Type 2 diabetes and inflammation : The role of toll like receptor signalling in pathophysiology of diabetes and complications related to diabetes.

Saket Gupta, Royal College of Surgeons in Ireland

A thesis submitted for the degree of Doctor of Medicine from the Royal College of Surgeons in Ireland in 2014.

Abstract

Aims:

The aim of this study was to determine association between inflammation, glucose control and type 2 diabetes (T2D) related complications.

We determined cytokines, adipokines & Toll-like receptors (TLR) mRNA expression in monocytes (M) and neutrophils (N) using QPCR in a cohort of 146 subjects: non-diabetic controls [NGT; n=34, BMI 26 (24-30) kg/m2, HbA1c 5.6 (5.4-5.7)%] and compared them with T2D with four different profiles: good glycaemic control without complications [GC; n=27, BMI 32 (29-38) kg/m2, HbA1c 6.4 (6.0-6.9)%], good glycaemic control with complications [GCC; n=32, BMI 31 (28-35) kg/m2, HbA1c 6.9 (6.4-7.4)%], poor glycemic control without complications [PC; n=21, BMI 35 (31-37) kg/m2, HbA1c 10.2 (9.2-11)%] and poor glycaemic control with complications [PCC; n=32, BMI 34 (29-37) kg/m2, HbA1c 9.6 (8.9-10.8)%]. Data are expressed as median (Inter quartile range).

Results:

The highest expressions of IL-6, TNFα, Rantes & IFNβ mRNA in neutrophils, and IL-6 and IFNβ mRNA in monocytes, were present in GC compared to NGT. In contrast, IL-1β mRNA expression was significantly decreased in monocytes from GCC, PC and PCC.

Retinol binding protein 4 (RBP4), Lipocalin 2 and adiponectin mRNA in neutrophils, and RBP4 mRNA in monocytes were significantly overexpressed in GC, compared to NGT. In contrast, Lipocalin 2 and adiponectin mRNA were significantly suppressed in monocytes from PC and PCC.

Similarly, TLRs mRNA 1-10, except TLR 2 in neutrophils, and TLR1, 3, 5, 7, 9 & 10 in monocytes were overexpressed from GC group compared to NGT.

Conclusions:

The overexpressed cytokine, adipokine & TLR mRNA levels in monocytes and neutrophils from GC group indicate an inflammatory milieu in T2D with good glycaemic control with no complications. In contrast, suppressed levels of inflammatory markers in PC, GCC & PCC indicate compromised innate immune state i.e. “burnt out” disease in poor glycaemic control, and in patients with complications.