PREVALENCE OF METFORMIN RESPONSE-PREDICTIVE POLYMORPHISMS IN POSTMENOPAUSAL DIABETICS NOT SUFFERING OR SUFFERING WITH CANCER: RELATION TO HORMONAL-METABOLIC PHENOTYPE

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: MON 796-817-Diabetes Genetics & Epidemiology
Translational
Monday, June 17, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board MON-815
Lev M Berstein*, Aglaya Iyevleva, Dmitry Vasilyev and Evgeny Imyanitov
N.N.Petrov Research Institute of Oncology, St.Petersburg, Russia
Objectives: Metformin (MF) is one of the leading contemporary medications for treatment of type 2 diabetes (DM) and pretends to be included also into the list of drugs for anticancer treatment. Notwithstanding of certain achievements in experimental studies with tumor models, data received by present with MF in clinical cancer field are not so convincing. Among the possible causes of controversial response to MF some constitutive genetic distinctions deserve to be mentioned, while in cancer patients these characteristics were not so far studied.  Materials and methods:   The allele specific real time PCR with DNA isolated from blood cells was used with the aim to study distribution of allelic polymorphisms of organic cation transporter 1/OCT1, C11orf65 (located near ATM gene) and serine/threonine kinase STK11/LKB1 in 156 postmenopausal women. The group consisted of 37 healthy females, 32 DM patients without cancer, 64 cancer patients with DM, and 23 cancer patients without DM. Results: Genotypes of OCT1, associated with potentially low response to MF, were discovered least often in DM patients without cancer (R61C, 9.4%), in diabetics suffering with cancer (G465R, 4.7%), and in cancer patients without DM (rs622342, 4.3%). In healthy females these genotypes were revealed, respectively, in 18.9%, 13.5%, and 16.2%. The significant differences were detected here merely in regard of R61C variant for group of cancer without DM (34.8%) vs DM without cancer (9.4%, p 0.02) and vs all females with DM (11.5%, n=96, p 0.03).  Genotypes of STK11/LKB1 and C11orf65 associated with potentially positive reaction to MF were found most often respectively in the group of cancer without DM (21.7% vs 11.5% in all diabetic females, p 0.3) and in diabetics without cancer (31.3% vs 16.2% in healthy females, p 0.14). In this material, the importance of family history (FH) of DM was demonstrated only in regard of STK11/LKB1 genotypes distribution (5.7% in FH+ vs 18.0% in FH-, p 0.05).  Diabetics not having cancer - carriers of OCT1 R61C and C11orf65 genotypes potentially responsive to MF were somewhat younger, had higher waist/hip ratio, BMI, visceral fat content, HOMA index and blood triglycerides while similar FINDRISK score, serum HDL-cholesterol and SHBG levels in comparison with potential non-responders. In cancer patients with not treated diabetes, which carried STK11/LKB1 variant predictive for better MF response, the tendency to higher levels of HbA1c and fasting glucose as well as to lower leptinemia was discovered. Conclusions: 1. Diabetics suffering or not suffering with cancer may differ in pattern of genotypes which are considered to be potential predictors of metformin response. 2. Carries of distinct predictive genotypes do not have similar hormonal-metabolic characteristics. 3. Genotypes signaling about MF metabolic and antiblastomogenic response supposedly can be different that warrants further study.

Nothing to Disclose: LMB, AI, DV, EI

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