Acute modulation of toll-like receptors by insulin

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 IT and served as control subjects. Blood samples were collected before and at 2, 4, and 6 h. TLR expression was determined in mononuclear cells (NINCS). RESULTS - Insulin infusion significantly suppressed TLRI, -2, -4, -7, and -9 mRNA expression in MNCs within 2 h of the infusion,with a maximum fall at 4 h by 24 +/- 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) by 4 IT in MNCs. 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.