The effect of acute hyperglycaemia and insulin on systemic inflammation in COPD

JRH Archer1, CE Wells2, AW Hitchings2, JW Dodd2, EH Baker2. 1Guy's and St Thomas' NHS Foundation Trust, London, UK, 2St George's, University of London, London, UK

COPD patients hospitalised with acute exacerbations commonly have elevated blood sugar. Acute hyperglycaemia (>7mM) is associated with a 15% increase in risk of death or prolonged hospital stay for every 1mM increase in admission blood glucose (1), failure of non-invasive ventilation in COPD patients with type 2 respiratory failure (2) and increased isolation of multiple pathogens or S.aureus from sputum (1). The relationship between hyperglycaemia and adverse COPD outcomes is not fully understood but hyperglycaemia may augment infection, inflammation and myopathy. The aim of this study was to investigate the effect of acute hyperglycaemia and insulin therapy on systemic inflammation in COPD patients.

8 stable COPD patients (4 male, 66±8yrs, FEV1 44±16% predicted) underwent oral glucose tolerance testing (OGTT) to assess homeostatic modelling, including insulin resistance (HOMA-IR) and pancreatic function (HOMA2-%B). Patients with fasting glucose <7mM then underwent a hyperglycaemic hyperinsulinamic pancreatic clamp. A continuous octreotide infusion was administered to inhibit pancreatic function followed by glucose and insulin infusions over 4 consecutive 60min periods to achieve: low glucose (fasting) with low insulin (0.3mU.kg-1.min-1), high glucose (hyperglycaemia: 10mM above fasting levels) with low insulin, high glucose with high insulin (1.5mU.kg-1.min-1) and low glucose with high insulin. Cytokines were measured in blood samples at the end of each 60min period using a Bio-Plex system (Bio-Rad).

COPD patients had HOMA-IR and HOMA2-%B of 1.3(0.8-1.8) and 126(81-82) respectively. There were no correlations between baseline glucose, insulin resistance or pancreatic beta-cell function and cytokine concentrations. Acute hyperglycaemia (high glucose, low insulin) increased cytokines with a T-cell helper 1 (Th1) bias including IP-10 by 48(12-181)% (median (interquartile range), TNFα by 28(8-54)% and IL-12 by 16(2-34)% from low glucose, low insulin (p<0.05). Overall blood glucose control at therapeutic insulin levels had a consistent effect in reducing serum concentration of 7/23 (30%) cytokines measured but specifically suppressed IP-10, TNFα and IL-12 to starting concentrations (p<0.05).

This study demonstrates that acute hyperglycaemia can amplify systemic inflammation in COPD. In particular it enhances cytokine secretion in a pattern consistent with a Th1 response. A Th1 predominance in peripheral T cells has been implicated in the pathogenesis of COPD and is associated with poor lung function and increased pulmonary inflammation (3). A possible mechanism underlying the effect of acute hyperglycaemia may be that hyperglycaemia acts as an endogenous trigger leading to increased Toll-like receptor (TLR) activation on immune cells in the systemic circulation and lung. This in turn activates NF-κβ and pro-inflammatory cytokine production (4). Th1 activation by hyperglycaemia could therefore increase disease severity and worsen outcome. The effect of insulin on inflammation in COPD patients during acute exacerbations has not been studied. The anti-inflammatory potential of blood glucose control with insulin or insulin-sensitising drugs requires further investigation.

1) Baker EH et al. (2006) Thorax 61:284-9. 2) Chakrabarti et al. (2009) Thorax 64:857-62. 3) Shirai, T et al. (2010) Allergol. Int. 59(1):75-82. 4) Dasu et al. (2008) Diabetes 57(11):3090-3098