Abstract 2580: Synergistic effect of magnesium with metformin for the prevention of liver and colorectal cancer
Authors: Fan Lei , Yu Danxia , Zhu Xiangzhu , Zhang Xuehong , Huang Xiang , Murff Harvey J. , Azcarate-Peril M. Andrea , Shrubsole Martha J. , Dai Qi 
Published: July 2021

Abstract
The obesity epidemic has dramatically increased the type 2 diabetes (T2D) prevalence in the US over the past two decades. Previous studies have relatively consistently found individuals with T2D are at increased risks of cancer, including liver and colorectal cancer in which insulin resistance may play an important role. However, the mechanism remains largely unknown. Metformin, the primary first-line medication for the treatment of T2D, has been shown to improve insulin resistance and be linked to a reduced risk of hepatocellular carcinoma (HCC) and colorectal cancer (CRC). Two recent Cell and Cell metabolism publications identified that imidazole propionate (ImP), a microbial metabolite of histidine, significantly increased in patients with T2D and causally induced insulin resistance in mice. Furthermore, the therapeutic effects of metformin on insulin resistance disappeared when ImP was elevated, indicating that ImP plays a key role in developing insulin resistance and resistance to metformin treatment. Our recent work together with a subsequent study from others demonstrated higher magnesium (Mg) intake is associated with a substantially reduced risk of HCC, HCC mortality and mortality from liver diseases. Accumulative evidence, including our prior work, has also linked higher Mg intake to a reduced risk of colorectal neoplasia. Previous studies found that the process of the histidine utilization (Hut) system to metabolize histidine in some bacterial taxa depends on concentrations of divalent metal ion Mg2+. We hypothesize that low availability of Mg2+ in gut microbiota could terminate the Hut system and increase the production of intermediate metabolites, including ImP, over other end products. This will lead to increased levels of ImP in the gut and, in turn, liver and circulation. We tested our hypothesis in the Personalized Prevention of Colorectal Cancer Trial (PPCCT) (registered at clinicaltrials.gov as NCT01105169), a precision-based randomized trial enrolling 240 participants at high risk of Mg deficiency. Among 68 participants (34 treatment/34 placebo), we found that compared to the placebo, Mg treatment significantly reduced ImP by 39.9% compared to a 6.0% increase in the placebo arm after adjustment for baseline ImP (P=0.02). However, we found Mg treatment did not significantly affect the levels of trans-urocanate, the precursor of ImP. Since Mg deficiency leads to insulin resistance and as high as 50% of patients with T2D have hypomagnesemia, Mg deficiency may lead to an increased risk of ImP and, in turn, resistance to metformin which subsequently increases risk of HCC and CRC. Thus, futures studies should evaluate whether the joint use of Mg supplementation and metformin synergistically maximizes the efficacy of metformin and minimizes the treatment resistance on insulin resistance and, subsequently, prevention of HCC and CRC.
Citation Format: Lei Fan, Danxia Yu, Xiangzhu Zhu, Xuehong Zhang, Xiang Huang, Harvey J. Murff, M. Andrea Azcarate-Peril, Martha J. Shrubsole, Qi Dai. Synergistic effect of magnesium with metformin for the prevention of liver and colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2580.