contentLife Extension Magazine February 2013 Elevated Glucose Increases Incidence of Breast Cancer and Brain Shrinkage By William Faloon, Luke Huber, ND, and Kira Schmid, ND Analysis of 12 Studies of Glucose Levels and Breast Cancer Risk This column represents a summary of the findings from 12 separate studies that evaluate blood glucose levels and breast cancer risk: Study #1: Muti P, Quattrin T, Grant BJB, et al. Fasting glucose is a risk factor for breast cancer: A Prospective study. Cancer Epidemiology Biomarkers Prev. 2002;11(11):1361-8. Between 1987 and 1992, 10,786 women ages 35–69 were recruited in a prospective case controlled study in Italy. At recruitment, fasting blood glucose samples were collected. After 5.5 years, 144 breast cancer cases were identified among the participants of the cohort. Four matched controls were chosen for each breast cancer case from members of the cohort who did not develop breast cancer during the follow-up period. In premenopausal women, glucose was associated with breast cancer risk: the age, body mass index, and reproductive variable adjusted relative risk (RR) for the highest quartile of serum glucose versus the lowest was 2.8. In premenopausal women, those with a blood sugar of >84 mg/dL had more than 150% increase in breast cancer incidence compared to those with lower levels. Editor's note: Fasting glucose above 84 mg/dL resulted in over a 150% increase in breast cancer incidence compared to those with lower levels. Study #2: Mink PJ, Shahar E, Rosamond WD, et al. Serum insulin and glucose levels and breast cancer incidence: The Atherosclerosis Risk in Communities Study. Am J Epidemiol. 2002;156(4):349-52. The authors examined the association of breast cancer incidence with serum levels of insulin and glucose in a cohort of 7,894 women aged 45–64 years from four US communities. Anthropometric factors and fasting levels of insulin and glucose were measured at baseline (1987–1989). Over an average follow-up period of 7.1 years (1987–1995), 187 breast cancer cases were ascertained. Compared to those with a fasting glucose <100 mg/dL, those with a blood glucose of 100-125 mg/dL was associated with a 23% increased risk of breast cancer after multivariate analysis. Multivariate analysis: Age-, race-, and center-adjusted relative risks of breast cancer were 1.32 for fasting glucose levels of 100–125 mg/dL and 1.60 for diabetic women in comparison with the normal level (<100 mg/dL). After adjustment for age, race, and study center the relative risk for the association between diabetes and breast cancer decreased from 1.60 to 1.48 after additional adjustment for body mass index, and the risk was further attenuated to 1.39. After adjustments for age, race, study center, body mass index, age at menarche, age at menopause, age at first live birth, family history of breast cancer in a mother or sister, number of sisters, alcohol intake, and pack-years of smoking the RR dropped to 1.23 in the 100-125 mg/dL blood glucose group. Editor's note: Fasting glucose at or above 100 mg/dL was associated with a 23% increase in breast cancer incidence compared to those with lower levels. If threshold had been reduced to under 86 mg/dL, the magnitude of the increase may have been much greater. Study #3: Sieri S, Muti P, Claudia A, et al. Prospective study on the role of glucose metabolism in breast cancer occurrence. Int J Cancer. 2011;130(4):921-9. A prospective cohort study of 10,633 women from Italy (the ORDET study) found significant relationships between blood sugar levels and breast cancer risk. Women with the highest glucose quartile (median 96 mg/dL) had a 63% increased risk for breast cancer compared to those in the lowest quartile (median 73 mg/dL) after being “fully adjusted” for multiple variables. Women in the highest fasting serum glucose quartile (median = 96 mg/dL) had a significantly greater risk of breast cancer than those in the lowest glucose quartile (median = 73 mg/dL). The results were adjusted for age, education, age at first birth, age at menarche, parity, family history of breast cancer, oral contraceptive use, breastfeeding, alcohol intake and smoking. Editor's note: Fasting glucose median of 96 mg/dL resulted in 63% increase in breast cancer incidence compared to median fasting glucose of 73 mg/dL. Shows benefit of keeping glucose at the low range of “normal”. Study #4: Kabat GC, Kim M, Caan BJ, et al. Repeated measures of serum glucose and insulin in relation to postmenopausal breast cancer. Int J Cancer.2009;125:2704–10. Longitudinal study of postmenopausal breast cancer risk using 6% sample of women in the Women’s Health Initiative trial whose fasting blood samples provided at baseline and at years 1, 2 and 6 were analyzed for glucose and insulin. Mean serum glucose and insulin levels were higher in breast cancer cases compared to non-cases at baseline and at years 1 and 3, but the differences were not statistically significant. Although there was little to no association between blood glucose and breast cancer risk in most of the data analysis, two aspects of the analysis did show a significant relationship: In an analysis of “all available measurements (but excluding measurements made within 1 year of diagnosis)” there was a significant relationship when examining all participants. Compared to participants with a glucose of <89.5 mg/dL, those with glucose levels of 89.5-99.4 mg/dL had a 44% increased risk of breast cancer, and those with >99.5 mg/dL 66% increase in breast cancer risk. Women who were past users of hormone replacement therapy and who had a blood glucose of >89.5 had 3 times the risk of breast cancer compared to past hormone replacement therapy users with blood glucose levels of <89.5. (This finding indicate even unnatural-to-the-body estrogen and progestin drugs require higher glucose levels to induce breast tumors) Editor's note: Fasting glucose over 89.5 mg/dL had a 44% increase in breast cancer incidence and fasting glucose over 99.5 mg/dL had a 66% increased breast cancer risk compared to those with lower fasting glucose levels. Study #5: Stattin P, Björ O, Ferrari P, et al. Prospective Study of Hyperglycemia and Cancer Risk. Diabetes Care. 2007;30(3):561-7. Calculated relative risk of cancer for fasting glucose levels Examined fasting glucose and post load glucose concentrations for 33,293 women and 31,304 men Among women, relative risks of developing cancer (all sites) were statistically significantly increased with elevated plasma glucose concentrations with a relative risk of 1.26 and 1.31 for the top versus bottom quartile of fasting and postload glucose, respectively. Among women <49 years, relative risk (RR) of developing breast cancer was increased with fasting glucose (RR 2.13), for the top versus bottom quartile.* *Cut points for fasting glucose quartiles were not provided in the full text Conclusion: “The association of hyperglycemia with total cancer risk in women and men, independent of obesity, provides further evidence for an association between abnormal glucose metabolism and cancer.” Editor's note: Women under age 49 with higher fasting glucose 113% more likely to contract breast cancer compared to those with the lowest levels. Study #6: Bjorge T, Lukanova A, Jonsson H, et al. Metabolic syndrome and breast cancer in the Me-Can (metabolic syndrome and cancer) Project. Cancer Epidemiol Biomarkers Prev. 2010;19:1737-45. Examined the association between metabolic syndrome factors and risk of breast cancer incidence and mortality. Data on 288,834 European (Austria, Norway, Sweden) women enrolled during 1974-2005 was examined. Relative risk of breast cancer was estimated for BMI, blood pressure, glucose levels, cholesterol and triglycerides. The authors state: “Despite the inverse association of most MetS components with breast cancer before age 50, glucose was positively associated with risk. In women above age 60, blood pressure and glucose were associated with increased risk of breast cancer mortality.” Editor's note: Women over age 60 with higher glucose and blood pressure were more likely to die from breast cancer. Study #7: Garmendia ML, Pereira A, Alvarado ME, et al. Relation between insulin resistance and breast cancer among Chilean women. Ann Epidemiol. 2007;17(6):403-9. 171 pre and post-menopausal Chilean women ages 33-86. Insulin resistance was independently associated with breast cancer in postmenopausal women , but not in premenopausal women. Among all women, there were slightly increased odds of breast cancer with elevated plasma glucose level. Editor's note: Postmenopausal women with insulin resistance were 170% more likely to contract breast cancer than those without insulin resistance. Study #8: Rapp K, Schroeder J, Klenk J, et al. Fasting blood glucose and cancer risk in a cohort of more than 140,000 adults in Austria. Diabetologia. 2006;49(5):945-52. Investigation between fasting blood glucose and the incidence of cancer. A population-based cohort of more than 140,000 Austrian adults (63,585 men, 77,228 women) was followed over an average of 8.4 years. They found no increase in risk for breast cancer until blood glucose was >126 mg/dL. Editor's note: Breast cancer incidence did not increase until fasting glucose reached newly defined diabetic levels of over 126 mg/dL. Study #9: Manjer J, Kaaks R, Riboli E, et al. Risk of breast cancer in relation to anthropometry, blood pressure, blood lipids and glucose metabolism: a prospective study within the Malmö Preventive Project. Eur J Cancer Prev. 2001;10(1):33-42. Studied the relationship between breast cancer and obesity, hypertension, dyslipidemia, and glucose levels. Premenopausal women- Fasting glucose and relative risk (RR) of breast cancer by quartiles: <79 mg/dL, RR 1.0 >79- 85 mg/dL, RR 1.10 >85 – 90 mg/dL, RR 1.24 >90 mg/dL, RR 1.03 No significant differences in breast cancer risk were found for women from different quartiles of body mass index, blood pressure, serum triglycerides or blood glucose levels. Editor's note: Breast cancer incidence relatively unaffected by glucose mostly within normal ranges. Study # 10: Jee SH, Ohrr H, Sull JW, et al. Fasting serum glucose level and cancer risk in Korean men and women. JAMA. 2005;293(2):194-202. Examined the relationship between fasting serum glucose and diabetes and risk of all cancers and specific cancers in men and women in Korea. The main outcome measures were death from cancer and registry-documented incident cancer or hospital admission for cancer. Ten-year prospective cohort study of 1,298,385 Koreans (829,770 men and 468,615 women) aged 30 to 95 years. The highest fasting serum glucose (>140 mg/dL) had higher death rates from all cancers combined compared with the stratum with the lowest level (<90 mg/dL). By cancer site, the association was strongest for pancreatic cancer, comparing the highest and lowest strata in men and in women. 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. Age-adjusted mortality rate per 100,000 women due to breast cancer by fasting serum glucose level in Korean women, 1993-2002 is described below. Blood glucose <90 mg/dL, death rate 6 per 100,000 Blood glucose 90-109 mg/dL, death rate 7.5 per 100,000 Blood glucose 110-125 mg/dL, death rate 5.2 per 100,000 Blood glucose 126->140 mg/dL, death rate 6.1 per 100,000 Age-adjusted incidence rate of breast cancer per 100,000 women in relationship to blood glucose levels (1993-2002) is described below. Blood glucose <90 mg/dL, incidence rate 60.2 per 100,000, Blood glucose 90-109 mg/dL, incidence rate 63.8 per 100,000. Blood glucose 110-125 mg/dL, incidence rate 68.7 per 100,000 Blood glucose 126-139 mg/dL, incidence rate 65.2 per 100,000 Blood glucose >140 mg/dL, incidence rate 55.4 per 100,000 Editor's note: Breast cancer incidence unaffected by glucose within normal ranges. The reduced breast cancer rate in women in the highest glucose category may have been because the diabetic women were taking metformin, which is known to reduce breast cancer rates by 25% in a recent meta-analysis when used over 3 years.25 Study #11: Lawlor DA, Smith GD, and Ebrahim S. Hyperinsulinaemia and increased risk of breast cancer: findings from the British women’s heart and health study. Cancer Causes Control. 2004;15(3):267-75. Objective: To assess the association between fasting insulin levels and breast cancer. Participants: 3,868 women aged 60–79 years. There was a trend toward a higher fasting blood glucose level in women with breast cancer (109.73 mg/dL) vs. those without breast cancer (106.13 mg/dL). The authors state in the discussion: “…although some estimates were imprecise, fasting glucose, HOMA score [a measure of insulin resistance], diabetes and gestational glycosuria or diabetes were also positively associated with breast cancer risk, suggesting that previous exposure to high circulating insulin levels, as well as contemporary exposure, is related to increased risk of breast cancer. There was a positive linear association across the distribution of fasting insulin and diabetes with breast cancer.” Editor's note: Breast cancer incidence increased with poor glycemic control, possibly high levels of insulin and insulin resistance syndrome. Study #12: Osaki Y, Taniguchi S, Tahara A, et al. Metabolic syndrome and incidence of liver and breast cancers in Japan. Cancer Epidemiol. 2012;36(2):141-7. Evaluated the relationship between the presence of metabolic syndrome and the incidence of cancer in the general Japanese population. This was a retrospective cohort study among 8,329 males and 15,386 females between 1992 and 2000. A high glucose level, rather than metabolic syndrome, was the signiﬁcant associated factor for overall cancer and liver cancer development, whereas the metabolic syndrome was a signiﬁcant associated factor for breast cancer, even after adjusting for other components. Breast cancer was not associated with high glucose levels. Editor's note: The study found higher breast cancer in women with metabolic syndrome, higher overall cancer incidence associated with higher fasting glucose, but lower breast cancer incidence associated with higher glucose, possibly indicative of the breast cancer preventing effects of metformin prescribed to those with the highest fasting glucose. References Available at: http://www.womenshealthresearch.org/site/News2?page=NewsArticle&id=5361&news_iv_ctrl=0&abbr=press_. Accessed October 4, 2012. 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