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Serum Insulin, Glucose, Indices of Insulin Resistance, and Risk of Lung Cancer.

ABSTRACT: Background: Although insulin may increase the risk of some cancers, few studies have examined fasting serum insulin and lung cancer risk.Methods: We examined serum insulin, glucose, and indices of insulin resistance [insulin:glucose molar ratio and homeostasis model assessment of insulin resistance (HOMA-IR)] and lung cancer risk using a case-cohort study within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study of Finnish men. A total of 196 cases and 395 subcohort members were included. Insulin and glucose were measured in fasting serum collected 5 to 12 years before diagnosis. Cox proportional hazards models were utilized to estimate the relative risk of lung cancer.Results: The average time between blood collection and lung cancer was 9.6 years. Fasting serum insulin levels were 8.7% higher in subcohort members than cases. After multivariable adjustment, men in the fourth quartile of insulin had a significantly higher risk of lung cancer than those in the first quartile [HR = 2.10; 95% confidence interval (CI), 1.12-3.94]. A similar relationship was seen with HOMA-IR (HR = 1.83; 95% CI, 0.99-3.38). Risk was not strongly associated with glucose or the insulin:glucose molar ratio (Ptrend = 0.55 and Ptrend = 0.27, respectively).Conclusions: Higher fasting serum insulin concentrations, as well as the presence of insulin resistance, appear to be associated with an elevated risk of lung cancer development.Impact: Although insulin is hypothesized to increase risk of some cancers, insulin and lung cancer remain understudied. Higher insulin levels and insulin resistance were associated with increased lung cancer risk. Although smoking cessation is the best method of lung cancer prevention, other lifestyle changes that affect insulin concentrations and sensitivity may reduce lung cancer risk. Cancer Epidemiol Biomarkers Prev; 26(10); 1519-24. ©2017 AACR.

SUBMITTER: Argirion I

PROVIDER: S-EPMC5626607 | biostudies-other | 2017 Oct

REPOSITORIES: biostudies-other

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Serum Insulin, Glucose, Indices of Insulin Resistance, and Risk of Lung Cancer.

Argirion Ilona I Weinstein Stephanie J SJ Männistö Satu S Albanes Demetrius D Mondul Alison M AM

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 20170711 10

<b>Background:</b> Although insulin may increase the risk of some cancers, few studies have examined fasting serum insulin and lung cancer risk.<b>Methods:</b> We examined serum insulin, glucose, and indices of insulin resistance [insulin:glucose molar ratio and homeostasis model assessment of insulin resistance (HOMA-IR)] and lung cancer risk using a case-cohort study within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study of Finnish men. A total of 196 cases and 395 subcohort member ...[more]

PMID: 28698186

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Project description:The mitogenic and growth-stimulatory effects of insulin-like growth factors appear to play a role in prostate carcinogenesis, yet any direct association of circulating insulin levels and risk of prostate cancer remains unclear.We investigated the relationship of the level of serum insulin, glucose, and surrogate indices of insulin resistance (ie, the molar ratio of insulin to glucose and the homeostasis model assessment of insulin resistance [HOMA-IR]) to the development of prostate cancer in a case-cohort study within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study cohort of Finnish men. We studied 100 case subjects with incident prostate cancer and 400 noncase subjects without prostate cancer from the larger cohort. Fasting serum was collected 5-12 years before diagnosis. We determined insulin concentrations with a double-antibody immunochemiluminometric assay and glucose concentrations with a hexokinase assay. Multivariable logistic regression models estimated relative risks as odds ratios (ORs), and all statistical tests were two-sided.Insulin concentrations in fasting serum that was collected on average 9.2 years before diagnosis among case subjects were 8% higher than among noncase subjects, and the molar ratio of insulin to glucose and HOMA-IR were 10% and 6% higher, respectively, but these differences were not statistically significant. Among subjects in the second through fourth insulin quartiles, compared with those in the first quartile, increased insulin levels were associated with statistically significantly increased risks of prostate cancer (OR = 1.50, 95% confidence interval [CI] = 0.75 to 3.03; OR = 1.75, 95% CI = 0.86 to 3.56; and OR = 2.55, 95% CI = 1.18 to 5.51; for the second through fourth insulin quartiles, respectively; P(trend) = .02). A similar pattern was observed with the HOMA-IR (OR = 2.10, 95% CI = 1.03 to 4.26; P(trend) = .02) for the highest vs lowest quartiles. Risk varied inconsistently with glucose concentration (P(trend) = .38). A stronger association between insulin level and prostate cancer risk was observed among leaner men and among men who were less physically active at work. Crude prostate cancer incidence was 154 prostate cancers per 100 000 person-years in the lowest quartile of fasting serum insulin vs 394 prostate cancers per 100 000 person-years in the highest quartile.Elevated fasting levels of serum insulin (but not glucose) within the normal range appear to be associated with a higher risk of prostate cancer.

Project description:ContextDelta like noncanonical notch ligand 1 (DLK1) is a paternally expressed imprinted gene that encodes an epidermal growth factor repeat-containing transmembrane protein. A bioactive, truncated DLK1 protein is present in the circulation and has roles in development and metabolism.ObjectiveWe sought to investigate links between maternal pregnancy circulating DLK1 concentrations and: (1) maternal and fetal DLK1 genotypes, (2) maternal insulin resistance and secretion, and (3) offspring size at birth.Patients, design, and settingWe measured third-trimester maternal serum DLK1 concentrations and examined their associations with parentally transmitted fetal and maternal DLK1 genotypes, indices of maternal insulin resistance and secretion derived from 75-g oral glucose tolerance tests performed around week 28 of pregnancy, and offspring size at birth in 613 pregnancies from the Cambridge Baby Growth Study.ResultsMaternal DLK1 concentrations were associated with the paternally transmitted fetal DLK1 rs12147008 allele (P = 7.8 × 10-3) but not with maternal rs12147008 genotype (P = 0.4). Maternal DLK1 concentrations were positively associated with maternal prepregnancy body mass index (P = 3.5 × 10-6), and (after adjustment for maternal body mass index) with both maternal fasting insulin resistance (Homeostatic Model Assessment of Insulin Resistance: P = 0.01) and measures of maternal insulin secretion in response to oral glucose (insulinogenic index: P = 1.2 × 10-3; insulin disposition index: P = 0.049). Further positive associations were found with offspring weight (P = 0.02) and head circumference at birth (P = 0.04).ConclusionThese results are consistent with a partial paternal or placental origin for the maternal circulating DLK1 which may lead to increased maternal circulating DLK1 concentrations, stimulation of maternal insulin resistance and compensatory hyperinsulinemia during pregnancy, and the promotion of fetal growth.

Project description:Background:To examine the association between changes in fasting insulin, homeostasis model assessment of insulin resistance (HOMA-IR), and insulin-glucose ratio (IGR) levels, over approximately 3?years with incident hypertension. Methods:A total of 2814 Iranian participants (1123 men) without hypertension and known diabetes at baseline and the first examination were followed for a median of 6.32?years. The associations between quartiles of changes in fasting insulin and IR indices with incident hypertension were assessed using multivariate Cox proportional hazard regression analyses with first quartile as reference. The models were adjusted for baseline values of insulin or each IR index, and age, sex, smoking, physical activity, educational levels, marital status, history of cardiovascular diseases, baseline levels of systolic and diastolic blood pressures, estimated glomerular filtration rate, triglycerides, total cholesterol, high-density lipoprotein cholesterol, fasting plasma glucose (only for insulin change) and both body mass index (BMI) per se, and its change. Akaike's information criteria (AIC) was applied as indicator for goodness of fit of each predictive model. The discrimination ability of models was calculated using the Harrell's C statistic. Results:During the study, 594 incident cases of hypertension (253 men) were identified. The 4th quartile of changes in insulin, HOMA-IR, and IGR showed hazard ratios (95% confidence interval) of 1.31 (1.01-1.69), 1.18 (0.92-1.52), and 1.53 (1.18-1.98) for hypertension, respectively, in fully-adjusted models. Changes in fasting insulin levels and IR indices showed significant increasing trends for incident hypertension, moving from 1st to 4th quartiles (all P-values < 0.05). Focusing on model fitness, no superiority was found between changes in fasting insulin, HOMA-IR, and IGR to predict incident hypertension. The discriminatory powers of changes in fasting insulin and IR indices as assessed by C index were similar (i.e. about 80%). Conclusion:Changes in fasting insulin and IR indices were significantly associated with developing hypertension among normotensive population even after considering BMI changes.

Project description:Background The interrelationships among the different stages of impaired glucose metabolism, insulin resistance, and hypertension are not fully understood. Methods and Results We investigated the impact of insulin resistance, plasma glucose, and serum immunoreactive insulin levels on hypertension in 19 166 participants with different stages of impaired glucose metabolism (7114 normal fasting glucose/normal glucose tolerance, 3543 isolated impaired fasting glucose [IFG], 2089 isolated impaired glucose tolerance, 2922 IFG plus impaired glucose tolerance, and 3498 diabetes mellitus]) determined by 75-g oral glucose tolerance tests. Participants were recruited from examinees who finished a general health checkup for atomic bomb survivors between 1982 and 2017. The profiles of plasma glucose and immunoreactive insulin during oral glucose tolerance tests were assessed using the total area under the curve. Insulin resistance was assessed using the homeostasis model assessment of insulin resistance. The rate of hypertension increased from 36.3% in participants with normal fasting glucose/normal glucose tolerance to 50.1%, 50.8%, 58.3%, and 63.8% in participants with isolated IFG, isolated impaired glucose tolerance, IFG plus impaired glucose tolerance, and diabetes mellitus, respectively. Homeostasis model assessment of insulin resistance was associated with hypertension regardless of the presence and the degree of impaired glucose metabolism. Furthermore, fasting plasma glucose and serum immunoreactive insulin levels and areas under the curve for plasma glucose and immunoreactive insulin during oral glucose tolerance tests were associated with hypertension in normal fasting glucose/normal glucose tolerance and isolated IFG, but such a relationship was diminished in other types of prediabetes and diabetes mellitus. Conclusions The prevalence of hypertension increases with worsening stages of impaired glucose metabolism; however, hyperglycemia and hyperinsulinemia are significant contributors to the presence of hypertension only in the early stages of impaired insulin metabolism.

Project description:Insulin receptor (Insr) protein can be found at higher levels in pancreatic b-cells than in most other cell types, but the consequences of b-cell insulin resistance remain enigmatic. Ins1cre allele was used to delete Insr specifically in b-cells of both female and male mice which were compared to Ins1cre-containing littermate controls at multiple ages and on multiple diets. RNA-seq of recombined b-cells revealed significant differences in multiple pathways previously implicated in insulin secretion and cellular fate, including rewired Ras and NFkB signaling. Male, but not female, bInsrKO mice had reduced oxygen consumption rate, while action potential and calcium oscillation frequencies were increased in Insr knockout b-cells from female, but not male mice. Female bInsrKO and bInsrHET mice exhibited elevated insulin release in perifusion experiments, during hyperglycemic clamps, and following i.p. glucose challenge. Deletion of Insr did not reduce b-cell mass up to 9 months of age, nor did it impair hyperglycemia-induced proliferation. Based on our data, we adapted a mathematical model to include b-cell insulin resistance, which predicted that b-cell Insr knockout would improve glucose tolerance depending on the degree of whole-body insulin resistance. Indeed, glucose tolerance was significantly improved in female bInsrKO and bInsrHET mice when compared to controls at 9, 21 and 39 weeks. We did not observe improved glucose tolerance in adult male mice or in high fat diet-fed mice, corroborating the prediction that global insulin resistance obscures the effects of b-cell specific insulin resistance. We further validated our in vivo findings using the Ins1-CreERT transgenic line and found improved glucose tolerance 4 weeks after tamoxifen-mediated Insr deletion. Collectively, our data show that loss of b-cell Insr alone is sufficient to drive glucose-induced hyperinsulinemia, thereby improving glucose homeostasis in otherwise insulin sensitive dietary and age contexts.

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Serum Insulin, Glucose, Indices of Insulin Resistance, and Risk of Lung Cancer.

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Serum Insulin, Glucose, Indices of Insulin Resistance, and Risk of Lung Cancer.

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