Cyanocobalamin prevents cardiomyopathy in type 1 diabetes by modulating oxidative stress and DNMT-SOCS1/3-IGF-1 signaling

Masao Kakoki,John R Hagaman,Nobuyo Maeda-Smithies,Oliver Smithies,J Charles Jennette,Ruriko Grant,Purushotham V Ramanathan,Joan M Taylor,Jennifer C Wilder

doi:10.1038/s42003-021-02291-y

Masao Kakoki, John R Hagaman + Show 7 more

Open Access

https://doi.org/10.1038/s42003-021-02291-y

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Abstract

Patients with long-standing diabetes have a high risk for cardiac complications that is exacerbated by increased reactive oxygen species (ROS) production. We found that feeding cyanocobalamin (B12), a scavenger of superoxide, not only prevented but reversed signs of cardiomyopathy in type 1 diabetic Elmo1H/HIns2Akita/+ mice. ROS reductions in plasma and hearts were comparable to those in mice treated with other antioxidants, N-acetyl-L-cysteine or tempol, but B12 produced better cardioprotective effects. Diabetes markedly decreased plasma insulin-like growth factor (IGF)-1 levels, while B12, but not N-acetyl-L-cysteine nor tempol, restored them. B12 activated hepatic IGF-1 production via normalization of S-adenosylmethionine levels, DNA methyltransferase (DNMT)-1/3a/3b mRNA, and DNA methylation of promoters for suppressor of cytokine signaling (SOCS)-1/3. Reductions of cardiac IGF-1 mRNA and phosphorylated IGF-1 receptors were also restored. Thus, B12 is a promising option for preventing diabetic cardiomyopathy via ROS reduction and IGF-1 retrieval through DNMT-SOCS1/3 signaling.

Highlights

Patients with long-standing diabetes have a high risk for cardiac complications that is exacerbated by increased reactive oxygen species (ROS) production
MRNA levels for SOCS1/3 were moderated by B12 in both Elmo1H/H Ins2Akita/+ mice and Elmo1H/H Ins2+/+ mice (Fig. 6f, g). As both SOCS1 and SOCS3 bind to Janus kinase (JAK) 233 and inhibit intracellular signaling of growth hormone (GH) receptors, our findings suggest that DNA methylation in the SOCS1/3 promoters enhanced by B12 supplementation leads to restored production of insulin-like growth factor (IGF)-1 and contributes to ROS-independent beneficial effects of B12 on diabetic cardiomyopathy
We demonstrated that a high oral dose of B12 that normalizes the plasma and tissue B12 levels protected diabetic mice from developing cardiomyopathy and effectively reversed early signs of their cardiac dysfunction, independently of blood glucose levels

Summary

Introduction

Patients with long-standing diabetes have a high risk for cardiac complications that is exacerbated by increased reactive oxygen species (ROS) production. We found that feeding cyanocobalamin (B12), a scavenger of superoxide, prevented but reversed signs of cardiomyopathy in type 1 diabetic Elmo1H/H Ins2Akita/+ mice. B12 is a promising option for preventing diabetic cardiomyopathy via ROS reduction and IGF-1 retrieval through DNMT-SOCS1/3 signaling. We further reported that mice with twice the normal expression of Elmo[1] (Elmo1H/H) in Akita diabetic background (Ins2Akita/+) develop severe cardiac dysfunction by about 16 weeks of age[10]. ELMO1 is a critical factor for reactive oxygen species (ROS) production via NOXs, which in turn trigger cellular signaling cascades towards tissue damage in diabetes mellitus. Since enhanced ROS production is the major factor of diabetic cardiomyopathy in the Elmo1H/H Ins2Akita/+ mice, we have chosen in the current study to evaluate the effects and mechanisms of cobalamins (B12) on this devastating diabetic complication. The documentation of its oral therapeutic use has been scarce, in part because its potential for inactivating ROS is normally limited because absorption of

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