Effects Of Glucagon-like Peptide-1 Analog Research Articles

Effects of glucagon-like peptide-1 analogs on prolactin: a randomized, double-blind, placebo-controlled crossover trial

Effects of glucagon-like peptide-1 analogs on prolactin: a randomized, double-blind, placebo-controlled crossover trial

Effects of Glucagon-Like Peptide-1 Analogs on Sexual Desire: A randomized, double-blind, placebo-controlled crossover trial

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Effects of Glucagon-Like-Peptide-1 Analogue Treatment in Genetic Obesity

Introduction: Obesity is highly prevalent, comes with serious health burden and is difficult to treat. In a minority, there is a genetic cause for the obesity. In these patients, therapy-resistant obesity is often observed despite intensive lifestyle treatment. Moreover, it is still unclear whether bariatric surgery is less successful in genetic obesity. Liraglutide is a Glucagon-Like-Peptide-1 (GLP-1) receptor agonist or GLP-1 analogue, showing positive effects on metabolic parameters, satiety and weight loss in lifestyle-induced obesity. We present our experiences of GLP-1 analogue treatment in patients with genetic obesity disorders. Methods: Adults with overweight or severe obesity and a molecularly proven genetic cause were treated with liraglutide 3,0 mg daily, in addition to ongoing intensive supportive lifestyle treatment. Anthropometrics, metabolic parameters, resting energy expenditure (REE), side effects, and subjectively reported satiety and quality of life were assessed. Results: Two patients with a heterozygous pathogenic melanocortin 4 recepter variant and two patients with 16p11.2 deletion syndrome, ranging in age between 21 and 32 years and in BMI between 28.1 and 55.7 kg/m2 at baseline, were treated. At end of follow-up, ranging between 33 weeks and 12 years, a mean change in BMI and waist circumference was observed of -5.7 ± 3.8 kg/m2 and -15.2 ± 21.1 cm, respectively. All patients reported better quality of life, three of them also reported improved satiety. Moreover, improvement of metabolic parameters was seen. No clear effect on REE was observed. Two patients experienced mild side effects, e.g. nausea and stomach pain, for a brief period. Conclusion: We here show beneficial effects of GLP-1 analogues on weight, metabolic parameters, and quality of life in four patients with genetic obesity. Satiety improved in three of the four patients. All patient achieved at least the clinically relevant 5–10% weight loss. Our findings suggest that GLP-1 analogue treatment might be an effective treatment option, in addition to a healthy lifestyle, for patients with genetic obesity.

Effects of Glucagon-like Peptide-1 Analogues and Dipeptidyl Peptidase-IV Inhibitors on Hepatic Oxidative Stress and Non-Alcoholic Steatohepatitis in Male Albino Rats

Background and Aim: Due to their importance in glucose metabolism and lipid accumulation, in addition to their prolonged action, overall safety and efficacy; glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase-IV inhibitors (DPP-IV inhibitors) are becoming one of the cornerstones for treatment of obesity, T2DM and NASH. This study aimed to distinguish between the effect of both Liraglutide (a long-acting GLP-1 analog) and Sitagliptin (a DPP-IV inhibitor) on nutritional steatohepatitis in adult male rats. Methods: A total of 40 male Sprague-Dawley rats were divided into four groups; the normal control group and the steatohepatitis placebo group; steatohepatitis liraglutide- treated and steatohepatitis sitagliptin-treated groups. Liver weight and functions, lipid profile, glycemic status, hepatic oxidant-antioxidant parameters and histopathological analysis were assessed in comparison with the control rats. Results: Treatment of steatohepatitis in rats with either liraglutide or sitagliptin significantly reduced the levels of blood sugar, insulin, HOMA-IR, hepatic MDA and nitric oxide (NO). Moreover, they significantly increased the antioxidant enzyme activities, improved the histopathological changes compared to the control rats, with slightly superior effects for Liraglutide. Conclusion: Treatment with either GLP-1 RAs or DPP-IV inhibitors improved the hepatocyte viability. Treatment improved the hepatic fatty deposition, attenuated the progression of hepatic fibrosis and reduced the hepatic oxidative stress in male steatohepatitis rats, with slightly superior effects for GLP-1 RAs.

P4476Cardiovascular benefits of GLP-1 (liraglutide) treatment in experimental arterial hypertension are mediated by the endothelial GLP-1 receptor

Abstract Objective The LEADER trial demonstrated that glucagon-like peptide-1 (GLP-1) analogs like Liraglutide (Lira) reduce the risk of cardiovascular events in T2DM, an effect beyond glycemic control. A detailed evaluation of the precise mechanisms underlying the cardiovascular protective effects of GLP-1 has been hampered by the fact that the GLP-1 receptor is expressed on different cell types in the vasculature including platelets, neuronal, endothelial and inflammatory cells. We used endothelial and myeloid cell-specific knockout mice of the GLP-1 receptor (GLP-1r) in an angiotensin-II (ATII)-induced model of hypertension. The aim of the recent study was to investigate the cardioprotective effects of GLP-1 in ATII-induced arterial hypertension and to characterize the cell-specific contribution of GLP-1r signaling. Methods Arterial hypertension was induced by s.c. ATII administration (0.5mg/kg/d; 7 days) in WT (C57/BL6J) as well as endothelial and myeloid cell-specific GLP-1r knockout mice (Cdh5crexGLP-1rfl/fl and LysMcrexGLP-1rfl/fl mice). Animals were treated with Lira (2x30μg/d; 7 days). Blood pressure was measured by tail-cuff. Vascular function was tested by isometric tension recording. Aortic and cardiac tissue was used for Western blotting, qRT-PCR, FACS, IHC and HPLC to determine the extent of inflammation, oxidative stress and fibrosis. ELISA was used to determine GLP-1 and insulin levels in plasma. Results Endogenous GLP-1 (7–36 and 9–36) was reduced in hypertensive animals. Lira ameliorated blood pressure and improved endothelial dysfunction, vascular oxidative stress and inflammation caused by ATII, in both WT and myeloid cell-specific GLP-1r knockout mice. Hypertension led to infiltration of inflammatory monocytes (Ly6G-Ly6Chigh) and neutrophils (Ly6G+Ly6C+) into the vascular wall, which was prevented by Lira. In accordance, Lira suppressed vascular oxidative stress and mRNA expression of iNOS, CD11b and Nox2. Endothelial NO synthase (eNOS) was S-glutathionylated with ATII treatment indicating uncoupled eNOS. Thus, aortic NO levels were reduced, all of which was restored by Lira. Furthermore, vascular fibrosis and cardiac hypertrophy were tremendously reduced by GLP-1. Interestingly, all of these beneficial cardiovascular effects of GLP-1 were abolished in endothelial cell-specific GLP-1r knockout mice. Conclusion We show that Lira reduces blood pressure and improves vascular function, fibrosis and cardiac hypertrophy in experimental arterial hypertension in mice. Mechanistically, Lira prevents the infiltration of inflammatory cells to the vascular wall, leading to reduced oxidative stress and improved NO bioavailability. Beneficial effects of GLP-1 are mediated by the GLP-1r expressed on endothelial and not myeloid cells. With the present study we provide a mechanistic approach to explain the cardioprotective effects of GLP-1 analogs like Lira, for which the endothelial GLP-1 receptor is indispensable. Acknowledgement/Funding Deutsche Forschungsgesellschaft (DFG), Bundesministerium für Bildung und Forschung (BMBF)

Liraglutide Exerts Potential Anti-inflammatory Effect in Type 1 Diabetes by Inhibiting IFN-γ Production via Suppressing JAK-STAT Pathway

Type 1 diabetes is a T cell-mediated autoimmune disease. Interferon γ plays a critical role in the pathogenesis of type 1 diabetes. Signal transducer and activator of transcription transduces type I interferon cytokines in T cells, leading to Th1 cell differentiation and production of interferon γ. Recent studies suggest that liraglutide reduces the plasma concentration of C-reative protein in patients with type 1 diabetes and protects β cell function in the non-obese diabetic mouse. The study aimed to explore the effect of glucagon-like peptide-1 analogue on interferon γ production and the underlying signaling pathway in vitro. Jurkat E6-1 cells were intervened with different concentrations of glucose and liraglutide during different time periods. Protein was extracted from Jurkat E6-1 cells. The target proteins (total and activated Janus kinase 2, signal transducers and activators of transcription 4 and interferon γ) were detected by Western blot. Glucose stimulates interferon γ expression and activates Janus kinase 2/signal transducers and activators of transcription 4 signaling pathway in Jurkat E6-1 cells in a concentration and timedependent manner. Under high glucose condition, liraglutide inhibits interferon γ expression and Janus kinase 2/signal transducers and activators of transcription 4 signaling pathway in Jurkat E6-1 cells in a concentration and time-dependent manner. The Janus kinase responsible for liraglutide-inhibited signal transducers and activators of transcription 4 phosphorylation is Janus kinase 2, which is also required for the interferon γ induction. Finally, we demonstrated that under high glucose condition, liraglutide inhibits interferon γ expression via Janus kinase 2/signal transducers and activators of transcription 4 signaling pathway in Jurkat E6-1 cells. Liraglutide inhibits Jurkat E6-1 cells to produce interferon γ via the Janus kinase/signal transducers and activators of transcription signaling pathway under high glucose condition, which implies its potential in the immunoregulatory effect of type 1 diabetes.

Effects of glucagon-like peptide 1 analogs in combination with insulin on myocardial infarct size in rats with type 2 diabetes mellitus.

AIMTo evaluate the effects of glucagon-like peptide-1 analogs (GLP-1a) combined with insulin on myocardial ischemia-reperfusion injury in diabetic rats.METHODSType 2 diabetes mellitus (T2DM) was induced in male Wistar rats with streptozotocin (65 mg/kg) and verified using an oral glucose tolerance test. After anesthesia, the left coronary artery was occluded for 40 min followed by 80 min reperfusion. Blood glucose level was measured during surgery. Rats were randomized into six groups as follows: (1) control rats; (2) insulin (0.1 U/kg) treated rats prior to ischemia; (3) insulin (0.1 U/kg) treated rats at reperfusion; (4) GLP-1a (140 mg/kg) treated rats prior to ischemia; (5) GLP-1a (140 mg/kg) treated rats at reperfusion; and (6) rats treated with GLP-1a (140 mg/kg) prior to ischemia plus insulin (0.1 U/kg) at reperfusion. Myocardial area at risk and infarct size was measured planimetrically using Evans blue and triphenyltetrazolium chloride staining, respectively.RESULTSThere was no significant difference in the myocardial area at risk among groups. Insulin treatment before ischemia resulted in a significant increase in infarct size (34.7% ± 3.4% vs 18.6% ± 3.1% in the control rats, P < 0.05). Post-ischemic administration of insulin or GLP-1a had no effect on infarct size. However, pre-ischemic administration of GLP-1a reduced infarct size to 12% ± 2.2% (P < 0.05). The maximal infarct size reduction was observed in the group treated with GLP-1a prior to ischemia and insulin at reperfusion (8% ± 1.6%, P < 0.05 vs the control and GLP-1a alone treated groups).CONCLUSIONGLP-1a pre-administration results in myocardial infarct size reduction in rats with T2DM. These effects are maximal in rats treated with GLP-1a pre-ischemia plus insulin at reperfusion.

Effect of glucagon-like peptide-1 analogue; Exendin-4, on cognitive functions in type 2 diabetes mellitus; possible modulation of brain derived neurotrophic factor and brain Visfatin

BackgroundBrain derived neurotrophic factor (BDNF) is one of the most essential neurotrophic factors in the brain. BDNF is involved in learning, memory and locomotion suggesting it as a target in type 2 diabetes mellitus (T2DM) associated cognitive changes. Visfatin; an adipokine discovered to be expressed in the brain; was found to have multiple effects including its participation in keeping energy supply to the cell and is consequentially involved in cell survival. Its role in cognitive functions in T2DM was not studied before. Recent studies point to the possible neuro-protective mechanisms of glucagon-like peptide 1 analogue: Exendin-4 (Ex-4) in many cognitive disorders, but whether BDNF or Visfatin are involved or not in its neuro-protective mechanisms; is still unknown. Aimsto study the changes in cognitive functions in T2DM, either not treated or treated with Glucagon-like peptide 1 (GLP-1) analogue: Ex-4, and to identify the possible underlying mechanisms of these changes and whether BDNF and brain Visfatin are involved. MethodsA total of 36 adult male wistar albino rats were divided into 4 groups; Control, Exendin-4 control, Diabetic and Exendin-4 treated groups. At the end of the study, Y-maze and open field tests were done the day before scarification to assess spatial working memory and locomotion, respectively. Fasting glucose and insulin, lipid profile and tumor necrosis factor- alpha (TNF-α) were measured in the serum. Homeostasis model assessment insulin resistance was calculated. In the brain tissue, malondialdehyde (MDA) level, gene expression and protein levels of BDNF and Visfatin, area of degenerated neurons, area of glial cells and area % of synaptophysin immunoexpression were assessed. ResultsCompared with the control, the untreated diabetic rats showed insulin resistance, dyslipidemia and elevation of serum TNF-α. The brain tissue showed down-regulation of BDNF gene expression and reduction of its protein level, up-regulation of Visfatin gene expression and elevation of its protein level, increase in MDA, area of degenerated neurons and area of glial cells and reduction in area % of synaptophysin immunoexpression. These changes were paralleled with significant deterioration in spatial working memory and locomotion. Treatment of diabetic rats with Ex-4 reversed all these changes. ConclusionT2DM has a negative impact on cognitive functions through different pathological and subcellular mechanisms. The current study provides evidence for involvement of BDNF and brain Visfatin in T2DM- associated cognitive dysfunction. BDNF and brain Visfatin were also found to contribute to the neuro-protective effect of Ex-4 via modulation of inflammation, oxidative stress, neuro-degeneration and synaptic function.

The effects of GLP-1 analogues on pre-diabetes of the children.

The aim of the study was to evaluate the clinical efficacy of glucagon-like peptide-1 (GLP-1) analogues in children of pre-diabetes to delay or reverse the development of pre-diabetes into the state of diabetes by early intervention. Prospective and randomized controlled clinical trials were performed in 42 cases of newly diagnosed pre-diabetes in children. The sample size was randomly divided into the two groups. The first group included 21 subjects comprising the lifestyle intervention group, i.e., control group, and the second group included 21 subjects comprising the lifestyle intervention+GLP-1 analogues liraglutide group, i.e., observation group. Interventions carried out lasted 3 months. A review of intervention was carried out at 1 month and after 3 months. Medical examinations were carried out at the the time following diagnosis with pre-diabetes and after the intervention of 3 months. The medical test examinations included the fasting blood glucose (FPG), 2-hour postprandial blood glucose (2hPG), detection of glycated hemoglobin A1c (HbA1C), total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), body mass index (BMI), insulin resistance (IR) and the islet cell functions. After 1 month of intervention, the observation group exhibited a better control on FPG and 2hPG compared with the control group (P<0.05). After 3 months of the intervention, FPG and 2hPG levels of the observation group were significantly lower than those of the control group (P<0.01). The levels of HbA1C, TC, TG, LDL-C, HDL-C, and BMI of the observation group were statistically better controlled, when compared with the control group after the intervention of 3 months. The IR index of the observation group was significantly decreased compared to that of the control group (P<0.05) and the islet function index of the β-cell of the observation group showed statistically higher values than that of the control group (P<0.05). In conclusion, GLP-1 analogues are a better regulator of blood sugar levels, effectively improve lipid profile, body mass, IR and islet β-cell function. Furthermore, GLP-1 analogues opens up a new way to intervene pre-diabetes in children.

Protective Effects of Glucagon-Like Peptide-1 Analog on Renal Tubular Injury in Mice on High-Fat Diet

Aims: The study aimed to investigate the renoprotective effect of glucagon-like peptide-1 (GLP-1) against renal tubular injury in C57BL/6 mice induced by a high-fat diet (HFD). Methods: Twenty C57BL/6 mice were fed HFD for 12 weeks. Ten of these mice were treated with GLP-1 at 200 µg/kg subcutaneously twice daily for 4 weeks (HFDG group), and the other ten mice received vehicle only (HFD group). Ten mice fed standard rodent chow served as controls (Con group). Body weight, kidney weight, food intake, and systolic blood pressure were measured. The expression of endoplasmic reticulum stress (ERS) markers (BIP, p-eIF2α, ATF4, and CHOP) and apoptosis in the kidney were examined utilizing western blotting, immunohistochemistry and TUNEL, respectively. Angiotensin II and angiotensin II type 1 receptor (AT1R) were examined by ELISA. Human proximal tubule epithelial cells (HK2) were treated with GLP-1(150 nM) followed by treatment with palmitic acid (500 nM [PA]) for 24 h. HK2 cells treated with BSA were used as controls. The protein levels of ERS markers, apoptosis-associated protein, and AT1R were measured by western blotting. Results: Increase of body weight, food intake, and systolic blood pressure was less pronounced in GLP-1 treated HFDG mice compared to HFD mice. The levels of ERS markers (BIP, p-eIF2α, ATF4, and CHOP) and apoptosis decreased following GLP-1 treatment in vivo and in vitro (p<0.05). Increased AT1R induced by HFD and PA were blocked with GLP-1 treatment. In contrast, the level of angiotensin II after GLP-1 treatment was not significantly different between the HFD and HFDG mice. Conclusion: The study indicated that saturated fatty acids induced ERS and apoptosis in the kidney and increased AT1R expression. GLP-1 treatment exerted renoprotective effects against saturated fatty acid-induced kidney tubular cell ERS and apoptosis together with inhibition of AT1R expression in vivo and in vitro.

Protective effect of glucagon-like peptide-1 analogue on cardiomyocytes injury induced by hypoxia/reoxygenation

To investigate the effect of glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide on hypoxia/reoxygenation (H/R)-induced cardiomyocytes death under high glucose condition and the potential mechanisms. H9C2 cardiomyocytes were divided into 4 groups: normal glucose (N, 5 mmol/L), high glucose (G, 20 mmol/L), high glucose in combination with liraglutide (L, 100 nmol/L), high glucose in combination with liraglutide and wortmannin (W, 25 nmol/L). The apoptosis of H9C2 was detected by TUNEL assay. Nitric oxide synthetase(eNOS), nitric oxide (NO) and reactive oxygen(ROS) in supernatants were measured by enzymatic analysis. p-PI3K, PI3K, p-Akt, Akt, Bcl-2, caspase-3 were examined by western blotting. Compared with cells in N group, the apoptosis of H9C2 cells induced by H/R was markedly increased [(15.79±3.92)% vs (9.74±1.14)%, P=0.028] in G group. The same was true for ROS [(489.63±21.01) U/ml vs (338.50±43.60) U/ml, P<0.001] and caspase-3 levels (1.87±0.03 vs 1.15±0.04, P<0.001), but not for Bcl-2 protein expression (1.79±0.06 vs 1.89±0.03, P=0.047). Pretreatment of cells with liraglutide (100 nmol/L) prevented the cell death induced by high glucose and H/R together with decrease of ROS and caspase-3 levels and increase of Bcl-1 expression. Moreover, treatment of cells with liraglutide also significantly increased phosphorylation of PI3K and Akt (p-PI3K/PI3K: 0.87±0.07 vs 0.59±0.09, P=0.002; p-Akt/Akt: 0.34±0.01 vs 0.08±0.01, P<0.001), eNOS[(41.29±0.56)μmpl/L vs (37.20±0.52)μmpl/L, P<0.001)and NO [(31.24±0.40)μmpl/L vs (26.66±0.53)μmpl/L, P<0.001)levels. Furthermore, addition of PI3K/Akt inhibitor wortmanin markedly inhibited the expression of p-PI3K/PI3K, p-Akt/Akt, reversed the changes of eNOS, NO, caspase-3 and Bcl-2 by liraglutide, and abolished the protective effect of liraglutide on cell apoptosis. GLP-1 receptor agonist liraglutide treatment could alleviate cardiomyocytes apoptosis induced by high glucose and H/R through the activation of PI3K-Akt-eNOS-NO signaling pathway and inhibition of oxidative stress.

Exenatide enhances cognitive performance and upregulates neurotrophic factor gene expression levels in diabetic mice.

Exenatide is a potent and selective agonist for the GLP-1 (glucagon-like peptide-1) receptor. Recent studies are focused on the effects of GLP-1 analogues on hippocampal neurogenesis, cognition, learning and memory functions. The aim of this study was to assess the effects of chronic exenatide treatment (0.1 μg/kg, s.c, twice daily for 2 weeks) on spatial memory functions by using the modified elevated plus maze (mEPM) test and emotional memory functions by using the passive avoidance (PA) test in streptozotocin/nicotinamide (STZ-NA)-induced diabetic mice. As the genes involved in neurite remodelling are among the primary targets of regulation, the effects of diabetes and chronic administration of exenatide on brain-derived neurotrophic factor (BDNF) and cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) messenger ribonucleic acid (mRNA) levels in the hippocampus of mice were also determined using quantitative real-time polymerase chain reaction (RT-PCR). This study revealed that in the mEPM and PA tests, type-2 diabetes-induced mice exhibited significant impairment of learning and memory which were ameliorated by GLP-1 receptor agonist exenatide. Quantitative RT-PCR revealed that CREB and BDNF gene expression levels were downregulated in diabetic mice, and these alterations were increased by exenatide treatment. Since, exenatide improves cognitive ability in STZ/NA-induced diabetic mice and activates molecular mechanisms of memory storage in response to a learning experience, it may be a candidate for alleviation of mood and cognitive disorder.

Fatty liver-induced changes in stereotypic behavior in rats and effects of glucagon-like peptide-1 analog on stereotypy

Although understanding the relation between psychotic behavior and immune abnormalities has been the focus of research for many years, it remains to be elucidated whether the changes in cytokine levels are part of etiology or a result of the stress associated with the disorder. In accordance with previous studies on changes in cytokine levels due to metabolic changes and psychosis, we hypothesized that fatty liver may potentiate apomorphine-induced stereotypy in a rodent model and that a synthetic glucagon-like peptide-1 analog exenatide would ameliorate this effect. In this study, 18 male Sprague Dawley albino mature rats were used. We induced hepatosteatosis in these rats by feeding them with 30% fructose dissolved in drinking water for 8 weeks. The animals were divided into three groups, namely, the normal group, the intracerebroventricular (ICV) exenatide group, and the ICV NaCl group. Apomorphine-induced stereotypic behavior test was performed in all groups and the liver was removed for histopathological examination after all the rats were euthanized. In the nonalcoholic fatty liver (NAFL) group, stereotypy scores were significantly increased compared with the control group rats (p < 0.00001). A significant decrease in stereotypy scores were observed in the ICV exenatide group with NAFL when compared with the ICV saline group with NAFL (p < 0.005). In addition, brain malondialdehyde and tumor necrosis factor-α levels decreased in the ICV exenatide group. The results of this study showed that fatty liver enhances the effect of apomorphine on stereotypy, which was reversed by exenatide possibly by antioxidant and anti-inflammatory effects.

PSCs and GLP-1R: occurrence in normal pancreas, acute/chronic pancreatitis and effect of their activation by a GLP-1R agonist

There is increasing concern about the development of pancreatitis in patients with diabetes mellitus who received long-term glucagon-like peptide-1 (GLP-1) analog treatment. Its pathogenesis is unknown. The effects of GLP-1 agonists on pancreatic endocrine cells are well studied; however, there is little information on effects on other pancreatic tissues that might be involved in inflammatory processes. Pancreatic stellate cells (PSCs) can have an important role in pancreatitis, secreting various inflammatory cytokines/chemokines, as well as collagen. In this study, we investigated GLP-1R occurrence in normal pancreas, acute pancreatitis (AP)/chronic pancreatitis (CP), and the effects of GLP-1 analog on normal PSCs, their ability to stimulate inflammatory mediator secretion or proliferation. GLP-1 receptor (GLP-1R) expression/localization in normal pancreas and pancreatitis (AP/CP) tissues were evaluated with histological/immunohistochemical analysis. PSCs were isolated from male Wistar rats. GLP-1R expression and effects of GLP-1 analog on activated PSCs was examined with real-time PCR, MTS assays and western blotting. In normal pancreas, pancreatic β cells expressed GLP-1R, with only low expression in acinar cells, whereas in AP or CP, acinar cells, ductal cells and activated PSCs expressed GLP-1R. With activation of normal PSCs, GLP-1R is markedly increased, as is multiple other incretin-related receptors. The GLP-1 analog, liraglutide, did not induce inflammatory genes expression in activated PSCs, but induced proliferation. Liraglutide activated multiple signaling cascades in PSCs, and the extracellular signal-regulated kinase pathway mediated the PSCs proliferation. GLP-1Rs are expressed in normal pancreas and there is marked enhanced expression in AP/CP. GLP-1-agonist induced cell proliferation of activated PSCs without increasing release of inflammatory mediators. These results suggest chronic treatment with GLP-1R agonists could lead to proliferation/chronic activation of PSCs, which may lead to important effects in the pancreas.

Glucagon-Like Peptide-1 Analogues and Anxiety and Abnormal Eating Behaviours in Type 2 Diabetes: A Case Report

Psychological and psychiatric problems are common in diabetes. Glucagon-like peptide-1 (GLP-1) analogues are effective in the management of type 2 diabetes as second or third-line treatment, and are thought to have a central effect on appetite regulation. There is little evidence regarding the effect of GLP-1 analogues on anxiety. This is a case report of a patient with type 2 diabetes, obesity, anxiety and disordered eating who was commenced on Liraglutide, a glucagon-like peptide-1 (GLP-1) analogue. This patient reported, in addition to improved glycaemic control, a marked improvement in the anxiety which had been present all her life, and had driven her binge eating. This anxiety had persisted despite anxiolytic medications and cognitive behaviour therapy. Any medication which could have a positive effect on anxiety and diabetes both would be valuable. Glucagon like peptide analogues may have a role in the management of co-morbid anxiety and type 2 diabetes. Further research is required into this area.

Effects of Glucagon-Like Peptide-1 Analog on the Early Phase of Revascularization of Transplanted Pancreatic Islets at Subcutaneous Site

Effects of Glucagon-Like Peptide-1 Analog on the Early Phase of Revascularization of Transplanted Pancreatic Islets at Subcutaneous Site

Synthesis and Bioactivity Evaluation of Dipeptidyl Peptidase IV Resistant Glucagon-like Peptide-1 Analogues

Glucagon-like peptide -1 (GLP-1) is an incretin hormone displaying glucose-dependent stimulation of insulin secretion and trophic effects on the pancreatic β-cells. However, GLP-1 is rapidly degraded to GLP-1(9-36) by dipeptidyl peptidase-IV (DPP-IV), which removes the N-terminal dipeptide His(7)-Ala(8). The rapid inactivation of GLP-1 in the blood circulation limits its clinical application. Hence, we replaced the enzymatic hydrolyzation position Ala(8) with other natural amino acids. The GLP-1 analogues were synthesized rapidly and efficiently under microwave irradiation, using Fmoc/tBu orthogonal protection strategy. Studies on blood-glucose-lowering effect of GLP-1 analogues in vivo were undertaken using 10-week-old male Kunming mice. The metabolic stability was tested by incubation with dipeptidyl peptidase-IV (DPP-IV). Generally, Xaa(8)-GLP-1 analogues exhibit resistance to DPP-IV degradation in vitro and stronger hypoglycemic effect than GLP-1. This may help to understand the structure-activity relationship of GLP-1 analogues.