A Cohort Study of Gallstones and Incidence of Diabetes in a Korean Population

Article information

Korean J Health Promot. 2015;15(4):217-224

Publication date (electronic) : 2015 December 19

doi : https://doi.org/10.15384/kjhp.2015.15.4.217

Department of Occupational and Environmental Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University, School of Medicine, Seoul, Korea

Corresponding author：Byung Seong Suh, MD, PhD Department of Occupational and Environmental Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University, School of Medicine, 29 Saemunan-ro, Jongno-gu, Seoul 03181, Korea Tel: +82-2-2001-1863, Fax: +82-2-2001-2748 E-mail: byungseong.suh@samsung.com

Received 2015 October 27; Accepted 2015 November 13.

Abstract

Background

Gallstones are associated with insulin resistance but the relation between gallstone disease and the risk of developing diabetes mellitus (DM) is unclear. We examined if gallstones are associated with an increased incidence of DM compared to no gallstones.

Methods

A cohort study was performed in 41,518 Koreans aged 30-59 without DM, who underwent a health checkup during 2005-2006 and then were followed annually or biennially until December 2011. Throughout the study period, gallstones were defined as ultrasound-documented gallstones by standard criteria and DM was defined as fasting serum glucose ≥7.0 mmol l^-1, A1c ≥6.5%, or use of DM medications.

Results

During 192999 person-years of follow-up, 2,232 participants developed DM (incidence rate 11.6 per 1,000 person-years). The incidence of DM was higher in subjects with gallstones or cholecystectomy than in those without gallstones for women but not for men. In multivariate-adjusted models, the hazard ratios (95% confidence intervals) for DM comparing gallstones and cholecystectomy vs. no gallstones were 0.95 (0.63-1.42) and 1.13 (0.53-2.38), respectively, in men and 1.64 (1.13-2.40) and 2.04 (1.01-4.11), respectively, in women. These associations did not differ significantly between relevant subgroups.

Conclusions

In an apparently healthy population, gallstones were independently and modestly associated with increased incidence for DM in women but not in men. Women with gallstones should be provided with adequate measures for preventing DM.

Keywords: Gallstones; Diabetes mellitus; Insulin resistance; Cohort study; Incidence

Figure 1.

Flow diagram for the selection of study subjects.

Table 1.

Baseline characteristics of study population according to gallstone diseases (GSD)

Table 2.

Development of type 2 diabetes according to gallstone diseases (GSD)

References

1. Shaffer EA. Epidemiology and risk factors for gallstone disease: has the paradigm changed in the 21st century? Curr Gastroen-terol Rep 2005;7(2):132–40.

2. Everhart JE, Ruhl CE. Burden of digestive diseases in the United States Part III: Liver, biliary tract, and pancreas. Gastroenterology 2009;136(4):1134–44.

3. Mendez-Sanchez N, Bahena-Aponte J, Chavez-Tapia NC, Motola-Kuba D, Sanchez-Lara K, Ponciano-Radriguez G, et al. Strong association between gallstones and cardiovascular disease. Am J Gastroenterol 2005;100(4):827–30.

4. Grimaldi CH, Nelson RG, Pettitt DJ, Sampliner RE, Bennett PH, Knowler WC. Increased mortality with gallstone disease: results of a 20-year population-based survey in Pima Indians. Ann Intern Med 1993;118(3):185–90.

5. Ruhl CE, Everhart JE. Gallstone disease is associated with increased mortality in the United States. Gastroenterology 2011;140(2):508–16.

6. Biddinger SB, Haas JT, Yu BB, Bezy O, Jing E, Zhang W, et al. Hepatic insulin resistance directly promotes formation of cholesterol gallstones. Nat Med 2008;14(7):778–82.

7. Nervi F, Miquel JF, Alvarez M, Ferreccio C, García-Zattera MJ, González R, et al. Gallbladder disease is associated with insulin resistance in a high risk Hispanic population. J Hepatol 2006;45(2):299–305.

8. Chang Y, Sung E, Ryu S, Park YW, Jang YM, Park M. Insulin resistance is associated with gallstones even in non-obese, nondiabetic Korean men. J Korean Med Sci 2008;23(4):644–50.

9. Hendel HW, Hojgaard L, Andersen T, Pedersen BH, Paloheimo LI, Rehfeld JF, et al. Fasting gall bladder volume and lith- ogenicity in relation to glucose tolerance, total and intra-abdominal fat masses in obese non-diabetic subjects. Int J Obes Relat Metab Disord 1998;22(4):294–302.

10. Weikert C, Weikert S, Schulze MB, Pischon T, Fritsche A, Bergmann MM, et al. Presence of gallstones or kidney stones and risk of type 2 diabetes. Am J Epidemiol 2010;171(4):447–54.

11. Portincasa P, Moschetta A, Palasciano G. Cholesterol gallstone disease. Lancet 2006;368(9531):230–9.

12. Stinton LM, Shaffer EA. Epidemiology of gallbladder disease: cholelithiasis and cancer. Gut Liver 2012;6(2):172–87.

13. Everhart JE, Khare M, Hill M, Maurer KR. Prevalence and ethnic differences in gallbladder disease in the United States. Gastroenterology 1999;117(3):632–9.

14. Mathiesen UL, Franzen LE, Aselius H, Resjo M, Jacobsson L, Foberg U, et al. Increased liver echogenicity at ultrasound examination reflects degree of steatosis but not of fibrosis in asymptomatic patients with mild/moderate abnormalities of liver transaminases. Dig Liver Dis 2002;34(7):516–22.

15. Ryu S, Chang Y, Kim SG, Cho J, Guallar E. Serum uric acid levels predict incident nonalcoholic fatty liver disease in healthy Korean men. Metabolism 2011;60(6):860–6.

16. Royston P, Parmar MK. Flexible parametric proportional-hazards and proportional-odds models for censored survival data, with application to prognostic modelling and estimation of treatment effects. Stat Med 2002;21(15):2175–97.

17. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985;28(7):412–9.

18. Ruhl CE, Everhart JE. Association of diabetes, serum insulin, and C-peptide with gallbladder disease. Hepatology 2000;31(2):299–303.

19. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 2010;33(Suppl 1):S62–9.

20. Schafmayer C, Hartleb J, Tepel J, Albers S, Freitag S, Volzke H, et al. Predictors of gallstone composition in 1025 symptomatic gallstones from Northern Germany. BMC Gastroenterol 2006;6:36.

21. Stinton LM, Myers RP, Shaffer EA. Epidemiology of gallstones. Gastroenterol Clin North Am 2010;39(2):157–69. vii.

22. Ranelletti FO, Piantelli M, Farinon AM, Zanella E, Capelli A. Estrogen and progesterone receptors in the gallbladders from patients with gallstones. Hepatology 1991;14(4 Pt 1):608–12.

23. Bennion LJ, Grundy SM. Effects of obesity and caloric intake on biliary lipid metabolism in man. J Clin Invest 1975;56(4):996–1011.

24. Wang SN, Yeh YT, Yu ML, Wang CL, Lee KT. Serum adiponectin levels in cholesterol and pigment cholelithiasis. Br J Surg 2006;93(8):981–6.

25. Yoo EH, Lee SY. The prevalence and risk factors for gallstone disease. Clin Chem Lab Med 2009;47(7):795–807.

26. Shaffer EA. Gallstone disease: Epidemiology of gallbladder stone disease. Best Pract Res Clin Gastroenterol 2006;20(6):981–96.

27. Twisk J, Hoekman MF, Lehmann EM, Meijer P, Mager WH, Princen HM. Insulin suppresses bile acid synthesis in cultured rat hepatocytes by down-regulation of cholesterol 7 alpha-hydroxylase and sterol 27-hydroxylase gene transcription. Hepatology 1995;21(2):501–10.

28. Misciagna G, Guerra V, Di Leo A, Correale M, Trevisan M. Insulin and gall stones: a population case control study in southern Italy. Gut 2000;47(1):144–7.

29. Bonora E, Tuomilehto J. The pros and cons of diagnosing diabetes with A1C. Diabetes Care 2011;34(Suppl 2):S184–90.

30. Huffman JL, Schenker S. Acute acalculous cholecystitis: a review. Clin Gastroenterol Hepatol 2010;8(1):15–22.

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Figure 1.

Flow diagram for the selection of study subjects.

Table 1.

Baseline characteristics of study population according to gallstone diseases (GSD)

Characteristics	Men		P value	Women		P value^d
Characteristics	No GSD	GSD	P value	No GSD	GSD	P value^d
Number	26,057	498		14,587	376
Age, y^a	37.0 (4.6)	38.3 (4.9)	＜0.001	36.4 (4.2)	37.5 (4.4)	＜0.001
BMI, kg m^-2a	24.3 (2.8)	24.9 (3.1)	＜0.001	21.7 (2.7)	22.8 (3.3)	＜0.001
Current smoke, %	48.1	45.0	0.171	2.2	2.7	0.505
Alcohol intake, %^c	43.1	37.6	0.014	9.4	9.6	0.930
Regular exercise, %^c	45.9	47.2	0.554	35.3	39.1	0.125
Obesity, %	38.9	45.8	0.002	11.0	23.9	＜0.001
Hypertension, %	11.9	14.1	0.150	2.7	5.1	0.005
Metabolic syndrome, %	17.7	21.7	0.021	3.9	8.0	＜0.001
Fatty liver on ultrasound,%	37.8	44.8	0.001	6.8	15.7	＜0.001
Systolic BP, mmHg^a	115.9 (12.4)	116.4 (12.0)	0.446	105.9 (11.2)	108.9 (11.9)	＜0.001
Diastolic BP, mmHg^a	75.3 (8.7)	76.4 (8.7)	0.006	67.3 (7.9)	69.1 (8.3)	＜0.001
Glucose, mmol l^-1a	5.2 (0.4)	5.3 (0.5)	0.028	5.0 (0.4)	5.1 (0.4)	＜0.001
HbA1c, %	5.3 (0.3)	5.4 (0.3)	0.880	5.4 (0.3)	5.4 (0.3)	0.283
Total cholesterol, mmol l^-1a	5.0 (0.8)	4.9 (0.9)	0.159	4.6 (0.8)	4.6 (0.8)	0.733
LDL-C, mmol l^-1a	2.9 (0.7)	2.9 (0.8)	0.415	2.5 (6.4)	2.6 (0.7)	0.283
HDL-C, mmol l^-1a	1.3 (0.3)	1.3 (0.2)	0.001	1.5 (0.3)	1.5 (0.3)	0.004
Uric acid, μmol l^-1a	370.0 (70.2)	371.2 (71.4)	0.758	245.7 (49.4)	249.8 (48.8)	0.137
Triglycerides, mmol l^-1b	1.4 (1.0-2.0)	1.4 (1.0-1.9)	0.271	0.9 (0.7-1.2)	0.9 (0.7-1.3)	0.027
AST, U l^-1b	24 (20-29)	25 (20-29)	0.310	20 (17-23)	20 (17-24)	0.808
ALT, U l^-1b	26 (19-37)	27 (19-39)	0.011	16 (13-20)	16 (13-21)	0.622
GGT, U l^-1b	27 (18-44)	29.5 (20-55)	0.049	11 (8-15)	12 (9-17)	＜0.001
hsCRP, mg l^-1b	0.50 (0.30-1.10)	0.60 (0.30-1.40)	0.007	0.30 (0.20-0.70)	0.40 (0.20-1.00)	0.903
HOMA-IR^b	1.98 (1.58-2.55)	2.15 (1.67-2.80)	＜0.001	1.79 (1.45-2.28)	1.95 (1.57-2.63)	＜0.001

Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; BP, blood pressure; GGT, 약어풀이; HDL-C, high-density lipoprotein-cholesterol; hsCRP, high sensitivity C-reactive protein; HOMA-IR, homeostasis model assessment of insulin resistance. LDL-C, low-density lipoprotein cholesterol. Data are

Mean (standard deviation),

Median (interquartile range), or percentage.

≥ once time per week.

-test and student t-test were used.

Table 2.

Development of type 2 diabetes according to gallstone diseases (GSD)

	Number	Person-years	Incident case	Incidence density (1000 person-year)	Age-adjusted HR (95% CI)	Multivariate HR^a (95% CI)		HR (95% CI)^b in the model using time-dependent variables
	Number	Person-years	Incident case	Incidence density (1000 person-year)	Age-adjusted HR (95% CI)	Model 1	Model 2	HR (95% CI)^b in the model using time-dependent variables
Men	26,555
No GSD	26,057	122,403.3	1,343	11.0	1.00 (reference)	1.00 (reference)	1.00 (reference)	1.00 (reference)
GSD	498	2,377.1	31	13.0	1.10 (0.77-1.58)	0.97 (0.68-1.38)	0.98 (0.69-1.40)	0.88 (0.63-1.23)
Gallstone	406	1,945.6	24	12.3	1.06 (0.71-1.59)	0.96 (0.64-1.44)	0.95 (0.63-1.42)	0.88 (0.60-1.29)
Cholecystectomy	92	431.5	7	16.2	1.26 (0.60-2.65)	0.98 (0.46-2.07)	1.13 (0.53-2.38)	0.87 (0.43-1.77)
P for trend					0.520	0.866	0.975	0.456
Women	14,963
No GSD	14,587	66,578.6	821	12.3	1.00 (reference)	1.00 (reference)	1.00 (reference)	1.00 (reference)
GSD	376	1,640.3	37	22.6	1.88 (1.35-2.62)	1.66 (1.14-2.42)	1.74 (1.24-2.43)	1.73 (1.24-2.42)
Gallstone	300	1,312.2	29	22.1	1.83 (1.26-2.64)	1.66 (1.14-2.42)	1.64 (1.13-2.40)	1.67 (1.14-2.44)
Cholecystectomy	76	328.1	8	24.4	2.14 (1.06-4.29)	2.08 (1.03-4.18)	2.04 (1.01-4.11)	2.00 (1.003-3.97)
P for trend					＜0.001	0.001	0.001	0.001
P for interaction by gender					0.124	0.202	0.236	0.202

Abbreviations: CI, confidence intervals; HR, hazard ratio.

Estimated from Parametric Cox models

Model 1: adjusted for age, smoking status, alcohol intake regular exercise, and BMI; model 2: model 1 plus adjusted for total cholesterol, triglyceride, HDL-cholesterol, and HOMA-IR.

Estimated from a pooled logistic regression models with GSD as a time-dependent categorical variable adjusted for other covariates (smoking status, alcohol intake, regular exercise, triglyceride, HDL-cholesterol, and HOMA-IR over time as time-dependent variables).