Endocrinol Metab.  2017 Sep;32(3):383-388. 10.3803/EnM.2017.32.3.383.

The Role of Circulating Slit2, the One of the Newly Batokines, in Human Diabetes Mellitus

• Kang YE
• Choung S
• Lee JH
• Kim HJ
• Ku BJ

• KMID: 2389820
• DOI: http://doi.org/10.3803/EnM.2017.32.3.383

Abstract

BACKGROUND
Slit2 is a new secreted protein from adipose tissue that improves glucose hemostasis in mice; however, there is no study about the serum levels and precise role of Slit2 in human. The aim of this study is to explore the serum level of Slit2 in human, and to identify the role of Slit2 in diabetes mellitus (DM).
METHODS
The participants of this study consist of 38 subjects with newly diagnosed DM, and 75 healthy subjects as a control group. Serum Slit2 levels were measured using an enzyme-linked immunosorbent assay. Relationship between circulating Slit2 and diabetic related factors was investigated in diabetic group compared with non-diabetic group. Additionally, the correlations between the serum level of Slit2 and diverse metabolic parameters were analyzed.
RESULTS
Circulating Slit2 level was more decreased in diabetic group than in control group, but there was no significant difference statistically. Interestingly, serum levels of Slit2 were significantly negatively correlated to the serum concentrations of fasting glucose (coefficient r=-0.246, P=0.008), the serum concentrations of postprandial glucose (coefficient r=-0.233, P=0.017), and glycosylated hemoglobin (HbA1c; coefficient r=-0.357, P<0.001).
CONCLUSION
From our study, the first report of circulating Slit2 levels in human, circulating Slit2 level significantly negatively correlated with serum glucose and HbA1c. Our results suggest that the circulating Slit2 may play a role in maintainence of glucose homeostasis in human, even though exact contribution and mechanism are not yet known.

Keyword

Slit2; Batokine; Adipose tissue, brown; Adipokines; Diabetes mellitus

MeSH Terms

Adipokines
Adipose Tissue
Adipose Tissue, Brown
Animals
Blood Glucose
Diabetes Mellitus*
Enzyme-Linked Immunosorbent Assay
Fasting
Glucose
Healthy Volunteers
Hemoglobin A, Glycosylated
Hemostasis
Homeostasis
Humans*
Mice
Adipokines
Glucose

Reference

1. Villarroya F, Cereijo R, Villarroya J, Giralt M. Brown adipose tissue as a secretory organ. Nat Rev Endocrinol. 2017; 13:26–35.

2. Cannon B, Nedergaard J. Brown adipose tissue: function and physiological significance. Physiol Rev. 2004; 84:277–359.

3. Ku CR, Cho YH, Hong ZY, Lee H, Lee SJ, Hong SS, et al. The effects of high fat diet and resveratrol on mitochondrial activity of brown adipocytes. Endocrinol Metab (Seoul). 2016; 31:328–335.

4. Svensson KJ, Long JZ, Jedrychowski MP, Cohen P, Lo JC, Serag S, et al. A secreted Slit2 fragment regulates adipose tissue thermogenesis and metabolic function. Cell Metab. 2016; 23:454–466.

5. Brose K, Tessier-Lavigne M. Slit proteins: key regulators of axon guidance, axonal branching, and cell migration. Curr Opin Neurobiol. 2000; 10:95–102.

6. Mehlen P, Delloye-Bourgeois C, Chedotal A. Novel roles for Slits and netrins: axon guidance cues as anticancer targets? Nat Rev Cancer. 2011; 11:188–197.

7. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2010; 33:Suppl 1. S62–S69.

8. Kang YE, Kim JM, Joung KH, Lee JH, You BR, Choi MJ, et al. The roles of adipokines, proinflammatory cytokines, and adipose tissue macrophages in obesity-associated insulin resistance in modest obesity and early metabolic dysfunction. PLoS One. 2016; 11:e0154003.

9. Shin MY, Kim JM, Kang YE, Kim MK, Joung KH, Lee JH, et al. Association between growth differentiation factor 15 (GDF15) and cardiovascular risk in patients with newly diagnosed type 2 diabetes mellitus. J Korean Med Sci. 2016; 31:1413–1418.

10. Wong K, Park HT, Wu JY, Rao Y. Slit proteins: molecular guidance cues for cells ranging from neurons to leukocytes. Curr Opin Genet Dev. 2002; 12:583–591.

11. Kramer SG, Kidd T, Simpson JH, Goodman CS. Switching repulsion to attraction: changing responses to slit during transition in mesoderm migration. Science. 2001; 292:737–740.

12. Wu JY, Feng L, Park HT, Havlioglu N, Wen L, Tang H, et al. The neuronal repellent Slit inhibits leukocyte chemotaxis induced by chemotactic factors. Nature. 2001; 410:948–952.

13. Wang B, Xiao Y, Ding BB, Zhang N, Yuan Xb, Gui L, et al. Induction of tumor angiogenesis by Slit-Robo signaling and inhibition of cancer growth by blocking Robo activity. Cancer Cell. 2003; 4:19–29.

14. Yang XM, Han HX, Sui F, Dai YM, Chen M, Geng JG. Slit-Robo signaling mediates lymphangiogenesis and promotes tumor lymphatic metastasis. Biochem Biophys Res Commun. 2010; 396:571–577.

15. Brose K, Bland KS, Wang KH, Arnott D, Henzel W, Goodman CS, et al. Slit proteins bind Robo receptors and have an evolutionarily conserved role in repulsive axon guidance. Cell. 1999; 96:795–806.

16. Kidd T, Brose K, Mitchell KJ, Fetter RD, Tessier-Lavigne M, Goodman CS, et al. Roundabout controls axon crossing of the CNS midline and defines a novel subfamily of evolutionarily conserved guidance receptors. Cell. 1998; 92:205–215.

17. Zhou W, Yu W, Xie W, Huang L, Xu Y, Li X. The role of SLIT-ROBO signaling in proliferative diabetic retinopathy and retinal pigment epithelial cells. Mol Vis. 2011; 17:1526–1536.

18. Zhao H, Anand AR, Ganju RK. Slit2-Robo4 pathway modulates lipopolysaccharide-induced endothelial inflammation and its expression is dysregulated during endotoxemia. J Immunol. 2014; 192:385–393.

19. Seale P, Conroe HM, Estall J, Kajimura S, Frontini A, Ishibashi J, et al. Prdm16 determines the thermogenic program of subcutaneous white adipose tissue in mice. J Clin Invest. 2011; 121:96–105.