Acute modulation of toll-like receptors by insulin

Abstract

OBJECTIVE - Low-dose insulin infusion has been shown to exert a prompt and powerful anti-inflammatory effect. Toll-like receptors (TLRs) are major determinants of the inflammatory response to viral and bacterial pathogens. We have now hypothesized that low-dose insulin infusion in obese type 2 diabetic patients suppresses TLR expression. RESEARCH DESIGN AND METHODS - Ten type 2 diabetic patients were infused with a low dose of insulin (2 units/h) and dextrose to maintain normoglycemia for 4 h, while another 14 type 2 diabetic patients were infused with either dextrose or saline for 4 h and served as control subjects. Blood samples were collected before and at 2,4, and 6 h. TLR expression was determined in mononuclear cells (MNCs). RESULTS - Insulin infusion significantly suppressed TLR1,-2,-4,-7, and-9 mRNA expression in MNCs within2hofthe infusion, with a maximum fall at 4 h by24 ± 9%, 21 ± 5%, 30 ± 8%, 28 ± 5%, and 27 ± 10% (P < 0.05, for all), respectively, below the baseline. TLR2 protein was suppressed by 19 ± 7% (P < 0.05) below the baseline at 4 h. The DNA binding of PU.1, a major transcription factor regulating many TLR genes, was concomitantly suppressed by 24 ±10% (P < 0.05) by4hinMNCs. There was no change in TLR expression or DNA binding by PU.1 following dextrose or saline infusion in the control groups. CONCLUSIONS - Insulin suppresses the expression of several TLRs at the transcriptional level, possibly through its suppressive effect on PU.1. © 2008 by the American Diabetes Association.