Insulin Resistance and Cancer: In Search for a Causal Link.
15 Oct 2021-International Journal of Molecular Sciences (Multidisciplinary Digital Publishing Institute)-Vol. 22, Iss: 20, pp 11137
TL;DR: In this paper, the authors provide a concise overview of the most recent literature in this field and discuss how different but interrelated molecular pathways may impact on tumor development, whereas potential chemopreventive properties have been attributed to some commonly used antidiabetic medications.
Abstract: Insulin resistance (IR) is a condition which refers to individuals whose cells and tissues become insensitive to the peptide hormone, insulin. Over the recent years, a wealth of data has made it clear that a synergistic relationship exists between IR, type 2 diabetes mellitus, and cancer. Although the underlying mechanism(s) for this association remain unclear, it is well established that hyperinsulinemia, a hallmark of IR, may play a role in tumorigenesis. On the other hand, IR is strongly associated with visceral adiposity dysfunction and systemic inflammation, two conditions which favor the establishment of a pro-tumorigenic environment. Similarly, epigenetic modifications, such as DNA methylation, histone modifications, and non-coding RNA, in IR states, have been often associated with tumorigenesis in numerous types of human cancer. In addition to these observations, it is also broadly accepted that gut microbiota may play an intriguing role in the development of IR-related diseases, including type 2 diabetes and cancer, whereas potential chemopreventive properties have been attributed to some of the most commonly used antidiabetic medications. Herein we provide a concise overview of the most recent literature in this field and discuss how different but interrelated molecular pathways may impact on tumor development.
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TL;DR: The Obesity Medicine Association (OMA) Clinical Practice Statement (CPS) as mentioned in this paper provides an overview of cancer and increased body fat, including the increased risk of cancers among patients with obesity, cancer risk factor population-attributable fractions, genetic and epigenetic links between obesity and cancer, adiposopathic and mechanistic processes accounting for increased cancer risk among patients having obesity, the role of oxidative stress, and obesity-related cancers based upon Mendelian randomization and observational studies.
Abstract: This Obesity Medicine Association (OMA) Clinical Practice Statement (CPS) provides an overview of cancer and increased body fat. The scientific information for this CPS is based upon published scientific citations, clinical perspectives of OMA authors, and peer review by the Obesity Medicine Association leadership. Topics include the increased risk of cancers among patients with obesity, cancer risk factor population-attributable fractions, genetic and epigenetic links between obesity and cancer, adiposopathic and mechanistic processes accounting for increased cancer risk among patients with obesity, the role of oxidative stress, and obesity-related cancers based upon Mendelian randomization and observational studies. Other topics include nutritional and physical activity principles for patients with obesity who either have cancer or are at risk for cancer, and preventive care as it relates to cancer and obesity. Obesity is the second most common preventable cause of cancer and may be the most common preventable cause of cancer among nonsmokers. This Obesity Medicine Association (OMA) Clinical Practice Statement (CPS) on cancer is one of a series of OMA CPSs designed to assist clinicians in the care of patients with the disease of obesity. Patients with obesity are at greater risk of developing certain types of cancers, and treatment of obesity may influence the risk, onset, progression, and recurrence of cancer in patients with obesity.
15 citations
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TL;DR: In this review, the most recent evidence supporting the potential role of the mechanisms linking obesity to TC will be discussed.
Abstract: Thyroid cancer (TC) is the most common endocrine malignancy worldwide and its incidence has increased dramatically in recent years. In parallel, the prevalence of overweight and obesity has also increased, suggesting a possible link between these two diseases. Indeed, low-grade chronic inflammation, altered cytokine levels, insulin resistance, oxidative stress, and hormonal changes that occur in obese patients are all factors that contribute to the occurrence and growth of TC. In this review, the most recent evidence supporting the potential role of the mechanisms linking obesity to TC will be discussed.
15 citations
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TL;DR: This review focuses primarily on the potential of In1-ghrelin as a biomarker for cancer progression, the unique characteristics of UAG and AG, the importance of the two known receptor variants GHSR-1a and 1b, as well as the possible mechanisms through which the ghrelin axis acts.
Abstract: Ghrelin, a hormone produced and secreted from the stomach, is prim arily known as an appetite stimulant. Recently, it has emerged as a potential regulator/biomarker of cancer progression. Inconsistent results on this subject make this body of literature difficult to interpret. Here, we attempt to identify commonalities in the relationships between ghrelin and various cancers, and summarize important considerations for future research. The main players in the ghrelin family axis are unacylated ghrelin (UAG), acylated ghrelin (AG), the enzyme ghrelin O-acyltransferase (GOAT), and the growth hormone secretagogue receptor (GHSR). GOAT is responsible for the acylation of ghrelin, after which ghrelin can bind to the functional ghrelin receptor GHSR-1a to initiate the activation cascade. Splice variants of ghrelin also exist, with the most prominent being In1-ghrelin. In this review, we focus primarily on the potential of In1-ghrelin as a biomarker for cancer progression, the unique characteristics of UAG and AG, the importance of the two known receptor variants GHSR-1a and 1b, as well as the possible mechanisms through which the ghrelin axis acts. Further understanding of the role of the ghrelin axis in tumor cell proliferation could lead to the development of novel therapeutic approaches for various cancers.
6 citations
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TL;DR: A novel metabolic score for insulin resistance (METS-IR) was considered as alternative marker of IR and was non-linearly associated with all-cause and CVDs-related mortality in patients with diabetes.
Abstract: Background Growing studies have shown that insulin resistance (IR) is associated with poor prognoses among patients with diabetes, whereas the association between IR and mortality has not been determined. Hence we aimed to evaluate the associations between IR and all-cause, cardiovascular diseases (CVDs) and cancer-related mortality in patients with diabetes. Methods We enrolled 2,542 participants with diabetes with an average age of 57.12 ± 0.39 years and 52.8% men from the 1999–2014 National Health and Nutrition Examination Survey (NHANES 1999–2014). A novel metabolic score for insulin resistance (METS-IR) was considered as alternative marker of IR. Mortality data were obtained from the National Death Index records and all participants were followed up until December 31, 2015. Cox proportional hazards regression, restricted cubic spline and Kaplan-Meier survival curves were performed to evaluate the associations between METS-IR and all-cause and cause-specific mortality in patients with diabetes. Results During 17,750 person-years of follow-up [median (months), 95% CI: 90, 87–93], 562 deaths were documented, including 133 CVDs-related deaths and 90 cancer-related deaths. Multivariate Cox regression showed that compared with Quintile 1 (METS-IR ≤ 41), METS-IR in Quintile 2, 3, and 4 was all associated with all-cause mortality (Q2 vs. Q1: HR 0.65, 95% CI 0.49–0.87, P = 0.004; Q3 vs. Q1: HR 0.69, 95% CI 0.50–0.96, P = 0.029; Q4 vs. Q1: HR 0.57, 95% CI 0.36–0.91, P = 0.019; respectively). Restricted cubic spline indicated that METS-IR was non-linearly associated with all-cause and CVDs-related mortality. Threshold effect analyses determined that threshold values of METS-IR for all-cause and CVDs-related mortality were both 33.33. Only METS-IR below the threshold was negatively associated with all-cause and CVDs-related mortality (HR 0.785, 95% CI 0.724–0.850, P < 0.001; HR 0.722, 95% CI 0.654–0.797, P < 0.001; respectively). Sensitivity analyses showed that when excluding participants who died within 1 years of follow-up, the results of threshold effect analyses remained consistent, whereas excluding participants with CVDs, METS-IR below the threshold was only negatively correlated with all-cause mortality. Subgroup analyses indicated that for all-cause mortality, the results were still stable in all subgroups except newly diagnosed diabetes, but for CVDs-related mortality, the association persisted only in participants who were ≤ 65 years, male, White, non-White, already diagnosed diabetes, or uesd oral drugs, insulin, insulin sensitizing drugs. Conclusion METS-IR was non-linearly associated with all-cause and CVDs-related mortality in patients with diabetes, and METS-IR below the threshold was negatively associated with all-cause and CVDs-related mortality.
5 citations
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10 Oct 2022
TL;DR: 2-DG as mentioned in this paper is a modified form of D-glucose, that shows anticancer, anti-inflammatory, and anti-viral effects, and it is converted into 2-deoxy-D-GLucose-6-phosphate with the help of hexokinase.
Abstract: Chronic exposure to high glucose inside the human body helps in the progression of cancer by activating various signaling pathways including PI3K, Akt, mTOR, Ras, Raf, MAPK, and PKC. Hyperglycemia induces ROS and AGE production and decreases the functional activities of the cellular antioxidant system. By downregulating the prolyl hydroxylase, it stabilizes HIF-α leading to EMT-induced cancer progression and inhibition of apoptosis. High glucose level increases inflammation by creating a pro-inflammatory environment through the production of certain pro-inflammatory mediators (cytokines, chemokines, leukotrienes), and by influencing the recruitment of immune cells, leukocytes in the inflamed region. High glucose impairs the immune response and dysregulates ROS formation through the alteration in ETC and glutaminolysis which makes hyperglycemic patients more susceptible to viral infection. 2-DG is a modified form of D-glucose, that shows anticancer, anti-inflammatory, and anti-viral effects. It enters the cells through GLUT transporters and is converted into 2-deoxy-D-glucose-6-phosphate with the help of hexokinase. It inhibits the glycolysis, the TCA cycle, and the pentose phosphate pathway leading to ATP depletion. By downregulating glucose uptake and energy (ATP) production it halts various pathways responsible for cancer progression. It promotes the formation of anti-inflammatory mediators, and macrophage polarization, and also modulates immune function, which decreases inflammation. 2-DG inhibits PI3K/Akt/mTOR and upregulates the AMPK pathway, causing activation of the SIRT-4 gene that reduces lipogenesis, glucose uptake, nucleotide formation, and alters viral replication thus reducing the chances of infection.
4 citations
References
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TL;DR: The possibility is raised that resistance to insulin-stimulated glucose uptake and hyperinsulinemia are involved in the etiology and clinical course of three major related diseases— NIDDM, hypertension, and CAD.
Abstract: Resistance to insulin-stimulated glucose uptake is present in the majority of patients with impaired glucose tolerance (IGT) or non-insulin-dependent diabetes mellitus (NIDDM) and in ∼25% of nonobese individuals with normal oral glucose tolerance. In these conditions, deterioration of glucose tolerance can only be prevented if the β-cell is able to increase its insulin secretory response and maintain a state of chronic hyperinsulinemia. When this goal cannot be achieved, gross decompensation of glucose homeostasis occurs. The relationship between insulin resistance, plasma insulin level, and glucose intolerance is mediated to a significant degree by changes in ambient plasma free-fatty acid (FFA) concentration. Patients with NIDDM are also resistant to insulin suppression of plasma FFA concentration, but plasma FFA concentrations can be reduced by relatively small increments in insulin concentration.Consequently, elevations of circulating plasma FFA concentration can be prevented if large amounts of insulin can be secreted. If hyperinsulinemia cannot be maintained, plasma FFA concentration will not be suppressed normally, and the resulting increase in plasma FFA concentration will lead to increased hepatic glucose production. Because these events take place in individuals who are quite resistant to insulinstimulated glucose uptake, it is apparent that even small increases in hepatic glucose production are likely to lead to significant fasting hyperglycemia under these conditions. Although hyperinsulinemia may prevent frank decompensation of glucose homeostasis in insulin-resistant individuals, this compensatory response of the endocrine pancreas is not without its price. Patients with hypertension, treated or untreated, are insulin resistant, hyperglycemic, and hyperinsulinemic. In addition, a direct relationship between plasma insulin concentration and blood pressure has been noted. Hypertension can also be produced in normal rats when they are fed a fructose-enriched diet, an intervention that also leads to the development of insulin resistance and hyperinsulinemia. The development of hypertension in normal rats by an experimental manipulation known to induce insulin resistance and hyperinsulinemia provides further support for the view that the relationship between the three variables may be a causal one. However, even if insulin resistance and hyperinsulinemia are not involved in the etiology of hypertension, it is likely that the increased risk of coronary artery disease (CAD) in patients with hypertension and the fact that this risk if not reduced with antihypertensive treatment are due to the clustering of risk factors for CAD, in addition to high blood pressure, associated with insulin resistance. These include hyperinsulinemia, IGT, increased plasma triglyceride concentration, and decreased high-density lipoprotein cholesterol concentration, all of which are associated with increased risk for CAD. It is likely that the same risk factors play a significant role in the genesis of CAD in the population as a whole. Based on these considerations the possibility is raised that resistance to insulin-stimulated glucose uptake and hyperinsulinemia are involved in the etiology and clinical course of three major related diseases— NIDDM, hypertension, and CAD.
12,460 citations
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TL;DR: It is proposed that the metabolism of cancer cells, and indeed all proliferating cells, is adapted to facilitate the uptake and incorporation of nutrients into the biomass needed to produce a new cell.
Abstract: In contrast to normal differentiated cells, which rely primarily on mitochondrial oxidative phosphorylation to generate the energy needed for cellular processes, most cancer cells instead rely on aerobic glycolysis, a phenomenon termed “the Warburg effect.” Aerobic glycolysis is an inefficient way to generate adenosine 5′-triphosphate (ATP), however, and the advantage it confers to cancer cells has been unclear. Here we propose that the metabolism of cancer cells, and indeed all proliferating cells, is adapted to facilitate the uptake and incorporation of nutrients into the biomass (e.g., nucleotides, amino acids, and lipids) needed to produce a new cell. Supporting this idea are recent studies showing that (i) several signaling pathways implicated in cell proliferation also regulate metabolic pathways that incorporate nutrients into biomass; and that (ii) certain cancer-associated mutations enable cancer cells to acquire and metabolize nutrients in a manner conducive to proliferation rather than efficient ATP production. A better understanding of the mechanistic links between cellular metabolism and growth control may ultimately lead to better treatments for human cancer.
12,380 citations
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TL;DR: It was agreed that there should not be an obligatory component, but that waist measurement would continue to be a useful preliminary screening tool, and a single set of cut points would be used for all components except waist circumference, for which further work is required.
Abstract: A cluster of risk factors for cardiovascular disease and type 2 diabetes mellitus, which occur together more often than by chance alone, have become known as the metabolic syndrome. The risk factors include raised blood pressure, dyslipidemia (raised triglycerides and lowered high-density lipoprotein cholesterol), raised fasting glucose, and central obesity. Various diagnostic criteria have been proposed by different organizations over the past decade. Most recently, these have come from the International Diabetes Federation and the American Heart Association/National Heart, Lung, and Blood Institute. The main difference concerns the measure for central obesity, with this being an obligatory component in the International Diabetes Federation definition, lower than in the American Heart Association/National Heart, Lung, and Blood Institute criteria, and ethnic specific. The present article represents the outcome of a meeting between several major organizations in an attempt to unify criteria. It was agreed that there should not be an obligatory component, but that waist measurement would continue to be a useful preliminary screening tool. Three abnormal findings out of 5 would qualify a person for the metabolic syndrome. A single set of cut points would be used for all components except waist circumference, for which further work is required. In the interim, national or regional cut points for waist circumference can be used.
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TL;DR: It is demonstrated through metagenomic and biochemical analyses that changes in the relative abundance of the Bacteroidetes and Firmicutes affect the metabolic potential of the mouse gut microbiota and indicates that the obese microbiome has an increased capacity to harvest energy from the diet.
Abstract: The worldwide obesity epidemic is stimulating efforts to identify host and environmental factors that affect energy balance. Comparisons of the distal gut microbiota of genetically obese mice and their lean littermates, as well as those of obese and lean human volunteers have revealed that obesity is associated with changes in the relative abundance of the two dominant bacterial divisions, the Bacteroidetes and the Firmicutes. Here we demonstrate through metagenomic and biochemical analyses that these changes affect the metabolic potential of the mouse gut microbiota. Our results indicate that the obese microbiome has an increased capacity to harvest energy from the diet. Furthermore, this trait is transmissible: colonization of germ-free mice with an 'obese microbiota' results in a significantly greater increase in total body fat than colonization with a 'lean microbiota'. These results identify the gut microbiota as an additional contributing factor to the pathophysiology of obesity.
10,126 citations
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TL;DR: Current patterns of overweight and obesity in the United States could account for 14 percent of all deaths from cancer in men and 20 percent of those in women, and increased body weight was associated with increased death rates for all cancers combined and for cancers at multiple specific sites.
Abstract: background The influence of excess body weight on the risk of death from cancer has not been fully characterized. methods In a prospectively studied population of more than 900,000 U.S. adults (404,576 men and 495,477 women) who were free of cancer at enrollment in 1982, there were 57,145 deaths from cancer during 16 years of follow-up. We examined the relation in men and women between the body-mass index in 1982 and the risk of death from all cancers and from cancers at individual sites, while controlling for other risk factors in multivariate proportional-hazards models. We calculated the proportion of all deaths from cancer that was attributable to overweight and obesity in the U.S. population on the basis of risk estimates from the current study and national estimates of the prevalence of overweight and obesity in the U.S. adult population. results The heaviest members of this cohort (those with a body-mass index [the weight in kilograms divided by the square of the height in meters] of at least 40) had death rates from all cancers combined that were 52 percent higher (for men) and 62 percent higher (for women) than the rates in men and women of normal weight. For men, the relative risk of death was 1.52 (95 percent confidence interval, 1.13 to 2.05); for women, the relative risk was 1.62 (95 percent confidence interval, 1.40 to 1.87). In both men and women, body-mass index was also significantly associated with higher rates of death due to cancer of the esophagus, colon and rectum, liver, gallbladder, pancreas, and kidney; the same was true for death due to non-Hodgkin’s lymphoma and multiple myeloma. Significant trends of increasing risk with higher body-mass-index values were observed for death from cancers of the stomach and prostate in men and for death from cancers of the breast, uterus, cervix, and ovary in women. On the basis of associations observed in this study, we estimate that current patterns of overweight and obesity in the United States could account for 14 percent of all deaths from cancer in men and 20 percent of those in women. conclusions Increased body weight was associated with increased death rates for all cancers combined and for cancers at multiple specific sites.
7,095 citations