2017 update on the relationship between diabetes and colorectal cancer: epidemiology, potential molecular mechanisms and therapeutic implications

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Term Occurence Count Dictionary
prednisone 1 endocrinologydiseasesdrugs
Insulin 2 endocrinologydiseasesdrugs
acarbose 1 endocrinologydiseasesdrugs
everolimus 1 endocrinologydiseasesdrugs
hyperinsulinemia 7 endocrinologydiseases
metformin 18 endocrinologydiseasesdrugs
calcitriol 1 endocrinologydiseasesdrugs
calcium carbonate 1 endocrinologydiseasesdrugs
diabetes mellitus 3 endocrinologydiseases
type 2 diabetes mellitus 1 endocrinologydiseases
repaglinide 1 endocrinologydiseasesdrugs
simvastatin 1 endocrinologydiseasesdrugs
dapagliflozin 1 endocrinologydiseasesdrugs
hyperglycemia 11 endocrinologydiseases
hyperlipidemia 4 endocrinologydiseases
obesity 9 endocrinologydiseases
paricalcitol 1 endocrinologydiseasesdrugs

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Select Drug Character Offset Drug Term Instance
Insulin 18920 kidney disease. Obesity is a known risk factor for both colorectal cancer and diabetic kidney disease. Insulin Insulin and insulin-like growth factor (IGF)-1 have growth factor and antiapoptotic properties in a variety
Insulin 18927 disease. Obesity is a known risk factor for both colorectal cancer and diabetic kidney disease.Insulin Insulin and insulin-like growth factor (IGF)-1 have growth factor and antiapoptotic properties in a variety
acarbose 44880 compared to insulin-based therapies or other oral glucose-lowering drugs [[216]]. In other reports, acarbose was associated with reduced the risk of incident CRC in patients with diabetes in a dose-dependent manner
calcitriol 50655 (NCT00217477). Additionally, vitamin D has been explored for colon cancer prevention. However, a combination of calcitriol , aspirin, and calcium carbonate or vitamin D/calcium did not prevent recurrence of colorectal adenomas
calcium carbonate 50680 D has been explored for colon cancer prevention. However, a combination of calcitriol, aspirin, and calcium carbonate or vitamin D/calcium did not prevent recurrence of colorectal adenomas over a 3- to 5-year period [[267],
dapagliflozin 45429 warning was issued by the FDA regarding bladder and breast cancer risk from early clinical trials of dapagliflozin but not for CRC (http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM262994.pdf).
everolimus 50951 agents and also improve experimental DKD [[99], [269]]. The mTOR inhibitors RAD001 (NCT01058655) and everolimus and the dual PI3K/mTOR inhibitor PF-05212384 (NCT01937715, NCT01154335) are undergoing clinical trials
metformin 2184 mechanism involved. Although evidence is limited, insulin use has been associated with increased and metformin with decreased incidence of colorectal cancer. In addition, colorectal cancer shares some cellular and
metformin 8106 (Supplementary Table 1). The preferred initial and most widely used pharmacological agent for T2DM is metformin , which decreases glucose production by inhibiting the mitochondrial glycerophosphate dehydrogenase (GPDH,
metformin 37950 ESR1, MAX, MYC, PPARGC1A, SP1, and STK11) and one novel MYC-centered pathway that might play a role in metformin antidiabetic and anticancer effects [[201]]. Interestingly, PPARGC1A protects from kidney injury and
metformin 39423 cancer or CRC [[204]]. However, the initial antidiabetic agent recommended for standard T2DM patients, metformin , has been associated with decreased incidence or better outcomes in cancer patients [[205]–[207]].
metformin 39606 cancer patients [[205]–[207]]. Thus, even if prospective clinical studies confirmed the superiority of metformin on cancer incidence or outcome, this would not change the current standard therapeutic approach for
metformin 40268 insulin or analogs are associated to an increased risk of CRC (and cancer in general) [[209]] and whether metformin is associated with a decreased risk of CRC [[210]]. This may represent two sides of the same coin: if
metformin 40564 the risk in the opposite direction. Confounders may exist. Thus, insulin is generally prescribed and metformin remains formally contraindicated in advanced chronic kidney disease (CKD), a late event in the course
metformin 41297 diabetes from observational studies and randomized controlled trials (RCTs), respectively, suggested that metformin or thiazolidinediones were associated with a lower risk of all cancer incidence, while insulin, sulfonylureas
metformin 42436 patients) found that in observational studies the risk of CRC was 17% lower among DM patients treated with metformin than in those not on metformin [[210]]. In a meta-analysis of 21 observational studies metformin was
metformin 42467 studies the risk of CRC was 17% lower among DM patients treated with metformin than in those not on metformin [[210]]. In a meta-analysis of 21 observational studies metformin was associated with a reduction in
metformin 42533 with metformin than in those not on metformin [[210]]. In a meta-analysis of 21 observational studies metformin was associated with a reduction in cancer-specific mortality, including a reduction in mortality for
metformin 42764 studies, HR 0.65, 0.56-0.76) [[205], [220]]. Several mechanisms may account for the antitumor effect of metformin . It reduces circulating insulin, promotes weight loss and activates 5’ adenosine monophosphate-activated
metformin 42993 kinase (AMPK), thus inhibiting growth of colon cancer cells [[221], [222]]. In mice with Apc mutations, metformin suppressed polyp growth [[223]] and in diabetic mice metformin, alone or in combination with oxaliplatin,
metformin 43056 [222]]. In mice with Apc mutations, metformin suppressed polyp growth [[223]] and in diabetic mice metformin , alone or in combination with oxaliplatin, reduced the severity of colorectal tumors [[224]]. Older
metformin 43245 tumors [[224]]. Older literature described increased expression of mitochondrial GPDH, the target of metformin , in rapidly growing, undifferentiated tumors [[225], [226]]. However, there are no data on CRC expression
metformin 43435 no data on CRC expression of mitochondrial GPDH. In non-diabetic subjects, oral short-term low-dose metformin suppressed the development of colorectal aberrant crypt foci in a clinical trial [[227]]. In phase 3
metformin 43573 of colorectal aberrant crypt foci in a clinical trial [[227]]. In phase 3 RCT, low-dose (250 mg/day) metformin was safe and reduced the prevalence and number of metachronous adenomas or polyps after polypectomy
metformin 52939 antidiabetic drugs with colorectal cancer. The most convincing evidence is on a protective effect of metformin Preclinical data suggest that the diabetic environment may promote both colorectal cancer and diabetic
paricalcitol 50502 RCTs [[265]] and may also slow cancer cell growth [[266]]. Phase I trials have tested combinations of paricalcitol and chemotherapeutic agents (NCT00217477). Additionally, vitamin D has been explored for colon cancer
prednisone 50159 receptor antagonist atrasentan is undergoing RCTs for DKD [[260], [261]], and as add-on to docetaxel and prednisone for stage IV hormone therapy-resistant prostate cancer bone metastases (NCT00134056) [[262]–[264]].
repaglinide 44739 [[229], [236], [237]]. A cohort of 275, 164 T2DM patients found no evidence for altered cancer risk for repaglinide or α-glucosidase inhibitors compared to insulin-based therapies or other oral glucose-lowering drugs
simvastatin 49560 pitavastatin prevented carcinogenesis and inhibited colon proliferation and inflammation [[255]], while simvastatin inhibited the release of inflammatory cytokines by colorectal cell lines [[256]]. Clinical trials are
Select Disease Character Offset Disease Term Instance
diabetes mellitus 1491 AcknowledgmentsPublication date (collection): 3/2017Publication date (epub): 1/2017AbstractWorldwide deaths from diabetes mellitus (DM) and colorectal cancer increased by 90% and 57%, respectively, over the past 20 years. The risk
diabetes mellitus 52283 detailed studies (Table 6).Table 5Key pointsAn epidemiological association has been reported between diabetes mellitus , especially type 2 diabetes mellitus , and colorectal cancerHowever, the association has evolved over
diabetes mellitus 52320 pointsAn epidemiological association has been reported between diabetes mellitus, especially type 2 diabetes mellitus , and colorectal cancerHowever, the association has evolved over time, there are differences between
hyperglycemia 5384 prevent or treat CRC in DM patients. A Pubmed search with the key words “(diabetes OR insulin OR hyperglycemia ) AND (colon OR colorectal) AND cancer” was performed with no time cut-off points and further references
hyperglycemia 6930 Europe. Korea is an example of low DM/high CRC country in Asia.DIABETES MELLITUSDM is characterized by hyperglycemia resulting from defects in insulin secretion and/or insulin action. Chronic hyperglycemia is associated
hyperglycemia 7019 characterized by hyperglycemia resulting from defects in insulin secretion and/or insulin action. Chronic hyperglycemia is associated with injury to the kidneys, heart, nerves, eyes and blood vessels [[5]]. In type 1 DM
hyperglycemia 18009 between T2DM and cancer but epidemiological data suggest a potential contribution of hyperinsulinemia, hyperglycemia or DM therapy [[4], [46], [47]] (Figure 2). Additionally, the DM microenvironment, such as advanced
hyperglycemia 19476 cells in DKD, and selective podocyte insulin resistance reproduces features of DKD in the absence of hyperglycemia [[52]]. The mTOR and p21-activated protein kinase-1 (PAK-1)/Wnt/β-catenin intracellular pathways are
hyperglycemia 20138 higher in db/db mice with Apc mutations than in non-diabetic mice [[58]]. However, the relative role of hyperglycemia , hyperinsulinemia or obesity was not characterized.The role of hyperinsulinemia was studied in a normoglycemic
hyperglycemia 23140 to contribute to the pathogenesis of DKD [[77]].Few preclinical studies have addressed the impact of hyperglycemia per se (i.e. T1DM) on colon cancer. Streptozotocin-induced hyperglycemia, an insulin-deficiency DM model,
hyperglycemia 23213 have addressed the impact of hyperglycemia per se (i.e. T1DM) on colon cancer. Streptozotocin-induced hyperglycemia , an insulin-deficiency DM model, increased liver metastasis of mouse colon cancer cells, while glycemic
hyperglycemia 23423 glycemic control with either insulin or gliclazide was protective [[78]]. These studies suggest that hyperglycemia per se may favor colorectal tumor growth and that hyperglycemia may be a more powerful stimulus for
hyperglycemia 23487 [[78]]. These studies suggest that hyperglycemia per se may favor colorectal tumor growth and that hyperglycemia may be a more powerful stimulus for tumorigenesis than insulin in experimental animals.Wnt/β-catenin
hyperglycemia 39080 considered: <8% in the absence of metastases and <8.5% for patients with metastatic cancer. If indeed hyperglycemia underlies the higher incidence of colon cancer in DM, these higher thresholds may theoretically impair
hyperinsulinemia 17991 shared risk factors between T2DM and cancer but epidemiological data suggest a potential contribution of hyperinsulinemia , hyperglycemia or DM therapy [[4], [46], [47]] (Figure 2). Additionally, the DM microenvironment, such
hyperinsulinemia 20153 mice with Apc mutations than in non-diabetic mice [[58]]. However, the relative role of hyperglycemia, hyperinsulinemia or obesity was not characterized.The role of hyperinsulinemia was studied in a normoglycemic model of
hyperinsulinemia 20215 However, the relative role of hyperglycemia, hyperinsulinemia or obesity was not characterized.The role of hyperinsulinemia was studied in a normoglycemic model of mammary cancer growth, but results do not necessarily extrapolate
hyperinsulinemia 20436 extrapolate to CRC [[59]]. A tyrosine kinase inhibitor specific to the insulin and IGF-1 receptors aggravated hyperinsulinemia but prevented insulin signaling and cancer growth. However, tyrosine kinase inhibitors are promiscuous
hyperinsulinemia 20820 of insulin. CL-316243, a β3-adrenergic receptor agonist that sensitizes to insulin action, reduced hyperinsulinemia and phosphorylation of insulin and IGF-1 receptors and attenuated mammary tumor progression, supporting
hyperinsulinemia 20952 phosphorylation of insulin and IGF-1 receptors and attenuated mammary tumor progression, supporting a role for hyperinsulinemia in T2DM associated tumor progression [[60]].HyperglycemiaHyperglycemia has been implicated both in colon
hyperinsulinemia 49438 curatively resected CRC [[254]]. In an obesity-related colon cancer model associated with hyperlipidemia and hyperinsulinemia , pitavastatin prevented carcinogenesis and inhibited colon proliferation and inflammation [[255]], while
hyperlipidemia 18154 (Figure 2). Additionally, the DM microenvironment, such as advanced glycation end-products (AGEs), hyperlipidemia , local inflammation/oxidative stress, extracellular matrix alterations, and altered microbiota or ischemia
hyperlipidemia 27108 anti-inflammatory and anti-fibrotic properties [[103], [104]]. Experimental and human diabetes, inflammation and hyperlipidemia are associated with decreased Klotho expression [[105]–[108]]. Loss of Klotho contributes to kidney
hyperlipidemia 49186 receptor, CXCR4: Chemokine Receptor type 4, CCL2: Chemokine Ligand 2Statins are commonly used to treat hyperlipidemia and have been linked with a small reduction in the risk for colon cancer in diabetic patients [[253]]
hyperlipidemia 49419 prognosis of curatively resected CRC [[254]]. In an obesity-related colon cancer model associated with hyperlipidemia and hyperinsulinemia, pitavastatin prevented carcinogenesis and inhibited colon proliferation and inflammation
obesity 16836 association between DM and CRC were adjusted by BMI. In this regard, there may be a relationship between obesity , insulin resistance and CRC. In a prospective European study, lower CRC risk was observed for metabolically
obesity 19869 increased incidence of azoxymethane-induced intestinal tract cancer was observed in preclinical models of obesity and T2DM, including obese Zucker rats and KK Ay, db/db and ob/ob mice [[55]–[57]]. The addition, the
obesity 20173 than in non-diabetic mice [[58]]. However, the relative role of hyperglycemia, hyperinsulinemia or obesity was not characterized.The role of hyperinsulinemia was studied in a normoglycemic model of mammary cancer
obesity 28392 [[119]–[121]]. The upstream kinase of this pathway, NIK, contributes to β cell failure in diet-induced obesity [[122]], promotes kidney injury [[123]] and underlies the sensitivity of Nlrp12−/− mice to gut inflammation
obesity 28883 between colon epithelial cells and the microbiota may confer susceptibility to both colon cancer and obesity . The inflammasome regulates the microbiota and the inflammatory response of epithelial cells to the
obesity 29547 co-housed individuals with the microbiota. The gut microbiota also impacts host metabolism, facilitating obesity , insulin resistance and T2DM [[129]]. Thus, inflammasome deficiency-related changes in gut microbiota
obesity 29700 inflammasome deficiency-related changes in gut microbiota are associated with insulin resistance and obesity [[130]]. In this regard, T2DM is one of three models of microbiome-associated human conditions to be
obesity 38876 recommended age- and sex-appropriate cancer screenings and to reduce their modifiable cancer risk factors ( obesity , smoking, physical inactivity) [[9]]. In the presence of cancer, higher HbA1c goals should be considered:
obesity 49368 cancer in diabetic patients [[253]] and improved prognosis of curatively resected CRC [[254]]. In an obesity -related colon cancer model associated with hyperlipidemia and hyperinsulinemia, pitavastatin prevented
type 2 diabetes mellitus 52313 6).Table 5Key pointsAn epidemiological association has been reported between diabetes mellitus, especially type 2 diabetes mellitus , and colorectal cancerHowever, the association has evolved over time, there are differences between

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