Life Extension Magazine

Life Extension Magazine February 2013

Abstracts

Glucose and Cancer, Reishi, Tocopherol, and Hawthorn

Glucose tolerance and cardiovascular mortality: comparison of fasting and 2-hour diagnostic criteria.

BACKGROUND: New diagnostic criteria for diabetes based on fasting blood glucose (FBG) level were approved by the American Diabetes Association. The impact of using FBG only has not been evaluated thoroughly. The fasting and the 2-hour glucose (2h-BG) criteria were compared with regard to the prediction of mortality. METHODS: Existing baseline data on glucose level at fasting and 2 hours after a 75-g oral glucose tolerance test from 10 prospective European cohort studies including 15,388 men and 7,126 women aged 30 to 89 years, with a median follow-up of  8.8 years, were analyzed. Hazards ratios for death from all causes, cardiovascular disease, coronary heart disease, and stroke were estimated. RESULTS: Multivariate Cox regression analyses showed that the inclusion of FBG did not add significant information on the prediction of 2h-BG alone (P>.10 for various causes), whereas the addition of 2h-BG to FBG criteria significantly improved the prediction (P<.001 for all causes and P<.005 for cardiovascular disease). In a model including FBG and 2h-BG simultaneously, hazards ratios (95% confidence intervals) in subjects with diabetes on 2h-BG were 1.73 (1.45-2.06) for all causes, 1.40 (1.02-1.92) for cardiovascular disease, 1.56 (1.03-2.36) for coronary heart disease, and 1.29 (0.66-2.54) for stroke mortality, compared with the normal 2h-BG group. Compared with the normal FBG group, the corresponding hazards ratios in subjects with diabetes on FBG were 1.21 (1.01-1.44), 1.20 (0.88-1.64), 1.09 (0.71-1.67), and 1.64 (0.88-3.07), respectively. The largest number of excess deaths was observed in subjects who had impaired glucose tolerance but normal FBG levels. CONCLUSION: The 2h-BG is a better predictor of deaths from all causes and cardiovascular disease than is FBG.

Arch Intern Med. 2001 Feb 12;161(3):397-405

Prospective study on the role of glucose metabolism in breast cancer occurrence.

High circulating glucose, insulin resistance and obesity appear to be associated with increased risk of breast cancer (BC). We sought further insight into the relation of these variables to BC. We assessed associations of BC risk with serum fasting glucose, insulin, homeostasis model assessment-insulin resistance (HOMA-IR) index and sex-binding hormone globulin (SHBG) in women recruited to the ORDET cohort who gave blood samples in 1987-1992. After a median 13.5 years of follow-up, 356 women developed BC. Four matched controls per case were selected by incidence density sampling, and rate ratios (RR) were estimated by conditional logistic regression. Women in the highest glucose quartile had a significantly greater risk of BC than those in the lowest glucose quartile (RR 1.63; 95% CI: 1.14-2.32; p for trend of 0.003). The association was significant in pre and post menopausal women separately and in women diagnosed after 55 years. Women in the highest HOMA-IR quartile had higher BC risk than the lowest quartile (RR 1.44; 95% CI: 1.03-2.02). Significantly increased BC risk in women diagnosed after 55 years was also present in the highest HOMA-IR quartile; in the same group decreased BC risk was significantly associated with high SHBG. The results of this study add to the existing epidemiological evidence that hyperglycemia and insulin resistance increase BC risk.

Int J Cancer.2012 Feb 15;130(4):921-9

Repeated measures of serum glucose and insulin in relation to postmenopausal breast cancer.

Experimental and epidemiological evidence suggests that circulating glucose and insulin may play a role in breast carcinogenesis. However, few cohort studies have examined breast cancer risk in association with glucose and insulin levels, and studies to date have had only baseline measurements of exposure. We conducted a longitudinal study of postmenopausal breast cancer risk using the 6% random sample of women in the Women's Health Initiative clinical trials whose fasting blood samples, provided at baseline and at years 1, 3, and 6, were analyzed for glucose and insulin. In addition, a 1% sample of women in the observational study, who had glucose and insulin measured in fasting blood samples drawn at baseline and in year 3, were included in the analysis. We used Cox proportional hazards models to estimate hazard ratios and 95% confidence intervals for the association of baseline and follow-up measurements of serum glucose and insulin with breast cancer risk. All statistical tests were 2-sided. Among 5,450 women with baseline serum glucose and insulin values, 190 incident cases of breast cancer were ascertained over a median of 8.0 years of follow-up. The highest tertile of baseline insulin, relative to the lowest, was associated with a 2-fold increase in risk in the total population (multivariable hazard ratio 2.22, 95% confidence interval 1.39-3.53) and with a 3-fold increase in risk in women who were not enrolled in the intervention arm of any clinical trial (multivariable hazard ratio 3.15, 95% confidence interval 1.61-6.17). Glucose levels showed no association with risk. Analysis of the repeated measurements supported the results of the baseline analysis. These data suggest that elevated serum insulin levels may be a risk factor for postmenopausal breast cancer.

Int J Cancer.2009 Dec 1;125(11):2704-10

Prospective study of hyperglycemia and cancer risk.

OBJECTIVE: To investigate whether hyperglycemia is associated with increased cancer risk. RESEARCH DESIGN AND METHODS: In the Västerbotten Intervention Project of northern Sweden, fasting and postload plasma glucose concentrations were available for 33,293 women and 31,304 men and 2,478 incident cases of cancer were identified. Relative risk (RR) of cancer for levels of fasting and postload glucose was calculated with the use of Poisson models, with adjustment for age, year of recruitment, fasting time, and smoking status. Repeated measurements 10 years after baseline in almost 10,000 subjects were used to correct RRs for random error in glucose measurements. RESULTS: Total cancer risk in women increased with rising plasma levels of fasting and postload glucose, up to an RR for the top versus bottom quartile of 1.26 (95% CI 1.09-1.47) (P(trend) <0.001) and 1.31 (1.12-1.52) (P(trend) = 0.001), respectively. Correction for random error in glucose measurements increased these risks up to 1.75 (1.32-2.36) and 1.63 (1.26-2.18), respectively. For men, corresponding uncorrected RR was 1.08 (0.92-1.27) (P(trend) = 0.25) and 0.98 (0.83-1.16) (P(trend) = 0.99), respectively. Risk of cancer of the pancreas, endometrium, urinary tract, and of malignant melanoma was statistically significantly associated with high fasting glucose with RRs of 2.49 (1.23-5.45) (P(trend) = 0.006), 1.86 (1.09-3.31) (P(trend) = 0.02), 1.69 (0.95-3.16) (P(trend) = 0.049), and 2.16 (1.14-4.35) (P(trend) = 0.01), respectively. Adjustment for BMI had no material effect on risk estimates. CONCLUSIONS: The association of hyperglycemia with total cancer risk in women and in women and men combined for several cancer sites, independently of obesity, provides further evidence for an association between abnormal glucose metabolism and cancer.

Diabetes Care. 2007 Mar;30(3):561-7

Association between diabetes mellitus and breast cancer risk: a meta-analysis of the literature.

AIM/HYPOTHESIS: Diabetes and breast cancer are both serious life-threatening diseases across the world. Some studies shows that diabetes is associated with many kinds of tumor, but links with breast cancer remain controversial. The aim of this study was to assess the association the available evidence. SUBJECTS AND METHODS: A meta-analysis was conducted including 16 studies published between 2000 and 2010 and summary relative risks (RRs) with 95% CIs were calculated using random-effects model. RESULTS: The combined evidence supports that diabetes was associated with a statistically significant 23% increased risk of breast cancer, especially in postmenopausal women (RR=1.25 95%CI 1.20-1.29). The correlation between diabetes and breast cancer was the most obvious in Europe (RR=1.88,95%CI:1.56-2.25), followed by America (RR=1.16, 95%CI:1.12-1.20). In Asia the result was not significant (RR=1.01, 95%CI=0.84-1.21). Diabetes also increased mortality from breast cancer overall (RR=1.44, 95%CI:1.31-1.58). CONCLUSIONS/INTERPRETATION: This meta-analysis indicated that diabetes can be considered as a risk factor for breast cancer. In addition, menstruation status as well as geographical distribution can affect the relationship.

Asian Pac J Cancer Prev.2011;12(4):1061-5

Metabolic syndrome and breast cancer: an overview.

Worldwide, breast cancer is the most frequently diagnosed life-threatening cancer in women and the most important cause of cancer-related deaths among women. This disease is on the rise in Turkey. Metabolic syndrome is a cluster of metabolic disturbances including insulin resistance, dyslipidemia, hypertension, abdominal obesity and high blood sugar. Several studies have examined the association of the individual components of the metabolic syndrome with breast cancer. More recent studies have shown it to be an independent risk factor for breast cancer. It has also been associated with poorer prognosis, increased incidence, a more aggressive tumor phenotype. Basic research studies are now in progress to illuminate the molecular pathways and mechanisms that are behind this correlation. Given the fact that all of the components of metabolic syndrome are modifiable risk factors, preventive measures must be established to improve the outcome of breast cancer patients. In this review we set the background by taking into account previous studies which have identified the components of metabolic syndrome individually as breast cancer risk factors. Then we present the latest findings which elaborate possible explanations regarding how metabolic syndrome as a single entity may affect breast cancer risk.

J BUON.2012 Apr-Jun;17(2):223-9.

Metabolic syndrome and breast cancer in the me-can (metabolic syndrome and cancer) project.

BACKGROUND: Few studies have assessed the metabolic syndrome (MetS) as an entity in relation to breast cancer risk, and results have been inconsistent. We aimed to examine the association between MetS factors (individually and combined) and risk of breast cancer incidence and mortality. METHODS: Two hundred ninety thousand women from Austria, Norway, and Sweden were enrolled during 1974-2005, with measurements of height, weight, blood pressure, and levels of glucose, cholesterol, and triglycerides. Relative risks (RR) of breast cancer were estimated using Cox proportional hazards regression for each MetS factor in quintiles and for standardized levels (z-scores) and for a composite z-score for the MetS. RESULTS: There were 4,862 incident cases of breast cancer and 633 deaths from breast cancer identified. In women below age 50, there was a decreased risk of incident cancer for the MetS (per 1-unit increment of z-score; RR, 0.83; 95% confidence interval, 0.76-0.90) as well as for the individual factors (except for glucose). The lowest risks were seen among the heaviest women. In women above age 60, there was an increased risk of breast cancer mortality for the MetS (RR, 1.23; 95% confidence interval, 1.04-1.45) and for blood pressure and glucose. The strongest association with mortality was seen for increased glucose concentrations. CONCLUSIONS: The MetS was associated with a decreased risk of incident breast cancer in women below age 50 with high body mass index, and with an increased risk of breast cancer mortality in women above 60. IMPACT: Lifestyle interventions as recommended for cardiovascular disease prevention may be of value to prevent breast cancer mortality in postmenopausal women.

Cancer Epidemiol Biomarkers Prev.2010 Jul;19(7):1737-45

Inflammation markers and metabolic characteristics of subjects with 1-h plasma glucose levels.

OBJECTIVE: To assess the association of 1-h plasma glucose (1hPG) and inflammation with normal glucose tolerance (NGT) and pre-diabetes. RESEARCH DESIGN AND METHODS: A cohort of 1,062 subjects was enrolled. After oral glucose load (oral glucose tolerance test), we compared subjects with NGT and pre-diabetes above and below the 1hPG cut point (155 mg/dl). Fibrinogen and leukocytes count (white blood cells [WBCs]) for subclinical inflammation, lipid ratios, insulin sensitivity (Matsuda index) were determined. RESULTS: Patients with NGT and pre-diabetes (1hPG >155 mg/dl) showed a significant increase of inflammatory markers and lipid ratios (for all, P < 0.05). In age-, sex-, and BMI-adjusted analysis, 1hPG was associated with a significantly higher WBC count and fibrinogen (P < 0.05). Patients with elevated 1hPG showed a highly significant lower insulin sensitivity than subjects <1hPG (P < 0.01). CONCLUSIONS: Elevated 1hPG in subjects with NGT and pre-diabetes is associated with subclinical inflammation, high lipid ratios, and insulin resistance. Therefore, 1hPG >155 mg/dl could be considered a new "marker" for cardiovascular risk.

Diabetes Care. 2010 Feb;33(2):411-3. Epub 2009 Nov 16

Higher normal fasting plasma glucose is associated with hippocampal atrophy: The PATH Study.

OBJECTIVES: Substantial evidence showing an association between type 2 diabetes (T2D) and cerebral atrophy, cognitive impairment, and dementia is accumulating. However, relatively little is known about the subclinical effects of high plasma glucose levels within the normal range. The aim of this study was to investigate the association between plasma glucose levels and hippocampal and amygdalar atrophy in a sample of 266 cognitively healthy individuals free of T2D, aged 60-64 years, taking part in a longitudinal study of aging. METHODS: Fasting plasma glucose was assessed at wave 1. Hippocampal and amygdalar volumes were manually traced on 1.5 T MRI scans collected at wave 1 and at wave 24 years later. General linear model analyses were used to assess the relationship between plasma glucose and incident medial temporal lobe atrophy after controlling for a range of sociodemographic and health variables. RESULTS: Plasma glucose levels were found to be significantly associated with hippocampal and amygdalar atrophy and accounted for 6%-10% in volume change after controlling for age, sex, body mass index, hypertension, alcohol, and smoking. CONCLUSIONS: High plasma glucose levels within the normal range (<6.1 mmol/L) were associated with greater atrophy of structures relevant to aging and neurodegenerative processes, the hippocampus and amygdala. These findings suggest that even in the subclinical range and in the absence of diabetes, monitoring and management of plasma glucose levels could have an impact on cerebral health. If replicated, this finding may contribute to a reevaluation of the concept of normal blood glucose levels and the definition of diabetes.

Neurology. 2012 Sep 4;79(10):1019-26

Coffee consumption and the incidence of type 2 diabetes in men and women with normal glucose tolerance: the Strong Heart Study.

BACKGROUND AND AIMS: It was reported that high coffee consumption was related to decreased diabetes risk. The aim of this study is to examine the association between coffee consumption and the incidence of type 2 diabetes in persons with normal glucose tolerance in a population with a high incidence and prevalence of diabetes. METHODS AND RESULTS: In a prospective cohort study, information about daily coffee consumption was collected at the baseline examination (1989-1992) in a population-based sample of American Indian men and women 45-74 years of age. Participants with normal glucose tolerance (N = 1141) at the baseline examination were followed for an average of 7.6 years. The incidence of diabetes was compared across the categories of daily coffee consumption. The hazard ratios of diabetes related to coffee consumption were calculated using Cox proportional hazards models, adjusted for potential confounders. Levels of coffee consumption were positively related to levels of current smoking and inversely related to body mass index, waist circumference, female gender, and hypertension. Compared to those who did not drink coffee, participants who drank 12 or more cups of coffee daily had 67% less risk of developing diabetes during the follow-up (hazard ratio: 0.33, 95% confidence interval: 0.13, 0.81). CONCLUSION: In this population, a high level of coffee consumption was associated with a reduced risk of deterioration of glucose metabolism over an average 7.6 years of follow-up. More work is needed to understand whether there is a plausible biological mechanism for this observation.

Nutr Metab Cardiovasc Dis. 2011 Jun;21(6):418-23

Reishi

Protective effects of Ganoderma lucidum spore on cadmium hepatotoxicity in mice.

The medicinal fungus Ganoderma lucidum has been shown to have hepatoprotective effects. G. lucidum contains triterpenes and polysaccharides, and the Sporoderm-broken G. lucidum powder is particular beneficial. This study utilized G. lucidum spore to examine its effect on [Cd(II)]-induced hepatotoxicity in mice and the mechanism of the protection. Mice were pretreated with G. lucidum spore (0.1, 0.5, and 1.0g/kg, po, for 7days), and subsequently challenged with a hepatotoxic dose of Cd(II) (3.7mg/kg, ip). Liver injury was evaluated 8h later. G. lucidum spore protected against Cd(II)-induced liver injury in a dose-dependent manner, as evidenced by serum alanine aminotransferase, aspartate aminotransferase and histopathology. To examine the mechanism of protection, subcellular distribution of Cd(II) was determined. G. lucidum spore decreased Cd(II) accumulation in hepatic nuclei, mitochondria, and microsomes, but increased Cd(II) distribution to the cytosol, where Cd(II) is sequestered by metallothionein, a protein against Cd(II) toxicity. Indeed, G. lucidum spore induced hepatic metallothionein-1 mRNA 8-fold, and also increased metallothionein protein as determined by the Cd(II)/hemoglobin assay. Cd(II)-induced oxidative stress was also decreased by G. lucidum spore, as evidenced by decreased formation of malondialdehyde. In summary, G. lucidum spore is effective in protection against Cd(II)-induced hepatotoxicity, and this effect is due, at least in part, to the induction of hepatic metallothionein to achieve beneficial effects.

Food Chem Toxicol.2012 May 29

Ganoderma lucidum polysaccharide accelerates refractory wound healing by inhibition of mitochondrial oxidative stress in type 1 diabetes.

BACKGROUND/AIMS: Refractory wounds in diabetic patients constitute a serious complication that often leads to amputation with limited treatment regimens. The present study was designed to determine the protective effect of Ganoderma lucidum polysaccharide (Gl-PS) on diabetic wound healing and investigate underlying mechanisms. METHODS: Streptozotocin (STZ)-induced type 1 diabetic mice with full-thickness excisional wounds were intragastrically administered with 10, 50 or 250 mg/kg/day of Gl-PS. RESULTS: Gl-PS dose-dependently rescued the delay of wound closure in diabetic mice. 50 and 250 mg/kg/day of Gl-PS treatment significantly increased the mean perfusion rate around the wound in diabetic mice. Diabetic conditions markly increased mitochondrial superoxide anion (O(2)·(-)) production, nitrotyrosine formation, and inducible nitric oxide synthase (iNOS) activity in wound tissues, which were normalized with Gl-PS treatment. In diabetic wound tissues, the protein level of manganese superoxide dismutase (MnSOD) was unchanged whereas MnSOD activity was inhibited and its nitration was potentiated; Gl-PS administration suppressed MnSOD nitration and increased MnSOD and glutathione peroxidase (GPx) activities. Moreover, Gl-PS attenuated the redox enzyme p66Shc expression and phosphorylation dose-dependently in diabetic mice skin. CONCLUSION: Gl-PS rescued the delayed wound healing and improved wound angiogenesis in STZ-induced type 1 diabetic mice, at least in part, by suppression of cutaneous MnSOD nitration, p66Shc and mitochondrial oxidative stress.

Cell Physiol Biochem.2012;29(3-4):583-94