Insulin therapy and colorectal cancer risk among type 2 diabetes mellitus patients: a systemic review and meta-analysis

Yin, Shu; Bai, Hua; Jing, Danqing

doi:10.1186/1746-1596-9-91

Cited by 32 publications

(32 citation statements)

References 30 publications

(24 reference statements)

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“…Unfortunately, the independent roles of hyperinsulinemia and hyperglycemia are difficult to probe in human subjects in vivo , because hyperinsulinemia typically occurs in the setting of hyperglycemia in insulin-resistant and diabetic individuals. Several studies have raised the possibility of a detrimental effect of exogenous insulin therapy on colon cancer risk in type 2 diabetes patients (Chung et al, 2008; Rosato et al, 2016; Yang et al, 2004; Yin et al, 2014). However, such retrospective pharmaco-epidemiologic data are controversial because of the difficulty in defining an appropriate control group, as doing so would require withholding insulin from patients for whom it is medically indicated.…”

Section: Discussionmentioning

confidence: 99%

Uncoupling Hepatic Oxidative Phosphorylation Reduces Tumor Growth in Two Murine Models of Colon Cancer

et al. 2018

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SUMMARY Obesity is associated with colon cancer pathogenesis, but the underlying mechanism is actively debated. Here, we confirm that diet-induced obesity promotes tumor growth in two murine colon cancer models and show that this effect is reversed by an orally administered controlled-release mitochondrial protonophore (CRMP) that acts as a liver-specific uncoupler of oxidative phosphorylation. This agent lowered circulating insulin, and the reduction of tumor growth was abrogated by an insulin infusion raising plasma insulin to the level of high-fat-fed mice. We also demonstrate that hyperinsulinemia increases glucose uptake and oxidation in vivo in tumors and that CRMP reverses these effects. This study provides evidence that perturbations of whole-organism energy balance or hepatic energy metabolism can influence neoplastic growth. Furthermore, the data show that glucose uptake and utilization by cancers in vivo are not necessarily constitutively high but rather may vary according to the hormonal milieu.

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Section: Discussionmentioning

confidence: 99%

Uncoupling Hepatic Oxidative Phosphorylation Reduces Tumor Growth in Two Murine Models of Colon Cancer

et al. 2018

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“…Among the mechanisms advocated to explain this association, hyperinsulinemia may play a pivotal role, acting as a potent cell mitogen capable of promoting colon cancer growth[8], an hypothesis that is corroborated by indirect findings of a harmful effect of insulin use for CRC risk[9,10]. Other proposed explanations for the increased risk include obesity-related insulin resistance (IR)[11] and cytokine production[12], which may directly influence CRC growth not only through promotion of angiogenesis[13,14], but also by inducing host inflammatory response[13,15] or decreasing natural killer (NK) lymphocyte cytotoxic activity and, thus, the immunological defense against cancer[16].…”

Section: Introductionmentioning

confidence: 99%

Prognostic value of glycated hemoglobin in colorectal cancer

Ferroni¹,

Formica²,

Della-Morte³

et al. 2016

WJG

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AIMTo investigate the clinical significance of routinely used glycemic parameters in a cohort of colorectal cancer (CRC) patients.METHODSPre-treatment fasting blood glucose, insulin, HbA1c and homeostasis model of risk assessment (HOMA-IR) were retrospectively evaluated in a case-control study of 224 CRC and 112 control subjects matched for sex, obesity and diabetes frequency and blood lipid profile. Furthermore, the prognostic value of routinely used glycemic parameters towards progression-free (PFS) and overall survival (OS) was prospectively evaluated.RESULTSFasting blood glucose, insulin, HOMA-IR and HbA1c (all P < 0.0001) levels were higher in non-diabetic CRC patients compared with obesity-matched controls. All parameters were associated with increased CRC risk at ROC analysis, but no relationship with clinical-pathological variables or survival outcomes was observed for glycemia, insulinemia or HOMA-IR. Conversely, advanced CRC stage (P = 0.018) was an independent predictor of increased HbA1c levels, which were also higher in patients who had disease progression compared with those who did not (P = 0.05). Elevated HbA1c levels showed a negative prognostic value both in terms of PFS (HR = 1.24) and OS (HR = 1.36) after adjustment for major confounders, which was further confirmed in a subgroup analysis performed after exclusion of diabetic patients.CONCLUSIONHbA1c might have a negative prognostic value in CRC, thus suggesting that glycemic metabolic markers should be carefully monitored in these patients, independently of overt diabetes.

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“…(2) Many previous studies have suggested the association between type 2 diabetes and the prevalence of various cancers, including colon, liver, breast, pancreas, and endometrial cancers. (3)(4)(5)(6)(7) Although insulin or insulin-like growth factor-1 has been associated with increased colon cancer risk in diabetic patients, (8,9) further studies are required to elucidate the mechanisms by which a diabetic condition increases the occurrence of colon cancer.…”

mentioning

confidence: 99%

Augmented O‐GlcNAcylation of AMP‐activated kinase promotes the proliferation of LoVo cells, a colon cancer cell line

Ishimura

Nakagawa²,

Moriwaki³

et al. 2017

Cancer Science

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Increasing incidence of various cancers has been reported in diabetic patients. O‐linked N‐acetylglucosamine (O‐GlcNAc) modification of proteins at serine/threonine residues (O‐GlcNAcylation) is an essential post‐translational modification that is upregulated in diabetic patients and has been implicated in tumor growth. However, the mechanisms by which O‐GlcNAcylation promotes tumor growth remain unclear. Given that AMP‐activated kinase (AMPK) has been thought to play important roles in suppressing tumor growth, we evaluated the involvement of AMPK O‐GlcNAcylation on the growth of LoVo cells, a human colon cancer cell line. Results revealed that treatment with Thiamet G (TMG), an inhibitor of O‐GlcNAc hydrolase, increased both anchorage‐dependent and ‐independent growth of the cells. O‐GlcNAc transferase overexpression also increased the growth. These treatments increased AMPK O‐GlcNAcylation in a dose‐dependent manner, which led to reduced AMPK phosphorylation and mTOR activation. Chemical inhibition or activation of AMPK led to increased or decreased growth, respectively, which was consistent with the data with genetic inhibition of AMPK. In addition, TMG‐mediated acceleration of tumor growth was abolished by both chemical and genetic inhibition of AMPK. To examine the effects of AMPK O‐GlcNAcylation in vivo, the LoVo cells were s.c. transplanted onto the backs of BALB/c‐nu/nu mice. Injection of TMG promoted the growth and enhanced O‐GlcNAcylation of the tumors of the mice. Consistent with in vitro data, AMPK O‐GlcNAcylation was increased, which reduced AMPK phosphorylation and resulted in activation of mTOR. Collectively, the higher colon cancer risk of diabetic patients could be due to O‐GlcNAcylation‐mediated AMPK inactivation and subsequent activation of mTOR.

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Insulin therapy and colorectal cancer risk among type 2 diabetes mellitus patients: a systemic review and meta-analysis

Cited by 32 publications

References 30 publications

Uncoupling Hepatic Oxidative Phosphorylation Reduces Tumor Growth in Two Murine Models of Colon Cancer

Uncoupling Hepatic Oxidative Phosphorylation Reduces Tumor Growth in Two Murine Models of Colon Cancer

Prognostic value of glycated hemoglobin in colorectal cancer

Augmented O‐GlcNAcylation of AMP‐activated kinase promotes the proliferation of LoVo cells, a colon cancer cell line

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