Insulin Resistance and Its Contribution to Colon Carcinogenesis

Komninou, Despina; Ayonote, Alexis; Richie, John P.; Rigas, Basil

doi:10.1177/153537020322800410

Cited by 133 publications

(104 citation statements)

References 85 publications

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“…Another dominant hypothesis, for colorectal malignancy in particular, is that hyperinsulinaemia and increased insulin-like growth factors in type 2 diabetes or insulin-resistant populations have a direct action on colonic mucosal cell proliferation, differentiation and carcinogenesis. This has been well reviewed recently, although causality is not established [33,34]. These mechanisms and the present suggestions are not mutually exclusive, and there may in fact be some overlap.…”

Section: Telomere Attrition and Increased Malignancy Risk In Type 2 Dmentioning

confidence: 94%

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Chromosomal telomere attrition as a mechanism for the increased risk of epithelial cancers and senescent phenotypes in type 2 diabetes

Sampson

Hughes

2006

Diabetologia

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Telomeres are the repeat DNA sequences at the end of chromosomes necessary for successful DNA replication and chromosomal integrity. Telomeres shorten at cell division at a rate determined by oxidative DNA damage, and cells are triggered into replicative senescence once telomeres shorten to a critical length. Telomere-related chromosomal maintenance also has a role in carcinogenesis. Type 2 diabetes is characterised by increased oxidative stress, increased oxidative DNA damage, senescent retinal and renal phenotypes, and an increased risk of epithelial malignancy. We suggest that increased oxidative DNA damage and telomere attrition in type 2 diabetes leads to: (1) carcinogenic telomere-dependent chromosomal nonreciprocal translocations, genomic instability, and the development of epithelial cancers; (2) senescent retinal and renal phenotypes (expressed as diabetic retinopathy and nephropathy); and (3) senescent vascular endothelial, monocyte-macrophage and vascular smooth muscle cells (expressed as endothelial dysfunction and accelerated atherogenesis). An adverse intrauterine environment leads to increased feto-placental oxidative stress and feto-placental oxidative DNA damage. We also suggest that intrauterine oxidative DNA damage and telomere shortening is another point at which increased oxidative stress could contribute to a pre-programmed increased risk of senescent phenotypes in adult offspring, characterised by type 2 diabetes and epithelial malignancy. These suggestions can be used to understand early glucose intolerance in the young children of type 1 diabetes pregnancies, poor cancer outcomes in type 2 diabetes, beta cell fatigue in type 2 diabetes and the absence of increased epithelial cancer risk in type 1 diabetes.

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Section: Telomere Attrition and Increased Malignancy Risk In Type 2 Dmentioning

confidence: 94%

“…Firstly, one potential confounding variable is exposure to an antecedent diet or lifestyle that contributes to an increased risk of both type 2 diabetes and cancer [33,34]. Secondly, obesity may be an independent contributor to both conditions [34].…”

Section: Telomere Attrition and Increased Malignancy Risk In Type 2 Dmentioning

confidence: 99%

Chromosomal telomere attrition as a mechanism for the increased risk of epithelial cancers and senescent phenotypes in type 2 diabetes

Sampson

Hughes

2006

Diabetologia

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“…42 The increased incidence of CRC in diabetic patients, mainly in those with type 2 diabetes, has been supported by a recent prospective, population-based cohort, case-control and meta-analysis studies. 5,43 Thus, there is an attractive hypothesis of insulin resistance-CRC, stating that insulin resistant may thus be associated with the development of CRC, 44 and this malignancy may therefore become a modifiable disease. 45 Regarding the mechanism of action, insulin resistance is associated with hyperinsulinemia, increased levels of growth factors, including IGF-1, and alterations in nuclear factor kappa B (NF-jB) and peroxisome proliferator-activated receptors signaling, which may promote CRC through their effect on the colonic cryptal cell kinetics.…”

Section: Discussionmentioning

confidence: 99%

“…51 Since our study focused on the effects of obesity and CUSM on the colonic premalignancies, not malignancies, further studies focusing the malignancies and NF-jB and IkappaB kinase 52,53 that can be activated through Ob-R1 14,44,46 and may thus play a critical role in obesity/diabetes-associated and colitisrelated colon carcinogenesis in which processes the leptin involved 29 are needed for the prevention and treatment of the malignancies associated with these conditions.…”

Section: Discussionmentioning

confidence: 99%

Diet supplemented with citrus unshiu segment membrane suppresses chemically induced colonic preneoplastic lesions and fatty liver in male db/db mice

Suzuki

Kohno

Yasui

et al. 2006

Intl Journal of Cancer

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The modulatory effects of dietary citrus unshiu segment membrane (CUSM) on the occurrence of aberrant crypt foci (ACF) and b-catenin accumulated crypts (BCACs) were determined in male C57BL/KsJ-db/db (db/db) mice initiated with azoxymethane (AOM). Male db/db, db/þ and þ/þ mice were given 5 weekly subcutaneous injections of AOM (15 mg/kg body weight), and then they were fed the diet containing 0.02%, 0.1% or 0.5% CUSM for 7 weeks. At Week 12, a significant increase in the numbers of ACF and BCAC was noted in the db/db mice in comparison with the db/ þ and þ/þ mice. Feeding with CUSM caused reduction in the frequency of ACF in all genotypes of mice and the potency was high in order of the db/db mice, db/þ mice and þ/þ mice. The number of BCACs was also reduced by feeding with CUSM, thus resulting in a 28-61% reduction in the db/db mice, possibly due to suppression of cell proliferation activity in the lesions by feeding with CUSM-containing diet. Clinical chemistry revealed a low serum level of triglyceride in mice fed CUSM. In addition, CUSM feeding inhibited fatty metamorphosis and fibrosis in the liver of db/db mice. Our findings show that CUSM in the diet has a chemopreventive ability against the early phase of AOM-induced colon carcinogenesis in the db/db as well as db/þ and þ/þ mice, indicating potential use of CUSM in cancer chemoprevention in obese people. ' 2006 Wiley-Liss, Inc.Key words: citrus unshiu segment membrane; ACF; BCAC; colon carcinogenesis; db/db mice The modern Western lifestyle, including a high caloric intake, high-fat diets and physical inactivity, results in a positive energy balance, diabetes and obesity. These lifestyle patterns might also be risk factors for the development of colorectal cancer (CRC), 1 which is one of the major causes of morbidity and mortality in the Western world. 2 This malignancy has also increased in Asia owing to the changes in lifestyle, such as the dietary habit of increased meat consumption. 2,3 Several prospective and case-control studies have addressed the relationship between obesity/diabetes and CRC. 1,4,5 C57BL/KsJ-db/db (db/db) mice are used as a genetically altered animal model with genotypes of obesity and diabetes mellitus. 6 A disruption of the leptin receptor (Ob-R) gene in these mice leads to an over-expression of leptin in the adipose tissue and a concomitantly high serum concentration of leptin. 7,8 The synthesis of leptin in adipocytes is influenced by insulin, 9 tumor necrosis factor-a, 10 glucocorticoids, 11 reproductive hormones 12 and prostaglandins 13 that may be involved in the neoplastic processes. 14 In addition, leptin can act as a growth factor in colonic epithelial cells 15 while modulating the proliferation of colonic cryptal cells. 16 In contrast, more leptin in the blood clearly decreased colon carcinogenesis in 3 different animal models. 17,18 Thus, leptin might be one of the biological factors involved in the development of CRC associated with obesity/diabetes. The db/db mouse, therefore, is a very useful model for elucidating ...

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“…Obezitenin kolon kanseri üzerine olumsuz etkisinin mekanizmalarından birisi obez kişilerde insülin ya da insülin ile ilgili büyüme faktörlerinin tümör gelişimini büyük oranda teşvik ediyor olmasıdır [7,18,19]. Yapılan çalışmalarda abdominal yağlanmanın iki ölçüsü olan bel çevresi veya BKO ve kolon kanseri ilişkisi, VKİ ile kanser arasındaki ilişkiden daha güçlü bulunmuştur [14,15,18]. Vücut kitle indeksi yüksek olan erkeklerde kolon kanseri riski artmış görülürken kadınlarda bu ilişki daha zayıf bulunmuştur.…”

Section: Obezite Ve Kolorektal Kanserunclassified

Kolorektal karsinogenez ve metabolik sendrom ilişkisi

Erarslan¹,

Yüksel²,

Haznedaroğlu³

2012

CMJ

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Metabolik sendrom obezite, dislipidemi, hiperglisemi ve hipertansiyon gibi hastalıkların toplamından oluşur. Metabolik sendrom bileşenlerinin çoğu tümör gelişimi ile bağlantılıdır. Metabolik sendrom ve visseral obezitenin genel populasyonda sıklık ve yaygınlığı giderek artmaktadır. Obezite son zamanlarda kanserlerin çoğunda mortalite ile bağlantılıdır. Kolorektal kanser önemli bir halk sağlığı problemidir. Son raporlar metabolik sendromlu bireylerde kolon veya rektum kanseri riskinin yüksek olduğunu göstermiştir. Metabolik sendrom ve kolorektal kanser arasındaki bağlantının patofizyolojik mekanizması çoğunlukla abdominal obezite ve insülin direnci ile ilişkilidir. Beslenme, egzersiz ve stresi azaltmayı kapsayan multidisipliner bir yaklaşım insülin direncini sınırlamada ve kanser sonuçlarını iyileştirmede çok önemli bir fırsat olabilir.Anahtar sözcükler: Metabolik sendrom, kanser, insülin direnci, obezite AbstractMetabolic syndrome consists of a cluster of diseases including obesity, dyslipidemia, hyperglycemia and hypertension. Most of the components of metabolic syndrome have been associated with the development of neoplasm. The metabolic syndrome and visceral obesity have an increasing prevalence and incidence in the general population. Obesity has recently been linked to mortality in the majority of cancers. Colorectal cancer is an important public health problem. Recent reports in individuals with metabolic syndrome showed a high risk of colon or rectal cancer. The pathophysiological mechanism that links metabolic syndrome and colorectal cancer is mostly related to abdominal obesity and insulin resistance. A multidisciplinary approach involving nutrition, exercise, and stress reduction may be an opportunity to limit the insulin-resistant state and improve cancer outcomes.

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Insulin Resistance and Its Contribution to Colon Carcinogenesis

Cited by 133 publications

References 85 publications

Chromosomal telomere attrition as a mechanism for the increased risk of epithelial cancers and senescent phenotypes in type 2 diabetes

Chromosomal telomere attrition as a mechanism for the increased risk of epithelial cancers and senescent phenotypes in type 2 diabetes

Diet supplemented with citrus unshiu segment membrane suppresses chemically induced colonic preneoplastic lesions and fatty liver in male db/db mice

Kolorektal karsinogenez ve metabolik sendrom ilişkisi

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