Association of gastrointestinal symptoms, metabolic parameters, quality of life, physical activity and rs11887534 of the ABCG8 gene in gallstone disease with t2dm women

Introduction. Gallstone disease (GSD) and type 2 diabetes mellitus (T2DM) are common diseases, but few studies evaluate the clinical course, risk factors, quality of life (QоL), and genetic markers in their comorbidity.
Aim. To identify possible associations of gastrointestinal symptoms and blood glucose (BG), HbA1c, insulin resistance indices (IR) – TyG, LAP, quality of life, physical activity (PA) and rs11887534 nucleotide sequence variants (NSV) of the ABCG8 gene in women with gallstone disease (GSD) combined with type 2 diabetes mellitus (T2DM).
Materials and methods. In an open, single-stage, single-center, observational, cross-sectional, uncontrolled case series study, 137 patients (women) with GSD were examined: group 1 consisted of 71 patients with GSD and T2DM, Group 2 – 66 patients with GSD without T2DM. The patients were comparable in age and BMI (p > 0.05). All patients receive clinical and biochemical examination: abdominal pain syndrome, dyspeptic symptoms, venous blood – GC, HbA1C; TyG, LAP indices; quality of life according to the SF-36 questionnaires and the specialized for GSD “Gallstone Impact Checklist” (GIC), PA – according to the “Short Questionnaire”, the NSV rs11887534 of the ABCG8 gene was studied using PCR.
Results. In patients of group 1, the frequency of abdominal pain syndrome and dyspeptic symptoms, BG indicators are higher than in patients of group 2. In group 1, we did not find an association of gastrointestinal symptoms with BG or HbA1c. In group 1, the TyG (5.09 [4.94; 5.28] and 102.00 [67.21; 130.68]) and LAP indices were higher than in group 2 (4.72 [4.52; 4.93] and 64.60 [36.16; 99.60]), respectively, p < 0.05. In group 1, the TyG and LAP indices were not associated with gastrointestinal symptoms. In group 1, the quality of life according to the SF-36 and GIC questionnaires was worse than in group 2 (p < 0.05); all scales of both questionnaires (except for the PH scale) demonstrated an inverse correlation between the quality of life and the presence and intensity of gastrointestinal symptoms. Patients in group 1 more often noted the absence of PA than in group 2 (71.8% and 40.9%, p < 0.001), less often – intense PA (12.7% and 34.8% in group 2, p < 0.05). In group 1, we did not find any relationships between the levels of PA and the presence of gastrointestinal symptoms. Among patients in group 1, the C allele (14.91%) and the CG genotype (29.82%) rs11887534 ABCG8 were less common than in group 2 (6.34 and 12.68%, p < 0.05). In group 1, we did not find any correlations of the rs11887534 VNP with gastrointestinal symptoms, BG, PA, or quality of life.
Conclusions. Among patients of group 1, an inverse correlation was demonstrated between the presence and intensity of gastrointestinal symptoms and quality of life on SF-36 and GIC. Among patients of group 1, we did not find an association of gastrointestinal symptoms with BG, HbA1c, TyG, LAP indices, PA levels or with VNP rs11887534.

1. Grigor’eva IN, Ragino YuI, Schakhtschneider EV, Ryabikov AN, Verevkin EG,Voevoda MI. Gallstone disease: results of our 20-year studies (Part 1: epidemiology, lipids of blood serum and bile, apolipoprotein E polymorphism). Dnevnik Kazanskoy Meditsinskoy Shkoly. 2016;(2):18–23. (In Russ.) Available at: https://elibrary.ru/wncxch.

2. Adiels M, Olofsson SO, Taskinen MR, Borén J. Diabetic dyslipidaemia. Curr Opin Lipidol. 2006;17(3):238–46. https://doi.org/10.1097/01.mol.0000226115.97436.c0.

3. Song ST, Shi J, Wang XH, Guo YB, Hu ФФ, Zhu F et al. Prevalence and risk factors for gallstone disease: A population-based cross-sectional study. J Dig Dis. 2020;21(4):237–245. https://doi.org/10.1111/1751-2980.12857.

4. Tereshchenko IV, Kamenskikh YaA, Kaiushev PE. The concurrence of diabetes mellitus and gallstone disease. Terapevticheskii Arkhiv. 2015;87(10):105–109. (In Russ.) https://doi.org/10.17116/terarkh20158710105-109.

5. Wang F, Wang J, Li Y, Yuan J, Yao P, Wei S et al. Gallstone Disease and Type 2 Diabetes Risk: A Mendelian Randomization Study. Hepatology. 2019;70(2):610–620. https://doi.org/10.1002/hep.30403.

6. Grigor’eva IN, Notova TE, Suvorova TS, Chikinev YuV, Tolstih GN, Nepomnyashchikh DL et al. Characteristics of arterial hypertension in patients with cholelithiasis combined with type 2 diabetes mellitus. Ateroscleroz. 2023;19(3):203–205. (In Russ.) https://doi.org/10.52727/2078-256X-2023-19-3-203-205.

7. Grigor’eva IN, Notova TE. Apolypoprotein E gene polymorphism, gallstone disease, diabetes 2 type and lipid metabolism disorders. Ateroscleroz. 2023;19(1):47–56. (In Russ.) https://doi.org/10.52727/2078-256X-2023-19-1-47-56.

8. Zein AA, Kaur R, Hussein TOK, Graf GA, Lee JY. ABCG5/G8: a structural view to pathophysiology of the hepatobiliary cholesterol secretion. Biochem Soc Trans. 2019;47(5):1259–1268. https://doi.org/10.1042/BST20190130.

9. Wittenburg H, Lyons MA, Li R, Kurtz U, Mössner J, Churchill GA et al. Association of a lithogenic Abcg5/Abcg8 allele on Chromosome 17 (Lith9) with cholesterol gallstone formation in PERA/EiJ mice. Mamm Genome. 2005;16(7):495–504. https://doi.org/10.1007/s00335-005-000.

10. Krawczyk M, Niewiadomska O, Jankowska I, Jankowski K, Więckowski S, Lebensztejn D et al. Common variant p.D19H of the hepatobiliary sterol transporter ABCG8 increases the risk of gallstones in children. Liver Int. 2022;42(7):1585–1592. https://doi.org/10.1111/liv.15186.

11. Teng M-S, Yeh K-H, Hsu L-A, Chou H-H, Er L-K, Wu S, Ko Y-L. Differential Effects of ABCG5/G8 Gene Region Variants on Lipid Profile, Blood Pressure Status, and Gallstone Disease History in Taiwan. Genes. 2023;14(3):754. https://doi.org/10.3390/genes14030754.

12. Siddapuram SP, Mahurkar S, Duvvuru NR, Mitnala S, Guduru VR, Rebala P, Mansard MJ. Hepatic cholesterol transporter ABCG8 polymorphisms in gallstone disease in an Indian population. J Gastroenterol Hepatol. 2010;25(6):1093–1098. https://doi.org/10.1111/j.1440-1746.2010.06309.x.

13. Lotta LA, Sharp SJ, Burgess S, Perry JRB, Stewart ID, Willems SM et al. Association Between Low-Density Lipoprotein Cholesterol-Lowering Genetic Variants and Risk of Type 2 Diabetes: A Meta-analysis. JAMA. 2016;316(13):1383–1391. https://doi.org/10.1001/jama.2016.14568.

14. Cederberg H, Gylling H, Miettinen TA, Paananen J, Vangipurapu J, Pihlajamäki J et al. Non-cholesterol sterol levels predict hyperglycemia and conversion to type 2 diabetes in Finnish men. PLoS ONE. 2013;8(6):e67406. https://doi.org/10.1371/journal.pone.0067406.

15. Grigor’eva IN, Notova TE, Tov NL. Apolipoprotein E gene polymorphism, blood lipids and clinical-biochemical values in gallstone disease with T2DM women. Ateroscleroz. 2024;20(4):421–429. (In Russ.) https://doi.org/10.52727/2078-256X-2024-20-4-421-429.

16. Dedov II, Shestakova MV, Mayorov AYu, Mokrysheva NG, Vikulova OK, Galstyan GR et al. Standards of specialized diabetes care. Diabetes Mellitus. 2021;24(1S):1–148. (In Russ.) https://doi.org/10.14341/DM12802.

17. Salazar J, Bermúdez V, Calvo M, Olivar LC, Luzardo E, Navarro C et al. Optimal cutoff for the evaluation of insulin resistance through triglyceride-glucose index: A cross-sectional study in a Venezuelan population. F1000Res. 2017;6:1337. https://doi.org/10.12688/f1000research.12170.3.

18. Kaneva AM, Potolitsyna NN, Bojko ER. Range of values for lipid accumulation product (LAP) in healthy residents of the European north of Russia. Obesity and Metabolism. 2020;17(2):179–186. (In Russ.) https://doi.org/10.14341/omet11278.

19. Mazidi M, Kengne AP, Katsiki N, Mikhailidis DP, Banach M. Lipid accumulation product and triglycerides/glucose index are useful predictors of insulin resistance. J Diabetes Complicat. 2018;32(3):266–270. https://doi.org/10.1016/j.jdiacomp.2017.10.007.

20. Grigor’eva IN, Efimova OV, Tov NL, Suvorova TS, Nepomnyashchikh DL. Metabolic Risk Factors and Their Impact on Quality of Life in Patients with Pancreatic Cancer, Acute or Exacerbated Chronic Pancreatitis. Russian Journal of Gastroenterology, Hepatology, Coloproctology. 2023;33(3):49–60. (In Russ.) https://doi.org/10.22416/1382-4376-2023-33-3-49-60.

21. Russell ML, Preshaw RM, Brant RF, Bultz BD, Page SA. Diseasespecific quality of life: the Gallstone Impact Checklist. Clin Invest Med. 1996;19(6):453–460. Available at: https://pubmed.ncbi.nlm.nih.gov/8959355.

22. Драпкина ОМ, Дроздова ЛЮ, Лищенко ОВ. Методические рекомендации по повышению физической активности. Воронеж: ООО «Канцтовары»; 2019. 54 с. Режим доступа: https://www.mgpu.ru/wp-content/uploads/2020/11/Fizicheskaya-aktivnost.-2019.pdf.

23. Chavez-Tapia NC, Kinney-Novelo IM, Sifuentes-Rentería SE, TorresZavala M, Castro-Gastelum G, Sánchez-Lara K et al. Association between cholecystectomy for gallstone disease and risk factors for cardiovascular disease. Ann Hepatol. 2012;11(1):85–89. https://doi.org/10.1016/S1665-2681(19)31490-5.

24. Li H, Jiang G, Yu W, Luo J, Li S, Xie L et al. J Gastroenterol Hepatol. 2025;40(2):404–412. https://doi.org/10.1111/jgh.16828.

25. Aksoy E, Ergenç Z, Ocak Ök, Ergenç H. Triglyceride-Glucose Index is a Reliable Predictor of Metabolic Disorder in Gallstones. Bezmialem Science. 2024;12(3):363–367. https://doi.org/10.14235/bas.galenos.2024.43043.

26. Wang H, Feng X, Huang Q, Zheng X. Association between lipid accumulation products and gallstones: an analysis of the National Health and Nutrition Examination Survey 2017–2020. BMC Gastroenterol. 2024;24(1):311. https://doi.org/10.1186/s12876-024-03410-9.

27. Li X, Wang J, Leng K. Lipid accumulation product and gallstone risk in US adults: A cross-sectional analysis of NHANES 2017–2020 data. PLoS ONE. 2024;19(12):e0315235. https://doi.org/10.1371/journal.pone.0315235.

28. Ayundini G, Astrella C, Tahapary D, Soewondo P. A Systematic Review on the Association between Lipid Accumulation Product Index and Type 2 Diabetes Mellitus. J ASEAN Fed Endocr Soc. 2019;34(1):16–20. https://doi.org/10.15605/jafes.034.01.04.

29. Ahn N, Baumeister SE, Amann U, Rathmann W, Peters A, Huth C et al. Visceral adiposity index (VAI), lipid accumulation product (LAP), and product of triglycerides and glucose (TyG) to discriminate prediabetes and diabetes. Sci Rep. 2019;9(1):9693. https://doi.org/10.1038/s41598-019-46187-8.

30. Grünhage F, Acalovschi M, Tirziu S, Walier M, Wienker TF, Ciocan A et al. Increased gallstone risk in humans conferred by common variant of hepatic ATP-binding cassette transporter for cholesterol. Hepatology. 2007;46(3):793–801. https://doi.org/10.1002/hep.21847.

31. Chauhan T, Mittal RD, Mittal B. Association of Common Single Nucleotide Polymorphisms of Candidate Genes with Gallstone Disease: A MetaAnalysis. Indian J Clin Biochem. 2020;35(3):290–311. https://doi.org/10.1007/s12291-019-00832-1.

32. Abed E, Jarrar Y, Alhawari H, Abdullah S, Zihlif M. The association of cytochrome 7A1 and ATP-binding cassette G8 genotypes with type 2 diabetes among Jordanian patients. Drug Metab Pers Ther. 2021;37(2):149–154. https://doi.org/10.1515/dmpt-2021-0164.