glucagon-like-peptide-1 and Critical-Illness

Critical illness afflicts millions of people worldwide and is associated with a high risk of organ failure and death or an adverse outcome with persistent physical or cognitive deficits. Spontaneous hyperglycemia is common in critically ill patients and is associated with an adverse outcome compared to normoglycemia. Insulin is used for treating hyperglycemia in the critically ill patients but may be complicated by hypoglycemia, which is difficult to detect in these patients and which may lead to serious neurological sequelae and death. The incretin hormone, glucagon-like peptide (GLP) 1, stimulates insulin secretion and inhibits glucagon release both in healthy individuals and in patients with type 2 diabetes (T2DM). Compared to insulin, GLP-1 appears to be associated with a lower risk of severe hypoglycemia, probably because the magnitude of its insulinotropic action is dependent on blood glucose (BG). This is taken advantage of in the treatment of patients with T2DM, for whom GLP-1 analogs have been introduced during the recent years. Infusion of GLP-1 also lowers the BG level in critically ill patients without causing severe hypoglycemia. The T2DM and critical illness share similar characteristics and are, among other things, both characterized by different grades of systemic inflammation and insulin resistance. The GLP-1 might be a potential new treatment target in critically ill patients with stress-induced hyperglycemia.

Topics: Blood Glucose; Critical Illness; Glucagon-Like Peptide 1; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Incretins; Insulin; Insulin Secretion

Topics: Blood Glucose; Critical Care; Critical Illness; Gastric Inhibitory Polypeptide; Gastrointestinal Tract; Glucagon-Like Peptide 1; Humans; Incretins; Insulin

Hyperglycaemia frequently occurs in the critically ill, in patients with diabetes, as well as those who were previously glucose-tolerant. The terminology 'stress hyperglycaemia' reflects the pathogenesis of the latter group, which may comprise up to 40% of critically ill patients. For comparable glucose concentrations during acute illness outcomes in stress hyperglycaemia appear to be worse than those in patients with type 2 diabetes. While several studies have evaluated the optimum glycaemic range in the critically ill, their interpretation in relation to clinical recommendations is somewhat limited, at least in part because patients with stress hyperglycaemia and known diabetes were grouped together, and the optimum glycaemic range was regarded as static, rather than dynamic, phenomenon. In addition to hyperglycaemia, there is increasing evidence that hypoglycaemia and glycaemic variability influence outcomes in the critically ill adversely. These three categories of disordered glucose metabolism can be referred to as dysglycaemia. While stress hyperglycaemia is most frequently managed by administration of short-acting insulin, guided by simple algorithms, this does not treat all dysglycaemic categories; rather the use of insulin increases the risk of hypoglycaemia and may exacerbate variability. The pathogenesis of stress hyperglycaemia is complex, but hyperglucagonaemia, relative insulin deficiency and insulin resistance appear to be important. Accordingly, novel agents that have a pathophysiological rationale and treat hyperglycaemia, but do not cause hypoglycaemia and limit glycaemic variability, are appealing. The potential use of glucagon-like peptide-1 (or its agonists) and dipeptyl-peptidase-4 inhibitors is reviewed.

Topics: Analysis of Variance; Biomarkers; Blood Glucose; Critical Illness; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Female; Glucagon; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Insulin; Insulin Resistance; Male; Risk Factors

To review literature evaluating the safety and efficacy of exogenous glucagon-like peptide-1 (GLP-1) for hyperglycemia in critically ill patients.. PubMed was queried (inception to September 3, 2011), using the search term glucagon-like peptide-1. The search was limited to studies published in English and conducted in humans. Regular and late-breaking abstracts from the American Diabetes Association Scientific Sessions in 2009 and 2010 were also searched using the same search term.. All abstracts were screened for eligibility, which consisted of studies reporting the effects of intravenous GLP-1 administration on glycemic control in critically ill patients. Data extracted from eligible trials included study and population characteristics, measures of glycemic efficacy, and safety.. Our search resulted in the identification of 2105 potentially relevant articles; of those, 7 were reviewed. All included publications evaluated the use of intravenous GLP-1 (1.2-3.6 pmol/kg/min) compared with insulin or placebo infused for 4.5-72 hours in critically ill patients. The majority (n = 4) of studies included only patients from a surgical intensive care setting, and 71% (n = 5) of trials included those with a history of diabetes. Relative to insulin or placebo, GLP-1 therapy effectively lowered blood glucose concentrations in all trials. Out of 81 total study participants receiving GLP-1, only 4 had documented hypoglycemia (<60 mg/dL), 4 reported nausea, and 2 experienced vomiting. No other serious adverse events were reported.. All trials reviewed suggest that GLP-1 may be a promising agent for the management of hyperglycemia in critically ill patients, regardless of diabetes status. Additional studies in more heterogeneous intensive care settings comparing GLP-1 with insulin, the current standard of care, are necessary. These studies should evaluate long-term safety and effectiveness of GLP-1 therapy on morbidity and mortality outcomes in critically ill populations.

Topics: Blood Glucose; Clinical Trials as Topic; Critical Care; Critical Illness; Glucagon-Like Peptide 1; Humans; Hyperglycemia; Hypoglycemic Agents; Treatment Outcome

Intravenous insulin therapy is the gold standard therapy for glycaemic control in hyperglycaemic critically ill adult patients. However, hypoglycaemia remains a major concern in critically ill patients, even in some populations who are not receiving infused insulin. Furthermore, the influence of factors such as glycaemic variability and nutritional support may conceal any benefit of strict glycaemic control on morbidity and mortality in these patients. The recently revised guidelines of the American Diabetic Association/American College of Clinical Endocrinologists no longer advocate very tight glycaemic control or normalization of glucose levels in all critically ill patients. In the light of various concerns over the optimal glucose level and means to achieve such control, the use of glucagon-like peptide-1 or its analogues administered intravenously may represent an interesting therapeutic option.

Topics: Blood Glucose; Critical Illness; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemia; Hypoglycemic Agents; Infusions, Intravenous; Insulin; Male; Treatment Outcome; United States

Multiorgan failure frequently develops in critically ill patients. While therapeutic efforts in such patients are often focused on the lungs, on the cardiovascular system as well as on the kidneys, it is important to also consider the functional alterations in gut motility and hormone secretion. Given the central regulatory functions of many gut hormones, such as glucagon-like peptide 1, glucagon-like peptide 2, ghrelin and others, exogenous supplementation of some of these factors may be beneficial under conditions of critical illness. From a pragmatic point of view, the most feasible way towards a restoration of gut hormone secretion in critically ill patients is to provide enteral nutritional supply as soon as possible.

Topics: Critical Illness; Gastrointestinal Tract; Glucagon-Like Peptide 1; Humans; Multiple Organ Failure

Numerous hormones secreted by the gut, during both the fasted state and in response to a meal, influence gastrointestinal motor and/or sensory function, and appear to contribute to the pathogenesis of delayed gastric emptying associated with gastroparesis, functional dyspepsia (FD) and feed intolerance in critical illness. Gut hormones are, accordingly, potential targets for the management of these patients.. This article will discuss the hypersensitivity to enteral fat and endogenous (nutrient-stimulated) and exogenous cholecystokinin (CCK) in patients with FD, and the elevation in both fasting and postprandial CCK levels evident in this group. It will review the use of pharmacological agonists of motilin and ghrelin, which accelerate gastric emptying, in the management of gastroparesis and FD. The frequent finding of markedly delayed gastric emptying in the critically ill will be examined; this is associated with elevated plasma CCK and peptide YY in both the fasted and postprandial states, which may account for the increase in small intestinal nutrient inhibitory feedback on gastric motility in this group. The concepts that the rate of gastric emptying is a major determinant of postprandial glycemic excursions in diabetes, and that modulation of gastric emptying may improve glycemic control, will be addressed; in type 1 and insulin-treated type 2 diabetic patients, co-ordination of insulin administration with nutrient delivery and absorption should be optimized, while type 2 patients who are not on insulin are likely to respond to dietary and/or pharmacological interventions which slow gastric emptying.

Topics: Adipose Tissue; Blood Glucose; Cholecystokinin; Critical Illness; Diabetes Mellitus; Dyspepsia; Gastric Emptying; Gastroparesis; Ghrelin; Glucagon-Like Peptide 1; Humans; Insulin; Peptide YY; Postprandial Period

To explore the effects of somatostatin on the levels of gastrointestinal hormones and clinical outcomes in critically ill infants after gastrointestinal surgery.. Using a random number table method, critically ill infants after gastrointestinal surgery who were admitted to the Intensive Care Unit of Xuzhou Children's Hospital from June 2019 to June 2021 were randomly divided into an observation group (29 cases) and a control group (30 cases). The control group received routine treatment such as anti-infection and hemostasis after surgery, while the observation group received somatostatin in addition to the routine treatment [3.5 μg/(kg·h) infusion for 7 days]. The levels of serum gastrin (GAS), motilin (MTL), insulin, and glucagon-like peptide-1 (GLP-1) before surgery, on the 3rd day after surgery, and on the 7th day after surgery were compared between the two groups. The recovery progress and incidence of complications after surgery were also compared between the two groups.. There was no significant difference in the levels of serum GAS, MTL, insulin, and GLP-1 between the two groups before surgery (. Somatostatin can increase the levels of serum GAS, MTL, insulin, and GLP-1 in critically ill infants after gastrointestinal surgery, promote the recovery of gastrointestinal function, and reduce the incidence of postoperative complications.

Topics: Child; Critical Illness; Digestive System Surgical Procedures; Glucagon-Like Peptide 1; Humans; Infant; Insulin; Prospective Studies; Somatostatin

Intensive insulin therapy for tight glycemic control in critically ill surgical patients has been shown to reduce mortality; however, intensive insulin therapy is associated with iatrogenic hypoglycemia and increased variability of blood glucose levels. The incretin glucagon-like peptide-1 (7-36) amide is both insulinotropic and insulinomimetic and has been suggested as an adjunct to improve glycemic control in critically ill patients. We hypothesized that the addition of continuous infusion of glucagon-like peptide-1 to intensive insulin therapy would result in better glucose control, reduced requirement of exogenous insulin administration, and fewer hypoglycemic events.. Prospective, randomized, double-blind, placebo-controlled clinical trial.. Surgical or burn ICU.. Eighteen patients who required intensive insulin therapy.. A 72-hour continuous infusion of either glucagon-like peptide-1 (1.5 pmol/kg/min) or normal saline plus intensive insulin therapy.. The glucagon-like peptide-1 cohort (n = 9) and saline cohort (n = 9) were similar in age, Acute Physiology and Chronic Health Evaluation score, and history of diabetes. Blood glucose levels in the glucagon-like peptide-1 group were better controlled with much less variability. The coefficient of variation of blood glucose ranged from 7.2% to 30.4% in the glucagon-like peptide-1 group and from 19.8% to 56.8% in saline group. The mean blood glucose coefficient of variation for the glucagon-like peptide-1 and saline groups was 18.0% ± 2.7% and 30.3% ± 4.0% (p = 0.010), respectively. The 72-hour average insulin infusion rates were 3.37 ± 0.61 and 4.57 ± 1.18 U/hr (p = not significant). The incidents of hypoglycemia (≤ 2.78 mmol/L) in both groups were low (one in the glucagon-like peptide-1 group, three in the saline group).. Glucagon-like peptide-1 (7-36) amide is a safe and efficacious form of adjunct therapy in patients with hyperglycemia in the surgical ICU setting. Improved stability of blood glucose is a favorable outcome, which enhances the safety of intensive insulin therapy. Larger studies of this potentially valuable therapy for glycemic control in the ICU are justified.

Topics: Adult; Aged; Aged, 80 and over; Blood Glucose; Critical Care; Critical Illness; Double-Blind Method; Drug Therapy, Combination; Female; Follow-Up Studies; Glucagon-Like Peptide 1; Hospital Mortality; Humans; Hyperglycemia; Hypoglycemic Agents; Infusions, Intravenous; Insulin; Intensive Care Units; Male; Middle Aged; Patient Safety; Pilot Projects; Postoperative Complications; Prospective Studies; Risk Assessment; Statistics, Nonparametric; Survival Rate; Treatment Outcome

Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) have additive insulinotropic effects when coadministered in health. We aimed to determine whether GIP confers additional glucose lowering to that of GLP-1 in the critically ill.. Twenty mechanically ventilated critically ill patients without known diabetes were studied in a prospective, randomized, double-blind, crossover fashion on 2 consecutive days. Between T0 and T420 minutes, GLP-1 (1.2 pmol/kg·min(-1)) was infused intravenously with either GIP (2 pmol/kg·min(-1)) or 0.9% saline. Between T60 and T420 minutes, nutrient liquid was infused into the small intestine at 1.5 kcal/min.. Adding GIP did not alter blood glucose or insulin responses to small intestinal nutrient. GIP increased glucagon concentrations slightly before nutrient delivery (P=0.03), but not thereafter.. The addition of GIP to GLP-1 does not result in additional glucose-lowering or insulinotropic effects in critically ill patients with acute-onset hyperglycemia.

Topics: Adult; Aged; Blood Glucose; Critical Illness; Cross-Over Studies; Double-Blind Method; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Humans; Hyperglycemia; Male; Middle Aged; Prospective Studies

Glucagon-like peptide-1 (GLP-1) attenuates the glycaemic response to small intestinal nutrient infusion in stress-induced hyperglycaemia and reduces fasting glucose concentrations in critically ill patients with type-2 diabetes. The objective of this study was to evaluate the effects of acute administration of GLP-1 on the glycaemic response to small intestinal nutrient infusion in critically ill patients with pre-existing type-2 diabetes.. Eleven critically ill mechanically-ventilated patients with known type-2 diabetes received intravenous infusions of GLP-1 (1.2 pmol/kg/minute) and placebo from t = 0 to 270 minutes on separate days in randomised double-blind fashion. Between t = 30 to 270 minutes a liquid nutrient was infused intraduodenally at a rate of 1 kcal/min via a naso-enteric catheter. Blood glucose, serum insulin and C-peptide, and plasma glucagon were measured. Data are mean ± SEM.. GLP-1 attenuated the overall glycaemic response to nutrient (blood glucose AUC30-270 min: GLP-1 2,244 ± 184 vs. placebo 2,679 ± 233 mmol/l/minute; P = 0.02). Blood glucose was maintained at < 10 mmol/l in 6/11 patients when receiving GLP-1 and 4/11 with placebo. GLP-1 increased serum insulin at 270 minutes (GLP-1: 23.4 ± 6.7 vs. placebo: 16.4 ± 5.5 mU/l; P < 0.05), but had no effect on the change in plasma glucagon.. Exogenous GLP-1 in a dose of 1.2 pmol/kg/minute attenuates the glycaemic response to small intestinal nutrient in critically ill patients with type-2 diabetes. Given the modest magnitude of the reduction in glycaemia the effects of GLP-1 at higher doses and/or when administered in combination with insulin, warrant evaluation in this group.. ANZCTR:ACTRN12610000185066.

Topics: Blood Glucose; Critical Care; Critical Illness; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Double-Blind Method; Enteral Nutrition; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Male; Middle Aged; Pylorus; Treatment Outcome

To determine the acute effects of exogenous glucagon-like peptide-1 on gastric emptying, glucose absorption, glycemia, plasma insulin, and glucagon in critically ill patients.. Randomized, double-blind, crossover study.. Intensive care unit.. Twenty-five mechanically ventilated patients, without known diabetes, studied on consecutive days.. Intravenous glucagon-like peptide-1 (1.2 pmol/kg/min) or placebo was infused between -30 and 330 mins. At 0 min, 100 mL liquid nutrient (1 kcal/mL) including 100 microg of 13C-octanoic acid and 3 grams of 3-O-methyl-glucose was administered.. Blood glucose, serum 3-O-methyl-glucose (as an index of glucose absorption), insulin and glucagon concentrations, as well as exhaled 13CO2 were measured. The gastric emptying coefficient was calculated to quantify gastric emptying. Data are presented as mean (sd). There was a nonsignificant trend for glucagon-like peptide-1 to slow gastric emptying (gastric emptying coefficient) (glucagon-like peptide-1, 2.45 [0.93] vs. placebo, 2.75 [0.83]; p = .09). In 11 of the 25 patients, gastric emptying was delayed during placebo infusion and glucagon-like peptide-1 had no detectable effect on gastric emptying in this group (1.92 [0.82] vs. 1.90 [0.68]; p = .96). In contrast, in patients who had normal gastric emptying during placebo, glucagon-like peptide-1 slowed gastric emptying substantially (2.86 [0.58] vs. 3.41 [0.37]; p = .006). Glucagon-like peptide-1 markedly reduced the rate of glucose absorption (3-O-methyl-glucose area under the curve(0-330), 37 [35] vs. 76 [51] mmol/L/min; p < .001), decreased preprandial glucagon (at 0 min change in glucagon, -15 [15] vs. -3 [14] pmol/L; p < .001), increased the insulin/glucose ratio throughout the infusion (area under the curve(-30-330), 1374 [814] vs. 1172 [649] mU/mmol/min; p = .041), and attenuated the glycemic response to the meal (glucose area under the curve(0-330), 2071 [353] vs. 2419 [594] mmol/L/min; p = .001).. Exogenous glucagon-like peptide-1 lowers postprandial glycemia in the critically ill. This may occur, at least in part, by slowing gastric emptying when the latter is normal but not when it is delayed.

Topics: 3-O-Methylglucose; Blood Glucose; Breath Tests; Critical Illness; Cross-Over Studies; Double-Blind Method; Gastric Emptying; Glucagon; Glucagon-Like Peptide 1; Glucose; Humans; Insulin; Intensive Care Units; Respiration, Artificial

Hyperglycaemia occurs frequently in the critically ill, affects outcome adversely, and is exacerbated by enteral feeding. Furthermore, treatment with insulin in this group is frequently complicated by hypoglycaemia. In healthy patients and those with type 2 diabetes, exogenous glucagon-like peptide-1 (GLP-1) decreases blood glucose by suppressing glucagon, stimulating insulin and slowing gastric emptying. Because the former effects are glucose-dependent, the use of GLP-1 is not associated with hypoglycaemia. The objective of this study was to establish if exogenous GLP-1 attenuates the glycaemic response to enteral nutrition in patients with critical illness induced hyperglycaemia.. Seven mechanically ventilated critically ill patients, not previously known to have diabetes, received two intravenous infusions of GLP-1 (1.2 pmol/kg/min) and placebo (4% albumin) over 270 minutes. Infusions were administered on consecutive days in a randomised, double-blind fashion. On both days a mixed nutrient liquid was infused, via a post-pyloric feeding catheter, at a rate of 1.5 kcal/min between 30 and 270 minutes. Blood glucose and plasma GLP-1, insulin and glucagon concentrations were measured.. In all patients, exogenous GLP-1 infusion reduced the overall glycaemic response during enteral nutrient stimulation (AUC30-270 min GLP-1 (2077 +/- 144 mmol/l min) vs placebo (2568 +/- 208 mmol/l min); P = 0.02) and the peak blood glucose (GLP-1 (10.1 +/- 0.7 mmol/l) vs placebo (12.7 +/- 1.0 mmol/l); P < 0.01). The insulin/glucose ratio at 270 minutes was increased with GLP-1 infusion (GLP-1 (9.1 +/- 2.7) vs. placebo (5.8 +/- 1.8); P = 0.02) but there was no difference in absolute insulin concentrations. There was a transient, non-sustained, reduction in plasma glucagon concentrations during GLP-1 infusion (t = 30 minutes GLP-1 (90 +/- 12 pmol/ml) vs. placebo (104 +/- 10 pmol/ml); P < 0.01).. Acute, exogenous GLP-1 infusion markedly attenuates the glycaemic response to enteral nutrition in the critically ill. These observations suggest that GLP-1 and/or its analogues have the potential to manage hyperglycaemia in the critically ill.. Australian New Zealand Clinical Trials Registry number: ACTRN12609000093280.

Topics: Adult; Aged; Area Under Curve; Blood Glucose; Critical Illness; Cross-Over Studies; Double-Blind Method; Enteral Nutrition; Female; Glucagon; Glucagon-Like Peptide 1; Humans; Hyperglycemia; Hypoglycemia; Incretins; Infusions, Intravenous; Insulin; Male; Middle Aged

Critical illness is associated with derangement in the metabolic and inflammatory response. Previous investigators have highlighted the cross-link between feeding, inflammation and gut homeostasis. Glucagon like peptide-1 (GLP-1) is a gut derived hormone that plays an important role in the modulation of energy metabolism through appetite regulation and promotion of gastric motility. Growing evidence suggests that GLP-1 might influence energy expenditure. The aim of this study was to assess the relationship between inflammatory activation and metabolic regulation of energy expenditure by assessing cytokine release, levels of GLP-1 and energy expenditure in a cohort of critically ill children.. This is a prospective study conducted in critically ill children. A blood sample was collected from each child during the first few days of critical illness, for the analysis of serum inflammatory cytokines (TNF-α, IL-10, IL-6 and IL-1β) and GLP-1 in 42 children. Indirect calorimetry (IC) measurements were performed concurrently in a subset of 21 children. The metabolic index was determined using the ratio of Measured Resting Energy Expenditure (MREE)/Predicted Resting Energy Expenditure (PREE) based on the Schofield equation. Correlation analysis was performed, followed by a stepwise linear regression analysis to assess factors affecting GLP-1 and the metabolic index.. A total of 42 children (0-14 years) were included in this study. The regression analysis indicated that CRP, TNF-α, IL-6 and IL-1β statistically influenced GLP-1 concentrations (p < 0.01). Where IC measurements were performed (N = 21), GLP-1 showed a statistically significant association with the metabolic index (p < 0.01). No evidence of statistical association was recorded between the inflammatory mediators and the metabolic index. Overall the results showed that circulating GLP-1 was increased in response to inflammatory stimuli in critically ill children. GLP-1 contributed to the changes observed in MREE induced by critical illness in our cohort.. Energy expenditure is extremely variable in critically ill children, our study suggests that changes in GLP-1 might contribute to a significant amount of this variation. If confirmed in larger studies, GLP-1 could be used as a correction factor for REE predictive equations in critically ill children.

Topics: Basal Metabolism; Calorimetry, Indirect; Child; Child, Preschool; Critical Illness; Cytokines; Energy Metabolism; Female; Glucagon-Like Peptide 1; Health Status Indicators; Humans; Infant; Inflammation; Intensive Care Units, Pediatric; Male; Pilot Projects; Prospective Studies; Regression Analysis; Respiration, Artificial

Adipokines play an important role in the regulation of metabolism. In critical illness, they alter serum levels and are suspected to worsen clinical outcomes. But the effect of the route of nutrition on adipokines is not known. The purpose of this study was to evaluate the association between the route of nutrition and adipokine levels in critically ill patients.. This prospective study was performed in an intensive care unit (ICU). Patients admitted to the ICU for least 72 h and receiving either enteral nutrition (EN) via tube feeding or parenteral nutrition (PN) were enrolled. Serum was obtained at baseline, 24 h, and 72 h for concentrations of leptin, adiponectin, resistin, glucagon–like peptide 1 (GLP–1), insulin–like growth factors 1 (IGF–1), and ghrelin.. A total of 26 patients were included in the study. Thirteen patients received EN and 13 patients received PN. In the PN group, leptin level significantly increased (P = 0.037), adiponectin and ghrelin significantly decreased during follow up (P = 0.037, P = 0.008, respectively). There was no significant change between all adipokines in the EN group and resistin, IGF–1 and GLP–1 in the PN group during follow up. Resistin levels were markedly lower in the EN group at both 24 h (P = 0.015) and 72 h (P = 0.006) while GLP–1 levels were higher in the EN group at baseline, 24 h, and 72 h (P = 0.018, P = 0.005, and P = 0.003, respectively). There were no differences in leptin, adiponectin, IGF–1, and ghrelin levels over time.. The delivery of EN in critical illness was associated with decreased resistin levels and increased GLP–1 levels. Thus, the route of nutrition may impact the clinical outcome in critical illness due to adipokines.

Topics: Adipokines; Adult; Aged; Biomarkers; Critical Illness; Female; Ghrelin; Glucagon-Like Peptide 1; Humans; Insulin-Like Growth Factor I; Leptin; Male; Middle Aged; Nutritional Support; Pilot Projects; Prospective Studies; Resistin

Glucagon-like peptide-1 (GLP-1) is a gut-derived incretin hormone that stimulates insulin secretion, cellular glucose uptake, and has immune-regulatory functions. Glucagon-like peptide-1 is markedly altered after trauma and sepsis, but the implications remain unclear.. 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.. The cohort included 157 septic surgical patients with significant physiologic derangement (Maximum Sequential Organ Failure Assessment [SOFA] score 8, interquartile range [IQR] 4 to 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 were low (n = 12, 7.6%). However, post-discharge 6-month mortality was nearly 3-fold higher (19.7%). Both GLP-1 and interleukin [IL]-6 levels were significantly elevated for 21 days (p ≤ 0.01) in patients who developed chronic critical illness (CCI) compared with 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).. Elevated GLP-1 within 24 hours of sepsis is a predictor of early death or persistent organ dysfunction. Among early survivors, persistently elevated GLP-1 levels at day 14 are strongly predictive of death or severe functional disability at 6 months. Persistently elevated GLP-1 levels may be a marker of a nonresolving catabolic state that is associated with muscle wasting and dismal outcomes after sepsis and chronic critical illness.

Topics: Aged; Biomarkers; Chronic Disease; Critical Illness; Female; Florida; Follow-Up Studies; Glucagon-Like Peptide 1; Humans; Incidence; Intensive Care Units; Male; Middle Aged; Prospective Studies; Sepsis; Surgical Wound Infection; Survival Rate; Time Factors

Topics: Chronic Disease; Critical Illness; Glucagon-Like Peptide 1; Humans; Sepsis

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.. 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.. 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.. 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.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers; Case-Control Studies; Critical Illness; Diabetes Mellitus, Type 2; Female; Follow-Up Studies; Glucagon-Like Peptide 1; Humans; Male; Middle Aged; Prognosis; Sepsis; Young Adult

Glucagon-like peptide 1 (GLP-1) is an incretin hormone, which stimulates glucose-dependent insulin secretion from the pancreas and holds immune-regulatory properties. A marked increase of GLP-1 has been found in critically ill patients. This study was performed to elucidate the underlying mechanism and evaluate its prognostic value.. GLP-1 plasma levels were determined in 3 different patient cohorts: 1) critically ill patients admitted to our intensive care unit (n = 215); 2) patients with chronic kidney disease on hemodialysis (n = 173); and 3) a control group (no kidney disease, no acute inflammation, n = 105). In vitro experiments were performed to evaluate GLP-1 secretion in response to human serum samples from the above-described cohorts.. Critically ill patients presented with 6.35-fold higher GLP-1 plasma level in comparison with the control group. There was a significant correlation of GLP-1 levels with markers for the severity of inflammation, but also kidney function. Patients with end-stage renal disease displayed 4.46-fold higher GLP-1 concentrations in comparison with the control group. In vitro experiments revealed a strong GLP-1-inducing potential of serum from critically ill patients, while serum from hemodialysis patients only modestly increased GLP-1 secretion. GLP-1 levels independently predicted mortality in critically ill patients and patients with end-stage renal disease.. Chronic and acute inflammatory processes like sepsis or chronic kidney disease increase circulating GLP-1 levels. This most likely reflects a sum effect of increased GLP-1 secretion and decreased GLP-1 clearance. GLP-1 plasma levels independently predict the outcome of critically ill and end-stage renal disease patients.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Biomarkers; Critical Care; Critical Illness; Female; Glucagon-Like Peptide 1; Humans; Kidney Failure, Chronic; Male; Middle Aged; Renal Dialysis; Sepsis; Young Adult

Topics: Animals; Awards and Prizes; Blood Glucose; Critical Illness; Glucagon-Like Peptide 1; Humans; Hyperglycemia; Insulin; Interleukin-6; Mice; Sepsis; Signal Transduction

Patients admitted to the intensive care unit often develop hyperglycaemia, but the underlying mechanisms have not been fully described. The incretin effect is reduced in patients with type 2 diabetes. Type 2 diabetes and critical illness have phenotypical similarities, such as hyperglycaemia, insulin resistance and systemic inflammation. Previous studies have shown beneficial effects of exogenous glucagon-like peptide (GLP)-1 on glycaemia in critically ill patients, a phenomenon also seen in patients with type 2 diabetes. In this study, we hypothesised that the incretin effect, which is mediated by the incretin hormones GLP-1 and glucose-dependent insulinotropic peptide (GIP), is impaired in critically ill patients.. The incretin effect (i.e., the relative difference between the insulin response to oral and intravenous glucose administration) was investigated in a cross-sectional case-control study. Eight critically ill patients without diabetes admitted to a mixed intensive care unit and eight healthy control subjects without diabetes, matched at group level by age, sex and body mass index, were included in the study. All subjects underwent an oral glucose tolerance test (OGTT) followed by an intravenous glucose infusion (IVGI) on the next day to mimic the blood glucose profile from the OGTT. Blood glucose, serum insulin, serum C-peptide and plasma levels of GLP-1, GIP, glucagon and proinflammatory cytokines were measured intermittently. The incretin effect was calculated as the increase in insulin secretion during oral versus intravenous glucose administration in six patients. The groups were compared using either Student's t test or a mixed model of repeated measurements.. Blood glucose levels were matched between the OGTT and the IVGI in both groups. Compared with control subjects, proinflammatory cytokines, tumour necrosis factor α and interleukin 6, were higher in patients than in control subjects. The endogenous response of GIP and glucagon, but not GLP-1, to the OGTT was greater in patients. The insulin response to the OGTT did not differ between groups, whereas the insulin response to the IVGI was higher in patients. Consequently, the calculated incretin effect was lower in patients (23 vs. 57%, p=0.003).. In critically ill patients, the incretin effect was reduced. This resembles previous findings in patients with type 2 diabetes.. ClinicalTrials.gov identifier: NCT01347801 . Registered on 2 May 2011.

Topics: Administration, Intravenous; Aged; Blood Glucose; Case-Control Studies; Critical Illness; Cross-Sectional Studies; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Humans; Hyperglycemia; Hypoglycemic Agents; Incretins; Insulin; Insulin Resistance; Male; Middle Aged

In health, the hormones amylin and glucagon-like peptide-1 (GLP-1) slow gastric emptying (GE) and modulate glycaemia. The aims of this study were to determine amylin and GLP-1 concentrations in the critically ill and their relationship with GE, glucose absorption and glycaemia.. In fasted critically ill and healthy subjects (n = 26 and 23 respectively), liquid nutrient, containing 100 mg (13) C-sodium octanoate and 3 g 3-O-methlyglucose (3-OMG), was administered via a nasogastric tube. Amylin, GLP-1, glucose and 3-OMG concentrations were measured in blood samples taken during fasting, and 30 min and 60 min after the 'meal'. Breath samples were taken to determine gastric emptying coefficient (GEC). Intolerance to intragastric feeding was defined as a gastric residual volume of ≥ 250 ml and/or vomiting within the 24 h prior to the study.. Although GE was slower (GEC: critically ill 2.8 ± 0.9 vs. health, 3.4 ± 0.2; P = 0.002), fasting blood glucose was higher (7.0 ± 1.9 vs. 5.7 ± 0.2 mmol/l; P = 0.005) and overall glucose absorption was reduced in critically ill patients (3-OMG: 9.4 ± 8.0 vs. 17.7 ± 4.9 mmol/l.60 min; P < 0.001), there were no differences in fasting or postprandial amylin concentrations. Furthermore, although fasting [1.7 (0.4-7.2) vs. 0.7 (0.3-32.0) pmol/l; P = 0.04] and postprandial [3.0 (0.4-8.5) vs. 0.8 (0.4-34.3) pmol/l; P = 0.02] GLP-1 concentrations were increased in the critically ill and were greater in feed intolerant when compared with those tolerating feed [3.7 (0.4-7.2) vs. 1.2 (0.7-4.6) pmol/l; P = 0.02], there were no relationships between GE and fasting amylin or GLP-1 concentrations.. In the critically ill, fasting GLP-1, but not amylin, concentrations are elevated and associated with feed intolerance. Neither amylin nor GLP-1 appears to substantially influence the rate of GE.

Topics: 3-O-Methylglucose; Adult; Aged; Aged, 80 and over; Blood Glucose; Breath Tests; Cohort Studies; Critical Illness; Female; Gastric Emptying; Glucagon-Like Peptide 1; Glucose; Humans; Islet Amyloid Polypeptide; Male; Middle Aged; Young Adult

Topics: Blood Glucose; Critical Illness; Glucagon-Like Peptide 1; Humans