Gallbladder Disease and Risk of Type 2 Diabetes in Postmenopausal Women

A Women's Health Initiative Study

Ako Adams Ako; Yvonne L. Michael; Lucy F. Robinson; Jean Wactawski-Wende; Aladdin H. Shadyab; Lorena Garcia; Bede N. Nriagu; Nazmus Saquib; Rami Nassir; Simin Liu; Robert B. Wallace


Am J Epidemiol. 2022;191(8):1374-1382. 

In This Article

Abstract and Introduction


Studies have suggested that adults with gallbladder disease have increased risk of type 2 diabetes. This prospective cohort study assessed the risk of type 2 diabetes in postmenopausal women with gallbladder disease. Data from women enrolled in the Women's Health Initiative from 1993 to 2005, aged 50–79 years (mean = 63.2; standard deviation, 7.2), were analyzed. Cox proportional hazards regression models were used to estimate the risk of type 2 diabetes associated with gallbladder disease. There were 8,896 new cases of type 2 diabetes after 1,025,486 person-years of follow-up. Gallbladder disease was significantly associated with type 2 diabetes (hazard ratio = 1.52; 95% confidence interval (CI): 1.38,1.67). The observed risk of type 2 diabetes in women with both gallbladder disease and central obesity was 37% higher than expected (relative excess risk due to interaction = 0.37, 95% CI: 0.11,0.63) on the additive scale. The hazard ratios for type 2 diabetes associated with gallbladder disease were 1.25 (95% CI: 1.19,1.32) and 1.48 (95% CI: 1.34,1.63) in women with and without central obesity, respectively, on the multiplicative scale. Results of this study support further studies to determine whether interventions in older women with gallbladder disease would reduce type 2 diabetes risk, especially among those with central obesity. Future research should examine the pathophysiological basis of the association between gallbladder disease and type 2 diabetes.


In the United States, an estimated 34.1 million adults had diabetes in 2018—13% of the adult population.[1] In the same year, 1.5 million new cases of diabetes were diagnosed among adults, with higher incidence rates recorded among individuals aged 45 years or older than among those aged 18–44 years.[1] The total cost (including direct medical expenditures and costs due to loss of productivity) of diagnosed diabetes was estimated to have climbed from $245 billion in 2012 to $327 billion in 2017.[2] Care for people with diabetes accounted for 1 out of every 4 dollars spent on health care in the United States.[2]

About 20 to 25 million persons in the United States have gallstones—about 10% to 15% of the adult population.[3,4] Gallstones are more prevalent among women,[4] and incidence increases with age, rising markedly after age 40.[3] Up to 80% of patients with gallstones remain asymptomatic and are likely to go undiagnosed.[5] Symptomatic gallstones—called gallstone disease or gallbladder disease—present as episodes of abdominal pain (biliary colic) and can be complicated by life-threatening inflammation of the gallbladder, bile ducts, and pancreas.[6,7] Cholecystectomy, the mainstay of treatment for gallbladder disease, is one of the most commonly performed elective surgical procedures in the United States, with about 403,000 cases performed in 2007.[8]

While much of prior research has focused on the increased risk of gallstones among people with diabetes,[9] emerging evidence suggests that this association is bidirectional. Recent prospective cohort studies have observed an increased risk of type 2 diabetes in persons with self-reported or ultrasound-diagnosed gallstones.[10–12] Potential pathophysiological mechanisms linking gallbladder disease to type 2 diabetes include gallstone-associated chronic inflammation of the pancreas[13–15] and the alteration of gut microbial composition (in favor of pro-inflammatory bacterial species, for example) that may be seen in lithogenic states.[16,17]

Furthermore, while one prospective study[12] found no significant difference in the risk of type 2 diabetes in persons with gallstones who had had a cholecystectomy, compared with persons with gallstones without cholecystectomy, a cross-sectional study[18] found that metabolic syndrome—a component of which is impaired glucose tolerance[19]—was significantly associated with cholecystectomy but not gallstones without cholecystectomy. The effect of cholecystectomy on type 2 diabetes risk in persons with gallbladder disease has not been sufficiently investigated.

Prior research[10,11] suggests interaction between gallbladder disease and central obesity on type 2 diabetes risk. The nature of this interaction remains to be fully clarified, however, as only multiplicative and not additive (biological interaction) was explored. Additionally, when men and women were studied separately, a significant association between gallstones and diabetes was found only in women.[11,12] In women, estrogen therapy has been linked to the formation of gallstones[20,21] and to decreased incidence of type 2 diabetes;[22–24] however, no published studies have, to our knowledge, examined the interaction between hormone therapy and gallbladder disease with respect to type 2 diabetes.

To explore previously unexamined associations and to further investigate the findings of previous studies, we used data from the Women's Health Initiative (WHI) clinical trial and observational study cohorts to examine the relationship between gallbladder disease and type 2 diabetes and assess potential multiplicative and additive interaction effects.