complications and T2DM patients without complications as compared to controls. Altered expression of the studied genes of RAAS pathway is associated with the development of microvascular diabetic complications.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Data Availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

References

  1. Paul S, Ali A, Katare R (2020) Molecular complexities underlying the vascular complications of diabetes mellitus–a comprehensive review. J Diabetes Complications 34(8):107613

    Article  PubMed  Google Scholar 

  2. Horton WB, Barrett EJ (2021) Microvascular dysfunction in diabetes mellitus and cardiometabolic disease. Endocr Rev 42(1):29–55

    Article  PubMed  Google Scholar 

  3. Eid S, Sas KM, Abcouwer SF, Feldman EL, Gardner TW, Pennathur S, Fort PE (2019) New insights into the mechanisms of diabetic complications: role of lipids and lipid metabolism. Diabetologia 62:1539–1549

    Article  PubMed  PubMed Central  Google Scholar 

  4. Jang HN, Moon MK, Koo BK (2022) Prevalence of diabetic retinopathy in undiagnosed diabetic patients: a nationwide population-based study. Diabetes Metab J 46(4):620

  5. Carmichael J, Fadavi H, Ishibashi F, Shore AC, Tavakoli M (2021) Advances in screening, early diagnosis and accurate staging of diabetic neuropathy. Front Endocrinol 12:671257

    Article  Google Scholar 

  6. Sagoo MK, Gnudi L (2020) Diabetic nephropathy: an overview. Diabetic Nephropathy: Methods Protoc 3–7

  7. Rahimi Z, Moradi M, Nasri H (2014) A systematic review of the role of renin angiotensin aldosterone system genes in diabetes mellitus, diabetic retinopathy and diabetic neuropathy. J Res Med Sci 19(11):1090

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Watson F, Austin P (2021) Physiology of human fluid balance. Anaesth Intensive Care Med 22(10):644–651

    Article  Google Scholar 

  9. Ghafar MTA (2020) An overview of the classical and tissue-derived renin-angiotensin-aldosterone system and its genetic polymorphisms in essential hypertension. Steroids 163:108701

    Article  PubMed  Google Scholar 

  10. Otsuka H, Abe M, Kobayashi H (2023) The effect of aldosterone on cardiorenal and metabolic systems. Int J Mol Sci 24(6):5370

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Valenzuela PL, Carrera-Bastos P, Gálvez BG, Ruiz-Hurtado G, Ordovas JM, Ruilope LM, Lucia A (2021) Lifestyle interventions for the prevention and treatment of hypertension. Nat Rev Cardiol 18(4):251–275

  12. Barrett EJ, Liu Z, Khamaisi M, King GL, Klein R, Klein BE, Hughes TM, Craft S et al (2017) Diabetic microvascular disease: an endocrine society scientific statement. The J Clin Endocrinol Metab 102(12):4343–4410

  13. Ceriello A, Prattichizzo F (2021) Variability of risk factors and diabetes complications. Cardiovasc Diabetol 20(1):1–11

    Article  Google Scholar 

  14. Wang L, Li X, Wang Z, Bancks MP, Carnethon MR, Greenland P, Feng Y-Q, H (2021) Trends in prevalence of diabetes and control of risk factors in diabetes among US adults, 1999–2018. JAMA 326(8):704–716

    Article  Google Scholar 

  15. Tan J, Wang Y, Liu S, Shi Q, Zhou X, Zhou Y, Yang X, Chen P et al. (2021) Long-acting metformin vs. metformin immediate release in patients with type 2 diabetes: a systematic review. Front Pharmacol 12.https://doi.org/10.3389/fphar.2021.669814

  16. Oruganti A, Kavi A, Walvekar PR (2019) Risk of developing diabetes mellitus among urban poor South Indian population using Indian diabetes risk score. J Family Med Prim Care 8(2):487–492. https://doi.org/10.4103/jfmpc.jfmpc_388_18

    Article  PubMed  PubMed Central  Google Scholar 

  17. Patil R, Gothankar J (2019) Risk factors for type 2 diabetes mellitus: an urban perspective. Indian J Med Sci 71(1):16–21

    Article  Google Scholar 

  18. Thanikachalam M, Fuller CH, Lane KJ, Sunderarajan J, Harivanzan V, Brugge D, Thanikachalam S (2019) Urban environment as an independent predictor of insulin resistance in a South Asian population. Int J Health Geogr 18(1):5. https://doi.org/10.1186/s12942-019-0169-9

    Article  PubMed  PubMed Central  Google Scholar 

  19. Gray N, Picone G, Sloan F, Yashkin A (2015) Relation between BMI and diabetes mellitus and its complications among US older adults. South Med J 108(1):29–36. https://doi.org/10.14423/smj.0000000000000214

    Article  PubMed  PubMed Central  Google Scholar 

  20. Verma S, Hussain ME (2017) Obesity and diabetes: an update. Diabetes Metab Syndr 11(1):73–79. https://doi.org/10.1016/j.dsx.2016.06.017

    Article  PubMed  Google Scholar 

  21. Campagna D, Alamo A, Di Pino A, Russo C, Calogero A, Purrello F, Polosa R (2019) Smoking and diabetes: dangerous liaisons and confusing relationships. Diabetol Metab Syndr 11(1):1–12

    Article  Google Scholar 

  22. Chang SA (2012) Smoking and type 2 diabetes mellitus. Diabetes Metab J 36(6):399–403

    Article  PubMed  PubMed Central  Google Scholar 

  23. Durlach V, Vergès B, Al-Salameh A, Bahougne T, Benzerouk F, Berlin I, Clair C, Mansourati J et al. (2022) Smoking and diabetes interplay: a comprehensive review and joint statement. Diabetes Metab 101370

  24. Lee D-Y, Yoo M-G, Kim H-J, Jang HB, Kim J-H, Lee H-J, Park SI (2017) Association between alcohol consumption pattern and the incidence risk of type 2 diabetes in Korean men: a 12-years follow-up study. Sci Rep 7(1):7322. https://doi.org/10.1038/s41598-017-07549-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Sia H-K, Kor C-T, Tu S-T, Liao P-Y, Wang J-Y (2022) Association between smoking and glycemic control in men with newly diagnosed type 2 diabetes: a retrospective matched cohort study. Ann Med 54(1):1385–1394

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Xia N, Morteza A, Yang F, Cao H, Wang A (2019) Review of the role of cigarette smoking in diabetic foot. J Diabetes Investig 10(2):202–215

    Article  PubMed  Google Scholar 

  27. Blomster JI, Zoungas S, Chalmers J, Li Q, Chow CK, Woodward M, Mancia G, Poulter N et al (2014) The relationship between alcohol consumption and vascular complications and mortality in individuals with type 2 diabetes. Diabetes Care 37(5):1353–1359

    Article  CAS  PubMed  Google Scholar 

  28. Campagna D, Alamo A, Di Pino A, Russo C, Calogero AE, Purrello F, Polosa R (2019) Smoking and diabetes: dangerous liaisons and confusing relationships. Diabetol Metab Syndr 11(1):85. https://doi.org/10.1186/s13098-019-0482-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Maghbooli Z, Pasalar P, Keshtkar A, Farzadfar F, Larijani B (2014) Predictive factors of diabetic complications: a possible link between family history of diabetes and diabetic retinopathy. J Diabetes Metab Disord 13(1):55. https://doi.org/10.1186/2251-6581-13-55

    Article  PubMed  PubMed Central  Google Scholar 

  30. Yamazaki D, Hitomi H, Nishiyama A (2018) Hypertension with diabetes mellitus complications. Hypertens Res 41(3):147–156

    Article  PubMed  Google Scholar 

  31. Kalra S, Aggarwal S, Khandelwal D (2019) Thyroid dysfunction and type 2 diabetes mellitus: screening strategies and implications for management. Diabetes Ther 10(6):2035–2044. https://doi.org/10.1007/s13300-019-00700-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Nishi M (2018) Diabetes mellitus and thyroid diseases. Diabetol Int 9(2):108–112. https://doi.org/10.1007/s13340-018-0352-4

    Article  PubMed  PubMed Central  Google Scholar 

  33. Barthel BD, Cabandugama PK, Khangura DS, Kurukulasuriya LR, Sowers JR (2020) The role of RAAS inhibitors in the prevention and treatment of chronic kidney disease in the diabetic population. Kidney Disease in Diabetes, 1. p 216-233

  34. Roca-Ho H, Riera M, Palau V, Pascual J, Soler MJ (2017) Characterization of ACE and ACE2 expression within different organs of the NOD mouse. Int J Mol Sci 18(3):563

    Article  PubMed  PubMed Central  Google Scholar 

  35. Huang K, Liang Y, Wang K, Ma Y, Wu J, Luo H, Yi B (2022) Elevated ACE levels indicate diabetic nephropathy progression or companied retina impaired. Front Clin Diabetes Healthc 3:831128. https://doi.org/10.3389/fcdhc.2022.831128

    Article  PubMed  PubMed Central  Google Scholar 

  36. Te Riet L, van Esch JH, Roks AJ, van den Meiracker AH, Danser AJ (2015) Hypertension: renin–angiotensin–aldosterone system alterations. Circ Res 116(6):960–975

    Article  Google Scholar 

  37. Patel Vaibhav B, Parajuli N, Oudit Gavin Y (2013) Role of angiotensin-converting enzyme 2 (ACE2) in diabetic cardiovascular complications. Clin Sci 126(7):471–482. https://doi.org/10.1042/cs20130344

    Article  Google Scholar 

  38. Gheblawi M, Wang K, Viveiros A, Nguyen Q, Zhong J-C, Turner AJ, Raizada MK, Grant MB, Oudit GY (2020) Angiotensin-converting enzyme 2: SARS-CoV-2 receptor and regulator of the renin-angiotensin system: celebrating the 20th anniversary of the discovery of ACE2. Circ Res 126(10):1456–1474

    Article  CAS  PubMed  Google Scholar 

  39. Shaikh R, Shahid SM, Mansoor Q, Ismail M, Azhar A (2014) Genetic variants of ACE (insertion/deletion) and AGT (M268T) genes in patients with diabetes and nephropathy. J Renin-Angiotensin-Aldosterone Syst 15(2):124–130

  40. Aksoy H, Karadag AS, Wollina U (2020) Angiotensin II receptors: impact for COVID-19 severity. Dermatol Ther 33(6):e13989

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Smith D, Layton A (2023) The intrarenal renin-angiotensin system in hypertension: insights from mathematical modelling. J Math Biol 86(4):58

    Article  PubMed  Google Scholar 

  42. Leung KK, Leung PS (2008) Effects of hyperglycemia on angiotensin II receptor type 1 expression and insulin secretion in an INS-1E pancreatic beta-cell line. Jop 9(3):290–299

  43. Wanka H, Lutze P, Staar D, Bracke K, Golchert J, Peters J (2020) Angiotensin dependent and angiotensin independent protective effects of renin-b in H9c2 cells after anoxia. Sci Rep 10(1):19689. https://doi.org/10.1038/s41598-020-76712-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Molina-Van den Bosch M, Jacobs-Cachá C, Vergara A, Serón D, Soler M (2021) The renin-angiotensin system and the brain. Hipertension y Riesgo Vascular 38(3):125–132

    Article  CAS  PubMed  Google Scholar 

  45. Patel DM, Bose M, Cooper ME (2020) Glucose and blood pressure-dependent pathways–the progression of diabetic kidney disease. Int J Mol Sci 21(6):2218

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Hirooka K, Kiuchi Y (2022) The retinal renin-angiotensin-aldosterone system: implications for glaucoma. Antioxidants 11(4):610

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Liu K, Zou H, Fan H, Hu H, Cheng Y, Liu J, Wu X, Chen B et al (2023) The role of aldosterone in the pathogenesis of diabetic retinopathy. Front Endocrinol 14:1163787

    Article  Google Scholar 

  48. Pelle MC, Provenzano M, Busutti M, Porcu CV, Zaffina I, Stanga L, Arturi F (2022) Up-date on diabetic nephropathy. Life 12(8):1202

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Lozano-Maneiro L, Puente-García A (2015) Renin-angiotensin-aldosterone system blockade in diabetic nephropathy. Present Evidences. J Clin Med 4(11):1908–1937. https://doi.org/10.3390/jcm4111908

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Al-Awaida WJ, Hameed WS, Al Hassany HJ, Al-Dabet MM, Al-Bawareed O, Hadi NR (2021) Evaluation of the genetic association and expressions of Notch-2 /Jagged-1 in patients with type 2 diabetes mellitus. Med Arch 75(2):101–108. https://doi.org/10.5455/medarh.2021.75.101-108

    Article  PubMed  PubMed Central  Google Scholar 

  51. Singh S, Gupta NR, Raza ST, Kapoor A, Singh P (2021) Association of hypertension and its risk factor in type II diabetes mellitus patients. Asian J Med Sci 12(1)

  52. Mancusi C, Izzo R, di Gioia G, Losi MA, Barbato E, Morisco C (2020) Insulin resistance the hinge between hypertension and type 2 diabetes. High Blood Press Cardiovasc Prev 27(6):515–526. https://doi.org/10.1007/s40292-020-00408-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Ghazi L, Drawz P (2017) Advances in understanding the renin-angiotensin-aldosterone system (RAAS) in blood pressure control and recent pivotal trials of RAAS blockade in heart failure and diabetic nephropathy. F1000Res 6.https://doi.org/10.12688/f1000research.9692.1

  54. Vischer AS, Kuster GM, Twerenbold R, Pfister O, Zhou Q, Villiger A, Poglitsch M, Krähenbühl S et al (2021) Influence of antihypertensive treatment on RAAS peptides in newly diagnosed hypertensive patients. Cells 10(3). https://doi.org/10.3390/cells10030534

Download references

Acknowledgements

We acknowledge all the patients who agreed to participate in the current study.

Funding

Prabhsimran Kaur is thankful to CSIR for providing financial assistance (grant no. 09/1051(0020)/2018-EMR-I). We are also thankful to DST for FIST grant (SR/FST/LS-I/2017/49) to the Department of Human Genetics and Molecular Medicine, Central University of Punjab.

Author information

Authors and Affiliations

  1. Department of Human Genetics and Molecular Medicine, Central University of Punjab, Bathinda, 151401, India

    Laxmipriya Jena, Prabhsimran Kaur, Tashvinder Singh, Kangan Sharma & Anjana Munshi

  2. MEDOC Department, Max Super Speciality Hospital, Bathinda, 151001, Punjab, India

    Sushil Kotru

Authors
  1. Laxmipriya Jena
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Prabhsimran Kaur
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tashvinder Singh
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kangan Sharma
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sushil Kotru
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Anjana Munshi
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Laxmipriya Jena, Prabhsimran Kaur, Tashvinder Singh, Sushil Kotru, and Anjana Munshi designed the research study. Laxmipriya Jena collected the samples with Sushil Kotru’s help. Laxmipriya Jena and Prabhsimran Kaur carried out experimental work. The statistical evaluation was done by Laxmipriya Jena, Prabhsimran Kaur, and Tashvinder Singh. Compilation of the results and manuscript was prepared by Laxmipriya Jena, Prabhsimran Kaur, Tashvinder Singh, Kangan Sharma, and Anjana Munshi. The manuscript was critically revised and edited by Anjana Munshi and Sushil Kotru.

Corresponding authors

Correspondence to Sushil Kotru or Anjana Munshi.

Ethics declarations

Ethics Approval

The institutional committee of Central University of Punjab, Bathinda, has approved the study.

Consent to Participate

Informed consent was obtained from all individual participants included in the study.

Consent for Publication

N/A.

Competing Interests

The authors declare no competing interests.

Research Involving Human Participants and/or Animals

The research study involves human blood samples.

Additional information

Publisher's Note

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

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 448 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jena, L., Kaur, P., Singh, T. et al. Gene Expression Analysis in T2DM and Its Associated Microvascular Diabetic Complications: Focus on Risk Factor and RAAS Pathway. Mol Neurobiol (2024). https://doi.org/10.1007/s12035-024-04127-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s12035-024-04127-2

Keywords

Search

Navigation