UNTREATED TYPE 1 DIABETES INCREASES SEPSIS-INDUCED MORTALITY WITHOUT INDUCING A PRELETHAL CYTOKINE RESPONSE

Diabetes mellitus is the leading comorbidity in patients with sepsis, but its impact upon survival and immunoinflammatory signaling in sepsis is undetermined. We investigated the effect of untreated diabetes mellitus upon survival and immunoinflammatory responses in the acute phase (days 1-5) of murine polymicrobial sepsis using the AKITA model of type 1 diabetes. Diabetic female C57BL/6-Ins2(Akita) (AKITA) and C57BL/6 wild-type (WT) mice underwent cecal ligation and puncture (CLP), blood (20 mu L) was sampled for 5 days, and survival was monitored for 28 days. By day 5, all 8 AKITA mice died compared with 10 of 28 deaths in WT mice. Blood glucose declined post-CLP in all groups (most dramatically in AKITAs by 75%). To compare the evolution of inflammatory profiles, mice were retrospectively divided based on outcome into AKITA, WT-Died, and WT-Survived (within days 1-5). Hypoglycemia developed in all groups, which resolved in WT-Survived (97 mg/dL at 96 h) but intensified in WT-Died and AKITAs (similar to 30 mg/dL). Dramatic increases in both proinflammatory and anti-inflammatory cytokines were observed in WT-Died (i.e., interleukin 6, 38.2 +/- 17.8 ng/mL at 24 h), which contrasted with a lack of prelethal cytokine response in AKITA mice (interleukin 6, 4.3 +/- 3.4 ng/mL at 24 h). A prelethal composite cytokine score was calculated on values obtained 24 h before death. This score was 3-fold lower for proinflammatory cytokines and 6-fold lower for anti-inflammatory mediators in the AKITA mice compared with the WT-Died mice but identical to the composite score in WT-Survived. These data demonstrate that untreated type I diabetes mellitus severely exacerbates sepsis mortality without inducing a prelethal release of systemic proinflammatory or anti-inflammatory cytokines.