Insulin, exercise, CR and breast cancer

[Guest guest]

Hi All,

The pdf-available below to me implicates the effects of CR and the

independent of our body mass index (BMI) in insulin level and

consequently

cancer risk. Breast cancer data is discussed as an example.

Are we to believe that the women had calorie intakes of less than

1600 while having only 29% that had a BMI less than 25?

Looking at the macronutrient ratios, the % calories across

increasing

quintiles of calorie intakes, values were fat, 31.57 to 38.69%,

protein was

16.1 to 15.5 and carbohydrates was 49.4 to 44.8. Is this not

inconsistent

with the idea that the current obesity trend in society is due to

reduced

fat and increased sugars?

So why does my sister have breast cancer, and why does it appear to

be so serious? She exercises plenty and has a low BMI, and always

did.

The breast cancer of Greta is now in bone

metastases are in her one should blade, back

from the neck to tail bone, ribs on both sides, hips and legs.

Three years ago:

`The initial biopsy revealed a ductal infiltrating right breast

carcinoma grade II/III. It was 1.7 cm minimum, had lymphatic

invasion and was estrogen receptor 3+, meaning very responsive

to estrogen and hence tamoxifen.

The tumor was infiltrating ductal carcinoma; local stage

T2pN1biii;

poorly differentiated, grade III/III; approximately 3.5 cm, having

extensive lymphatic invasion; and not completely removed by the

surgery. " An ill-defined hard stellate tumour mass, measuring

approximately 2.5 x 2.0 x 2.0 cm is present in the inferior central

aspect of the specimen. " '

They took the sentinel lymph node, three other separate nodes and

a

mass containing six nodes. The sentinel node was negative, one of

the other nodes had a metastatic infiltrating ductal carcinoma of 1

cm

with extra-nodal extension, another node was positive for metastatic

infiltrating ductal carcinoma and two separate nodes were negative.

I spoke with a pathologist friend and he said they probably got

all the lymph nodes out cleanly.

J Clin Oncol. 2004 Nov 15;22(22):4507-13.

Insulin, physical activity, and caloric intake in postmenopausal

women: breast

cancer implications.

Chlebowski RT, Pettinger M, Stefanick ML, BV, Mossavar-

Rahmani Y,

McTiernan A.

.... programs to reduce body mass index (BMI) with... decreased

caloric

intake have been proposed to reduce insulin as a potential mediator

of

breast cancer and other chronic diseases.

.... An ethnically diverse subsample of 2,996 mostly healthy

postmenopausal women with no prior cancer history was randomly

identified from

the 161,809 participants ... insulin levels were then compared

across quintiles of caloric intake and physical activity in linear

regression

model analyses controlled for BMI and other factors. RESULTS: Lower

BMI (P <

..0001), higher levels of physical activity (P < .0001), and lower

caloric intake

(P < .02) were all independently associated with significantly lower

mean

fasting insulin levels throughout the range of observed values.

Insulin levels

of 8.74 microU/mL +/- 4.16 SD were seen in the highest physical

activity and

lowest caloric intake quintile compared with insulin levels of 15.08

microU/mL

+/- 16.32 SD in the lowest physical activity and highest caloric

intake quintile

(P < .0001). CONCLUSION: These findings suggest that reduction in BMI

achieved

by increasing physical activity, reducing caloric intake, or both,

should lower

insulin levels, providing support for clinical trials evaluating

insulin level

change and breast cancer risk.

PMID: 15542801 [PubMed - in process]

INTRODUCTION

Obesity 1,2 and low physical activity 3,4 have

each been associated with increased breast

cancer risk in postmenopausal women,

whereas caloric restriction has been linked

to lower breast cancer incidence.5 Higher

fasting insulin levels has been proposed as

a potential mediating factor of these

observations because higher insulin levels

are associated with obesity 6 and low phys-ical

activity.7 Therefore, weight loss pro-

grams incorporating both increased

physical activity and decreased caloric in-take,

as well as exercise programs without

emphasis on weight loss, have been pro-posed

as strategies to reduce risk of breast

cancer.8,9 However, the relative contributions

of body mass index (BMI), caloric intake, and

physical activity on insulin levels in postmeno-pausal

women have received limited attention

and are poorly understood.

... questionaire ...

RESULTS

Study population age and characteristics are listed in Table

1. The study population was ethnically diverse, with more

than 70% overweight or obese. The demographic and cate-gorizing

information of women in the various caloric intake

and physical activity quintiles were similar (data not shown).

Macronutrient intake by quintile of total caloric intake

is listed in Table 2. The intakes of fat, protein, and carbohy-drate

were each closely correlated with total caloric intake

(Spearman correlation coefficients of 0.90, 0.88, and 0.90

respectively). When macronutrient intake was tested for

trend by quintile of total caloric intake, a statistically signif-

icant

(P < .0001) increasing trend in percentage of calo-ries

from fat was seen with increasing total calories and a

statistically significant inverse (P < .0001) trend was seen

between percentage of calories from protein and carbo-hydrates

with total calories (Table 2). Thus, as caloric

intake increased, the percentage of calories from fat in-

creased and the percentage of calories from protein and

carbohydrate decreased.

Fasting insulin levels by BMI category (normal, over-weight,

and obese) and physical activity and caloric intake

quintiles are listed in Table 3. Lower insulin levels were seen

in women with lower BMI, higher levels of physical activity,

and lower caloric intake. BMI (P < .0001), physical activity

(P < .0001), and caloric intake (P < .0001) were all signif-

icantly

associated with insulin levels after adjustment for

race or ethnicity, age, smoking, alcohol intake, and study

component. In addition, regression models were conducted

that serially excluded consideration of one of the three covari-ates

(caloric intake, physical activity, or BMI). In all three

models the two remaining covariates were significantly associ-ated

with insulin levels (P < .005, data not shown).

The associations among insulin level with quintiles of

physical activity and caloric intake are listed in Tables 4 and

5. The mean in each of the 25 cells in Table 4 is based on

values from 90 to 141 women. As shown, high physical

activity was associated with lower insulin levels in all quin-tiles

of caloric intake. Similarly, low caloric intake was asso-ciated

with lower insulin levels in all quintiles of physical

activity. Mean fasting insulin ranged from 8.74 microU/mL +/-

4.16 SD in the highest physical activity and lowest caloric

intake quintile to 15.08 microU/mL =/- 16.32 SD in the lowest

physical activity and highest caloric intake quintile. Figure 1

plots the difference between the mean insulin level in the

lowest caloric intake and highest physical activity quintile

and all other quintile categories. No interaction was seen

with respect to the association of lower insulin levels with

lower caloric intake and with higher physical activity, indi-cating

that the relationship of physical activity to insulin

level is the same in each quintile of caloric intake examined.

Similar, but less strong, trends for associations among insu-lin

level with physical activity and caloric intake quintiles

were seen in each of the three categories of BMI, but power

was limited by the smaller sample size.

A final regression model examined relationships

among BMI, physical activity, and caloric intake with insu-lin

levels. Higher physical activity and lower caloric intake

were each associated with significantly lower mean fasting

insulin levels independent of BMI. The linear regression

model revealed a highly significant association (P =.0001, 4

degrees of freedom test) between insulin level and the phys-ical

activity quintiles, after adjustment for total caloric in-take

and the remaining covariates. Caloric intake was also

significantly associated with insulin levels in the same

model (P = .021). Similar results were seen when BMI was

considered as a categoric variable instead of a log-transformed

variable. The analyses were essentially un-changed

if body weight was substituted for BMI (data not

shown). Interactions among physical activity, caloric in-take,

and BMI were evaluated in models adjusted for age,

smoking, race or ethnicity, alcohol, and WHI study compo-nent:

for BMI and physical activity interaction, P =.18; for

physical activity and caloric intake interaction, P = .82.

BMI was significantly associated with caloric intake,

P = .01. There was no interaction with race (P = .73).

DISCUSSION

In a large cohort of postmenopausal women, lower BMI,

higher levels of physical activity, and lower caloric intake

were all independently related to lower fasting insulin

levels. In analyses controlled for BMI, lower caloric intake

and higher physical activity were independently associated

with significantly lower fasting insulin levels throughout the

entire range of observed values.

Small, short-term randomized trials of modest 7 or rel-atively

intense exercise 15,16 and/or weight loss with 16 or

without 17 exercise or reduction in total fat and refined

carbohydrate intake 18 have in general 15-17 reported insulin

reduction with exercise or weight loss. These studies have

rarely examined the influence of modest changes in physical

activity or caloric intake or the relative contribution of these

interventions to insulin change. The current results from a

large population of predominantly inactive postmeno-pausal

women suggest that even relatively modest increases

in physical activity or decreases in caloric intake could con-tribute

to lower insulin levels.

The actual amount of recreational physical activity re-ported

by this cohort of postmenopausal women was quite

low. No recreational or walking physical activity whatsoever

was reported by one fifth of the women. The fourth most

active quintile (with 8.75 to 17.5 kcal/wk/kg of recreational

energy expenditure) represents about only 28 min/wk of

brisk walking equivalent. Despite this narrow range of rec-reational

physical activity differences, insulin levels were

approximately 40% lower in the highest physical activity

and lowest caloric intake compared with the lowest physical

activity and highest caloric intake groups.

Reduced caloric intake and increased physical activity

are now recognized cornerstones of effective weight loss

strategies.19,20 Given that higher insulin levels have been

proposed as a potential mediator of an increased risk of two

of the three most common malignancies in postmeno-pausal

women, namely breast cancer and colorectal can-cer,

21 these findings support consideration of a weight loss

strategy for cancer risk reduction trials.

A comprehensive review of insulin and cancer risk is

beyond the scope of this report. Although not without

controversy,22-24 the preponderance of studies suggest that

insulin may influence cancers that are more commonly seen

in Western populations.21,25 In breast cancer case-control

studies, Brunning et al 26 reported a dose-response between

c-peptide, a marker of pancreatic insulin secretion, and

breast cancer in both pre- and postmenopausal women. Del

Giudice et al 27 related higher insulin levels to premeno-pausal

breast cancer risk, whereas Yang et al 28 found an

increased breast cancer risk with increasing levels of

c-peptide as well. More recently, Hirose et al 29 reported

insulin levels as significant predictors of postmenopausal

breast cancer and a high ratio of c-peptide to fructosamine,

suggestive of insulin resistance, was significantly related to

both breast hyperplasia and breast cancer incidence in an-other

case-control analysis.30 In a cross-sectional study in-volving

3,868 postmenopausal women with 151 prevalent

breast cancers, hyperinsulinemia was positively associated

with breast cancer risk, an association unaltered by consid-eration

of BMI.31 A related parameter, higher fasting glu-cose,

has been associated with breast cancer risk in a

prospective study.32 Most recently, in a large cohort of

38,823 Norwegian women, low serum high-density li-poprotein

cholesterol, described by the authors as part of

the metabolic syndrome, was associated with increased

postmenopausal breast cancer risk.33

Other studies suggest interaction between insulin and

other breast cancer risk factors. An analysis from 400 case-control

pairs from the Shanghai Breast Cancer Study suggested

that insulin resistance and insulin-like growth factors may

synergistically increase breast cancer risk,34 whereas Yu et al 35

reported a synergistic effect on breast cancer risk for insulin-like

growth factor-I with hormones estrone or testosterone in

both pre and postmenopausal women.

The associations seen among physical activity, caloric

intake, and insulin have relevance for women with estab-lished

cancers as well. In a population of 535 newly diag-nosed

breast cancer patients, both higher fasting insulin

levels and obesity independently predicted increased recur-rence

risk and decreased survival.36 This observation was

supported by Borugian et al,37 who reported that high levels

of insulin were associated with significantly worse survival

in a cohort of 603 breast cancer patients. Most recently, a

moderate increase in physical activity has been associated

with reduced recurrence risk in women diagnosed with

breast cancer in the Nurses Health Study cohort.38

Other studies support the association of body weight

with clinical outcome in women with breast cancer. In a

recent review, a statistically significant association between

obesity and recurrence or survival was seen in 26 of 34

studies.9 In an earlier meta-analysis, the hazard ratio for

effect of body weight on recurrence was 1.78 (95% CI, 1.50

to 2.11).8 Most recently, Dignam et al 39 reported a signifi-cant

increase in all-cause mortality comparing obese versus

nonobese breast cancer patients receiving adjuvant tamox-ifen

therapy. Similarity, in International Breast Cancer

Study Group Trials involving 6,792 breast cancer patients,

BMI significantly influenced overall survival (P = .03), but

not disease-free survival.40

The strengths of this report include the large number of

fasting blood samples from a study population with a di-verse

racial or ethnic and age composition, and the ability to

evaluate modest differences in caloric intake and physical

activity using standardized data collection instruments and

procedures. The cross-sectional design is a limitation pre-cluding

causal conclusions. Given the close correlation of all

macronutrient intakes with total caloric intake, the relative

contribution of individual macronutrients to the insulin

levels differences cannot be separated.

In summary, the results of this study suggest that strat-egies

to reduce BMI and body weight involving either or

both increasing physical activity and decreasing caloric in-take

will reduce insulin levels. These observations support

prospective intervention trials incorporating these lifestyle

changes to test hypotheses relating insulin to cancer risk.

Consultant/Advisory Role: Rowan T. Chlebowski,

AstraZeneca, Novartis, Pfizer.

Hon-oraria: Rowan T. Chlebowski, AstraZeneca.

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Table 5. Results of Multiple Linear Regression Model of Fasting

Insulin

Parameter Estimate SE of Estimate P

Intercept -1.0195 0.2338 <.0001

Caloric intake > 2,204 kcal/day 0.0616 0.0266 .0209

Physical activity > 0-3.75 kcal/wk/kg 0.0309 0.0435 .4767

Physical activity > 3.75-8.75 kcal/wk/kg -0.0429 0.0391 .2727

Physical activity > 8.75-17.5 kcal/wk/kg -0.0359 0.0395 .3642

Physical activity > 17.5 kcal/wk/kg -0.1761 0.0420 <.0001

BMI (log-transformed) 0.9908 0.0687 <.0001

Alcohol intake > 1 drink/wk -0.0756 0.0271 .0054

Age (standardized) 0.0053 0.0018 .0035

NOTE. In the regression model, insulin was log-transformed. The

association between physical activity and insulin level was

significant

(F = 6.90; P <.0001). Abbreviation: BMI, body mass index.

Cheers, Alan Pater