The association of adipose-derived dimethylarginine dimethylaminohydrolase-2 with insulin sensitivity in experimental type 2 diabetes mellitus

Acta Biochim Biophys Sin (Shanghai). 2013 Aug;45(8):641-8. doi: 10.1093/abbs/gmt058. Epub 2013 May 23.

Abstract

Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase (NOS), which can be hydrolyzed by dimethylarginine-dimethylaminohydrolase (DDAH). It has been reported that adipocytes can produce DDAH/ADMA, but its role remains unknown. In the present study, we examined the effects of adipocyte-derived DDAH/ADMA on insulin sensitivity using animal and cell models. Results showed that in adipose tissue of high fat diet-fed diabetic rats, as well as in high glucose (25 mM) plus insulin (100 nM)-treated 3T3-L1 adipocytes, expression levels of insulin receptor substance-1 (IRS-1), glucose transporter-4 (GLUT-4), and DDAH isoform-2 (DDAH-2) were down-regulated compared with control, although DDAH-1 expression showed no significant changes. We also observed that nitric oxide bioavailability, DDAH and NOS activities were subsequently decreased, while the local ADMA content was elevated in diabetic adipose tissue. Transfection of human DDAH-2 gene into high glucose- and insulin-treated 3T3-L1 adipocytes significantly ameliorated DDAH activity, reduced ADMA contents, and up-regulated the mRNA expression levels of IRS-1 and GLUT-4. These findings suggested that in the development of type 2 diabetes mellitus, local DDAH-2 in adipocytes might play an important role in regulating insulin sensitivity.

Keywords: adipocyte; diabetes mellitus; dimethylarginine dimethylaminohydrolase; insulin resistance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3-L1 Cells
  • Adipose Tissue / enzymology*
  • Amidohydrolases / metabolism*
  • Animals
  • Base Sequence
  • DNA Primers
  • Diabetes Mellitus, Experimental / enzymology
  • Diabetes Mellitus, Experimental / physiopathology*
  • Diabetes Mellitus, Type 2 / enzymology
  • Diabetes Mellitus, Type 2 / physiopathology*
  • Insulin Resistance*
  • Male
  • Mice
  • Rats
  • Rats, Sprague-Dawley
  • Real-Time Polymerase Chain Reaction

Substances

  • DNA Primers
  • Amidohydrolases
  • dimethylargininase