Published online Apr 15, 2012. doi: 10.4239/wjd.v3.i4.60
Revised: March 3, 2012
Accepted: April 10, 2012
Published online: April 15, 2012
There is a consensus that both type 1 and type 2 diabetes are associated with a spectrum of cancers but the underlying mechanisms are largely unknown. On the other hand, there are ongoing debates about the risk association of insulin use with cancer. We have briefly reviewed recent related research on exploration of risk factors for cancer and pharmacoepidemiological investigations into drug use in diabetes on the risk of cancer, as well as the current understanding of metabolic pathways implicated in intermediary metabolism and cellular growth. Based on the novel findings from the Hong Kong Diabetes Registry and consistent experimental evidence, we argue that use of insulin to control hyperglycemia is unlikely to contribute to increased cancer risk and that dysregulations in the AMP-activated protein kinase pathway due to reduced insulin action and insulin resistance, the insulin-like growth factor-1 (IGF-1)-cholesterol synthesis pathway and renin-angiotensin system, presumably due to reduced insulin secretion and hyperglycemia, may play causal roles in the increased risk of cancer in diabetes. Further exploration into the possible causal relationships between abnormalities of these pathways and the risk of cancer in diabetes is warranted.
- Citation: Yang XL, Chan JC. Diabetes, insulin and cancer risk. World J Diabetes 2012; 3(4): 60-64
- URL: https://www.wjgnet.com/1948-9358/full/v3/i4/60.htm
- DOI: https://dx.doi.org/10.4239/wjd.v3.i4.60
The prevalence of diabetes has been rapidly increasing in China over the past decades[1], i.e., from 0.9% in 1980, to 3.1% in 1994[2] and further increased to 9.7% in 2008[3]. In addition to cardiovascular disease[4-6] and renal disease[7-8], type 1 and type 2 diabetes are also associated with a spectrum of cancers[9-15], except for prostate cancer with reports showing conflicting results[16-17]. Since the first few reports on increased incidence of cancer in insulin-treated patients, there are ongoing debates regarding the risk association of insulin use with cancer[18-19]. In 2010, the American Diabetes Association and the American Cancer Society reviewed the state of science concerning a number of issues regarding the association between diabetes and cancer, including diabetes treatment and cancer risk, and published a joint consensus report but without conclusions about many of these issues, including insulin usage and cancer risk[20-21]. Further contention about insulin usage and cancer risk has important implications since millions of people require insulin to control hyperglycemia. To address this issue, we need to consider two fundamental questions. Firstly, does endogenous insulin play a causal role in cancer development? Secondly, does insulin usage play a causal role in cancer development? Many authors suspect that insulin and insulin analogues may promote tumor proliferation[22-25] but the data from the Hong Kong Diabetes Registry and experimental evidence suggests a different story[18,26].
Circulating insulin levels in non-diabetic or prediabetic subjects are associated with some cancer subtypes[27]. This is often attributed to hyperinsulinemia due to obesity-associated insulin resistance which can promote carcinogenesis through several mechanisms[28]. The adenosine 5′-monophosphate (AMP)-activated protein kinase (AMPK) pathway is a gatekeeper for energy metabolism intimately related to cell cycles, and is considered a therapeutic target for diabetes, metabolic syndrome[29-31] and cancer[32-33]. Insulin resistance is associated with inhibition of the LKB1-AMPK pathway which promotes energy storage and obesity. In experimental studies, inhibition of the LKB1-AMPK was associated with protein synthesis and cancer development, while its activation by metformin reduced cancer risk. Many tumor cells express insulin and insulin growth factor (IGF-1) receptors which can activate the protein kinase B (Akt) and mitogen-activated protein kinase signaling networks in neoplastic tissues. Although more evidence is needed to confirm these mechanisms, they are supported by the association of cancer risk with circulating levels of insulin and IGF-1 in population-based studies[34-35].
However, these mechanisms are not likely to be relevant to people with diabetes, who often have insufficient insulin action and may require insulin to control hyperglycemia. Many of the cohort studies on the association of cancer with insulin use were flawed with biases which can only be addressed by randomized clinical trials. Importantly, insulin use is indicated for hyperglycemia. The latter can independently promote growth of cancer cells which thrive better than normal cells by obtaining energy from glycolysis rather than the tricarboxylic acid cycle in anerobic conditions[36]. In this regard, we reported a 52% (HR: 0.48, 95% CI: 0.32-0.73) reduction of cancer risk among insulin users compared to non users[18], using a validated approach largely free of drug use indication bias, prevent user bias and immortal time bias[37].
Several large cohort or case-control studies have reported a positive association between hyperglycemia and cancer[38-41]. To date, none of the randomized clinical trials of blood-glucose lowering drugs have included cancer as a predefined clinical endpoint. In a prospective cohort, including new insulin users with carefully matched non-insulin users, we first reported the marked reduction in cancer risk in insulin users and an 18% increase in cancer risk for every 1% increase in glycated hemoglobin (A1c)[18]. These novel findings were corroborated by a meta-analysis of blood glucose lowering trials where intensive glycemic control with 0.3%-0.9% reduction in A1c was associated with 9% (95% CI: 0.79-1.05) reduction in cancer risk[42], although individual trials of intensive glycemic control did not observe a reduction in cancer risk[43]. In a tumor-prone animal model, researchers have reported an increased number and size of liver tumors with reduced apoptosis in insulin-deficient hyperglycemic animals compared to insulin-sufficient mice, which was reversed by insulin therapy[44].
The risk association of A1c with cancer has led us to further examine the possible associations of lipids with the risk of cancer, which are tightly linked with glucose metabolism. Using a well characterized prospective cohort, the Hong Kong Diabetes Registry, we first reported the V-shaped risk associations of cancer with various lipid parameters, including low density lipoprotein cholesterol (LDL-C) levels < 2.80 mmol/L and ≥ 3.80[45], high density lipoprotein cholesterol (HDL-C) levels < 1.0 mmol/L and ≥ 1.30 mmol/L[46] and triglyceride < 1.70 mmol/L[47].
Here, the risk association of cancer with low HDL-C has been reported in the general population and may be causal[48]. There are consistent reports that show a protective effect of metformin on the risk of cancer[49-50] and cancer mortality[51-52]. In Chinese type 2 diabetic patients, we have further reported the anti-cancer effects of metformin which is enhanced among patients with low HDL-C < 1.0 mmol/L[46]. Since both apolipoprotein (Apo) A-I, the main lipoprotein of HDL-C[53], and metformin can increase insulin sensitivity by activating the AMPK pathway[54], the interactive effects of metformin and HDL-C on cancer risk suggest that an abnormal AMPK pathway may link diabetes and cancer.
Although the risk association of low LDL-C and cancer has been reported in the general population, its nature remains elusive[55]. In Chinese type 2 diabetic patients, the presence of albuminuria or low triglyceride (< 1.7 mmol/L) greatly enhanced the low LDL-C-cancer associations but not low LDL-C alone[26,56]. This low LDL-C associated cancer risk was markedly attenuated by use of statins[47,56]. Intriguingly, high HDL-C (≥ 1.30 mmol/L) also amplified the cancer-promoting effect of co-presence of low LDL-C and albuminuria[26]. Based on these novel findings and literature search, we were able to find evidence to suggest that insulin (or its action) insufficiency and hyperglycemia may increase cancer risk by up-regulating the cholesterol biosynthesis pathway.
The family of sterol regulatory element-binding proteins (SREBPs), including SREBP-1a, 1c and 2[57], are transcription factors which control lipid metabolism through feedback mechanisms. While SREBP-1a and 2 mainly regulate synthesis of enzymes involved in sterol biosynthesis, SREBP-1c regulates synthesis of enzymes involved in free fatty acid and triglyceride[57]. Since insulin selectively activates SREBP-1c[58], we argue that low triglyceride and low LDL-C may reflect insufficient insulin action with impaired activation of the SREBP-1c. The latter may be accompanied by upregulation of the SREBP-1a pathways to increase cholesterol synthesis with increased production of Ras molecules, the latter known to promote oncogenesis. These hypotheses are supported by the anti-cancer effects of statin, an inhibitor of the hydroxymethylglutaryl-CoA reductase, especially in subjects with the subphenotype of low LDL-C+ low triglyceride[47].
Adding to this complexity are the effects of hyperglycemia on oxidative stress, renin-angiotensin system and inflammation, the latter being reflected by albuminuria[59]. In this regard, we have reported cross-talks between cholesterol synthesis and renin angiotensin pathways in promoting carcinogenesis and the additive effects of statins and inhibitors of the renin-angiotensin pathways on cancer risk[60]. While low HDL-C may be pro-atherogenic, high HDL-C can be pro-inflammatory, especially in the presence of systemic inflammation[61]. Thus, the complex synergistic effects among low LDL-C, albuminuria and high HDL-C in increasing cancer risk and the prominent anticancer effects of statins in patients with co-presence of these risk factors strongly suggest that dysregulation of the cholesterol biosynthesis pathway, secondary to hyperglycemia systemic inflammation and activation of the renin angiotensin system, may play a pivotal role linking diabetes and cancer.
The associations between obesity and cancer incidenceand mortality in general populations have been repeatedly reported for a member of site-specific cancers[62,63]. In type 2 diabetes, the association between body mass index (BMI) and cancer is not a simple linear one but in a V-shaped manner[64]. Both type 2 diabetic patients with BMI < 24.0 kg/m2 and ≥ 27.6 kg/m2 are at increased risk of cancer compared to those who have a BMI at ≥ 24.0 kg/m2 and < 27.6 kg/m2[64]. Obesity impairs insulin action and results in insulin resistance and compensatory hyperglycemia[65]; thus potentially confounding the association between insulin levels and cancer, as well as that between insulin usage and cancer. In this regard, one study reported that the association between obesity and cancer is mediated via the AMPK pathway[66], although many authors believe that insulin and the IGF axis may play a role in obesity-related high cancer risk[67]. With the Hong Kong Diabetes Registry, we reported that insulin usage is associated with a reduced risk of cancer[18] and the hazard ratio is unchanged after further adjusting for the non-linear association between BMI and cancer (unpublished data). Obesity and type 2 diabetes share common characteristic changes in lipid profiles: high triglyceride, low HDL-C and increased concentration of small dense LDL-C particles[68,69]. What is interesting among type 2 diabetes is that low HDL-C but not high triglyceride predicts cancer[46-47,64]. Thus, the lipid-cancer risk associations may only partially explain the obesity-cancer association because the V-shaped association between BMI and cancer among type 2 diabetes was observed after adjusting for the non-linear associations of lipids and cancer risk[64]. To this end, the observed insulin usage and reduced cancer risk is independent of BMI-cancer and lipid-cancer associations[18].
Based on a series of pharmacoepidemiological analysis and our current understanding of metabolic pathways implicated in intermediary metabolism and cellular growth, it is unlikely that use of insulin to control hyperglycemia will contribute to increased cancer risk. Several lines of evidence further suggest that dysregulation of cholesterol synthesis and the renin-angiotensin system, possibly due to insufficient insulin action and/or hyperglycemia, may play causal roles linking diabetes and cancer, in addition to insulin resistance. While these epidemiological findings require independent replication, experimental studies are needed to define these molecular mechanisms. Meanwhile, there is an urgent need to conduct randomized clinical trials to demonstrate whether normalizing these metabolic abnormalities, including hyperglycemia, dyslipidemia, renin-angiotensin system and inflammation, can attenuate cancer risk in diabetes.
Peer reviewers: Dr. Manju Sharma, Assistant Professor, Department of Pharmacology, Hamdard University, 150, Shivalik Apartments, Alaknanda, New Delhi-110062, India; Fernando Guerrero-Romero, MD, PhD, Mexican Social Security Institute, Siqueiros 225, Esq Castaneda, Durango 34000, Mexico
S-Editor Wu X L- Editor Roemmele A E- Editor Wu X
1. | Chan JC, Malik V, Jia W, Kadowaki T, Yajnik CS, Yoon KH, Hu FB. Diabetes in Asia: epidemiology, risk factors, and pathophysiology. JAMA. 2009;301:2129-2140. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 1411] [Cited by in F6Publishing: 1418] [Article Influence: 94.5] [Reference Citation Analysis (0)] |
2. | Pan XR, Yang WY, Li GW, Liu J. Prevalence of diabetes and its risk factors in China, 1994. National Diabetes Prevention and Control Cooperative Group. Diabetes Care. 1997;20:1664-1669. [PubMed] [Cited in This Article: ] |
3. | Yang W, Lu J, Weng J, Jia W, Ji L, Xiao J, Shan Z, Liu J, Tian H, Ji Q. Prevalence of diabetes among men and women in China. N Engl J Med. 2010;362:1090-1101. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 2186] [Cited by in F6Publishing: 2250] [Article Influence: 160.7] [Reference Citation Analysis (2)] |
4. | Yang X, So WY, Kong AP, Ma RC, Ko GT, Ho CS, Lam CW, Cockram CS, Chan JC, Tong PC. Development and validation of a total coronary heart disease risk score in type 2 diabetes mellitus. Am J Cardiol. 2008;101:596-601. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 85] [Cited by in F6Publishing: 85] [Article Influence: 5.3] [Reference Citation Analysis (0)] |
5. | Yang X, So WY, Kong AP, Ho CS, Lam CW, Stevens RJ, Lyu RR, Yin DD, Cockram CS, Tong PC. Development and validation of stroke risk equation for Hong Kong Chinese patients with type 2 diabetes: the Hong Kong Diabetes Registry. Diabetes Care. 2007;30:65-70. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 89] [Cited by in F6Publishing: 90] [Article Influence: 5.3] [Reference Citation Analysis (0)] |
6. | Yang X, Ma RC, So WY, Kong AP, Ko GT, Ho CS, Lam CW, Cockram CS, Tong PC, Chan JC. Development and validation of a risk score for hospitalization for heart failure in patients with Type 2 diabetes mellitus. Cardiovasc Diabetol. 2008;7:9. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 39] [Cited by in F6Publishing: 41] [Article Influence: 2.6] [Reference Citation Analysis (0)] |
7. | Yang XL, So WY, Kong AP, Ho CS, Lam CW, Ng MH, Lyu RR, Yin DD, Chow CC, Cockram CS. Modified end-stage renal disease risk score for Chinese type 2 diabetic patients--the Hong Kong Diabetes Registry. Diabetologia. 2007;50:1348-1350. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 13] [Cited by in F6Publishing: 13] [Article Influence: 0.8] [Reference Citation Analysis (0)] |
8. | Yang XL, So WY, Kong AP, Clarke P, Ho CS, Lam CW, Ng MH, Lyu RR, Yin DD, Chow CC. End-stage renal disease risk equations for Hong Kong Chinese patients with type 2 diabetes: Hong Kong Diabetes Registry. Diabetologia. 2006;49:2299-2308. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 55] [Cited by in F6Publishing: 55] [Article Influence: 3.1] [Reference Citation Analysis (0)] |
9. | Everhart J, Wright D. Diabetes mellitus as a risk factor for pancreatic cancer. A meta-analysis. JAMA. 1995;273:1605-1609. [PubMed] [Cited in This Article: ] |
10. | El-Serag HB, Hampel H, Javadi F. The association between diabetes and hepatocellular carcinoma: a systematic review of epidemiologic evidence. Clin Gastroenterol Hepatol. 2006;4:369-380. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 581] [Cited by in F6Publishing: 559] [Article Influence: 31.1] [Reference Citation Analysis (0)] |
11. | Friberg E, Orsini N, Mantzoros CS, Wolk A. Diabetes mellitus and risk of endometrial cancer: a meta-analysis. Diabetologia. 2007;50:1365-1374. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 351] [Cited by in F6Publishing: 351] [Article Influence: 20.6] [Reference Citation Analysis (0)] |
12. | Larsson SC, Orsini N, Brismar K, Wolk A. Diabetes mellitus and risk of bladder cancer: a meta-analysis. Diabetologia. 2006;49:2819-2823. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 219] [Cited by in F6Publishing: 211] [Article Influence: 11.7] [Reference Citation Analysis (0)] |
13. | Mitri J, Castillo J, Pittas AG. Diabetes and risk of Non-Hodgkin's lymphoma: a meta-analysis of observational studies. Diabetes Care. 2008;31:2391-2397. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 106] [Cited by in F6Publishing: 109] [Article Influence: 6.8] [Reference Citation Analysis (0)] |
14. | Larsson SC, Orsini N, Wolk A. Diabetes mellitus and risk of colorectal cancer: a meta-analysis. J Natl Cancer Inst. 2005;97:1679-1687. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 719] [Cited by in F6Publishing: 729] [Article Influence: 38.4] [Reference Citation Analysis (0)] |
15. | Larsson SC, Mantzoros CS, Wolk A. Diabetes mellitus and risk of breast cancer: a meta-analysis. Int J Cancer. 2007;121:856-862. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 598] [Cited by in F6Publishing: 613] [Article Influence: 36.1] [Reference Citation Analysis (0)] |
16. | Tseng CH. Diabetes and risk of prostate cancer: a study using the National Health Insurance. Diabetes Care. 2011;34:616-621. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 93] [Cited by in F6Publishing: 97] [Article Influence: 7.5] [Reference Citation Analysis (0)] |
17. | Jee SH, Park JY, Kim HS, Lee TY, Samet JM. White blood cell count and risk for all-cause, cardiovascular, and cancer mortality in a cohort of Koreans. Am J Epidemiol. 2005;162:1062-1069. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 71] [Cited by in F6Publishing: 75] [Article Influence: 3.9] [Reference Citation Analysis (0)] |
18. | Yang X, Ko GT, So WY, Ma RC, Yu LW, Kong AP, Zhao H, Chow CC, Tong PC, Chan JC. Associations of hyperglycemia and insulin usage with the risk of cancer in type 2 diabetes: the Hong Kong diabetes registry. Diabetes. 2010;59:1254-1260. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 127] [Cited by in F6Publishing: 117] [Article Influence: 8.4] [Reference Citation Analysis (0)] |
19. | Johnson JA, Pollak M. Insulin, glucose and the increased risk of cancer in patients with type 2 diabetes. Diabetologia. 2010;53:2086-2088. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 28] [Cited by in F6Publishing: 31] [Article Influence: 2.2] [Reference Citation Analysis (0)] |
20. | Giovannucci E, Harlan DM, Archer MC, Bergenstal RM, Gapstur SM, Habel LA, Pollak M, Regensteiner JG, Yee D. Diabetes and cancer: a consensus report. Diabetes Care. 2010;33:1674-1685. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 1291] [Cited by in F6Publishing: 1379] [Article Influence: 98.5] [Reference Citation Analysis (0)] |
21. | Giovannucci E, Harlan DM, Archer MC, Bergenstal RM, Gapstur SM, Habel LA, Pollak M, Regensteiner JG, Yee D. Diabetes and cancer: a consensus report. CA Cancer J Clin. 2010;60:207-221. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 585] [Cited by in F6Publishing: 630] [Article Influence: 45.0] [Reference Citation Analysis (0)] |
22. | Pollak M, Russell-Jones D. Insulin analogues and cancer risk: cause for concern or cause célèbre? Int J Clin Pract. 2010;64:628-636. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 33] [Cited by in F6Publishing: 36] [Article Influence: 2.6] [Reference Citation Analysis (0)] |
23. | Ruiter R, Visser LE, van Herk-Sukel MP, Coebergh JW, Haak HR, Geelhoed-Duijvestijn PH, Straus SM, Herings RM, Stricker BH. Risk of cancer in patients on insulin glargine and other insulin analogues in comparison with those on human insulin: results from a large population-based follow-up study. Diabetologia. 2012;55:51-62. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 87] [Cited by in F6Publishing: 89] [Article Influence: 7.4] [Reference Citation Analysis (0)] |
24. | Werner H, Weinstein D, Yehezkel E, Laron Z. Controversies in the use of insulin analogues. Expert Opin Biol Ther. 2011;11:199-209. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 13] [Cited by in F6Publishing: 13] [Article Influence: 1.0] [Reference Citation Analysis (0)] |
25. | Yehezkel E, Weinstein D, Simon M, Sarfstein R, Laron Z, Werner H. Long-acting insulin analogues elicit atypical signalling events mediated by the insulin receptor and insulin-like growth factor-I receptor. Diabetologia. 2010;53:2667-2675. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 31] [Cited by in F6Publishing: 31] [Article Influence: 2.2] [Reference Citation Analysis (0)] |
26. | Yang X, So WY, Ma RC, Kong AP, Xu G, Chan JC. Diabetes and cancer: the mechanistic implications of epidemiological analyses from the Hong Kong Diabetes Registry. Diabetes Metab Res Rev. 2012;Epub ahead of print. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 34] [Cited by in F6Publishing: 35] [Article Influence: 2.9] [Reference Citation Analysis (0)] |
27. | Pisani P. Hyper-insulinaemia and cancer, meta-analyses of epidemiological studies. Arch Physiol Biochem. 2008;114:63-70. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 233] [Cited by in F6Publishing: 192] [Article Influence: 12.0] [Reference Citation Analysis (0)] |
28. | Godsland IF. Insulin resistance and hyperinsulinaemia in the development and progression of cancer. Clin Sci (Lond). 2010;118:315-332. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 143] [Cited by in F6Publishing: 149] [Article Influence: 9.9] [Reference Citation Analysis (0)] |
29. | Hegarty BD, Turner N, Cooney GJ, Kraegen EW. Insulin resistance and fuel homeostasis: the role of AMP-activated protein kinase. Acta Physiol (Oxf). 2009;196:129-145. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 55] [Cited by in F6Publishing: 47] [Article Influence: 3.1] [Reference Citation Analysis (0)] |
30. | Kraegen EW, Bruce C, Hegarty BD, Ye JM, Turner N, Cooney G. AMP-activated protein kinase and muscle insulin resistance. Front Biosci. 2009;14:4658-4672. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 12] [Cited by in F6Publishing: 12] [Article Influence: 0.8] [Reference Citation Analysis (0)] |
31. | Ruderman NB, Saha AK. Metabolic syndrome: adenosine monophosphate-activated protein kinase and malonyl coenzyme A. Obesity (Silver Spring). 2006;14 Suppl 1:25S-33S. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 47] [Cited by in F6Publishing: 50] [Article Influence: 2.8] [Reference Citation Analysis (0)] |
32. | Kuhajda FP. AMP-activated protein kinase and human cancer: cancer metabolism revisited. Int J Obes (Lond). 2008;32 Suppl 4:S36-S41. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 67] [Cited by in F6Publishing: 77] [Article Influence: 5.1] [Reference Citation Analysis (0)] |
33. | Wang W, Guan KL. AMP-activated protein kinase and cancer. Acta Physiol (Oxf). 2009;196:55-63. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 123] [Cited by in F6Publishing: 131] [Article Influence: 8.7] [Reference Citation Analysis (0)] |
34. | Pollak M. Insulin and insulin-like growth factor signalling in neoplasia. Nat Rev Cancer. 2008;8:915-928. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 1484] [Cited by in F6Publishing: 1526] [Article Influence: 95.4] [Reference Citation Analysis (0)] |
35. | Shackelford DB, Shaw RJ. The LKB1-AMPK pathway: metabolism and growth control in tumour suppression. Nat Rev Cancer. 2009;9:563-575. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 1314] [Cited by in F6Publishing: 1423] [Article Influence: 94.9] [Reference Citation Analysis (0)] |
36. | Warburg O. On the origin of cancer cells. Science. 1956;123:309-314. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 9117] [Cited by in F6Publishing: 9428] [Article Influence: 138.6] [Reference Citation Analysis (0)] |
37. | Yang XL, Ma RC, So WY, Kong AP, Xu G, Chan JC. Addressing different biases in analysing drug use on cancer risk in diabetes in non-clinical trial settings-what, why and how? Diabetes Obes Metab. 2011;Epub ahead of print. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 40] [Cited by in F6Publishing: 43] [Article Influence: 3.6] [Reference Citation Analysis (0)] |
38. | Muti P, Quattrin T, Grant BJ, Krogh V, Micheli A, Schünemann HJ, Ram M, Freudenheim JL, Sieri S, Trevisan M. Fasting glucose is a risk factor for breast cancer: a prospective study. Cancer Epidemiol Biomarkers Prev. 2002;11:1361-1368. [PubMed] [Cited in This Article: ] |
39. | Takahashi H, Mizuta T, Eguchi Y, Kawaguchi Y, Kuwashiro T, Oeda S, Isoda H, Oza N, Iwane S, Izumi K. Post-challenge hyperglycemia is a significant risk factor for the development of hepatocellular carcinoma in patients with chronic hepatitis C. J Gastroenterol. 2011;46:790-798. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 26] [Cited by in F6Publishing: 27] [Article Influence: 2.1] [Reference Citation Analysis (0)] |
40. | Stattin P, Björ O, Ferrari P, Lukanova A, Lenner P, Lindahl B, Hallmans G, Kaaks R. Prospective study of hyperglycemia and cancer risk. Diabetes Care. 2007;30:561-567. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 246] [Cited by in F6Publishing: 257] [Article Influence: 15.1] [Reference Citation Analysis (0)] |
41. | Saydah SH, Platz EA, Rifai N, Pollak MN, Brancati FL, Helzlsouer KJ. Association of markers of insulin and glucose control with subsequent colorectal cancer risk. Cancer Epidemiol Biomarkers Prev. 2003;12:412-418. [PubMed] [Cited in This Article: ] |
42. | Johnson JA, Bowker SL. Intensive glycaemic control and cancer risk in type 2 diabetes: a meta-analysis of major trials. Diabetologia. 2011;54:25-31. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 110] [Cited by in F6Publishing: 99] [Article Influence: 7.6] [Reference Citation Analysis (0)] |
43. | Stefansdottir G, Zoungas S, Chalmers J, Kengne AP, Knol MJ, Leufkens HG, Patel A, Woodward M, Grobbee DE, De Bruin ML. Intensive glucose control and risk of cancer in patients with type 2 diabetes. Diabetologia. 2011;54:1608-1614. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 28] [Cited by in F6Publishing: 25] [Article Influence: 1.9] [Reference Citation Analysis (0)] |
44. | Yamasaki K, Hayashi Y, Okamoto S, Osanai M, Lee GH. Insulin-independent promotion of chemically induced hepatocellular tumor development in genetically diabetic mice. Cancer Sci. 2010;101:65-72. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 28] [Cited by in F6Publishing: 27] [Article Influence: 1.9] [Reference Citation Analysis (0)] |
45. | Yang X, So W, Ko GT, Ma RC, Kong AP, Chow CC, Tong PC, Chan JC. Independent associations between low-density lipoprotein cholesterol and cancer among patients with type 2 diabetes mellitus. CMAJ. 2008;179:427-437. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 63] [Cited by in F6Publishing: 68] [Article Influence: 4.3] [Reference Citation Analysis (0)] |
46. | Yang X, So WY, Ma RC, Kong AP, Lee HM, Yu LW, Chow CC, Ozaki R, Ko GT, Chan JC. Low HDL cholesterol, metformin use, and cancer risk in type 2 diabetes: the Hong Kong Diabetes Registry. Diabetes Care. 2011;34:375-380. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 53] [Cited by in F6Publishing: 60] [Article Influence: 4.6] [Reference Citation Analysis (0)] |
47. | Yang X, Ma RC, So WY, Yu LW, Kong AP, Ko GT, Xu G, Ozaki R, Tong PC, Chan JC. Low triglyceride and nonuse of statins is associated with cancer in type 2 diabetes mellitus: the Hong Kong Diabetes Registry. Cancer. 2011;117:862-871. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 17] [Cited by in F6Publishing: 18] [Article Influence: 1.3] [Reference Citation Analysis (0)] |
48. | Jafri H, Alsheikh-Ali AA, Karas RH. Baseline and on-treatment high-density lipoprotein cholesterol and the risk of cancer in randomized controlled trials of lipid-altering therapy. J Am Coll Cardiol. 2010;55:2846-2854. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 113] [Cited by in F6Publishing: 121] [Article Influence: 8.6] [Reference Citation Analysis (0)] |
49. | Libby G, Donnelly LA, Donnan PT, Alessi DR, Morris AD, Evans JM. New users of metformin are at low risk of incident cancer: a cohort study among people with type 2 diabetes. Diabetes Care. 2009;32:1620-1625. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 778] [Cited by in F6Publishing: 782] [Article Influence: 52.1] [Reference Citation Analysis (0)] |
50. | Lee MS, Hsu CC, Wahlqvist ML, Tsai HN, Chang YH, Huang YC. Type 2 diabetes increases and metformin reduces total, colorectal, liver and pancreatic cancer incidences in Taiwanese: a representative population prospective cohort study of 800,000 individuals. BMC Cancer. 2011;11:20. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 314] [Cited by in F6Publishing: 340] [Article Influence: 26.2] [Reference Citation Analysis (0)] |
51. | Landman GW, Kleefstra N, van Hateren KJ, Groenier KH, Gans RO, Bilo HJ. Metformin associated with lower cancer mortality in type 2 diabetes: ZODIAC-16. Diabetes Care. 2010;33:322-326. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 385] [Cited by in F6Publishing: 405] [Article Influence: 28.9] [Reference Citation Analysis (0)] |
52. | Lee JH, Kim TI, Jeon SM, Hong SP, Cheon JH, Kim WH. The effects of metformin on the survival of colorectal cancer patients with diabetes mellitus. Int J Cancer. 2011;Epub ahead of print. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 143] [Cited by in F6Publishing: 159] [Article Influence: 12.2] [Reference Citation Analysis (0)] |
53. | Han R, Lai R, Ding Q, Wang Z, Luo X, Zhang Y, Cui G, He J, Liu W, Chen Y. Apolipoprotein A-I stimulates AMP-activated protein kinase and improves glucose metabolism. Diabetologia. 2007;50:1960-1968. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 116] [Cited by in F6Publishing: 98] [Article Influence: 5.8] [Reference Citation Analysis (0)] |
54. | Ben Sahra I, Le Marchand-Brustel Y, Tanti JF, Bost F. Metformin in cancer therapy: a new perspective for an old antidiabetic drug? Mol Cancer Ther. 2010;9:1092-1099. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 351] [Cited by in F6Publishing: 356] [Article Influence: 25.4] [Reference Citation Analysis (0)] |
55. | Alsheikh-Ali AA, Trikalinos TA, Kent DM, Karas RH. Statins, low-density lipoprotein cholesterol, and risk of cancer. J Am Coll Cardiol. 2008;52:1141-1147. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 80] [Cited by in F6Publishing: 82] [Article Influence: 5.1] [Reference Citation Analysis (0)] |
56. | Yang X, So WY, Ma RC, Ko GT, Kong AP, Zhao H, Luk AO, Lam CW, Ho CS, Tong PC. Low LDL cholesterol, albuminuria, and statins for the risk of cancer in type 2 diabetes: the Hong Kong diabetes registry. Diabetes Care. 2009;32:1826-1832. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 37] [Cited by in F6Publishing: 39] [Article Influence: 2.6] [Reference Citation Analysis (0)] |
57. | Brown MS, Goldstein JL. The SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor. Cell. 1997;89:331-340. [PubMed] [Cited in This Article: ] |
58. | Shimomura I, Bashmakov Y, Ikemoto S, Horton JD, Brown MS, Goldstein JL. Insulin selectively increases SREBP-1c mRNA in the livers of rats with streptozotocin-induced diabetes. Proc Natl Acad Sci USA. 1999;96:13656-13661. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 587] [Cited by in F6Publishing: 591] [Article Influence: 23.6] [Reference Citation Analysis (0)] |
59. | Kalaitzidis R, Bakris G. Pathogenesis and treatment of microalbuminuria in patients with diabetes: the road ahead. J Clin Hypertens (Greenwich). 2009;11:636-643. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 23] [Cited by in F6Publishing: 25] [Article Influence: 1.8] [Reference Citation Analysis (0)] |
60. | Yang X, Zhao H, Sui Y, Ma RC, So WY, Ko GT, Kong AP, Ozaki R, Yeung CY, Xu G. Additive interaction between the renin-angiotensin system and lipid metabolism for cancer in type 2 diabetes. Diabetes. 2009;58:1518-1525. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 34] [Cited by in F6Publishing: 33] [Article Influence: 2.2] [Reference Citation Analysis (0)] |
61. | Nakamura M, Onoda T, Itai K, Ohsawa M, Satou K, Sakai T, Segawa T, Sasaki J, Tonari Y, Hiramori K. Association between serum C-reactive protein levels and microalbuminuria: a population-based cross-sectional study in northern Iwate, Japan. Intern Med. 2004;43:919-925. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 72] [Cited by in F6Publishing: 71] [Article Influence: 3.6] [Reference Citation Analysis (0)] |
62. | Basen-Engquist K, Chang M. Obesity and cancer risk: recent review and evidence. Curr Oncol Rep. 2011;13:71-76. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 326] [Cited by in F6Publishing: 283] [Article Influence: 21.8] [Reference Citation Analysis (0)] |
63. | Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med. 2003;348:1625-1638. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 5430] [Cited by in F6Publishing: 5101] [Article Influence: 242.9] [Reference Citation Analysis (0)] |
64. | Yang X, So WY, Ma RC, Ko GT, Kong AP, Wang Q, Cockram CS, Chow CC, Chan JC, Tong PC. Predicting values of lipids and white blood cell count for all-site cancer in type 2 diabetes. Endocr Relat Cancer. 2008;15:597-607. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 35] [Cited by in F6Publishing: 36] [Article Influence: 2.3] [Reference Citation Analysis (0)] |
65. | Benito M. Tissue specificity on insulin action and resistance: past to recent mechanisms. Acta Physiol (Oxf). 2011;201:297-312. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 25] [Cited by in F6Publishing: 18] [Article Influence: 1.4] [Reference Citation Analysis (0)] |
66. | Brown KA, Simpson ER. Obesity and breast cancer: progress to understanding the relationship. Cancer Res. 2010;70:4-7. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 93] [Cited by in F6Publishing: 96] [Article Influence: 6.4] [Reference Citation Analysis (0)] |
67. | Donohoe CL, Doyle SL, Reynolds JV. Visceral adiposity, insulin resistance and cancer risk. Diabetol Metab Syndr. 2011;3:12. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 156] [Cited by in F6Publishing: 161] [Article Influence: 12.4] [Reference Citation Analysis (0)] |
68. | Tonstad S, Després JP. Treatment of lipid disorders in obesity. Expert Rev Cardiovasc Ther. 2011;9:1069-1080. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 32] [Cited by in F6Publishing: 31] [Article Influence: 2.6] [Reference Citation Analysis (0)] |
69. | Mooradian AD. Dyslipidemia in type 2 diabetes mellitus. Nat Clin Pract Endocrinol Metab. 2009;5:150-159. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 415] [Cited by in F6Publishing: 509] [Article Influence: 33.9] [Reference Citation Analysis (0)] |