exenatide and Burns

This systematic review investigated the effectiveness and safety of intensive insulin therapy (IIT), insulin secretagogues and sensitisers in burn patients. PubMed, Embase, clinicaltrials.gov and Cochrane central were searched from 1990 to 2016. Title/abstract screening, full-text review, critical appraisal and data extraction were carried out by two independent reviewers. Inclusion criteria were hospitalised burn patients, IIT, insulin sensitisers or secretagogues and the outcomes mortality, length of stay, resting energy expenditure, blood glucose, catabolism, or complications. We identified 594 potential studies of which 13 were included. Five studies investigated IIT in paediatric patients, 3 investigated IIT in adults and 5 investigated sensitisers or secretagogues. Glycaemic targets differed with age group - paediatric studies compared IIT to loose glycaemic control while adult studies compared IIT to more moderate control. Meta-analyses were limited by differences in outcome reporting, however mortality was increased in children by loose glycaemic control (OR=3.78, 95%CI 1.19-12.02) but not significantly affected in adults by moderate compared to tight control. Meta-analyses could not be performed for sensitisers or secretagogues. These findings support recommendations that moderate insulin administration (130-150mg/dL) is the prudent approach in burn patients. The evidence is relatively sparse and further research is warranted.

Topics: Burns; Dipeptidyl-Peptidase IV Inhibitors; Disease Management; Exenatide; Glipizide; Humans; Hyperglycemia; Hypoglycemic Agents; Incretins; Insulin; Insulin Resistance; Metformin; Pioglitazone; Rosiglitazone; Secretagogues; Sulfonylurea Compounds

Intensive insulin treatment (IIT) has been shown to improve outcomes post-burn in severely burnt patients. However, it increases the incidence of hypoglycemia and is associated with risks and complications. We hypothesized that exenatide would decrease plasma glucose levels post-burn to levels similar to those achieved with IIT, and reduce the amount of exogenous insulin administered.. This open-label study included 24 severely burned pediatric patients. Six were randomized to receive exenatide, and 18 received IIT during acute hospitalization (block randomization). Exenatide and insulin were administered to maintain glucose levels between 80 and 140 mg/dl. We determined 6 AM, daily average, maximum and minimum glucose levels. Variability was determined using mean amplitude of glucose excursions (MAGE) and percentage of coefficient of variability. The amount of administered insulin was compared in both groups.. Glucose values and variability were similar in both groups: Daily average was 130 ± 28 mg/dl in the intervention group and 138 ± 25 mg/dl in the control group (P = 0.31), MAGE 41 ± 6 vs. 45 ± 12 (respectively). However, administered insulin was significantly lower in the exenatide group than in the IIT group: 22 ± 14 IU patients/day in the intervention group and 76 ± 11 IU patients/day in the control group (P = 0.01). The incidence rate of hypoglycemia was similar in both groups (0.38 events/patient-month).. Patients receiving exenatide received significantly lower amounts of exogenous insulin to control plasma glucose levels. Exenatide was well tolerated and potentially represents a novel agent to attenuate hyperglycemia in the critical care setting.. NCT00673309.

Topics: Blood Glucose; Burns; Child; Energy Metabolism; Exenatide; Female; Humans; Hypoglycemic Agents; Insulin; Male; Peptides; Venoms

To determine if Exendin-4 could be a therapeutic agent for burn-induced hyperglycemia.. Male Balb/c mice received a bolus of Exendin-4 intraperitoneally immediately after 15% total body surface area scald injury. Tail glucose levels were recorded and T-cell functions were analyzed at 4 h and 24 h postburn (pb). Pancreatic pathology was observed consecutively. The secretions of cytokines were detected in serum, spleen, and lung. Apoptosis of splenic CD3+ T-cells was examined by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling and flow cytometry.. Although Exendin-4 could attenuate burn-induced hyperglycemia in mice at 4 h pb, it accelerated their survival dose dependently with progressive depletion of splenocyte number. T-cell function underwent two-phasic changes following Exendin-4 treatment. Compared to placebo mice, T-cell from Exendin-4-treated mice was manifested with increased proliferation, while decreased IL-2 secretion and lower ratio of IL-4/IFN-γ at 4 h pb. However, at 24 h pb, it showed decreased proliferation, while increased IL-2 secretion and higher ratio of IL-4/IFN-γ. Exendin-4 could elicit higher circulating IL-6 and IL-10 levels at 4 h pb, which were pronounced in the lung at 24 h pb. In the meanwhile, severe inflammation could be found in the pancreas. At 24 h pb, the numbers of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling or caspase-3 positive cells and the apoptosis of CD3+ T-cells were significantly increased in the spleens of Exendin-4 mice relative to placebo mice.. These data support a pathogenic role of Exendin-4 signaling during thermal injury, warning against its clinical application in acute insults.

Topics: Animals; Burns; Caspase 3; Cytokines; DNA Nucleotidylexotransferase; Exenatide; Glucose; Hyperglycemia; Interleukin-10; Interleukin-2; Interleukin-4; Interleukin-6; Male; Mice; Mice, Inbred BALB C

Glucagon-like peptide-1 (GLP-1)-based therapy via G protein-coupled receptor (GPCR) GLP-1R, to attenuate hyperglycemia in critical care has attracted great attention. However, the exaggerated inflammation by GLP-1R agonist, Exendin-4, in a mouse model of burn injury was quite unexpected. Recent studies found that GPCR might elicit proinflammatory effects by switching from Gαs to Gαi signaling in the immune system. Thus, we aimed to investigate the possible Gαs to Gαi switch in GLP-1R signaling in monocyte following burn injury.. Splenic monocytes from sham and burn mice 24 h following burn injury were treated with consecutive doses of Exendin-4 alone or in combination with an inhibitor of Gαi signaling (pertussis toxin, PTX), or a blocker of protein kinase A (H89). Cell viability was assessed by CCK-8, and the supernatant was collected for cytokine measurement by ELISA. Intracellular cAMP level, phosphorylated PKA activity, and nuclear NF-κB p65 were determined by ELISA, ERK1/2 activation was analyzed by Western blot. The expression of GLP-1R downstream molecules, Gαs, Gαi and G-protein coupled receptor kinase 2 (GRK2) were examined by immunofluorescence staining and Western blot.. Exendin-4 could inhibit the viability of monocyte from sham rather than burn mice. Unexpectedly, it could also reduce TNF-α secretion from sham monocyte while increase it from burn monocyte. The increased secretion of TNF-α by Exendin-4 from burn monocyte could be reversed by pretreatment of PTX or H89. Accordingly, Exendin-4 could stimulates cAMP production dose dependently from sham instead of burn monocyte. However, the blunt cAMP production from burn monocyte was further suppressed by pretreatment of PTX or H89 after 6-h incubation. Nevertheless, phosphorylated PKA activity was significantly increased by low dose of Exendin-4 in sham monocyte, by contrast, it was enhanced by high dose of Exendin-4 in burn monocyte after 1-h incubation. Following Exendin-4 treatment for 2 h ex vivo, total nuclear NF-κB and phosphorylated NF-κB activity, as well as cytoplasmic pERK1/2 expressions were reduced in sham monocyte, however, only pERK1/2 was increased by Exendin-4 in burn monocytes. Moreover, reduced expressions of GLP-1R, GRK-2 and Gαs in contrast with increased expression of Gαi were identified in burn monocyte relative to sham monocyte.. This study presents an unexpected proinflammatory switch from Gαs to Gαi signaling in burn monocyte, which promotes ERK1/2 and NF-κB activation and the downstream TNF-α secretion. This phenomenon is most probably responsible for proinflammatory response evoked by Gαs agonist Exendin-4 following burn injury.

Topics: Animals; Burns; Chromogranins; Cyclic AMP; Exenatide; Glucagon-Like Peptide-1 Receptor; GTP-Binding Protein alpha Subunits, Gi-Go; GTP-Binding Protein alpha Subunits, Gs; Inflammation; Male; MAP Kinase Signaling System; Mice; Mice, Inbred BALB C; Monocytes; Peptides; Signal Transduction; Spleen; Transcription Factor RelA; Venoms

The aim of this article was to observe the intracellular insulin content of islets isolated from severely scalded and Exendin-4-treated rats and to evaluate the stimulation of insulin mRNA synthesis and secretion by β cells at different glucose concentrations and during different periods of time. A 50% TBSA full-thickness scalded rat model was used. Rats were treated with Exendin-4, followed by islet isolation and functional measurements. Serum was collected for detection of serum insulin, glucose, and glucagon levels. Intracellular insulin content was determined by transmission electron microscopy. Isolated islets were incubated with different glucose concentrations for 1 or 24 hours to assess the effect of scalding with or without Exendin-4 treatment on functional parameters. Insulin secretion was analyzed by enzyme-linked immunosorbent assay. Intracellular insulin and proinsulin content were analyzed by immunoprecipitation. Islet preproinsulin mRNA expression was examined by real-time polymerase chain reaction. Transmission electron microscopy analyses showed that severe thermal injury significantly reduced the number of insulin granules per micrometer2. Insulin secretion and intracellular insulin and proinsulin levels were markedly reduced in islets stimulated with different glucose concentrations; chronic high-glucose-stimulated islet preproinsulin mRNA expression was also impaired. Exendin-4 treatment after thermal trauma improved the number of intracellular insulin granules. Exendin-4 improved both insulin secretion and intracellular insulin reserves under different glucose stimulation conditions. Islet insulin mRNA expression was also restored by Exendin-4 treatment. Exendin-4 can restore the islet β cell insulin reserve following severe scald injury and may also improve insulin secretion, insulin reserve, and mRNA expression in islet β cells.

Topics: Animals; Blood Glucose; Burns; Disease Models, Animal; Exenatide; Glucagon; Insulin; Islets of Langerhans; Male; Rats; Rats, Wistar; RNA, Messenger

It has been established that glucagon-like peptide 1 (GLP 1) inhibits pancreatic β-cell apoptosis, increases insulin secretion, and improves glucose tolerance in scald injury. However, the effects of Exendin-4, a long-acting incretin similar to GLP 1, remained unclear in severe scald injury. Hence, this study attempted to investigate whether Exendin-4 had similar effects by protecting the histology of pancreas in severely scalded rats.. One hundred sixty-two adult Wistar rats were equally randomized to sham burn group, burn group and burn with Exendin-4 treatment group. Rats were subjected to full skin thickness scald injuries (total body surface area: 50%) and were injected subcutaneously with Exendin-4 (4 μg/kg) twice daily. The histological changes of islets, the apoptosis of β cells, the amount of glucagon and insulin, and the concentration of plasma glucagon and insulin were observed; and the intraperitoneal glucose tolerance test was performed as well.. The islets and β cells were injured and the number of secretory granules decreased in the scalded rats, but less histopathological changes were seen in the rats treated with Exendin-4. The apoptosis index of treated rats was significantly lower than that of the scalded rats (p < 0.05). There was significant difference in β-cell density postinjury between the two groups (p < 0.05). More insulin and less glucagon in islets and plasma were found in the treated rats (p < 0.05), suggesting improved intraperitoneal glucose tolerance (p < 0.05) and fasting blood glucose (p < 0.05) in this group.. Based on our previous finding that GLP-1 could control hyperglycemia by increasing insulin secretion and inhibiting β-cell apoptosis in severe scald injuries, this study further confirmed that Exendin-4 could increase glycemic control following severe scald by preserving the histology of β cells in pancreatic islets and inhibiting their apoptosis.

Topics: Animals; Burns; Exenatide; Glucagon; Glucose Tolerance Test; Hyperglycemia; Insulin; Islets of Langerhans; Rats; Rats, Wistar

To observe the effect of exendin-4 on cardiomyocyte apoptosis in the early stage after scald injury in rats and explore the mechanisms.. Fifty-four healthy adult SD rats were randomly divided into normal control group (n=6), scald group (n=24) and scald with exendin-4 treatment group (n=24). In the latter two groups, the rats were subjected to 30% TBSA full-thickness scald burns on the back, and Parkland formula was used for determining the resuscitation fluid volume. In exendin-4 treatment group, the rats received intraperitoneal injection of 5 µg/kg exendin-4 after the scald. Apoptosis of the cardiomyocytes from the left ventricle was determined by TUNEL assay and the activity of caspase-3 in the myocardium was assessed.. In the scald group, the apoptotic index of the cardiomyocytes was increased at 6 h post-burn, reaching the peak level at 12 h, and maintained a significantly higher level than that in the normal control at 48 h (P<0.05). Myocardial caspase-3 activity in the scald group was increased at 6 h post-burn and reached the peak at 12 h, still maintaining a high levels at 24 h (P<0.05). In exendin-4 treatment group, the apoptotic index of the cardiomyocytes was significantly lower than that in the scald group at 6, 12, 24 and 48 h post-burn (P<0.05), and so was the caspase-3 activity at 6, 12 and 48 h (P<0.05). A significant positive correlation was found between the apoptotic index of the cardiomyocytes and myocardial caspase-3 activity in the rats (P<0.05).. Exdendin-4 can inhibit rat cardiomyocyte apoptosis early after scald injury possibly by suppressing caspase-3 activity in the myocardium.

Topics: Animals; Apoptosis; Burns; Caspase 3; Exenatide; Myocytes, Cardiac; Peptides; Rats; Rats, Sprague-Dawley; Venoms