Blood glucose and cancer

[Guest guest]

Hi All,

It seems that our lower generally but within the normal

range glucose levels protect us from cancers.

Now, a new report, its review and its summary on our

blood sugar level and our risk of cancers has been

presented in the latest issue of JAMA.

BMI had no effect on the risk of all cancers. The

subjects had relatively low BMIs.

Please see the below.

No. 2, January 12, 2005

This Week in JAMA

JAMA. 2005;293:135.

Fasting Serum Glucose and Cancer Risk

Several studies suggest an association between diabetes and

increased cancer risk. To further investigate this association, Jee

and colleagues (SEE ARTICLE) analyzed data on fasting serum glucose,

diabetes, and incident cancers and cancer deaths from a prospective

cohort study of nearly 1.3 million Korean adults. They found dose-

response relationships between fasting serum glucose levels and rates

of overall cancer mortality and cancer incidence. Mortality and

incidence risks were higher for persons with diabetes compared with

persons without, and adjustment for body mass index did not alter the

findings. In an editorial, Cooney and Gruber (SEE ARTICLE) discuss

how hyperglycemia and diabetes may influence cancer incidence and

mortality and the public health significance of this association.

Editorials

Hyperglycemia, Obesity, and Cancer Risks on the Horizon

Kathleen A. Cooney; B. Gruber

JAMA. 2005;293:235-236.

The prevalence of diabetes mellitus has increased substantially

over the past several decades, in part because of the growing

epidemic of obesity.1 Approximately 8% of the US population has

diabetes,2 with more than 90% of cases classified as type 2 diabetes,

and with insulin resistance as the major underlying pathophysiology.

Much of the emphasis in diabetes management focuses on reducing end-

organ complications, including retinopathy, neuropathy, nephropathy,

and macrovascular disease. Several recent epidemiological studies,

including the report by Jee et al3 in this issue of JAMA, have also

shown an association between diabetes and several common cancers,

including pancreas and colon cancer. How important is this effect and

what are the public health implications?

The prospective cohort study of nearly 1.3 million people

conducted by Jee et al3 took advantage of data collected by the

insurance provider for all government employees, teachers, and their

dependents in Korea. A cohort of individuals was enrolled over 4

years at the time of required biennial medical examinations and was

then followed up for as long as a decade. Outcomes were measured

through national registration of death certificates, a national

cancer registry, and hospitalization records. The main finding was

that elevated fasting serum glucose levels were associated with a 27%

increase in cancer mortality among men and a 31% increase among

women. A dose-response trend was evident, with higher fasting glucose

levels associated with higher cancer mortality rates. Cancer

incidence rates followed similar patterns.

One of the unique aspects of this study3 is that Korea has a low

rate of obesity in the population. The average body mass index (BMI)

in the study population was 23.2, with approximately one fourth of

the population considered overweight (defined as BMI 25.0). By

comparison, recent National Health and Nutrition Examination Survey

data demonstrate that approximately 65% of US men and women are

overweight or obese, nearly one third are obese (defined as BMI 30),

and 5% are extremely obese (defined as BMI 40).4 If current trends

continue, 40% of the US population will be classified as obese in

2010.5 In the United States, diabetes is tightly linked to obesity,

and the proportion of individuals with diabetes who meet the

definitions of overweight and obese is higher than in the general

population (79% and 46%, respectively).6 For the first time, this

Korean study has made significant progress toward separating the

specific effects of elevated blood glucose from the compendium of

other metabolic abnormalities observed in obesity. The investigators

were able to demonstrate a direct relationship between fasting serum

glucose levels and cancer mortality across all BMI groups (<20, 20 to

<23, and >23).

A wealth of epidemiological data supports the association between

obesity and various types of malignancies, including postmenopausal

breast cancer and cancers of the colon, pancreas, endometrium,

esophagus (adenocarcinoma), kidney, gallbladder, and gastric cardia.7

The link between obesity and cancer may be mediated by insulin

resistance and hyperinsulinemia. However, several complex

physiological changes also result from obesity, including alterations

in sex steroid levels. For example, obesity is associated with

increased levels of bioavailable estrogen due to enhanced

biosynthesis in adipocytes and reduced sex hormone–binding globulin

levels.7 Thus, in the complex setting of obesity, it is difficult to

tease out the specific molecular alterations that lead to cancer, and

these contributions are likely to be site-specific.

Well-designed cohort studies can provide compelling observational

data, and the study by Jee et al3 has several methodological

strengths. First, it is likely that the cohort is reasonably

representative of Korea, since the insurance provider covers more

than 10% of the Korean population, and only 2.1% of the participants

were excluded on the basis of incomplete data. Second, important

information about other risk factors was collected by these

investigators through use of a lifestyle and medical history

questionnaire. In contrast, many other population-based cohort

studies rely on national linkage registries that do not have this

type of information, thereby limiting the ability to adjust for

potential confounders. Third, the study cohort is extremely large,

which increases the ability to recognize and distinguish very small

relative risks as statistically significant.

This last attribute is important, because small risks can be

meaningful. Tangible elevations in cancer risk were observed in

Korean men and women who had fasting serum glucose measurements that

were below the commonly recognized threshold of 125 mg/dL for a

diagnosis of diabetes. Indeed, a fasting glucose level from 90 to 109

mg/dL was associated with a 4% increase in risk of cancer mortality

among men (hazard ratio, 1.04; 95% confidence interval, 1.01-1.07).

Even though this relative risk is minuscule, what it reflects in the

broader context of this study is that elevated fasting glucose levels

confer risk on a continuous scale. Just as clinical thresholds for

hypertension and serum lipids are not easily categorized

into " healthy " and " diseased, " the same appears to be true for

fasting serum glucose.

Of course, no observational study is perfect, and this study has

its limitations. The strongest relative risks were associated with

pancreatic cancer, and despite the appropriate methodological

approaches used in this study, the possibility that hyperglycemia was

caused by the pancreatic cancer through endocrine insufficiency

cannot be excluded definitively. In addition, since this study is not

randomized, the exposed and unexposed groups might not have been

appropriately balanced in the analysis. It is also possible that

individuals with hyperglycemia were followed up more carefully by

physicians, which would lead to more cancer diagnoses. However, this

would not explain the strong findings with respect to cancer

mortality. Moreover, cancer is not a single disease, and the case for

hyperglycemia as a risk factor for " all cancer " is driven primarily

by the data from the digestive cancers among men.

Among women, the summary result is related primarily to risks

measured for pancreatic cancer. While this study did not describe the

risks of endometrial cancer associated with hyperglycemia, both

diabetes and obesity are recognized risk factors for this disease.8

Similarly, the analysis of breast cancer leaves more questions than

answers. The modest elevation in breast cancer incidence with

elevated fasting blood glucose observed by Jee et al3 was not

statistically significant, although addition of women identified

through use of medication for diabetes was associated with a

significantly increased risk (hazard ratio, 1.51; 95% confidence

interval, 1.26-1.80). These findings raise questions about how

hyperglycemia might operate differently in premenopausal and

postmenopausal women and suggest that various aspects of diabetes

treatment should be addressed in future analyses of the data.

How may these results be interpreted in the context of cancer

incidence and mortality in the population? Fortunately, the relative

risks are modest and, therefore, the fraction of cancers attributable

to elevated fasting glucose in the Korean population is small, in

part because of the relatively low prevalence of diabetes in Korea

(5%). Based on data provided in this study, an estimated 3.9% of

cancer deaths in men and 0.8% of cancer deaths in women are

attributable to diabetes, representing 846 of the total 26 473 cancer

deaths observed in this study. However, these numbers may not reflect

unmeasured confounding or effect modification.9 Some of these cancer

deaths may be preventable, and further studies will be required to

demonstrate that reductions in hyperglycemia and diabetes will lead

to declines in cancer mortality. This is especially true in light of

data from the Diabetes Prevention Program Research Group

demonstrating a reduction in the incidence of diabetes through

lifestyle interventions, including dietary modification and

introduction of a regular exercise routine.10 Since the hazard ratios

reported by Jee et al3 are derived from a Korean population, they

cannot be directly implemented to increase understanding of the

population-attributable fraction of cancer that may be due to

diabetes in the United States. But since the prevalence of diabetes

is higher in the United States than in Korea, it is possible that

preventing diabetes may have a more important effect in the United

States.

As diabetes becomes an increasing public health concern in modern

societies, the cancer risks looming on the horizon are now being

recognized. Strategies to address the emerging epidemics of diabetes

and obesity are likely to have a broad impact on public health.

Indeed, these approaches may ultimately diminish the burden of cancer

for future generations.

Fasting Serum Glucose Level and Cancer Risk in Korean Men and

Women

Sun Ha Jee; Heechoul Ohrr; Jae Woong Sull; Ji Eun Yun; Min Ji;

M. Samet

JAMA. 2005;293:194-202.

ABSTRACT

Context Diabetes is a serious and costly disease that is becoming

increasingly common in many countries. The role of diabetes as a

cancer risk factor remains unclear.

Objective To examine the relationship between fasting serum

glucose and diabetes and risk of all cancers and specific cancers in

men and women in Korea.

Design, Setting, and Participants Ten-year prospective cohort

study of 1 298 385 Koreans (829 770 men and 468 615 women) aged 30 to

95 years who received health insurance from the National Health

Insurance Corp and had a biennial medical evaluation in 1992-1995

(with follow-up for up to 10 years).

Main Outcome Measures Death from cancer and registry-documented

incident cancer or hospital admission for cancer.

Results During the 10 years of follow-up, there were 20 566

cancer deaths in men and 5907 cancer deaths in women. Using

proportional hazards models and controlling for smoking and alcohol

use, the stratum with the highest fasting serum glucose (140 mg/dL

[7.8 mmol/L]) had higher death rates from all cancers combined

(hazard ratio

---

, 1.29; 95% confidence interval [CI], 1.22-1.37 in

men and HR, 1.23; 95% CI, 1.09-1.39 in women) compared with the

stratum with the lowest level (<90 mg/dL [<5.0 mmol/L]). By cancer

site, the association was strongest for pancreatic cancer, comparing

the highest and lowest strata in men (HR, 1.91; 95% CI, 1.52-2.41)

and in women (HR, 2.05; 95% CI, 1.43-2.93). Significant associations

were also found for cancers of the esophagus, liver, and colon/rectum

in men and of the liver and cervix in women, and there were

significant trends with glucose level for cancers of the esophagus,

colon/rectum, liver, pancreas, and bile duct in men and of the liver

and pancreas in women. Of the 26 473 total cancer deaths in men and

women, 848 were estimated as attributable to having a fasting serum

glucose level of less than 90 mg/dL. For cancer incidence, the

general patterns reflected those found for mortality. For persons

with a diagnosis of diabetes or a fasting serum glucose level greater

than 125 mg/dL (6.9 mmol/L), risks for cancer incidence and mortality

were generally elevated compared with those without diabetes.

Conclusion In Korea, elevated fasting serum glucose levels and a

diagnosis of diabetes are independent risk factors for several major

cancers, and the risk tends to increase with an increased level of

fasting serum glucose.

INTRODUCTION

Diabetes mellitus is a serious and costly disease that is

becoming increasingly common in many countries, including Korea.1

Recent data show that approximately 150 million people have diabetes

mellitus worldwide, and this number may double by 2025, especially in

developing countries, because of population growth, aging, unhealthy

diets, obesity, and sedentary lifestyles.2 The association between

diabetes mellitus and cardiovascular mortality is well established.3

However, while the role of diabetes as a risk factor for cancer is

still uncertain, having diabetes or an elevated glucose level is of

interest because of the effect of insulin on cell growth and of the

systemic inflammation associated with diabetes and the metabolic

syndrome.4-5

Recent observational studies have provided consistent evidence on

associations of diabetes with increased risk of cancers of the

pancreas,5 liver,6 endometrium,7 and colon/rectum.8 Data on cancers

of the esophagus, stomach, prostate, and breast are more limited and

have been inconsistent.8-9 This lack of consistency may be

attributable to the limited number of studies and their small sample

sizes.

We conducted a prospective cohort investigation, the Korean Cancer

Prevention Study (KCPS), among more than 1 million Koreans to assess

associations of fasting serum glucose and of a diagnosis of diabetes

with cancer risk.10 In addition, we explored modification of this

risk by obesity in a population with a low average body weight

compared with those of Western countries.

....

RESULTS

The population was primarily middle-aged, with approximately twice

as many men as women (Table 1). By the criteria of self-report and

fasting serum glucose level, the prevalence rates of diabetes were

about 5% in men and 4.5% in women. The population had a low body mass

index (BMI; calculated as weight in kilograms divided by the square

of height in meters) on average, and only 23.8% and 0.8% of men and

27.0% and 2.5% of women had BMI values of 25 or above and above 30,

respectively. Both smoking and alcohol use were substantially more

common in men.

Overall Pattern of All-Cause Mortality and Fasting Serum Glucose

Level

During the 10 years of follow-up, 54 385 deaths occurred among men

and 20 362 among women. As shown in Figure 1, fasting serum glucose

level was positively associated with all-cause mortality rates. In

the adjusted proportional hazards model, this effect persisted,

with persons in the highest stratum of fasting serum glucose (140

mg/dL) having a higher HR for all causes combined (HR, 2.09; 95%

confidence interval [CI], 2.03-2.16 in men and HR, 2.35; 95% CI, 2.24-

2.48 in women) compared with the lowest stratum (<90 mg/dL) (Table 2

and Table 3).

Cancer Mortality

A total of 20 566 cancer deaths occurred among men and 5907 deaths

occurred among women during the 10 years of follow-up. In general, HR

estimates were above unity for male participants in the higher strata

of serum glucose level and among those with a diagnosis of diabetes

(Table 2). In fact, all point estimates were somewhat elevated in

association with a diagnosis of diabetes. We explored the

relationship between duration of diabetes and cancer risk and did not

find consistent associations, with the exception of pancreatic cancer

in men. Among men with diabetes, the HRs for pancreatic cancer death

with diabetes durations of less than 4.9 years, 5.0 to 9.9 years, and

10 years or more were 2.0 (95% CI, 1.2-3.3), 2.4 (95% CI, 1.4-4.3),

and 3.0 (95% CI, 1.8-5.0), respectively, compared with those without

diabetes.

We observed linear trends in mortality with increasing fasting

serum glucose level for all cancers combined and for cancers of

several sites (Table 2). Compared with the reference category (<90

mg/dL), men with a fasting serum glucose level above 140 mg/dL had

significantly elevated HRs of death from cancers of the esophagus

(HR, 1.44; 95% CI, 1.08-1.93), liver (HR, 1.57; 95% CI, 1.40-1.76),

pancreas (HR, 1.91; 95% CI, 1.52-2.41), and colon/rectum (HR, 1.31;

95% CI, 1.03-1.67). Significant associations were also found for

bladder cancer and leukemia for those with a fasting serum glucose

level of 126 mg/dL or higher. Men with a fasting serum glucose level

of 110 to 125 mg/dL had significantly elevated HRs of death from

esophageal, stomach, colon/rectal, liver, and pancreatic cancers. Of

the total of 20 566 cancer deaths in men, 802 were estimated as

attributable to having a fasting serum glucose level of less than 90

mg/dL.

For women, the overall pattern of association was similar to that

in men (Table 3), with all point estimates increased for those with

diabetes. Significant positive linear trends in death rates were

observed for pancreatic cancer; HRs ranged from 1.70 (95% CI, 1.17-

2.46) at fasting serum glucose levels of 110 to 125 mg/dL to 2.05

(95% CI, 1.43-2.93) at fasting serum glucose levels of 126 mg/dL or

higher (Table 3). Significant associations with diabetes were also

found for cancers of the liver, lung, breast, and cervix, while

associations were not observed for risk of death from cancers of the

stomach or colon/rectum. Of the total 5907 cancer deaths in women, 46

were estimated as attributable to having a fasting serum glucose

level less than 90 mg/dL.

Cancer Incidence

The numbers of incident cases during the 10 years of follow-up

were 37 759 among men and 16 074 among women. Trends were generally

similar for mortality and incidence. We observed positive linear

trends in cancer incidence with increasing fasting serum glucose

levels for cancers of the liver, pancreas, and kidney (Table 4).

However, fasting serum glucose level was inversely associated with

prostate cancer incidence among men with a fasting glucose level of

at least 126 mg/dL. The association of fasting serum glucose level

and cancer incidence was similar whether the analysis was based on

the total population or on those who had at least a 5-year follow-up

period (data not shown). Furthermore, the incidence findings were

unchanged with adjustment for BMI. For example, men with diabetes had

similar HRs of death from pancreatic cancer before (HR, 1.71; 95% CI,

1.42-2.06) and after (HR, 1.73; 95% CI, 1.42-2.07) BMI adjustment.

In women, positive linear trends were observed in incidence of

pancreatic cancer with increasing fasting serum glucose level (Table

5). We observed a significant association for liver cancer for the

stratum with fasting serum glucose levels of 110 to 125 mg/dL. The

observed associations in women were unchanged with adjustment for BMI

(data not shown).

Cancer Mortality and Incidence and Fasting Glucose Levels

According to BMI in Men

To control for potential confounding by obesity and to evaluate

effect modification, the data were further stratified by BMI (<20, 20

to <23, and 23). Because of limited numbers for some cancer sites,

the analyses were carried out for all sites combined and for cancers

of the colon/rectum, liver, and pancreas. For all cancers, a trend

was evident in mortality risk by fasting serum glucose level in each

stratum of BMI (Figure 2). Positive trends in death rates were

observed for cancers of the liver and pancreas in all BMI groups as

well. The risk of death due to liver and pancreatic cancers

associated with fasting serum glucose level was not modified by BMI.

For cancer incidence, the association of fasting serum glucose level

with risk for liver cancer remained consistent and lacked evidence of

effect modification by obesity. The association of pancreatic cancer

incidence with fasting serum glucose level was not as consistent as

for mortality, although all strata showed increased risk compared

with the reference category.

We also assessed potential modification of the effect of serum

glucose level by smoking and alcohol consumption. We did not find

significant interactions for cancer incidence or mortality in either

men or women.

COMMENT

This cohort of Koreans, in comparison with Western populations, is

notable for the low frequency of obesity in its participants. The

average BMI was 23.2, and only one fourth of participants had a BMI

above 25. Based on other studies in Korea, almost all cases of

diabetes could be expected to be type 2.16 Nonetheless, we

documented, as in Western populations, that serum glucose level and

presence of diabetes are associated with cancer incidence and

mortality.

Other studies have addressed diabetes or glucose intolerance and

risk for cancer. Although diverse in design and in their measures of

glucose intolerance, the majority have shown that increased cancer

risk, either overall or for particular cancer sites, is associated

with glucose intolerance. The magnitude of the association of glucose

intolerance or diabetes with risk for all cancers was small in the

KCPS but was within the range found in some studies.5-6,17 The

multicancer site effect is consistent with postulated mechanisms of

systemic consequences of hyperinsulinemia.4-5 In interpreting the

findings of these studies and of the KCPS, potential confounding by

obesity is of concern. In the KCPS, we found that the increased

cancer risk associated with high serum glucose or diabetes was

unchanged when controlling for BMI; additionally, most KCPS

participants were not overweight. The association of serum glucose

level with cancer risk did not vary by BMI (Figure 2).

The study confirmed the excess risk of digestive cancers reported

in several studies,5-6,8 particularly of cancers of the pancreas,

liver, esophagus, and colon among persons with diabetes. For

pancreatic cancer, a 1995 meta-analysis of cohort and case-control

studies estimated a 2-fold increase in risk of pancreatic cancer,

comparing patients with and without diabetes.18 The KCPS estimates

were similar, and the HR increased with increasing fasting serum

glucose level (Table 2 and Table 3), as found in a Chicago cohort

study.4 Our prospective results, along with the unchanged findings

with exclusion of the first 5 years of follow-up, weigh against the

possibility that the presence of pancreatic cancer increases blood

glucose levels; ie, reverse causality. In the KCPS, we observed a

significant positive linear trend for risk of pancreatic cancer with

fasting glucose level: the HR was 1.7 (95% CI, 1.4-2.1) in men with

diabetes and 1.5 (95% CI, 1.2-1.9) when data were restricted to men

with at least 5 years of follow-up time. The complementary findings

with these exposure measures, serum glucose level, and report of

diabetes, and the presence of a dose-response relationship with

fasting serum glucose level support a causal interpretation of these

associations.

The findings for several other cancer sites further support this

interpretation. In men, we found increased risks of cancers of the

esophagus, liver, stomach, colon/rectum, kidney, and bladder and

leukemia (Table 2), while in women, risk was increased for cancers of

the liver, lung, breast, and cervix (Table 3). Other studies have

also found increased risk for these cancer sites.19-20 In Korea,

hepatitis B infection is common and is an important cause of liver

cancer.21 Serum glucose level was not associated with hepatitis B

surface antigen status in the subset of participants with assay

results, indicating that hepatitis B does not confound the results

for liver cancer. On hospital admission diagnoses, we found little

mention of nonalcoholic steatotic hepatitis, suggesting that the

increased risk of liver cancer associated with higher serum glucose

level reflects a direct pathway rather than an indirect pathway

through obesity and fatty liver damage.

For prostate cancer, for both incidence and mortality, we found no

evidence for an association with either fasting serum glucose level

or diabetes (Table 2 and Table 4), consistent with other reports. One

large, population-based Swedish cohort study found that men with

diabetes had a 10% lower risk of developing prostate cancer than the

general male population.22 A reduced risk for men with diabetes was

found in a case-control study in New York.23 In contrast, the

American Cancer Society's Cancer Prevention Study showed no

association between diabetes at baseline and prostate cancer

mortality,24 and a study of incidence in 823 participants in the

Baltimore Longitudinal Study of Aging also found association with

fasting insulin and glucose levels.20 The lack of association for

prostate cancer weighs against observation bias as contributing to

the positive associations for other sites; the medical care and

frequent blood chemistries associated with diabetes might be expected

to increase the opportunity for detecting prostate cancer, but the

negative association is inconsistent with such bias.

Hyperinsulinemia has been cited as a possible risk factor for

breast cancer, and supporting laboratory findings have been

reported,5 but results of epidemiological studies have been mixed.25

In a recent publication based on the Nurses' Health Study, women with

type 2 diabetes had a small increase in risk (HR, 1.17; 95% CI, 1.01-

1.35). The association was apparent among postmenopausal women but

not among premenopausal women.25 We did not find an association,

although 95% CIs for our estimates covered the value from the Nurses'

Health Study. With stratification at age 55 years, we did not find

increased risk in the older stratum, corresponding to an age range

when most women would be postmenopausal.

The potential limitations of our study result primarily from using

data collected for clinical purposes. Serum glucose was measured

under fasting conditions using clinical laboratories operating with

standard quality assurance and control protocols in place. A single

measurement of fasting serum glucose made for clinical purposes is

used as a diagnostic standard and matches the World Health

Organization's recommended approach for epidemiological studies.26 We

further relied on self-report of a diagnosis of diabetes; the serum

glucose level of those with reported history of diabetes was 66 mg/dL

higher than for those not reporting diabetes, suggesting that the

self-reported information was valid. We do not anticipate that these

clinical data would artifactually introduce association of cancer

risk with fasting serum glucose level.

Cancer mortality is subject to misclassification on death

certificates, particularly with regard to attribution to a particular

site. The limitations of death certificate data on cancer have been

characterized in some countries,27-28 but we are uncertain as to the

applicability of the findings of these studies in Korea. A small

study within KCPS showed high validity for a death certificate

listing of lung cancer.29 Additionally, we have found that of KCPS

participants with incident liver cancer, 73% of their deaths were

attributed to liver cancer over a follow-up interval of at least 5

years. In Korea, cancer registration is not yet complete nationwide;

it is currently estimated at 90%.30 Consequently, we used hospital

admission for cancer as a further indication of cancer incidence. We

were able to take potential confounding by smoking and alcohol

consumption into account and explored effect modification by obesity.

We cannot attribute the associations of fasting serum glucose level

and diabetes to uncontrolled confounding, particularly given the dose-

response relationships observed with glucose.

While the generalizability of the findings is uncertain, we have

shown that fasting serum glucose level and diabetes are associated

with cancer risk in a population far leaner than the Western

populations in other studies. These associations do not reflect

confounding by obesity, suggesting that the mechanism of increased

cancer risk reflects the consequences of hyperinsulinemia. Glucose

intolerance may be one pathway by which obesity increases cancer

risk, and rising obesity may increase future cancer rates.