J Diabetes Res. 2014;2014:862473.

miR-375 and miR-30d in the effect of chromium-containing Chinese medicine moderating glucose metabolism.

Qian Zhang, Xinhua Xiao,Ming Li, Wenhui Li,Miao Yu, Huabing Zhang, Fan Ping, Zhixin Wang, Jia Zheng, and HongDing Xiang
Key Laboratory of Endocrinology, Ministry of Health, Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China
Correspondence should be addressed to Xinhua Xiao; xiaoxinhua@medmail.com.cn

 

Abstract

In China, TianMai Xiaoke tablet (TM) is used to treat type 2 diabetes. However, the exact mechanism of TMis not clear. This study is to investigate the effect of TM on glucose metabolism in diabetic rats and to identify whether TM takes a direct action through microRNAs on islet. Rats were divided into control group, diabetic group, low dose of TM group (TML), and high dose of TM group (TMH). Pancreas samples were analyzed using microRNA array and Q-PCR. Eight-week treatment with TM significantly decreased fasting blood glucose. The blood glucose was significantly reduced in TM-treated groups before and after oral glucose administration. Fasting insulin and HOMA-IR were suppressed in TM-treated groups. miR-448, let-7b, miR-540, miR 296, miR-880, miR-200a, miR-500, miR-10b, miR-336, miR-30d, miR-208, let-7e, miR-142-5p, miR-874, miR-375, miR-879, miR-501, and miR-188 were upregulated, while miR-301b, miR-134, and miR-652 were downregulated in TMH group. Through target gene analysis and real-time PCR verification, we found that these miRNAs, especially miR-375 and miR-30d, can stimulate insulin secretion in islet. Our data suggest that TM can improve blood glucose in diabetic rats which involved increasing the expression of miR-375 and miR-30d to activate insulin synthesis in islet.

PMID: 24812635

 

Supplement:

It is known that chromium deficiency will lead to impaired glucose tolerance due to insulin resistance and hyperglycemia [1]. Trivalent chromium is an essential mineral, which is thought to be necessary for normal glucose and lipid homeostasis [2, 3]. TianMai (TM) Xiaoke Tablet comprises chromiumpicolinate (1.6mg per tablet, equaling 200 ug Cr), Radix trichosanthis (snake gourd root), Radix ophiopogonis (dwarf lilyturftuber), and Fructus schisandrae chinensis (Chinese magnolia vine fruit) and in the ratio of 1.6 : 62.5 : 62.5 : 25. TianMaiXiaokeTablet is approved by the State Food and Drug Administration of China (State Medical License no. Z20049007). TianMai Xiaoke Tablet can decrease HbA1c level [4]. MicroRNAs (miRNAs) are small noncoding RNAs of 18–25 nucleotides in length that bind to complementary 3’UTR regions of target mRNAs, inducing the degradation of transcriptional repression of the target [5].

fig1

Fig 1 miRNA array result

Zhang et al. found that the treatment of TianMai Xiaoke Tablet to DMrats significantly reduced fasting blood glucose, fasting insulin, and HOMA-IR. The results suggest that TianMai Xiaoke Tablet can moderate glucose and ameliorate oral glucose tolerance and insulin resistance. In gene array and real-time PCR experiment (Fig1, Fig2), we found that TM could increase the expression of miR-375 in islet of diabetic rats. miR-375 is a regulator in the process of exocytosis of insulin during glucose-stimulated insulin release. It is highly expressed in pancreatic islets. Poy et al. found that inhibition of endogenous miR-375 function enhanced insulin secretion [6]. In addition, mice lacking miR375 (375KO) are hyperglycemic and exhibit increased total pancreatic alpha-cell numbers and decreased pancreatic beta-cell mass [7]. PDX-1 (3’-phosphoinositide-dependent protein kinase-1) is one of the validated target genes of miR-375. Ouaamari et al. found that miR-375 acts as a direct function with the 3’ untranslated region (3’UTR) of PDK1 mRNA, thus decreasing PDK1 protein, and it may impact on cell proliferation given its key role in the PI 3-kinase/PKB cascade. The expression of miR-375 is decreased in diabetic Goto-Kakizaki (GK) rats, compared withWistar rats [8]. Moreover, TM could increase the expression of miR-30d in islet of diabetic rats.Tang et al. found that overexpression of miR-30d increased insulin gene expression, while inhibition of miR-30d abolished glucose stimulation of insulin expression. These data suggest thatmiR-30d is important for downregulation of an unidentified transcriptional repressor(s) of the insulin gene [9].

To sum up, TM can moderate glucose metabolism and insulin sensitivity. These actions may be through activating miR-375 and miR-30d to increase insulin secretion and action.

fig2

Fig 2 the comparison of differential expression miRNA between array and real time PCR

 

Reference:

[1] W. T. Cefalu and F. B. Hu, “Role of chromium in human health and in diabetes,” Diabetes Care, vol. 27, no. 11, pp. 2741–2751, 2004.

[2] M. Abdollahi, A. Farshchi, S. Nikfar et al., “Effect of chromium on glucose and lipid profiles in patients with type 2 diabetes, a meta-analysis review of randomized trials,” Journal of Pharmaceutical Sciences, vol. 16, no. 1, pp. 99–114, 2013.

[3] S. Schachter, R. W. Nelson, and C. A. Kirk, “Oral chromium picolinate and control of glycemia in insulin-treated diabetic dogs,” Journal of Veterinary Internal Medicine, vol. 15, no. 4, pp.379–384, 2001.

[4] C. Shao, X. F. Lv, X. H. Xiao et al., “Efficacy of Tianmaixiaoke tables in the treatment of newly diagnosed type 2 diabetes mellitus in China,” National Medical Journal of China, vol. 92, no. 22, pp. 1522–1526, 2012.

[5] D. P. Bartel, “MicroRNAs: target recognition and regulatory functions,” Cell, vol. 136, no. 2, pp. 215–233, 2009.

[6] M. N. Poy, L. Eliasson, J. Krutzfeldt et al., “A pancreatic isletspecific microRNAregulates insulin secretion,” Nature, vol. 432, no. 7014, pp. 226–230, 2004.

[7] M. N. Poy, J. Hausser, M. Trajkovski et al., “miR-375 maintains normal pancreatic a- and b-cell mass,” Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 14, pp. 5813–5818, 2009.

[8] A. E. Ouaamari, N. Baroukh, G. A. Martens, P. Lebrun, D. Pipeleers, and E. Van Obberghen, “MiR-375 targets 3’l-Phosphoinositide-Dependent protein Kinase-1 and regulates Glucose-Induced biological responses in pancreatic b-cells,” Diabetes, vol. 57, no. 10, pp. 2708–2717, 2008.

[9] X. Tang, L. Muniappan, G. Tang, and S. Ozcan, “Identification of glucose-regulated miRNAs from pancreatic b cells reveals a role for miR-30d in insulin transcription,” RNA, vol. 15, no. 2, pp. 287–293, 2009.

 

fig3Contacts:

Xinhua Xiao MD. Head of Diabetes Center,

Peking Union Medical College Hospital, China.

xiaoxinhua@medmail.com.cn

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