Molecular-genetic characteristics of patients with diabetes mellitus. Vestsi Natsyyanal’nai akademii navuk Belarusi

The article discusses the prospects for studying polymorphic variants of peroxisome proliferator-activated receptor genes (PPARs) of three types (PPARα, PPARδ, and PPARγ) in diabetes mellitus (DM), taking into account their key role in the regulation of energy homeostasis, production of pro-inflammatory cytokines, and lipid characteristics and glycemia control. The main emphasis is on the use of screening methods for testing patients for carriage of single nucleotide polymorphisms (SNPs) in order to improve approaches to identifying risk groups for the formation of DM and associated diseases, and subsequent personification of corrective measures. The clinical, laboratory and molecular genetic characteristics of groups of patients with type 1 and 2 diabetes, healthy volunteers are presented. The prevalence of SNPs in the genes of receptors activated by the peroxisome proliferator in patients with DM was studied in comparison with the control group. Among the evaluated SNPs of the rs135551 gene, PPARA showed the clearest association with the presence of DM. Four variants of haplotypes highly associated with DM1 and DM2 were identified. The expediency of further clarification of the clinical and genetic heterogeneity of cases of diabetes within the DM1 and DM2 groups is discussed. The prospects of this direction for the development of preventive technologies in diabetology, long-term epidemiological molecular genetic screenings are assessed.

1. Kurkela O., Forma L., Ilanne-Parikka P., Nevalainen J., Rissanen P. Association of diabetes type and chronic diabetes complications with early exit from the labour force: register-based study of people with diabetes in Finland. Diabetologia, 2021, vol. 64, no. 4, pp. 795‒804. https://doi.org/10.1007/s00125-020-05363-6

2. Vainilovich E. G., Lushchik M. L., Sretenskaya Zh. L., Zapol’skii S. A., Danilova L. I. Frequency of abdominal obesity and associated metabolic disorders in children 7‒13 years old. Problemy endokrinologii [Endocrinology problems], 2011, vol. 57, no. 5, pp. 15‒23 (in Russian).

3. Locke A. E., Kahali B., Berndt S. I., Justice A. E., Pers T. H., Day F. R. [et al.] Genetic studies of body mass index yield new insights for obesity. Nature, 2015, vol. 518, no. 7538, pp. 197‒206. https://doi.org/10.1038/nature14177

4. Chen J., Spracklen C. N., Marenne G., Varshney A., Corbin L. J., Luan J. [et al.] The trans-ancestral genomic architecture of glycemic traits. Nature Genetics, 2021, vol. 53, no. 6, pp. 840‒860. https://doi.org/10.1038/s41588-021-00852-9

5. Goodarzi M. O., Rotter J. I. Genetics insights in the relationship between type 2 diabetes and coronary heart disease. Circulation Research, 2020, vol. 126, no. 11, pp. 1526–1548. https://doi.org/10.1161

6. Day F., Karaderi T., Jones M. R., Meun C., Chunyan He, Drong A. [et al.]. Large-scale genome-wide meta-analysis of polycystic ovary syndrome suggests shared genetic architecture for different diagnosis criteria. PLOS Genetics, 2018, vol. 14, no. 12, pp. 1‒20. https://doi.org/10.1371/journal.pgen.1007813

7. Groop L. New approaches beyond genetics: towards precision medicine in diabetes. Diabetologia, 2016, vol. 59, no. 12, pp. 2495‒2496. https://doi.org/10.1007/s00125-016-4014-4

8. American Diabetes Association. Standards of medical care in diabetes-2019 abridged for primary care providers. Clinical Diabetes, 2019, vol. 37, no. 1, pp. 11‒34. https://doi.org/10.2337/cd18-0105

9. Pollanen P. M., Ryhanen S. J., Toppari J. Dynamics of islet autoantibodies during prospective follow-up from birth to age 15 years. Journal of Clinical Endocrinology & Metabolism, 2020, vol. 105, no. 12, pp. e4638–e4651. https://doi.org/10.1210/clinem/dgaa624

10. Draznin B., Aroda V. R., Bakris G., Benson G., Brown F. M., Freeman R. [et al.]. American Diabetes Association Professional Practice Committee. Classification and diagnosis of diabetes: standarts of medical care of diabetes-2022. Diabetes Care, 2022, vol. 45, suppl. 1, pp. S17‒S38. https://doi.org/10.2337/dc22-S002

11. Alberti K. G., Zimmet P., Shaw J. Metabolic syndrome ‒ a new world-wide definition. A Consensus Statement from the International Diabetes Federation. Diabetic Medicine, 2006, vol. 23, no. 5, pp. 469–480. https://doi.org/10.1111/j.1464-5491.

12. Khosla T., Lowe C. R. Indices of obesity derived from body weight and height. Journal of Epidemiology and Community Health, 1967, vol. 21, no. 3, pp. 122‒128. https://doi.org/10.1136/jech.21.3.122

13. Li C., Liu M., An Y., Tian Y., Di Guan, Wu H., Pei Z. Risk assessment of type 2 diabetes in northern China based on the logistic regression model. Technology and Health Care, 2021, vol. 29, no. S1, pp. S351–S358. https://doi.org/10.3233/THC-218033

14. Rebrova O. Yu. Statistical analysis of medical data. Using the STATISTICA Application Package. Moscow, Mediasfera Publ., 2002. 305 p. (in Russian).

15. Riddle M. C., Cefalu W. T., Evans P. H., Gerstein H. C., Nauck M. A., Oh W. K. [et al.]. Consensus report: definition and interpretation of remission in type 2 diabetes. Diabetologia, 2021, vol. 64, no. 11, pp. 2359‒2366. https://doi.org/10.1007/s00125-021-05542-z

16. Botta M., Audano M., Sahebkar A., Sirtori C. R., Mitro N., Ruscica M. PPAR agonists and metabolic syndrome: an established role? International Journal of Molecular Sciences, 2018, vol. 19, no. 4, art. 1197. https://doi.org/10.3390/ijms19041197

17. Mirza A. Z., Althagafi I. I., Shamshad H. Role of PPAR receptor in different diseases and their ligands: physiological importance and clinical implications. European Journal of Medicinal Chemistry, 2019, vol. 166, pp. 502‒513. https://doi.org/10.1016/j.ejmech.2019.01.067

18. Guo Z., Priefer R. Current progress in pharmacogenomics of type 2 diabetes: a systemic overview. Diabetes and Metabolic Syndrome, 2021, vol. 15, no. 5, p. 20, 102239. https://doi.org/10.1016/j.dsx.2021.102239

19. Cheng H. S., Tan W. R., Low Z. S., Marvalim Ch., Hao Leе J. Y., Tan N. S. Exploration and development of PPAR modulators in health and disease: an update of clinical evidence. International Journal of Molecular Sciences, 2019, vol. 20, no. 20, art. 5055. https://doi.org/10.3390/ijms20205055

20. Wang L., Waltenberger B., Pferschy-Wenzig E. M., Blunder M., Liu X., Malainer C. [et al.]. Natural product agonists of peroxisome proliferator-activated receptor gamma (PPARγ): a review. Biochemical Pharmacology, 2014, vol. 92, no. 1, pp. 73‒89. https://doi.org/10.1016/j.bcp.2014.07.018

21. Han L., Shen W. J., Bittner S., Kraemer F. B., Azhar S. PPARs: regulators of metabolism and as therapeutic targets in cardiovascular disease. Part II: PPAR-β/δ and PPAR-γ. Future Cardiology, 2017, vol. 13, no. 3, pp. 279‒296. https://doi.org/10.2217/fca-2017-0019

22. Dubois V., Eeckhoute J., Lefebvre P., Staels B. Distinct but complementary contributions of PPAR isotypes to energy homeostasis. Journal of Clinical Investigation, 2017, vol. 127, no. 4, pp. 1202‒1214. https://doi.org/10.1172/JCI88894

23. Muzio G., Barrera G., Pizzimenti S. Peroxisome proliferator-activated receptors (PPARs) and oxidative stress in physiological conditions and in cancer. Antioxidants (Basel), 2021, vol. 10, no. 11, art. 1734. https://doi.org/10.3390/antiox10111734

24. Thamer C., Machann J., Stefan N., Schäfer S. A., Machicao F., Staiger H. [et al.]. Variations in PPARD determine the change in body composition during lifestyle intervention: a whole-body magnetic resonance study. Journal of Clinical Endocrinology and Metabolism, 2008, vol. 93, no. 4, pp. 1497‒500. https://doi.org/10.1210/jc.2007-1209

25. Skogsberg J., McMahon A. D., Karpe F., Hamsten A., Packard C. J., Ehrenborg E. West of Scotland Coronary Prevention Study. Peroxisome proliferator activated receptor delta genotype in relation to cardiovascular risk factors and risk of coronary heart disease in hypercholesterolaemic men. Journal of Internal Medicine, 2003, vol. 254, no. 6, pp. 597‒604. https://doi.org/10.1111/j.1365-2796.2003.01236.x

26. Luo W., Guo Z., Wu M., Hao C., Hu X., Zhou Z., Zhou Z., Yao X., Zhang L., Liu J. Association of peroxisome proliferatoractivated receptor α/δ/γ with obesity, and gene-gene interaction, in the Chinese Han population. Journal of Epidemiology, 2013, vol. 23, no. 3, pp. 187–194. https://doi.org/10.2188/jea.je20120110

27. Fan W., Shen C., Wu M., Zhou Z. Y., Guo Z. R. Association and interaction of PPARα, δ, and γ gene polymorphisms with low-density lipoprotein-cholesterol in a Chinese Han population. Genetic Testing and Molecular Biomarkers, 2015, vol. 19, no. 7, pp. 379‒386. https://doi.org/10.1089/gtmb.2015.0002

28. Janusz P., Pawlak-Adamska E., Bolanowski M., Daroszewski J. The role of peroxisome proliferator-activated receptors α polymorphisms in Graves’ disease and orbitopathy. Endocrine Abstracts, 2014, art. P1028. https://doi.org/10.1530/endoabs.35.P1028

29. Lv X., Zhang L., Sun J., Cai Z., Gu Q., Zhang R., Shan A. Interaction between peroxisome proliferator-activated receptor gamma polymorphism and obesity on type 2 diabetes in a Chinese Han population. Diabetology and Metabolic Syndrome, 2017, vol. 19, art. 7. https://doi.org/10.1186/s13098-017-0205-5

30. Lu L., Wu Y., Qi Q., Liu C., Gan W., Zhu J. [et al.] Associations of type 2 diabetes with common variants in PPARD and the modifying effect of vitamin D among middle-aged and elderly Chinese. PLoS ONE, 2012, vol. 7, no. 4, p. e34895. https://doi.org/10.1371/journal.pone.0034895

31. Du F., Yang K.-J., Piao L.-S. Correlation between PPARGC1A gene rs8192678 G>A polymorphism and susceptibility to type-2 diabetes. Open Life Sciences, 2019, vol. 14, no. 1, pp. 43‒52. https://doi.org/10.1515/biol-2019-0006

32. Bhatta P., Bermano G., Williams H. C., Knott R. M. Meta-analysis demonstrates Gly482Ser variant of PPARGC1A is associated with components of metabolic syndrome within Asian populations. Genomics, 2020, vol. 112, no. 2, pp. 1795‒1803. https://doi.org/10.1016/j.ygeno.2019.10.011

33. Ahlqvist Е., Prasad R. B. Subtypes of type 2 diabetes determined from clinical parameters. Diabetes, 2020, vol. 69, no. 10, pp. 2086–2093. https://doi.org/10.2337/dbi20-0001

34. Tuomi T., Santoro N., Caprio S., Cai M., Weng J., Groop L. The many faces of diabetes: a disease with increasing heterogeneity. Lancet, 2014, vol. 383, no. 9922, pp. 1084–1094. https://doi.org/10.1016/S0140-6736(13)62219-9

35. Pearson E. R. Type 2 diabetes: a multifaceted disease. Diabetologia, 2019, vol. 62, pp. 1107–1112. https://doi.org/10.1007/s00125-019-4909-y

36. Leslie R. D., Palmer J., Schloot N. C., Lernmark A. Diabetes at the crossroads: relevance of disease classification to pathophysiology and treatment. Diabetologia, 2016, vol. 59, no. 1, pp. 13‒20. https://doi.org/10.1007/s00125-015-3789-z

37. Cleland S. J., Fisher B. M., Colhoun H. M., Sattar N., Petrie J. R. Insulin resistance in type 1 diabetes: what is ‘double diabetes’ and what are the risks? Diabetologia, 2013, vol. 56, pp. 1462–1470. https://doi.org/10.1007/s00125-013-2904-2

38. Hughes A. E., Hattersley T. A., Flanagan S. E., Freathy R. M. Two decades since the fetal insulin hypothesis: what have we learned from genetics? Diabetologia, 2021, vol. 64, no. 3, pp. 717‒726. https://doi.org/10.1007/s00125-021-05386-7

39. Wolosowicz M., Lukaszuk B., Chabowski A. The causes of insulin resistance in type 1 Diabetes Mellitus: is there a place for quaternary prevention? International Journal of Environmental Research and Public Health, 2020, vol. 17, no. 22, art. 8651. https://doi.org/10.3390/ijerph17228651

40. Franks P. W., Merino J. Gene-lifestyle interplay in type 2 diabetes. Current Opinion in Genetics and Development, 2018, vol. 50, no. 6, pp. 35–40. https://doi.org/10.1016/j.gde.2018.02.001

41. Mayoral L. P., Andrade G. M., Mayoral E. P., Huerta T. H., Canseco S. P., Rodal Canales F. J. [et al.]. Obesity subtypes, related biomarkers & heterogeneity. Indian Journal of Medical Research, 2020, vol. 151, no. 1, pp. 11‒21. https://doi.org/10.4103/ijmr.IJMR_1768_17