Persistently Elevated Glucagon-Like Peptide-1 Levels among Critically Ill Surgical Patients after Sepsis and Development of Chronic Critical Illness and Dismal Long-Term Outcomes

Abstract

Background: Glucagon-like peptide-1 (GLP-1) is a gut derived incretin hormone that stimulates insulin secretion, cellular glucose uptake and has immune-regulatory functions. GLP-1 is markedly altered following trauma and sepsis, but the implications remain unclear. Study design:We performed an analysis of a prospective, longitudinal cohort study of critically-ill surgical patients with sepsis. Patient characteristics, and clinical data were collected, as well as peripheral blood sampling for biomarker analysis, out to 28 days after sepsis onset. We prospectively adjudicated sepsis diagnosis, severity, clinical outcomes and 6-month follow-up. Results:The cohort included 157 septic surgical patients with significant physiologic derangement (Max. SOFA score 8, IQR 4-11), a high rate of multiple organ failure (50.3%) and septic shock (24.2%). Despite high disease severity, both early death (<14 days; n=4, 2.9%) and overall inpatient mortality was low (n=12, 7.6%). However, post-discharge 6-month mortality was nearly 3-fold higher (19.7%). Both GLP-1 and IL-6 levels were significantly elevated for 21 days (p≤0.01) in patients that developed CCI compared to patients with a rapid recovery. Elevated GLP-1 at 24 hours was a significant independent predictor for the development of CCI after controlling for IL-6 and glucose levels (p=0.027), and at day 14 for death or severe functional disability at 6 months (WHO/Zubrod score 4-5, p=0.014).

Gut Luminal and Clinical Benefits of Early Enteral Nutrition in Shock

“…In the same study, patients had significantly higher serum concentrations of pro-inflammatory markers TNF-a and IL-1b and an increased intestinal barrier disruption was associated with higher serum intestinal fatty acid binding protein (I-FABP), ileal bileacid binding protein (I-BABP), and zonulin-1 [12]. Survivors of shock states may have long term elevations in inflammatory mediators which are predictive of higher mortality and worse outcomes [13].…”

Plasma levels of glucagon but not GLP-1 are elevated in response to inflammation in humans

“…Increased concentrations of glucagon and GLP-1 were recently reported in sepsis ( 11 , 12 ) and critically ill patients ( 13 ), in mice following LPS injection ( 23 ), and in humans with burn lesions ( 24 ). Estimation of plasma GLP-1 in mice is troublesome due to the rapid degradation by neprilysin ( 25 , 26 ), and the assays employed in the current human study and in other previously published studies also cross-react with GLP-1 1–36NH 2 that is co-secreted with glucagon ( 17 ).…”

“…Increased blood glucose levels are frequently observed in septic patients, independent of pre-existing disturbances in glucose metabolism ( 8 , 9 ), and hyperglycemia is significantly associated with their increased mortality ( 10 ). Some studies have reported that glucagon and GLP-1 concentrations are elevated during trauma, inflammation and or sepsis ( 11 , 12 , 13 , 14 , 15 ). However, sequence homology between glucagon and GLP-1, close resemblance to other circulating proglucagon-derived peptides, and the fact that they circulate in low (picomolar) concentrations, make accurate measurements of these hormones difficult ( 16 , 17 , 18 , 19 ).…”

Sepsis therapies: learning from 30 years of failure of translational research to propose new leads

“…Examples include insulin, the incretins (GLP‐1 and GIP), ghrelin, and leptin. High and persisting levels of glucagon‐like peptide‐1 in septic patients are associated with an increase in mortality and functional disability (Brakenridge et al , ). Ghrelin, involved in appetite stimulation, increases in the plasma of septic patients (Nikitopoulou et al , ), and active ghrelin levels are inversely correlated with the SOFA organ dysfunction score and length of ICU stay.…”