Elevated Serum Insulin is an Independent Risk Factor for Hepatocellular Carcinoma: A Case Control Study from Nepal

Aim: To investigate associations of fasting insulin and glucose levels in serum with hepatocellular carcinomarisk. Materials and Methods: This hospital based study was carried out using data retrieved from the registermaintained in the Department of Biochemistry of the Nepalese Army Institute of Health Sciences, between1st December, 2011 and 31st June, 2013. The variables collected were age, fasting plasma glucose, fastingplasma insulin and ALT. Quantitative determination of human insulin concentrations was accomplished bychemiluminescence enzyme immunoassay. Results: Of the total 220 subjects enrolled in our present study, 20cases were of HCC and 200 were healthy controls. The maximum number of cases of hepatocellular carcinomain category cutpoints of fasting insulin levels fell in the range of >6.10 μU/ml. The highest insulin levels (>6.10μU/ml) were seen to be associated with an 2.36 fold risk of HCC when compared with fasting insulin levels of(<2.75 μU/ml). Furthermore, the insulin levels (2.75-4.10 μU/ml) of category cutpoints also conferred a 1.57fold risk for HCC when compared with lowest fasting insulin levels of (<2.75 μU/ml). Conclusions: The effectof an insulin level in increasing HCC risk appeared consistent, influencing incidence, risk of recurrence, overallsurvival, and treatment-related complications in HCC patients.     

Reversal of tumor-induced biochemical abnormalities by insulin treatment in rats

In F344 rats bearing transplantable 3-methylcholanthrene (CAS: 56-49-5)-induced sarcomas, plasma concentrations of immunoreactive insulin were decreased following the development of mild or severe anorexia. Plasma levels of immunoreactive glucagon and lactate were elevated in severely anorectic tumor-bearing (TB) rats, while plasma glucose concentrations remained normal. Both groups of TB rats exhibited decreased plasma levels of serine, glutamine, citrulline, and tryptophan and increased concentrations of alanine. Plasma levels of proline and phenylalanine were also elevated in the severely anorectic TB rats. In a second experiment, 7 daily treatments with insulin corrected the anorexia for 6 days and increased body weights of TB rats. Plasma concentrations of lactate and immunoreactive glucagon were decreased, and the abnormal plasma concentrations of glutamine, proline, analine, and phenylalanine were altered toward normal following the insulin treatments. Therefore, these data are consistent with insulin treatments benefiting the TB host by increasing feeding, increasing body weight, reducing tumor glycolysis and metabolism, reducing gluconeogenesis, and reducing host catabolism, while not stimulating tumor growth. Thus insulin therapy may have potential benefits in cancer treatment by shifting glucose metabolism toward the host and away from the tumor.     

Glucose Intolerance, Plasma Insulin Levels, and Colon Adenomas in Japanese Men

Hyperinsulinemia may be related to colon carcinogenesis. Several studies have suggested that diabetes mellitus is related to increased risk of colon cancer. We examined cross-sectionally the relation of fasting plasma insulin levels and glucose tolerance status to colon adenomas. In a consecutive series of 951 men undergoing total colonoscopy for a health examination at the Japan Self Defense Forces Fukuoka Hospital from April 1998 to August 1999, we identified 233 cases of colon adenomas and 497 controls with normal colonoscopy. Glucose tolerance status was determined by a 75-g oral glucose tolerance test, and subjects were classified as normal, unpaired glucose tolerance (IGT) or non-insulin dependent diabetes mellitus (NIDDM). Plasma insulin levels were measured after subjects had fasted overnight. Logistic regression analysis and analysis of covariance was used to control for age and obesity. While plasma insulin levels were unrelated to colon adenomas, NIDDM was associated with a significantly increased risk of colon adenomas. There was no association between IGT and colon adenomas. NIDDM was more strongly associated with proximal colon adenomas. The findings suggest that long-term hyperinsulinemic status associated with NIDDM may increase the risk of colon adenomas, and subsequently of colon cancer.     

Glucose intolerance, plasma insulin levels, and colon adenomas in Japanese men.

Hyperinsulinemia may be related to colon carcinogenesis. Several studies have suggested that diabetes mellitus is related to increased risk of colon cancer. We examined cross-sectionally the relation of fasting plasma insulin levels and glucose tolerance status to colon adenomas. In a consecutive series of 951 men undergoing total colonoscopy for a health examination at the Japan Self Defense Forces Fukuoka Hospital from April 1998 to August 1999, we identified 233 cases of colon adenomas and 497 controls with normal colonoscopy. Glucose tolerance status was determined by a 75-g oral glucose tolerance test, and subjects were classified as normal, impaired glucose tolerance (IGT) or non-insulin dependent diabetes mellitus (NIDDM). Plasma insulin levels were measured after subjects had fasted overnight. Logistic regression analysis and analysis of covariance was used to control for age and obesity. While plasma insulin levels were unrelated to colon adenomas, NIDDM was associated with a significantly increased risk of colon adenomas. There was no association between IGT and colon adenomas. NIDDM was more strongly associated with proximal colon adenomas. The findings suggest that long-term hyperinsulinemic status associated with NIDDM may increase the risk of colon adenomas, and subsequently of colon cancer.     

Mechanism of impaired glucose tolerance in patients with neoplasia.

The disappearance rate (k) of i.v. glucose was measured in cachectic and non-cachectic cancer patients and tumour-free controls. The respective k values were found to be 1.06 +/- 0.27 (mean +/- s.d.), 1.64 +/- 0.34 and 1.63 +/- 0.23. Of the other parameters measured, only plasma albumin level was found to vary significantly amongst the 3 categories, the mean level being the lowest in cachectic cancer patients. The means of total plasma protein, fasting blood glucose and plasma liver enzyme concentrations were similar in the 3 groups. Glucagon, a potent insulin secretogogue, failed to augment the fasting insulin level in cachectic but did so in non-cachectic cancer patients. Taken together, the findings suggest that the reduced glucose tolerance in patients with neoplasia is due to impairment of insulin release exhibited predominantly by ill-nourished advanced cancer patients having a moderate to sever degree of hypoalbuminemia.     

Whole body hyperthermia improves obesity-induced insulin resistance in diabetic mice.

AIM: In this study, we examined the efficacy of whole body hyperthermia (WBH) on obesity-induced insulin resistance in diabetic mice. METHODS: Male db/db mice were treated with WBH 3 times per week for 12 weeks. The rectal temperature of mice reached 38.0 degrees C 5 min after heating, and was kept at 38.0 degrees C for 30 min. At the end of each week, tail snip glucose levels were determined under fasting conditions. The GLUT-4 gene expression of muscle tissue was analyzed by real-time PCR. RESULTS: (1) WBH-treated db/db mice showed a significant decrease in fasting blood glucose level as compared with untreated db/db mice (p < 0.01). (2) Plasma insulin levels in untreated db/db mice at the age of 10 weeks were significantly increased compared with those of db/+ mice (p < 0.0001). On the other hand, the reduction (31%) in insulin levels in WBH-treated mice indicated improved insulin sensitivity. (3) The ability of WBH to increase insulin sensitivity was further established in glucose tolerance tests and insulin tolerance tests. (4) Urine albumin of db/db mice significantly increased compared with those of db/+ mice at 18 weeks of age (p < 0.001). This increase in urinary albumin was significantly inhibited by WBH (p < 0.01). (5) WBH up-regulated the expression of GLUT4 mRNA in skeletal muscle. CONCLUSION: Although the mechanisms have not yet been completely investigated, WBH may provide a new therapeutic or preventive modality against obesity-related diseases such as T2DM and metabolic or insulin resistance syndrome.     

Effects of transplantation and resection of a radiation-induced rat insulinoma on glucose homeostasis and the endocrine pancreas

Twenty-one days after s.c. subscapular transplantation of a radiation-induced insulinoma, male NEDH rats exhibited hyperinsulinaemia and hypoglycaemia. These features were associated with islet atrophy, degenerative changes in pancreatic A and B cells, and decreases in the pancreatic contents of insulin, glucagon and somatostatin. The immunoreactive glucagon and somatostatin contents of extrapancreatic tissues of insulinoma-bearing rats were unchanged. Surgical resection of the tumour resulted in an immediate fall of plasma insulin, attaining concentrations similar to those of anaesthetised control rats by 10 min. The estimated half-life of insulin was 3.5 min. Hypoglycaemia persisted until 60 min after resection, followed by hyperglycaemia of 1-2 days duration. Glucose tolerance was impaired 1 day after tumour resection despite the coexistence of raised insulin concentrations. Evidence for abnormal pancreatic B cell function was gained by injection of arginine which failed to evoke a plasma insulin response in the resected rats. Two days after resection, plasma glucose and insulin concentrations were similar to those of control rats. Plasma glucose and insulin responses to glucose and arginine were suggestive of tumour recurrence by 12 days. A single large encapsulated tumour was eventually observed in each rat, with resection giving a 17-56 day prolongation of life.     

Homeostasis model assessment to detect insulin resistance and identify patients at high risk of breast cancer development: National Cancer Institute of Naples experience

Background

Metabolic Syndrome (MS) has been correlated to breast carcinogenesis. MS is common in the general population (34%) and increases with age and body mass index. Although the link between obesity, MS and hormone related cancer incidence is now widely recognized, the molecular mechanisms at the basis of such increase are still poorly characterized. A crucial role is supposed to be played by the altered insulin signalling, occurring in obese patients, which fuels cancer cell growth, proliferation and survival. Therefore we focused specifically on insulin resistance to investigate clinically the potential role of insulin in breast carcinogenesis.

Methods

975 patients were enrolled and the association between MS, insulin resistance, and breast cancer was evaluated. Women were stratified by age and menopausal status. Insulin resistance was measured through the Homeostasis Model Assessment score (HOMA-IR). The cut off value to define insulin resistance was HOMA-IR ≥ 2.50.

Results

Higher prevalence of MS (35%) was found among postmenopausal women with breast cancer compared to postmenopausal healthy women (19%) [OR 2.16]. A broad range of BMI spanning 19–48 Kg/m² was calculated. Both cases and controls were characterized by BMI ≥ 25 Kg/m² (58% of cases compared to 61% of controls). Waist circumference >88 cm was measured in 53% of cases - OR 1.58- (95% CI 0.8-2.8) and in 46% of controls. Hyperinsulinemia was detected in 7% of cases – OR 2.14 (95% CI 1.78-2.99) and only in 3% of controls. HOMA-IR score was elevated in 49% of cases compared to 34% of controls [OR 1.86], suggesting that insulin resistance can nearly double the risk of breast cancer development. Interestingly 61% of women operated for breast cancer (cases) with HOMA-IR ≥ 2.5 presented subclinical insulin resistance with fasting plasma glucose levels and fasting plasma insulin levels in the normal range. Both android fat distribution and insulin resistance correlated to MS in the subgroup of postmenopausal women affected by breast cancer.

Conclusions

Our results further support the hypothesis that MS, in particular insulin resistance and abdominal fat, can be considered as risk factors for developing breast cancer after menopause. We suggest that HOMA-IR, rather than fasting plasma glucose and fasting plasma insulin levels alone, could be a valuable tool to identify patients with subclinical insulin resistance, which could be relevant for primary prevention and for high risk patient screening.     

Insulin, glucose and hepatocellular carcinoma risk in male hepatitis B carriers: results from 17-year follow-up of a population-based cohort

This study aimed to investigate the association of fasting insulin and glucose levels with hepatocellular carcinoma (HCC) risk in a case-cohort study within a cohort (1989-2006) of 2903 male government employees chronically infected with hepatitis B virus (HBV) in Taiwan. Insulin, glucose and HBV-related factors were assayed in baseline plasma among 124 HCC cases and a random subcohort of 1084 of the total cohort. After adjustment for demographics and HBV-related factors, including viral load and genotype, the HCC risk was higher for the highest [>6.10 μU/ml, hazard ratio (HR) = 2.36, 95% confidence interval (CI): 1.43-3.90] and lowest (<2.75 μU/ml, HR = 1.57, 95% CI: 0.96-2.58) categories of insulin, compared with insulin of 2.75-4.10 μU/ml. The dose-response relationship between insulin and HCC varied by follow-up time, with stronger association for the HCC cases that occurred ≥8 years after baseline (P for trend <0.0001). The effect of higher insulin on HCC risk remained after adjustment for other metabolic factors, and was fairly consistent across strata of age, body mass index, and HBV genotypic variants. However, it was more profound among those with viral load <4.39 log(10) copies/ml at recruitment (>6.10 μU/ml, HR = 6.15, 95% CI: 2.48-15.22). Higher insulin was also associated with an increased risk for cirrhosis diagnosed by ultrasonography and elevated alanine aminotransferase. No association with either cirrhosis or HCC was noted for glucose or diabetes after adjusting for insulin. In conclusion, elevated insulin levels are an independent risk factor for HCC among HBV carriers, especially for those with lower viral load.     

2型糖尿病合并胃癌患者血清IGF-1、IGFBP-3的变化

目的:研究2型糖尿病（diabetes mellitus,DM）合并胃癌（gastric cancer,GC）患者血清胰岛素样生长因子-1（insulin-like growth factor-1,IGF-1）、胰岛素样生长因子结合蛋白-3(insulin-like growth factor binding protein-3,IGFBP-3)的变化。方法:选择2型DM患者30例（DM组）、2型DM合并GC患者48例（DM并GC组）为研究对象,ELISA 法测定血清IGF-1、 IGFBP-3水平;同时测定空腹血糖、空腹胰岛素、血脂水平。 结果:DM并GC组的IGF-1、IGF-1/IGFBP-3比值高于DM组（P<0.05）,IGFBP-3在两组之间无统计学差异（P>0.05）。IGF-1、IGF-1/IGFBP-3比值与空腹胰岛素水平呈正相关（r=0.598,0.626,P=0.000）,IGF-1/IGFBP-3比值是DM并GC患者淋巴结转移的危险因素（OR=2.142,P=0.001）。结论:IGF-1可能参与2型DM合并GC的发生及淋巴结转移。     

Insulin resistance, apoptosis, and colorectal adenoma risk.

Compelling evidence from epidemiologic studies indicates that elevated circulating insulin-like growth factor (IGF)-I, insulin resistance, and associated complications, such as elevated fasting plasma insulin, glucose and free fatty acids, glucose intolerance, increased body mass index, and visceral adiposity, are linked with increased risk of colorectal cancer. However, the role of insulin and markers of glucose control in the development of adenomas, precursors to colorectal cancer, has not been fully explored. We evaluated the relationship between plasma insulin, glucose, IGF-I, IGF-II, IGF-binding protein-3 (IGFBP-3), apoptosis, and colorectal adenomas in a case-control study. Participants were drawn from consenting patients undergoing colonoscopy at the University of North Carolina hospitals (Chapel Hill, NC). Participants were classified as cases or controls based on whether they had one or more colorectal adenomatous polyps. Fasting plasma insulin, IGF-I, IGF-II, and IGFBP-3 levels were assessed by ELISA. Glucose was measured by glucose hexokinase assay. Apoptosis was assessed by morphology on H&E-stained sections. Dietary and lifestyle information were obtained by telephone interview. Logistic regression was used to examine the association between adenoma status and insulin-IGF markers. Adenoma cases (n = 239) and adenoma-free controls (n = 517) provided rectal biopsies and/or blood samples and interview data. Consistent with prior findings, cases were more likely to be males, older, have higher waist-to-hip ratio, lower calcium intake, lower apoptosis, and less likely to report nonsteroidal anti-inflammatory drug use. Those in the highest quartile of insulin (adjusted odds ratio, 2.2; 95% confidence interval, 1.1-4.2) and glucose (adjusted odds ratio, 1.8; 95% confidence interval, 0.9-3.6) were more likely to have an adenoma compared with the lowest quartile. Similarly, subjects in the highest two quartiles of insulin were more likely to be in the lowest two quartiles of apoptosis. Overall, there were no significant differences between mean circulating levels of glucose, IGF-I, IGF-II, and IGFBP-3 among cases and controls and no association between these variables and apoptosis. The results provide novel evidence that elevated insulin and glucose are associated with increased adenoma risk and decreased apoptosis in normal rectal mucosa. These findings suggest that insulin may act early in the adenoma-carcinoma sequence to promote the development of colorectal adenoma by decreasing apoptosis in the normal mucosa.     

原发性肝癌患者糖代谢的临床分析

目的探讨原发性肝癌患者糖代谢的临床特征。方法检测原发性肝癌患者82例及健康对照组35例空腹及服糖后血糖、胰岛素、C肽水平，计算胰岛素抵抗指数（IR）、胰岛β细胞功能指数（IS）及胰岛素指数（INSindex）。结果与对照组比较，肝癌组空腹血糖差异无统计学意义（P〉0．05），服糖后血糖显著升高（P〈0．05）；肝癌组空腹及服糖后胰岛素和C肽值均呈显著性升高（P〈0．001）。肝癌患者空腹IR、IS均明显高于对照组（P〈0．05），而INSindex值显著低于对照组（P〈0．05）。结论原发性肝癌患者在空腹血糖正常时已存在胰岛素抵抗、空腹高胰岛素血症和糖负荷后的胰岛素分泌障碍，故极易发生糖代谢异常，且发病隐匿。肝源性糖代谢异常的防治应从血糖正常时开始，保护胰岛β细胞功能尤其重要。     

Postprandial hypoglycemia in islet beta cell hyperplasia with adenomatosis of the pancreas.

Organic hyperinsulinism causing hypoglycemia in adults is caused by insulinoma, islet hyperplasia, or a combination of adenomata and hyperplasia. We present a patient with long-standing symptoms of postprandial hypoglycemia occurring within 15 minutes of meals in the absence of fasting hypoglycemic symptoms. An intravenous glucagon stimulation test resulted in a rise of plasma insulin from 194 to 21,883 pmol/L at 7.5 minutes. Blood glucose simultaneously rose from 4.9 to 5.9 mmol/L. A glucose tolerance test revealed an exuberant insulin response. A euglycemic hyperinsulinemic clamp demonstrated incomplete suppression of plasma C-peptide. At surgery, three nodules were found and a 50-60% distal pancreatectomy was performed. The pancreas revealed a combination of multiple beta-cell islet adenomata and islet hyperplasia with no evidence of nesidioblastosis. The coexistence of islet adenomata with hyperplasia must be considered in the differential diagnosis of postprandial hypoglycemia.     

Relationship of hepatic glucose production to growth hormone and severity of malnutrition in a population with colorectal carcinoma

To define the influence of weight loss on the severity of metabolic abnormalities in patients with the same stage and primary site of cancer, hepatic glucose production (HGP) and nutritional status were determined in 44 patients with advanced, Stage D colorectal carcinoma and compared to values in seven cancer-free controls. The colorectal cancer patients were divided into three groups based upon percentage of ideal body weight. HGP was determined in all participants after an overnight fast by using a 3- or 4-h primed, continuous infusion of [6-3H]glucose. Fasting glucose, insulin, cortisol, thyroxine, triiodothyronine, and growth hormone values were also determined. Mean HGP was significantly elevated in colorectal carcinoma patients versus normal subjects (2.35 +/- 0.89 (SD) mg/kg/min versus 1.75 +/- 0.16; P less than 0.01). The most severely malnourished group (ideal body weight less than 90%) demonstrated the greatest increase in HGP (2.98 +/- 0.73 mg/kg/min). Growth hormone mean fasting levels were significantly elevated in the colorectal carcinoma population compared to the normal subjects (2.9 +/- 3.1 ng/ml versus 0.5 +/- 0.2; P less than 0.001). The most severely malnourished group also demonstrated the highest growth hormone levels. The rate of HGP was significantly correlated with fasting growth hormone levels (r = 0.71; P less than 0.001) and not significantly correlated to cortisol, insulin, thyroxine, triiodothyronine, or glucose levels in carcinoma patients. Thus, the elevation in HGP seen in patients with colorectal carcinoma is related to the severity of weight loss and is associated with elevations in fasting growth hormone.     

Association of plasma total and high-molecular-weight adiponectin with risk of colorectal cancer: an observational study in Chinese male

The research is to investigate the association between plasma concentrations of total and high-molecular-weight (HMW) adiponectin and risk of early and advanced colorectal cancer. One hundred and sixty-five male colorectal cancer patients and one hundred and two controls were enrolled; based on the T factor of the TNM system, intraepithelial carcinoma and submucosally invasive carcinoma were defined as early cancer, and invasion into the muscularis propria or deeper was defined as advanced cancer. The plasma levels of glucose, fasting insulin, total cholesterol, triglyceride, and total and HMW adiponectin levels were measured. Each factor level was designated as low or high, and the risk of cancer was estimated by univariate and multivariate logistic regression analyses. In the patients with early cancer, high waist/hip ratio (WHR), high fasting insulin, high HOMA model insulin resistance index (HOMA-IR), low total adiponectin and HMW adiponectin were all associated with a significant increase in the odds ratio (OR) by univariate analysis. In multivariate analysis, WHR, HOMA-IR, total adiponectin and HMW adiponectin were all related to increased cancer risk. However, in the patients with advanced cancer, only low HMW adiponectin was associated with a significant increase in the OR by univariate analysis. In multivariate analysis, a low HMW adiponectin level was still related to increased cancer risk, with an adjusted OR of 3.971 (P?=?0.036). In conclusion, a decreased level of adiponectin was a strong risk factor not only for early colorectal cancer but also for advanced colorectal in Chinese male patients. HMW adiponectin might be more closely associated with colorectal cancer risk than total adiponectin.     

Pancreatic cancer in rats and hamsters does not induce IAPP-related hyperglycaemia

Many patients with exocrine pancreatic cancer develop diabetes mellitus due to insulin resistance. This may relate to concurrent over-production of islet amyloid polypeptide (IAPP) by the pancreatic beta cells. We investigated the effects of pancreatic cancer on circulating IAPP and glucose homeostasis in azaserine-treated rats (developing acinar pancreatic tumours) and BOP-treated hamsters (developing ductular pancreatic tumours). Glucose, insulin and IAPP levels in plasma were neither affected in azaserine-only treated rats nor in animals with enhanced carcinogenesis after chronic caerulein treatment. Azaserine-treated rats on a high-fat diet had decreased insulin levels and enhanced IAPP/insulin ratios in plasma, without hyperglycaemia. All BOP-treated hamsters showed pancreatic carcinogenesis at 6 months post-treatment. Supranormal plasma glucose levels in animals on a low-fat diet were the only change observed. After a second 6-month period, subnormal plasma glucose levels, at least 4-fold decreased plasma insulin and up to 2-fold decreased plasma IAPP levels were present in all hamsters. Remarkably, both in azaserine-treated rats on high-fat and in BOP-treated hamsters, decreased insulin levels and elevated IAPP/insulin ratios are not associated with hyperglycaemia. In contrast to humans with pancreatic cancer, IAPP over-production and hyperglycaemia do not develop in rats and hamsters with (pre-)neoplastic pancreatic lesions. Int. J. Cancer 72:637–641, 1997. © 1997 Wiley-Liss, Inc.     

Hyperglycemia and insulin resistance in men with prostate carcinoma who receive androgen-deprivation therapy

BACKGROUND: Prostate carcinoma (PCa) is one of the most common malignancies in men. Androgen-deprivation therapy (ADT) is used frequently in the treatment of recurrent and metastatic PCa, rendering these men hypogonadal. Because male hypogonadism is associated with an unfavorable metabolic profile, and men with PCa have high cardiovascular mortality, the authors evaluated the effects of long-term ADT on fasting glucose levels, insulin levels, and insulin resistance. METHODS: To evaluate the long-term effects of ADT on fasting glucose and insulin resistance in men with PCa who received ADT and to determine whether these metabolic alterations are a result of hypogonadism, the authors conducted a cross-sectional study at a university-based research institution in the United States. In total, 53 men were evaluated, including 18 men with PCa who received ADT for at least 12 months prior to the onset of the study (the ADT group), 17 age-matched men with nonmetastatic PCa who had undergone prostatectomy and/or received radiotherapy and who were not receiving ADT (the non-ADT group), and 18 age-matched controls (the control group). None of the men had a known history of diabetes mellitus. RESULTS: The mean age was similar in all 3 groups (P=0.33). Serum total testosterone levels (P<0.0001) and free testosterone levels (P<0.0001) were significantly lower in the ADT group compared with the other groups. Men in the ADT group had a higher BMI compared with the other groups (overall P=0.005). After adjustment for age and BMI, men in the ADT group had significantly higher fasting levels of the following parameters: 1) Glucose levels were 131.0+/-7.43 mg/dL in the ADT group compared with 103.0+/-7.42 mg/dL in the non-ADT group (P=0.01) and 99.0+/-7.58 mg/dL in the control group (P<0.01). 2) Insulin levels were 45.0+/-7.25 uU/mL in the ADT group compared with 24.0+/-7.24 uU/mL in the non-ADT group (P=0.05) and 19.0+/-7.39 uU/mL in the control group (P=0.02). 3) Leptin levels were 25.0+/-2.57 ng/mL in the ADT group compared with 12.0+/-2.56 ng/mL in the non-ADT group (P<0.01) and 6.0+/-2.62 ng/mL in the control group (P<0.01). 4) The homeostatic model assessment for insulin resistance (HOMAIR)=17.0+/-2.78 in the ADT group compared with HOMAIR=6.0+/-2.77 in the non-ADT group (P<0.01) and HOMAIR=5.0+/-2.83 in the control group (P=0.01). There was a significant negative correlation between total and free testosterone levels with fasting glucose, insulin, leptin, and HOMAIR. CONCLUSIONS: The current data suggested that men with PCa who are receiving long-term ADT are at risk for developing insulin resistance and hyperglycemia, thus leading to their increased risk of cardiovascular disease. This adverse metabolic profile developed independent of age and BMI and appeared to be a direct result of androgen deprivation.     

Relations of Insulin Resistance and Serum Concentrations of Estradiol and Sex Hormone-binding Globulin to Potential Breast Cancer Risk Factors

There is a hypothesis that hyperinsulinemia or insulin resistance may be a mediator for breast cancer risk factors. On the other hand, some, but not all, of the well-known risk factors of breast cancer have been associated with serum estrogen concentrations. We assessed the relationships of potential breast cancer risk factors to indicators of insulin resistance, fasting plasma insulin concentration and homeostasis model assessment insulin resistance (HOMA-R), in 88 postmenopausal Japanese women. We also examined whether insulin resistance would explain the association of breast cancer risk factors with serum estradiol and sex hormone-binding globulin (SHBG). Information on potential breast cancer risk factors, such as demographic characteristics, smoking and drinking habits, diet, exercise, menstrual and reproductive factors, was obtained by self-administered health questionnaire including a validated semiquantitative food frequency questionnaire. Body mass index (BMI) was significantly correlated with the ratio of estradiol to SHBG (Spearman r =0.30, P =0.0004), fasting plasma insulin ( r =0.45) and HOMA-R ( r =0.43, P =0.0001) after controlling for age. The correlations were still significant between BMI and estradiol/SHBG ratio ( r =0.21, P =0.047) after controlling for fasting plasma insulin and between BMI and fasting plasma insulin ( r =0.40, P =0.0001) as well as HOMA-R ( r =0.38, P =0.0003) after controlling for estradiol/SHBG ratio. There is a possibility that effect of BMI on breast cancer risk is mediated by both insulin resistance and estrogen metabolism.     

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. © 2009 UICC