Article Text

  1. J. N. Martel
  1. Reno, NV


Lipopolysaccharide (LPS) induced inflammation is associated with the profound activation and interaction between the neuroendocrine and immune systems which in turn alter glucose metabolism. In most animal models the initial response to this acute inflammatory stress (AIS) is characterized by marked hyperglycemia, a gradual increase in glucose clearance, and then a steady decrease in arterial blood glucose such that hypoglycemia proceeds in proportion to LPS dose. The specific role of IL-6 in this pathogenesis is unclear. Given that IL-6 is the only classical cytokine (IL-1β, TNFα, IL-6) remaining appreciably elevated during the hypoglycemic phase of AIS, we hypothesized that IL-6 exerts most of its influence on the later, hypoglycemic phase of AIS resulting from its effect (direct or indirect) on glucose clearance. Using E.coli (0111:B4) LPS endotoxin, a non-lethal AIS was induced in IL-6 -/-, IL-6 +/-, and wildtype mice using the conscious, chronically catheterized mouse model (sample from left common carotid artery and infuse in right jugular vein). Hormones and blood glucose were periodically assayed, blood pressure and heart rate monitored, whole-body glucose metabolism elucidated via 3-[3H]-D-glucose tracer, tissue specific glucose uptake determined using [2-14C] deoxy-D-glucose tracer, and the extent of STAT3 activation (intracellular IL-6 effector) was verified. There were significant differences in arterial blood glucose (mg/dL) levels between groups (P≤.005). While +/+ and +/- mice exhibited the characteristic hyperglycemia at 60 min. (130 ± 17.0 in +/+ and 128 ± 24.2 in +/-) and the subsequent hypoglycemia at 4 hrs. (78.0 ± 4.80 in +/+ and 82.2 ± 8.68 in +/-), -/- mice exhibited a more profound hyperglycemia at 60 min. (184 ± 17.4) and a subsequent euglycemia at 4 hrs. (109 ± 14.2). Glucose clearance (mL/kg/min) increased in +/+ (16.7 ± 1.36 to 20.3 ± 2.19) and +/- (16.8± 5.02 to 19.4 ± 3.97) mice, but decreased in -/- mice (14.0 ± 2.15 to 12.2 ± 2.07); glucose turnover did not change in +/- mice, slightly decreased in +/+ mice, and decreased most in -/- mice. Additionally, all groups had a similar rise in catecholamines, but +/+ and +/- mice exhibited a fall in insulin and a rise in glucagon, while -/- mice had a rise in insulin with a slight increase in glucagon. These data suggest IL-6 dampens the initial counter-regulatory response to AIS and contributes to the development of late onset hypoglycemia, and perhaps hormonal response changes or the lack of a direct IL-6 effect produces the glucose kinetics alteration in -/- mice. Thus, IL-6 plays a key role in the pathogenesis of LPS induced inflammation by influencing the metabolic and endocrine response.

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