Diabetes Linked to Increased Kidney Cancer Risk, But Only in Slim

Pam Harrison

August 13, 2020

Diabetes increases the risk of kidney cancer in postmenopausal women, but paradoxically, only in nonobese women, as defined by body mass index (BMI) and waist circumference, according to a new analysis from the Iowa Women's Health Study (IWHS).

"Many studies have linked a history of diabetes to the increased risk of kidney cancer [but] it is unclear whether diabetes is a risk factor for kidney cancer independent of other risk factors such as obesity and hypertension," write Shuo Wang, PhD, of the School of Public Health, University of Minnesota, Minneapolis, and colleagues.

"[While we found that] an association between diabetes and kidney cancer was not statistically significant among the whole cohort...a positive, statistically significant association was observed among nonobese women (BMI < 30 kg/m2) or waist circumference < 34.6 inches (87.9 cm)," the authors suggest.

And although they acknowledge "these findings should be validated in larger or pooled prospective studies," they stress that "patients with new-onset diabetes may require more thorough surveillance for cancer including kidney cancer."

The results were published online August 11 in Maturitas.

Associated Between Kidney Cancer and Diabetes in 3 Different Models

The IWHS was launched in 1986 when a baseline questionnaire was completed by a total of 41,836 women.

Subsequent questionnaires were mailed in 1987, 1989, 1992, 1997, and 2004, returned by increasingly fewer respondents over the years.

The cohort for the current analysis included 36,975 women, mean age of 61.7 years, 6.4% of whom reported a diabetes diagnosis at baseline.

"At baseline, diabetes status was determined for each participant by one of two ways," the researchers explain.

Women were first asked if a physician had ever told them they had diabetes and were also asked whether they took pills for diabetes and/or insulin. A tape measure was included with the baseline questionnaire and women were asked to have their waist measured in a precise manner with a high degree of accuracy and reliability.

Between 1986 and 2011, investigators identified 257 cases of kidney cancer in their cohort.

They then examined the association between baseline and time-dependent diabetes and kidney cancer risk using three models, the first adjusted only for age, the second adjusted for age and BMI tertile, and the third was a multivariable-adjusted model.

The adjusted variables in the third model included age and indices of obesity, as reflected by BMI and waist-to-hip ratio (WHR), as well as physical activity levels, pack-years of smoking, total caloric intake, presence of hypertension, diuretic use, and alcohol intake.

Cutoffs used to define obesity included a BMI of 30 kg/m2, a WHR of 0.85, and a waist circumference of 34.6 inches.

Researchers also analyzed the association between duration of diabetes and kidney cancer risk using a nested-case control design within the IWHS cohort.

Over the course of follow-up, an additional 8.5% of women reported a new diagnosis of diabetes.

"Several characteristics were statistically significantly associated with kidney cancer risk," the authors note (Table 1).

"And time-dependent diabetes was associated with an increased risk of kidney cancer in models 1 and 2," they added.

Table 1. Increased Kidney Cancer Risk, Baseline Characteristics (Models 1, 2)

Baseline characteristic Kidney cancer risk P trend
BMI ≥ 30 vs < 25 kg/m2 +129% <0.01
WHR: 3rd vs lowest quartile
WHR: 4th vs lowest quartile
Hypertension vs no hypertension +80%
Current diuretic use vs nonuser +53% 0.01
Drinker* vs nondrinker Half as likely
*4 grams/day of alcohol
BMI = body mass index; WHR = waist-hip ratio

Multivariable Model: No Significant Link Between Obesity, Kidney Cancer

However, when investigators adjusted the association between time-dependent diabetes and kidney cancer risk in model 3, associations seen in models 1 and 2 were attenuated and no longer significant, the authors underscore.

In contrast, the risk of kidney cancer increased for women with diabetes.

Compared to women without diabetes, women with diabetes and a BMI < 30 kg/m2 had an 82% higher risk of kidney cancer, and those with diabetes and a waist circumference < 34.6 inches had an over twofold greater risk (Table 2).

Table 2. Interaction Between Diabetes, Weight in Kidney Ca Risk (Model 3)

Variable No diabetes, HR Diabetes, HR
BMI < 30 kg/m2 1.00 (reference) 1.82
BMI ≥ 30 kg/m2 1.00  1.24
WC < 34.6 inches 1.00  2.18
WC ≥ 34.6 inches 1.00  1.32
BMI = body mass index; HR = hazard ratio; WC = waist circumference

As the investigators point out, there are a number of possible explanations for these seemingly paradoxical findings.

Type 2 diabetes is associated with high blood glucose, which itself may increase uncontrolled cell growth and division.

This may help explain why investigators saw a stronger association with kidney cancer among those with a shorter diabetes duration, that is, "those who are more likely to have uncontrolled diabetes," they explain.

Investigators also point out: "Patients with type 2 diabetes (the majority of diabetes cases in our study) have high serum levels of insulin that promote the secretion and production of insulin-like growth factor 1 (IGF-1)."

IGF-1 is important in the regulation of cell proliferation and differentiation, and thus may promote the formation and growth of cancer, they add.

But there is a "nonlinear relationship between BMI and IGF-1 levels," the investigators observe. For example, one study found that IGF-1 concentrations in women increased as BMI increased up to a maximum of 26 kg/m2, after which IGF-1 concentrations decreased among women with higher BMIs.

"In line with this finding, we found an association among nonobese women...even in the fully adjusted model, but observed no association between diabetes and kidney cancer among obese women...which could be explained by lower levels of IGF-1 among obese women."

Previous epidemiologic findings from the IWHS did find evidence of an association between weight-related measures and kidney cancer risk; however, those with a BMI in the top quartile had an almost 2.5-fold greater risk of kidney cancer than those in the lowest BMI quartile.

The study was funded by the National Cancer Institute. The authors have reported no relevant financial relationships.

Maturitas. Published online August 11, 2020. Abstract

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