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

Abstract

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 antiinflammatory 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.

Severe and fatal COVID‐19 is characterised by increased circulating glucagon like peptide 1 and procalcitonin modulated by type 2 diabetes

“…Endogenous glucagon like peptide 1 (GLP‐1) hormone as well as exogenous GLP‐1 analogues are novel anti‐inflammatory immune modulators of the innate immunity response 13,14 . Others and we previously demonstrated significantly increased circulating GLP‐1 levels in non‐surviving patients with sepsis, while persistent elevated levels GLP‐1 after sepsis were found to predict poor long‐term outcome at 6 months 15–17 Moreover, we demonstrated that the hyperactive endogenous GLP‐1 system is closely associated with extreme early innate immune response in patients with severe Gram‐negative sepsis together with sharply increased PCT and lactate and modulated by type 2 diabetes (T2D) 18 …”

“…[15][16][17] Moreover, severe Gram-negative sepsis is specifically associated with GLP-1 hyperactivation, suggesting that endogenous GLP-1 response during COVID-19 may be upregulated by bacteria-induced systemic inflammation mediated by disrupted intestinal barrier integrity and higher microbial product translocation into the blood. 18,21 It should be noted that SARS-CoV-2 is able to infect not only the respiratory but also the intestinal tract through the ACE2 receptor, and the enteric infection increasing the tight junction permeability and translocation of bacterial products in circulation could probably contribute to the disease progression of COVID-19. [22][23][24] This concept is supported by the reported ability of LPSs to acutely induce GLP-1 secretion in humans and the increased GLP-1 secretion by injured ischaemic human gut.…”

“…13,14 Others and we previously demonstrated significantly increased circulating GLP-1 levels in non-surviving patients with sepsis, while persistent elevated levels GLP-1 after sepsis were found to predict poor longterm outcome at 6 months [15][16][17] Moreover, we demonstrated that the hyperactive endogenous GLP-1 system is closely associated with extreme early innate immune response in patients with severe Gramnegative sepsis together with sharply increased PCT and lactate and modulated by type 2 diabetes (T2D). 18 The aim of the study is to elucidate the involvement of the endogenous GLP-1 system in the innate immune response to COVID-19 and its association with the pro-inflammatory marker of bacterial infections, namely PCT during disease progression. In addition, we studied whether the pro-inflammatory/GLP-1 response is different in patients with and without T2D COVID-19.…”

Insight on Infections in Diabetic Setting

“…It has also been shown that activation of GLP-1 receptors can promote B and T cell expansion, particularly toward Treg1 differentiation, thereby contributing to the impaired inflammatory response in patients with sepsis [ 51 ]. In addition, the massive activation of the endogenous GLP-1 system during sepsis has been proposed as a predictor of early death or persistent organ dysfunction [ 70 , 71 ], particularly in patients infected by Gram-negative bacteria [ 51 , 72 ].…”

GLP-1 Receptor: A New Target for Sepsis

“…On the one hand, its over-activity is related to increased sCD14 levels, which activates the innate immune response to resist the invasion of pathogenic microorganisms. On the other hand, it may reduce excessive inflammation to prevent immune system disorders and the adverse consequences of sepsis ( Bloch et al, 2021 ).…”