Diabetes Cancer Risk Research Articles

Associations between polychlorinated biphenyls and cancer risk among type 2 diabetes: The modifying effects of lifestyle

A growing percentage of diabetes-related deaths has been attributed to cancer, with environmental factors playing important contributions. Thus, we studied the potential relationship between endocrine disruptors polychlorinated biphenyls (PCBs) and cancer risk in diabetes. We aimed to evaluate the association between serum seven indicator-PCB (PCB-28/52/101/118/138/153/180) levels and incident cancer, and further explore the possible modifying role of lifestyle. A total of 2806 type 2 diabetes mellitus (T2DM) cases were included from the Dongfeng-Tongji cohort at the baseline in 2008 and tracked until December 2018, and 320 incident cancers were identified during about 10-year follow-up. Cox proportional hazards models and competing risk regression models were used to reveal associations of baseline concentrations of PCBs with total cancer and specific cancer, respectively. Lifestyle score was determined by body mass index, waist circumference, physical activity, smoking, alcohol drinking, and diet. Each interquartile range (IQR) increment of non-dioxin-like PCBs (NDL-PCBs) generated an 8%–30% increase in cancer incidence. Individuals in the highest quartile for PCB-52, PCB-101, PCB-138, and lowly chlorinated PCBs had 1.44- to 1.68-fold higher cancer risk compared to those in the lowest quartile. Restricted cubic spline analyses and the quantile g-computation model showed similar results. Significant interactions were found between PCBs and fasting blood glucose or simplified insulin resistance assessment indicators. NDL-PCBs were positively and significantly associated with gastrointestinal cancer and respiratory cancer, especially with liver cancer, colorectal cancer, and lung cancer. Higher PCBs showed a significant increase in total cancer risk among participants with an unhealthy lifestyle, however, no associations were observed in those with a relatively healthy lifestyle (Pinteraction < 0.05). Our findings indicated an increased cancer risk associated with NDL-PCBs, highlighted the role of a healthy lifestyle in potentially reducing adverse impact, and provided preliminary data for environmental and public health interventions to alleviate the risk of cancer among diabetes.

Interrelationship between oxidative stress, DNA damage and cancer risk in diabetes (Type 2) in Riyadh, KSA.

Type 2 Diabetes Mellitus (T2DM) is the most widely known type of disorder of the endocrine system marked by hyperglycemia resulting either due to deficiency of insulin and or resistance. Persistent hyperglycemia induces oxidative stress and is suggested to play a prominent role in the pathophysiology underlying T2DM. Besides, oxidative stress can result in DNA damage leading to high cancer risk. Current study aimed to evaluate status of oxidative damage, damage to DNA and cancer biomarkers in regard to increased glucose in T2DM patients and to correlate the glycemic state with cancer. A total of 150 subjects consisting of control (50) and T2DM patients (1 0 0) were enrolled. Additionally, three tertiles were created among the two groups based on levels of HbA1c (Tertile I = 5.37 ± 0.34, n = 50; Tertile II = 6.74 ± 0.20, n = 50; Tertile III = 9.21 ± 1.47, n = 50). Oxidative stress parameters including malondialedehyde (MDA) and antioxidant enzymes were measured. Damage to DNA was analyzed by measuring the levels of DNA damage adduct-8 hydroxy deoxy Guanosine (8-OHdG). To detect cancer resulting from oxidative stress, cancer biomarkers CEA, AFP, CA125, CA-15, CA19-9, prolactin were measured in these subjects. All measurements were analysed by SPSS software. Levels of MDA and antioxidant enzymes altered significantly in T2DM group at p < 0.001 and p < 0.05 level of significance. Significant DNA damage accompanied with elevated levels of CEA, CA19-9 and decreased CA125, AFP and prolactin were noted in T2DM group. CA 19-9 and CEA levels increased at p < 0.05, whereas levels of prolactin decreased significantly (p < 0.001) in T2DM group compared to control. Additionally the mean values of DNA damage adduct 8-OHdG differ significantly at P < 0.01 between the two groups. However, no significant correlation in oxidative stress parameter, antioxidant enzymes, DNA damage and neither with the highest tertile of HbA1c (>7.5%) was noted. Based on the results obtained in the present study, we conclude that there is considerable change in oxidative stress and DNA damage in T2DM patients. Hence, assumption that the oxidative stress could cause cancer in T2DM as a result of hyperglycemic state was not speculated in this study.

Diabetes and risk of cancer

Recent epidemiological studies have revealed the association of elevated cancer risk and diabetes mellitus [1–13]. Because the prevalence of diabetes mellitus and cancer is increasing worldwide, understanding the higher risk of specific types of cancer is important in management of diabetic patients. The American Diabetes Association (ADA) and the American Cancer Society (ACS) produced a consensus report on the increased risk of liver, pancreas, endometrial, colorectal, breast, and bladder cancer among diabetic patients [14]. In 2013, the joint committee of the Japan Diabetes Society (JDS) and the Japanese Cancer Association (JCA) reported the association of diabetes and cancer, including colorectal, liver, and pancreatic cancer, among Japanese diabetic patients [15]. Although the mechanisms underlying this association are not fully understood, several potential mechanisms which promote oncogenesis in diabetes have been discussed. Chronic inflammation, insulin resistance associated with hyperinsulinemia, and hyperglycemia have been suggested as potential mechanisms. These factors may lead to increased risk of cancer in diabetes and promote oncogenesis in different ways. Numerous studies have suggested the effect of insulin and chronic inflammation on cancer progression in diabetes. The experimental and epidemiological evidence is most consistent with the hyperinsulinemia and chronic inflammation hypothesis. In particular, progression of hepatocellular carcinoma seems to be closely associated with chronic inflammation and insulin resistance related to hyperinsulinemia. In a large scale cohort study in Japan, diabetes led to a high risk of hepatocellular carcinoma [16]. A meta-analysis also showed that diabetes increases the risk of hepatocellular carcinoma [12] and diabetes is risk factor for hepatocellular carcinoma among patients with nonalcoholic fatty liver disease (NAFLD) [17]. A recent clinical review suggested that NAFLD and nonalcoholic steatohepatitis (NASH) patients, especially those with diabetes, should be monitored for the onset of hepatocellular carcinoma [18]. However, the involvement of hyperglycemia in cancer development is less clear and few studies have shown the contribution of hyperglycemia to cancer progression and metastasis. Cancer cells maintain an abnormally high rate of glycolysis, even in the presence of oxygen, a phenomenon called the Warburg effect [19]. Enhanced glucose uptake in cancer is revealed by positron emission tomography (PET) scans, a widely used method of cancer detection, and clinical use of PET scans is well established. Despite many years of investigation, the specific regulatory mechanisms responsible for the Warburg effect are not fully understood. Increased expression of glucose transporter 1 has been observed, and this enables cancer cells to absorb extracellular glucose [20]. Increased type 2 hexokinase activity in cancer has also been demonstrated [21–23]. Although hexokinase is involved in the first irreversible stage of glycolysis, it is not the late limiting enzyme of the process. Fructose 2,6-bisphosphate (F2,6BP) is a powerful allosteric activator of 6-phosphofructo-1-kinase (PFK-1), which is the rate-limiting enzyme of glycolysis [24]. F2,6BP increases the affinity of PFK-1 for fructose 6-phosphate and reduces the inhibitory effect of ATP. Previous work has revealed markedly elevated levels of F2,6BP in several cancer cell lines [25–27]. The intracellular concentration of F2,6BP depends on the activity of the bifunctional enzyme 6-phosphofructo-2-kinase/fructose2,6-bisphosphatase (PFK-2/FBPase) [28]. At least four & Toshiya Atsumi tatsumi@nissei-hp.com

Colorectal and Prostate Cancer Risk in Diabetes: Metformin, an Actor behind the Scene.

Both diabetes and cancer are prevalent diseases whose incidence rates are increasing worldwide, especially in countries that are undergoing rapid industrialization changes. Apparently, lifestyle risk factors including diet, physical inactivity and obesity play pivotal, yet preventable, roles in the etiology of both diseases. Epidemiological studies provide strong evidence that subjects with diabetes are at significantly higher risk of developing many forms of cancer and especially solid tumors. In addition to pancreatic and breast cancer, the incidence of colorectal cancer and prostate cancer is increased in type 2 diabetes. While diabetes (type 2) and cancer share many risk factors, the biological links between the two diseases are poorly characterized. In this review, we highlight the mechanistic pathways that link diabetes to colorectal and prostate cancer and the use of Metformin, a diabetes drug, to prevent and/or treat colorectal and prostate cancer. We review the role of AMPK activation in autophagy, oxidative stress, inflammation, apoptosis, and cell cycle progression.

CARING (CAncer Risk and INsulin analoGues): The Association of Diabetes Mellitus and Cancer Risk with Focus on Possible Determinants - A Systematic Review and a Meta-Analysis

Background: Patients suffering from diabetes mellitus (DM) may experience an increased risk of cancer; however, it is not certain whether this effect is due to diabetes per se.Objective: To examine the association between DM and cancers by a systematic review and meta-analysis according to the PRISMA guidelines.Data Sources: The systematic literature search includes Medline at PubMed, Embase, Cinahl, Bibliotek.dk, Cochrane library, Web of Science and SveMed+ with the search terms: “Diabetes mellitus”, “Neoplasms”, and “Risk of cancer”.Study Eligibility Criteria: The included studies compared the risk of cancer in diabetic patients versus non-diabetic patients. All types of observational study designs were included.Results: Diabetes patients were at a substantially increased risk of liver (RR=2.1), and pancreas (RR=2.2) cancer. Modestly elevated significant risks were also found for ovary (RR=1.2), breast (RR=1.1), cervix (RR=1.3), endometrial (RR=1.4), several digestive tract (RR=1.1-1.5), kidney (RR=1.4), and bladder cancer (RR=1.1). The findings were similar for men and women, and unrelated to study design. Meta-regression analyses showed limited effect modification of body mass index, and possible effect modification of age, gender, with some influence of study characteristics (population source, cancer- and diabetes ascertainment).Limitations: Publication bias seemed to be present. Only published data were used in the analyses.Conclusions: The systematic review and meta-analysis confirm the previous results of increased cancer risk in diabetes and extend this to additional cancer sites. Physicians in contact with patients with diabetes should be aware that diabetes patients are at an increased risk of cancer.

Hepatocellular cancer risk in diabetes: Not all diabetics are the same

Hepatocellular cancer risk in diabetes: Not all diabetics are the same

Risk of Cancer in Diabetes: The Effect of Metformin

Cancer is the second cause of death. Association of diabetes as a growing and costly disease with cancer is a major health concern. Meanwhile, preexisting diabetes is associated with an increased risk of all-cause and cancer-specific mortalities. Presence of diabetes related comorbidities, poorer response to cancer treatment, and excess mortality related to diabetes are among the most important explanations. Although diabetes appear to be a risk factor for cancer and is associated with the mortality risk in cancer patients, several factors such as diabetes duration, multiple drug therapy, and the presence of diabetes comorbidities make the assessment of the effect of diabetes treatment on cancer risk and mortality difficult. Metformin is the drug of choice for the treatment of type 2 diabetes. The available evidence from basic science, clinical, and population-based research supports the anticancer effect of metformin. However, randomized controlled clinical trials do not provide enough evidence for a strong protective effect of metformin on cancer incidence or mortality. One of the most important limitations of these trials is the short duration of the followup. Further long-term randomized controlled clinical trials specifically designed to determine metformin effect on cancer risk are needed to provide the best answer to this challenge.

Latest insights into the risk of cancer in diabetes.

A growing body of evidence from observational studies and meta-analyses of the data suggest that diabetes mellitus is associated with an increased risk of cancer. Meta-analyses have shown that diabetes increases the risks of total cancer, and of site-specific cancers of the breast, endometrium, bladder, liver, colorectum and pancreas, and that it decreases the risk of prostate cancer. Insulin resistance and secondary hyperinsulinemia is the most frequently proposed hypothesis, and hyperglycemia itself might promote carcinogenesis. In addition to several facets of lifestyle including obesity, smoking and lack of exercise, treatment for diabetes might affect the risk of cancer. For instance, metformin, an insulin sensitizer, reportedly has a potential anticancer effect. In light of the exploding global epidemic of diabetes, even a modest increase in the cancer risk will translate into a substantial socioeconomic burden. The current insights underscore the need for clinical attention and better-designed studies of the complex interactions between diabetes and cancer.

Insulin Receptor Isoforms A and B as well as Insulin Receptor Substrates-1 and -2 Are Differentially Expressed in Prostate Cancer

Aims/HypothesisIn different cancers types, insulin receptor isoform composition or insulin receptor substrate (IRS) isoforms are different to healthy tissue. This may be a molecular link to increased cancer risk in diabetes and obesity. Since this is yet unclear for prostate cancer, we investigated IR isoform composition and IRS balance in prostate cancer compared to benign and tumor adjacent benign prostate tissue and brought this into relation to cell proliferation.MethodsWe studied 23 benign prostate samples from radical cystectomy or benign prostatic hyperplasia surgery, 30 samples from benign tissue directly adjacent to prostate cancer foci and 35 cancer samples from different patients. RNA expression levels for insulin receptor isoforms A and B, IRS-1, IRS-2, and IGF-1 receptor were assessed by quantitative real-time RT-PCR. In addition, RNA- and protein expression of the cell cycle regulator p27Kip1 was quantified by real-time RT-PCR and immunohistochemistry.ResultsInsulin receptor isoform A to B ratio was significantly higher in cancer as well as in tumor adjacent benign prostate tissue compared to purely benign prostates (p<0.05). IRS-1 to IRS-2 ratios were lower in malignant than in benign prostatic tissue (p<0.05). These altered ratios both in cancer and adjacent tissue were significantly associated with reduced p27Kip1 content (p<0.02). Interestingly, IGF-1 receptor levels were significantly lower in patients with type 2 diabetes (p = 0.0019).Conclusions/InterpretationWe found significant differences in the insulin signaling cascade between benign prostate tissue and prostate cancer. Histological benign tissue adjacent to cancer showed expression patterns similar to the malignancies. Our findings suggest a role of the insulin signaling pathway in prostate cancer and surrounding tissue and can hence be relevant for both novel diagnostic and therapeutic approaches in this malignancy.

Increased cancer risk with drug use among patients with diabetes: Are the biased methods the culprit?

Increased cancer risk with drug use among patients with diabetes: Are the biased methods the culprit?

Targeting Glycolysis and Compensatory Mitochondrial Metabolism in Multiple Myeloma with FDA Approved Ritonavir and Metformin Via Synthetic Lethality

Abstract 4016Multiple Myeloma (MM) is an incurable plasma cell malignancy accounting for 11,000 deaths annually in the US and 20% of deaths from all hematological malignancies. MM is one of myriad malignancies exhibiting enhanced glucose consumption associated with an aerobic glycolytic phenotype (i.e. the Warburg effect). We have recently published a study defining key glucose transporters responsible for facilitating glucose entry in myeloma and observed that MM cells exhibit reliance on constitutively cell surface-localized GLUT4 for basal glucose consumption. MM cells cultured in the absence of glucose or upon GLUT4 suppression exhibit either overt apoptosis (sensitive phenotype) or growth arrest (resistant phenotype). To further demonstrate the clinical utility of targeting GLUT4 for MM therapy we tested a HIV protease inhibitor ritonavir that has an off-target inhibitory effect on GLUT4. Treatment of MM cells with physiologically achievable concentrations of ritonavir blocks glucose entry resulting in MM cell death or growth suppression.The objective of this study was to define those metabolic pathways in resistant MM cell lines which compensate for the decrease in cellular glucose and protect the cells from toxicity caused by glucose-deprivation or GLUT4 suppression. We hypothesized that resistant cells (i.e. JJN3) cultured in the absence of glucose revert to mitochondrial metabolism or autophagy to prevent cell death. The autophagy inhibitor chloroquine did not sensitize resistant cells cultured in the absence of glucose, ruling out autophagy as a source of compensatory metabolites. We next established that the mitochondrial substrates 2-methyl pyruvate or galactose rescue sensitive cells from toxicity caused by culture in the lack of glucose (Fig. 1A). These results suggest the potential for mitochondrial metabolism to rescue cell death ensuing upon inhibition of glycolysis. We therefore treated the resistant JJN3 cells with mitochondrial inhibitors metformin or rotenone to determine if we could elicit toxicity upon glucose-withdrawal. Indeed, resistant cells were sensitized to glucose-withdrawal upon treatment with complex 1 inhibitors metformin (Figure 1B) or rotenone. Metformin treatment alone had a minimal impact on the viability of resistant cells cultured in the presence of glucose (Fig. 1B). To simulate glucose-withdrawal we tested the ability of ritonavir (HIV protease inhibitor that has an off target inhibitory effect on GLUT4) to elicit toxicity in combination with metformin in the resistant cells. Our studies revealed that addition of ritonavir with metformin synergizes to elicit toxicity in resistant cells (Fig. 1C). This synergy was also observed in additional MM cell lines (KMS11 and U266). The biguanide metformin is the most commonly prescribed anti-hyperglycemic drug for the treatment of Type II diabetes. Epidemiologic studies have correlated metformin with a reduced risk of cancer in diabetics earning the drug recognition as a possible anti-neoplastic agent for various types of malignancies. This combinatorial regimen of ritonavir and metformin was not toxic in normal PBMC. The selective tumor specific synthetic lethality induced in ritonavir treated resistant cells upon metformin treatment is detected at doses that are clinically achievable with both compounds. We have initiated studies to evaluate this combination in mouse models of myeloma and patient samples. HIV patients chronically treated with ritonavir who exhibit diabetic symptoms have been treated with metformin indicating this combination treatment is well tolerated in humans. Our studies reveal a potent combinatorial regimen involving repurposed, FDA approved, ritonavir and metformin for the treatment of MM and potentially other glucose-driven malignancies. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Diabetes and pancreatic cancer

Epidemiological studies clearly indicate that the risk of pancreatic cancer (PC) is increased in diabetic patients, but most studies focus on overall diabetes or type 2 diabetes mellitus (T2DM), and there are few studies on the risks of type 1 and type 3c (secondary) diabetes. Possible mechanisms for increased cancer risk in diabetes include cellular proliferative effects of hyperglycemia, hyperinsulinemia, and abnormalities in insulin/IGF receptor pathways. Recently, insulin and insulin secretagogues have been observed to increase the PC risk, while metformin treatment reduces the cancer risk in diabetic subjects. In addition, anticancer drugs used to treat PC may either cause diabetes or worsen coexisting diabetes. T3cDM has emerged as a major subset of diabetes and may have the highest risk of pancreatic carcinoma especially in patients with chronic pancreatitis. T3cDM is also a consequence of PC in at least 30% of patients. Distinguishing T3cDM from the more prevalent T2DM among new-onset diabetic patients can be aided by an assessment of clinical features and confirmed by finding a deficiency in postprandial pancreatic polypeptide release. In conclusion, diabetes and PC have a complex relationship that requires more clinical attention. The risk of developing PC can be reduced by aggressive prevention and treatment of T2DM and obesity and the prompt diagnosis of T3cDM may allow detection of a tumor at a potentially curable stage.

Addressing different biases in analysing drug use on cancer risk in diabetes in non‐clinical trial settings—what, why and how?

Motivated by recent reports on associations between diabetes and cancer, many researchers have used administrative databases to examine risk association of cancer with drug use in patients with diabetes. Many of these studies suffered from major biases in study design and data analysis, which can lead to erroneous conclusions if these biases are not adjusted. This article discusses the sources and impacts of these biases and methods for correction of these biases. To avoid erroneous results, this article suggests performing sensitivity and specificity analysis as well as using a drug with a known effect on an outcome to ascertain the validity of the proposed methods. Using the Hong Kong Diabetes Registry, we illustrated the impacts of biases of drug use indication and prevalent user by examining the effects of statins on cardiovascular disease. We further showed that 'immortal time bias' may have a neutral impact on the estimated drug effect if the hazard is assumed to be constant over time. On the contrary, adjustment for 'immortal time bias' using time-dependent models may lead to misleading results biased towards against the treatment. However, artificial inclusion of immortal time in non-drug users to correct for immortal time bias may bias the result in favour of the therapy. In conclusion, drug use indication bias and prevalent user bias but not immortal time bias are major biases in the design and analysis of drug use effects among patients with diabetes in non-clinical trial settings.

Diabetes, insulin and cancer risk

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.

The Role for Insulin and Insulin-like Growth Factors in the Increased Risk of Cancer in Diabetes

Patients with type 2 diabetes (T2D) are at increased risk of developing cancer. This evidence arises from numerous epidemiologic studies that relate a positive association between T2D and cancer. In-vitro and several in-vivo experiments have attempted to discern the potential mechanistic factors involved in this relationship. Candidates include hyperinsulinemia, insulin-like growth factor-1 (IGF-1), and insulin-like growth factor-2 (IGF-2) signaling. These studies demonstrated that increased insulin, IGF-1, and IGF-2 signaling through the insulin receptor and IGF-1 receptor can induce cancer development and progression.

New insulins and insulin therapy

The introduction of the so-called 'designer' insulins, the insulin analogues, has offered new opportunities in the clinical management of diabetes. Two additional new entities are close to reaching clinical practice. Linjeta™ (formally called VIAject) is not an analogue but rather a different formulation of human insulin which may give it a more rapid onset of action, potentially even faster than the currently available rapid-acting insulin analogues. Degludec™, on the other hand, is an insulin analogue molecule with an ultra-long clinical profile derived from the soluble multi-hexamer formation, resulting in a continuous slow and stable release of insulin degludec monomers which may last longer than currently available long-acting analogues. As with any new type of drug, the safety of the 'designer' insulins has to be closely scrutinised. Last year the increased cancer risk in diabetes entered the spotlight and the potential role of insulin analogues led to controversial discussions. In spite of recent new in vitro and observational data no new conclusive evidence became available. The need for multiple well-conducted and appropriately designed prospective observational studies to follow up the effectiveness and safety of the new insulins and the new insulin treatment regimens remains. In this chapter it was our mission to chose articles published about "new insulins" over the last year that have the most important contribution for the on-going development of ultra-fast- and ultra-long-acting insulin analogs and preparations and their potential side-effects, particularly cancer. This has been done by means of PubMed searches as well as a review of abstracts of the recent large international diabetes meetings such as ADA, EASD and ISPAD.

Diabetes, Insulin Use, and Cancer Risk: Are Observational Studies Part of the Solution–or Part of the Problem?

Cancer has overtaken cardiovascular disease as the leading cause of death in individuals under the age of 65 in the general population, but it is still overshadowed by cardiovascular disease in those with diabetes. People with type 2 diabetes are nonetheless more likely to develop cancer—and to die from it—than members of the general population, so cancer should be numbered among the complications of diabetes (1). Furthermore, the number of cancer victims with diabetes will inevitably rise in proportion to our success in combating vascular disease in the diabetic population. How can the increased cancer risk in diabetes be explained? To begin with, it should be noted that obesity, insulin resistance, and/or increased levels of IGF-1 and insulin are strongly associated with most (but not all) of the diabetes-related cancers in the nondiabetic population (1). This suggests that hyperglycemia does not play an essential role in the pathogenesis of these tumors, but does not exclude the possibility that it might have secondary effects such as enhanced tumor growth or resistance to anti-tumor therapy. IGF-1 and insulin offer a more plausible mechanistic explanation for the overlapping risk of cancer in the nondiabetic and diabetic populations. Both hormones are mitogenic (but not mutagenic), both are present at high levels in insulin-resistant states, and their receptors are overexpressed on the surface of cancer cells associated with diabetes. They thus have the potential to act as tumor growth factors in vivo as well as in vitro (2,3). On this argument, which we will refer to as the insulin supply hypothesis, drugs used to treat diabetes might influence the risk of cancer by modulating the insulin/IGF axis (1). There is, however, a possible alternative explanation for the increased risk of cancer in diabetes, which we refer to as the glucose supply hypothesis. …

Diabetes and cancer

Diabetes and cancer are two heterogeneous, multifactorial, severe, and chronic diseases. Because of their frequency, reciprocal influences - even minor influences - may have a major impact. Epidemiological studies clearly indicate that the risk of several types of cancer (including pancreas, liver, breast, colorectal, urinary tract, and female reproductive organs) is increased in diabetic patients. Mortality is also moderately increased. Several confounding factors, having general or site-specific relevance, make it difficult to accurately assess cancer risk in diabetic patients. These factors include diabetes duration, varying levels of metabolic control, different drugs used for therapy, and the possible presence of chronic complications. Hyperinsulinemia most likely favors cancer in diabetic patients as insulin is a growth factor with pre-eminent metabolic but also mitogenic effects, and its action in malignant cells is favored by mechanisms acting at both the receptor and post-receptor level. Obesity, hyperglycemia, and increased oxidative stress may also contribute to increased cancer risk in diabetes. While anti-diabetic drugs have a minor influence on cancer risk (except perhaps the biguanide metformin that apparently reduces the risk), drugs used to treat cancer may either cause diabetes or worsen a pre-existing diabetes. In addition to the well-known diabetogenic effect of glucocorticoids and anti-androgens, an increasing number of targeted anti-cancer molecules may interfere with glucose metabolism acting at different levels on the signaling substrates shared by IGF-I and insulin receptors. In conclusion, diabetes and cancer have a complex relationship that requires more clinical attention and better-designed studies.

DNA damage and repair in type 2 diabetes mellitus

DNA damage may be associated with type 2 diabetes mellitus (T2DM) and its complications mainly through oxidative stress. Little is known about DNA repair disturbances potentially contributing to the overall extent of DNA damage in T2DM, which, in turn, may be linked with genomic instability resulting in cancer. To assess whether DNA repair may be perturbed in 2DM we determined: (1) the level of endogenous basal DNA damage, this means damage recognized in the alkaline comet assay (DNA strand breaks and alkali labile sites) as well as endogenous oxidative and alkylative DNA damage (2) the sensitivity to DNA-damaging agents hydrogen peroxide and doxorubicin and the efficacy of removing of DNA damage induced by these agents in peripheral blood lymphocytes of T2DM patients and healthy individuals. The level of DNA damage and the kinetics of DNA repair was evaluated by the alkaline single cell gel electrophoresis (comet assay). Oxidative and alkylative DNA damage were assayed with the use of DNA repair enzymes endonuclease III (Endo III) and formamidopyrimidine-DNA glycosylase (Fpg), recognizing oxidized DNA bases and 3-methyladenine-DNA glycosylase II (AlkA) recognizing alkylated bases. The levels of basal endogenous and oxidative DNA damage in diabetes patients were higher than in control subjects. There was no difference between the level of alkylative DNA in the patients and the controls. Diabetes patients displayed higher susceptibility to hydrogen peroxide and doxorubicin and decreased efficacy of repairing DNA damage induced by these agents than healthy controls. Our results suggest that type 2 diabetes mellitus may be associated not only with the elevated level of oxidative DNA damage but also with the increased susceptibility to mutagens and the decreased efficacy of DNA repair. These features may contribute to a link between diabetes and cancer and metrics of DNA damage and repair, measured by the comet assay, may be markers of risk of cancer in diabetes.