insulin-glargine and Colorectal-Neoplasms

An association of insulin use and risk of cancer has been reported but evidence is conflicting and methodological issues have been identified.. To summarize results regarding insulin use and cancer risk by a systematic review and meta-analysis of cohort and case-control studies examining risk of cancer associated with insulin use in patients with diabetes.. Systematic literature search in 5 databases: PubMed, Embase, Web of Science, Scopus and Cochrane Library. STUDY ELIGIBILITY CRITERIA (PICOS):. diabetes patients.. Users of any exogenous insulin. Comparison: Diabetes patients with or without use of antidiabetic drugs.. Any incident cancer.. Cohort and case-control studies.. 42 eligible studies examined risk of any cancer and 27 site-specific cancers. Results of individual studies were heterogeneous. Meta-analyses were significant for: Insulin vs No Insulin: Increased risk for pancreas, liver, kidney, stomach and respiratory cancer, decreased risk for prostate cancer. Insulin vs Non-Insulin Antidiabetics: Increased risk for any, pancreatic and colorectal cancer. Glargine vs Non-Glargine Insulin: Increased risk for breast cancer, decreased risk for colon cancer.. Few studies available for most cancer sites and exposure contrasts, and few assess effect of dose and duration of exposure. Methodological issues in several studies. Availability of confounders.. Insulin use was associated with risk of cancer at several sites. Cautious interpretation of results is warranted as methodological issues and limitations in several of the included studies have been identified. Choice of study design may have a profound effect on estimated cancer risk.

Topics: Breast Neoplasms; Case-Control Studies; Cohort Studies; Colorectal Neoplasms; Diabetes Mellitus; Female; Humans; Hypoglycemic Agents; Insulin; Insulin Glargine; Insulin, Long-Acting; Neoplasms; Observational Studies as Topic; Publication Bias; Registries; Research Design

Several studies have shown a correlation between glargine use and cancer risk. However, the role of glargine in carcinogenesis, especially in colorectal cancer (CRC), is still inconclusive. The aim of this study was to investigate the influence of glargine on proliferation of CRC cells and its possible mechanism. Effect of glargine on the cell proliferation was tested in HCT-116 and SW480 cells by MTT assay, and apoptosis was measured by flow cytometry. The expression of microRNA-95 (miR-95) and sorting nexin 1 (SNX1) protein was also determined by real-time PCR and Western blotting, respectively. The results showed that high dose glargine (from 150 to 300 nM) promoted proliferation and inhibit2ed apoptosis of CRC cells compared with untreated cells. Moreover, glargine could upregulate miR-95 and downregulate SNX1 protein expression in CRC cells. These data show that glargine may indeed trigger cellular proliferation in CRC, probably by regulating miR-95.

Topics: Apoptosis; Cell Proliferation; Colorectal Neoplasms; Down-Regulation; Gene Expression Regulation, Neoplastic; HCT116 Cells; Humans; Insulin Glargine; MicroRNAs; Sorting Nexins; Up-Regulation

To examine whether use of insulin glargine, compared with another long-acting insulin, is associated with risk of breast, prostate, colorectal cancer, or all cancers combined.. Computerized health records from Kaiser Permanente Northern and Southern California regions starting in 2001 and ending in 2009 were used to conduct a population-based cohort study among patients with diabetes aged ≥18 years. With use of Cox regression modeling, cancer risk in users of insulin glargine (n = 27,418) was compared with cancer risk in users of NPH (n = 100,757).. The cohort had a median follow-up of 3.3 years during which there was a median of 1.2 years of glargine use and 1.4 years of NPH use. Among users of NPH at baseline, there was no clear increase in risk of breast, prostate, colorectal, or all cancers combined associated with switching to glargine. Among those initiating insulin, ever use or ≥2 years of glargine was not associated with increased risk of prostate or colorectal cancer or all cancers combined. Among initiators, the hazard ratio (HR) for breast cancer associated with ever use of glargine was 1.3 (95% CI 1.0-1.8); the HR for breast cancer associated with use of glargine for ≥2 years was 1.6 or 1.7 depending on whether glargine users had also used NPH.. Results of this study should be viewed cautiously, given the relatively short duration of glargine use to date and the large number of potential associations examined.

Topics: Adolescent; Adult; Aged; Breast Neoplasms; California; Colorectal Neoplasms; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Follow-Up Studies; Humans; Hypoglycemic Agents; Incidence; Insulin Glargine; Insulin, Long-Acting; Male; Middle Aged; Proportional Hazards Models; Prostatic Neoplasms; Retrospective Studies; Risk; Risk Assessment; Time Factors; Young Adult

Insulin analogues are widely used in the treatment of diabetes mellitus. Some insulin analogues were reported to display atypical activities in vitro that resemble those of insulin-like growth factor-I (IGF-I). The aim of this study was to investigate whether two long-acting insulin analogues [glargine (Lantus, Sanofi Aventis, Germany) and detemir (Levemir, Novo Nordisk, Denmark)] and two short-acting analogues [lispro (Humalog, Eli Lilly, Indianapolis, USA) and aspart (Novolog, Novo Nordisk, Denmark)] exhibit IGF-I-like activities on cultured cancer cells in comparison with IGF-I and regular human insulin.. HCT-116 (colorectal cancer), PC-3 (prostate cancer) and MCF-7 (breast adenocarcinoma) cell lines were treated with insulin, IGF-I or insulin analogues, and proliferation and protection from apoptosis were measured by cell counting and fluorescent-activated cell sorter (FACS) analysis, respectively. In addition, Western blots were used to identify signalling molecules activated by the analogues.. Glargine, detemir and lispro had proliferative effects that resemble IGF-I action. Insulin, however, did not stimulate cellular proliferation. In addition, glargine and detemir displayed an IGF-I-like anti-apoptotic activity. Glargine, like insulin and IGF-I, induced phosphorylation of both ERK and AKT, suggesting that the analogue is able to stimulate both the ras-raf-mitogen-activated protein kinase (MAPK) and PI3K-AKT pathways. Furthermore, glargine induced both insulin receptor (IR) and IGF-IR phosphorylation.. Glargine, detemir and lispro, unlike regular insulin, exhibit in vitro proliferative and anti-apoptotic activities in a number of cancer cell lines. These actions resemble some of the effects of IGF-I, a growth factor involved in cancer initiation and progression. Insulin had no increased IGF-I activity. The specific receptor/s involved in mediating analogues actions remains to be identified.

Topics: Adenocarcinoma; Apoptosis; Breast Neoplasms; Cell Division; Cell Line, Tumor; Colorectal Neoplasms; Dose-Response Relationship, Drug; Female; Humans; Insulin; Insulin Detemir; Insulin Glargine; Insulin Lispro; Insulin-Like Growth Factor I; Insulin, Long-Acting; Male; Prostatic Neoplasms; Tumor Cells, Cultured