Acute Modulation of Toll-Like Receptors by Insulin

• Published in: Diabetes care Vol. 31; no. 9; pp. 1827 - 1831
• Main Authors: Ghanim, Husam, Mohanty, Priya, Deopurkar, Rupali, Ling Sia, Ching, Korzeniewski, Kelly, Abuaysheh, Sanaa, Chaudhuri, Ajay, Dandona, Paresh
• Format: Journal Article
• Language: English
• Published: United States American Diabetes Association 01.09.2008
• Subjects: Acute coronary syndromes; administration & dosage; Adult; anti-inflammatory activity; Binding sites; blood; Critical care; Diabetes; Diabetes Mellitus, Type 2; Diabetes Mellitus, Type 2 - genetics; DNA; Dosage and administration; drug effects; Drug therapy; Female; gene expression; Gene Expression Regulation; Gene Expression Regulation - drug effects; genes; genetics; glucose; Gram-positive bacteria; Heart attacks; Heart surgery; Humans; inflammation; Infusion therapy; Infusions, Intravenous; Insulin; Insulin - administration & dosage; Insulin - pharmacology; insulin receptors; Male; messenger RNA; metabolism; Middle Aged; Monoclonal antibodies; noninsulin-dependent diabetes mellitus; pathogens; Pathophysiology/Complications; patients; Pattern recognition; pharmacology; Plasma; Properties; Proteins; Proto-Oncogene Proteins; Proto-Oncogene Proteins - drug effects; Proto-Oncogene Proteins - metabolism; Receptor antibodies; RNA, Messenger; RNA, Messenger - drug effects; RNA, Messenger - genetics; Rodents; Suppression, Genetic; Suppression, Genetic - drug effects; Toll-Like Receptors; Toll-Like Receptors - drug effects; Toll-Like Receptors - genetics; Trans-Activators; Trans-Activators - drug effects; Trans-Activators - metabolism; transcription (genetics); transcription factors; Type 2 diabetes; United States
• ISSN: 0149-5992; 1935-5548; 1935-5548
• DOI: 10.2337/dc08-0561

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 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 h 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.