Hyper-Activation of Endogenous GLP-1 System to Gram-negative Sepsis Is Associated With Early Innate Immune Response and Modulated by Diabetes.

BACKGROUND: Culture-positive gram-negative sepsis induces greater magnitude of early innate immunity /inflammatory response compared with culture-negative sepsis. We previously demonstrated increased activation of anti-inflammatory Glucagon Like Peptide-1 (GLP-1) hormone in initial phase of sepsis more pronounced in diabetes patients. However, whether GLP-1 system is hyperactivated during the early innate immune response to gram-negative sepsis and modulated by diabetes remains unknown. OBJECTIVES: Total and active GLP-1, soluble Dipeptidyl peptidase 4 (sDPP-4) enzyme, and innate immunity markers presepsin (sCD14) and procalcitonin (PCT) in plasma were determined by ELISA on admission and after 2 to 4 days in 37 adult patients with and without type 2 diabetes and gram-negative or culture-negative sepsis of different severity. RESULTS: Severe but not non-severe sepsis was associated with markedly increased GLP-1 system response, which correlated with PCT and the organ dysfunction marker lactate. Culture-positive gram-negative bacteria but not culture-negative sepsis induced hyper-activation of GLP-1 system, which correlated with increased innate immune markers sCD14, PCT, and lactate. GLP-1 inhibitory enzyme sDPP-4 was down regulated by sepsis and correlated negatively with sCD14 in gram-negative sepsis. Diabetic patients demonstrated increased GLP-1 response but significantly weaker innate immune response to severe and gram-negative sepsis. CONCLUSIONS: Early stage of gram-negative sepsis is characterized by endogenous GLP-1 system hyperactivity associated with over activation of innate immune response and organ dysfunction, which are modulated by diabetes. Total GLP-1 may be novel marker for rapid diagnosis of gram-negative sepsis and its severity.

Sepsis-induced activation of endogenous GLP-1 system is enhanced in type 2 diabetes.

BACKGROUND: High levels of circulating GLP-1 are associated with severity of sepsis in critically ill nondiabetic patients. Whether patients with type 2 diabetes (T2D) display different activation of the endogenous GLP-1 system during sepsis and whether it is affected by diabetes-related metabolic parameters are not known. METHODS: Serum levels of GLP-1 (total and active forms) and its inhibitor enzyme sDPP-4 were determined by ELISA on admission and after 2 to 4 days in 37 sepsis patients with (n = 13) and without T2D (n = 24) and compared to normal healthy controls (n = 25). Correlations between GLP-1 system activation and clinical, inflammatory, and diabetes-related metabolic parameters were performed. RESULTS: A 5-fold (P < .001) and 2-fold (P < .05) increase in active and total GLP-1 levels, respectively, were found on admission as compared to controls. At 2 to 4 days from admission, the level of active GLP-1 forms in surviving patients were decreased significantly (P < .005), and positively correlated with inflammatory marker CRP (r = 0.33, P = .05). T2D survivors displayed a similar but more enhanced pattern of GLP-1 response than nondiabetic survivors. Nonsurvivors demonstrate an early extreme increase of both total and active GLP-1 forms, 9.5-fold and 5-fold, respectively (P < .05). The initial and late levels of circulating GLP-1 inhibitory enzyme sDPP-4 were twice lower in all studied groups (P < .001), compared with healthy controls. CONCLUSIONS: Taken together, these data indicate that endogenous GLP-1 system is activated during sepsis. Patients with T2D display an enhanced and prolonged activation as compared to nondiabetic patients. Extreme early increased GLP-1 levels during sepsis indicate poor prognosis.