Liraglutide-treated Groups Research Articles

Antinociceptive Behavior, Glutamine/Glutamate, and Neopterin in Early-Stage Streptozotocin-Induced Diabetic Neuropathy in Liraglutide-Treated Mice under a Standard or Enriched Environment

Diabetic neuropathy (DN) is a common complication of long-lasting type 1 and type 2 diabetes, with no curative treatment available. Here, we tested the effect of the incretin mimetic liraglutide in DN in mice with early-stage type 1 diabetes bred in a standard laboratory or enriched environment. With a single i.p. injection of streptozotocin 150 mg/kg, we induced murine diabetes. Liraglutide (0.4 mg/kg once daily, i.p. for ten days since the eighth post-streptozotocin day) failed to decrease the glycemia in the diabetic mice; however, it alleviated their antinociceptive behavior, as tested with formalin. The second phase of the formalin test had significantly lower results in liraglutide-treated mice reared in the enriched environment vs. liraglutide-treated mice under standard conditions [2.00 (0.00–11.00) vs. 29.00 (2.25–41.50) s, p = 0.016]. Liraglutide treatment, however, decreased the threshold of reactivity in the von Fray test. A significantly higher neopterin level was demonstrated in the diabetic control group compared to treatment-naïve controls and the liraglutide-treated diabetic mice (p < 0.001). The glutamine/glutamate ratio in both liraglutide-treated groups, either reared under standard conditions (p = 0.003) or an enriched environment (p = 0.002), was significantly higher than in the diabetic controls. This study demonstrates an early liraglutide effect on pain sensation in two streptozotocin-induced diabetes mouse models by reducing some inflammatory and oxidative stress parameters.

Evaluating the effectiveness and safety of empagliflozin versus liraglutide in managing diabetic dyslipidemia: An observational study

Background: Diabetic dyslipidemia poses a significant risk factor for cardiovascular complications in patients with diabetes mellitus. Empagliflozin and liraglutide are two commonly used medications in diabetes management, yet their comparative efficacy and safety in treating diabetic dyslipidemia remain under-explored. Aims and Objectives: This study aimed to assess the effectiveness and safety of Empagliflozin versus liraglutide in managing diabetic dyslipidemia. Materials and Methods: The study enrolled 100 participants with diabetes and dyslipidemia, divided equally into empagliflozin and liraglutide treatment groups. Baseline characteristics, including age, gender distribution, ethnicity, and duration of diabetes, were assessed and compared between the groups. Lipid profiles, encompassing total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides, were evaluated at baseline and after 6 months of treatment. Safety outcomes, such as the occurrence of mild gastrointestinal symptoms, hypoglycemia, and serious adverse events, were also monitored. Results: Both treatment groups exhibited comparable baseline characteristics. Following 6 months of treatment, both empagliflozin and liraglutide demonstrated significant improvements in lipid profiles. Reductions in total cholesterol, LDL cholesterol, and triglycerides, along with increases in HDL cholesterol, were observed in both groups. Moreover, there were no significant differences in the occurrence of adverse events between the two treatment groups, indicating similar safety profiles. Conclusion: This study provides evidence supporting the effectiveness and safety of empagliflozin and liraglutide in managing diabetic dyslipidemia. These findings highlight the potential of both medications as viable therapeutic options for patients with diabetes and dyslipidemia.

Liraglutide Attenuates Aortic Valve Calcification in a High-Cholesterol-Diet-Induced Experimental Calcific Aortic Valve Disease Model in Apolipoprotein E-Deficient Mice.

Calcific aortic valve disease (CAVD) is a significant cause of morbidity and mortality among elderly people. However, no effective medications have been approved to slow or prevent the progression of CAVD. Here, we examined the effect of liraglutide on aortic valve stenosis. Male Apoe-/- mice were fed with a high-cholesterol diet for 24 weeks to generate an experimental CAVD model and randomly assigned to a liraglutide treatment group or control group. Echocardiography and immunohistological analyses were performed to examine the aortic valve function and morphology, fibrosis, and calcium deposition. Plasma Glucagon-like peptide-1 (GLP-1) levels and inflammatory contents were measured via ELISA, FACS, and immunofluorescence. RNA sequencing (RNA-seq) was used to identify liraglutide-affected pathways and processes. Plasma GLP-1 levels were reduced in the CAVD model, and liraglutide treatment significantly improved aortic valve calcification and functions and attenuated inflammation. RNA-seq showed that liraglutide affects multiple myofibroblastic and osteogenic differentiations or inflammation-associated biological states or processes in the aortic valve. Those liraglutide-mediated beneficial effects were associated with increased GLP-1 receptor (GLP-1R) expression. Liraglutide blocks aortic valve calcification and may serve as a potential therapeutic drug for CAVD treatment.

Efficacy and safety of liraglutide in patients with type 2 diabetes mellitus and severe obstructive sleep apnea

ObjectivesTo observe the efficacy and side effects of liraglutide in the treatment of type 2 diabetes mellitus (T2DM) patients with severe obstructive sleep apnea (OSA).MethodsThe study conducted in an outpatient setting was a two-center, prospective randomized controlled study. T2DM patients with severe OSA were randomized to the control group (continuous positive airway pressure [CPAP] and drug treatment without liraglutide) or the liraglutide group (CPAP and drug treatment including liraglutide). Demographic and clinical characteristics, sleep-disordered breathing indices, cardiac function indices, and side effects were evaluated and compared between the two groups before and after 3 months.ResultsOf 90 patients, 45 were randomized to the intervention arm (with liraglutide) and 45 to the control arm (without liraglutide). One patient in the liraglutide group dropped out of the study on day 8 after enrollment due to obvious gastrointestinal symptoms. No significant differences were found between the two groups in baseline demographics, clinical characteristics, cardiac function indicators, or sleep disorder respiratory indices (P > 0.05). After 3 months, the body mass index (BMI), apnea hypopnea index (AHI), and mean systolic blood pressure in the liraglutide treatment group were significantly lower than those in the control group (P < 0.05). The minimum oxygen saturation was significantly higher in the liraglutide group compared with that in the control group after 3 months of follow-up (P < 0.05). No difference was found between the two groups in the summary of side effects (P > 0.05).ConclusionsLiraglutide combined with CPAP can effectively reduce BMI, lower mean systolic blood pressure, and improve AHI scores and hypoxia in T2DM patients with severe OSA. Liraglutide did not increase side effects.

Liraglutide Inhibits Osteoclastogenesis and Improves Bone Loss by Downregulating Trem2 in Female Type 1 Diabetic Mice: Findings From Transcriptomics.

BackgroundThe mechanisms of bone fragility in type 1 diabetes (T1D) are not fully understood. Whether glucagon-like peptide-1 receptor (GLP-1R) agonists could improve bone quality in T1D context also remains elusive.AimsWe aimed to explore the possible mechanisms of bone loss in T1D and clarify whether liraglutide has effects on bone quality of T1D mice using transcriptomics.MethodsFemale streptozotocin-induced diabetic C57BL/6J mice were randomly divided into four groups and received the following treatments daily for 8 weeks: saline as controls, insulin, liraglutide, and liraglutide combined with insulin. These groups were also compared with non-STZ-treated normal glucose tolerance (NGT) group. Trunk blood and bone tissues were collected for analysis. Three tibia from each of the NGT, saline-treated, and liraglutide-treated groups were randomly selected for transcriptomics.ResultsCompared with NGT mice, saline-treated T1D mice manifested markedly hyperglycemia and weight loss, and micro-CT revealed significantly lower bone mineral density (BMD) and deficient microarchitectures in tibias. Eight weeks of treatment with liraglutide alone or combined with insulin rescued the decreased BMD and partly corrected the compromised trabecular microarchitectures. Transcriptomics analysis showed there were 789 differentially expressed genes mainly mapped to osteoclastogenesis and inflammation pathways. The RT-qPCR verified that the gene expression of Trem2, Nfatc1, Trap, and Ctsk were significantly increased in the tibia of T1D compared with those in the NGT group. Liraglutide treatment alone or combined with insulin could effectively suppress osteoclastogenesis by downregulating the gene expression of Trem2, Nfatc1, Ctsk, and Trap.ConclusionsTaken together, increased osteoclastogenesis with upregulated expression of Trem2 played an important role in bone loss of T1D mice. Liraglutide provided protective effects on bone loss in T1D mice by suppressing osteoclastogenesis.

Liraglutide inhibits the progression of prediabetes in rats by reducing Raf-1 kinase inhibitor protein.

BackgroundThe cleavage product of Raf-1 kinase inhibitor protein (RKIP), hippocampal cholinergic neurostimulating peptide (HCNP) is involved in the promotion of insulin secretion. Studies have shown that liraglutide can inhibit the progression of prediabetes. This study aims to investigate whether the above effects of liraglutide are related to RKIP and HCNP.MethodsInsulin-1 (INS-1) cells were divided into control group (CON), HCNP group, and HCNP + darifenacin group (H-DAR). The three groups were cultured with Roswell Park Memorial Institute (RPMI) 1640, synthetic HCNP (50 pg/mL) and RPMI 1640, and HCNP + RPMI 1640 + darifenacin respectively. Subsequently, twelve 12- to 14-week-old Otsuka Long-Evans Tokushima Fatty (OLETF) rats were randomly divided into 2 groups: the placebo group (PBO) and the liraglutide treatment group (LIRA). Six Long Evans Tokushima Otsuka (LETO) rats were used as the control group (CON). The LIRA group was given liraglutide 200 µg/kg intraperitoneally twice a day. After 12 weeks, body weight, fasting blood glucose, 2 hours postprandial blood glucose, and insulin resistance index were recorded. Western blot was used to detect expression level of C-RKIP, N-RKIP, and extracellular signal-regulated kinase of phosphorylation (p-ERK). Real-time quantitative polymerase chain reaction (qRT-PCR) to detect pancreatic tissue choline acetyltransferase (ChAT) and M3 cholinergic receptor (M3R) gene expression levels.ResultsAt glucose concentrations of 5.6 and 16.7 mmol/L, the insulin content in the HCNP group was higher than that in the CON and H-DAR groups (all P<0.01). The body weight and fasting serum insulin (FINS) of rats in the PBO group were higher than those in the LIRA group and the CON group (P<0.01). The relative content of C-RKIP protein in the PBO group was higher than that in the LIRA and CON groups (P<0.01). The relative content of N-RKIP protein and p-ERK protein was lower than that in the LIRA and CON group (P<0.05 and P<0.01, respectively). ChAT and M3R gene expression levels in PBO group were lower than those in LIRA and CON group (P<0.01).ConclusionsLiraglutide promotes the production of HCNP, can increase ChAT activity, activate M3R, and further promote the secretion of insulin.

A Review: Comparison of Efficacy of Liraglutide Versus Sitagliptin add-on-to Metformin in Type 2 Diabetes Mellitus patients

Background: The aim of this review is to compare the efficacy of liraglutide versus sitagliptin add-on-to metformin in patients with Type 2 Diabetes Mellitus and inadequate glycemic control for rational use of drugs. Methods: We searched for randomized controlled trials (RCT) in MEDLINE, Web of science, PubMed, Cochrane library, CNKI, and Wanfang database and extracted data from all randomized controlled trials (RCTs) up to July 11, 2019 of liraglutide versus sitagliptin given in combination with metformin. RCTs were selected only if they were RCTs comparing DPP-4 inhibitor (sitagliptin) monotherapy to metformin monotherapy with the GLP-1 Receptor Agonists (liraglutide), duration of treatment was ≥26 weeks and reported data on hemoglobin A1c (HbA1c) change, fasting plasma glucose (FPG) change, Odds ratio (OR), mean difference (MD), 95% confidence interval are used to analyze the outcomes. Results: A total of 2,257 patients from 6 RCTs were included in the study. When compared with sitagliptin (100mg) in combination with metformin group, the group of patients treated with liraglutide1.2mg and 1.8mg and metformin, produced greater reduction in HbA1c, FBG. (95% CI). The group of patients with 1.8mg liraglutide had significant weight loss. The incidence of nausea, hypoglycemic episodes, gastrointestinal problems was higher than the sitagliptin with metformin groups. Conclusions: The results of this study indicated that the liraglutide – metformin combination therapy could significantly lower the HbA1c level and increased reduction of body weight. ADRs such as gastrointestinal problems, hypoglycemic episodes were common in liraglutide treatment group.

Effect of liraglutide on endoplasmic reticulum stress in the renal tissue of type 2 diabetic rats.

BACKGROUNDLiraglutide is a glucagon-like peptide 1 receptor agonist analog that has been found to have a therapeutic effect in diabetes. In addition to its ability to treat diabetes, liraglutide has beneficial effects on the cardiovascular system and kidney as well as other beneficial effects, but its specific mechanism is not clear. In this study, a rat model of type 2 diabetes was established by administration of a high-sugar, high-fat diet combined with low-dose streptozotocin (STZ) to observe the effect of liraglutide on the kidneys of type 2 diabetes rats and the possible underlying mechanisms.AIMTo explore whether liraglutide has a protective effect on type 2 diabetic rat kidneys and the underlying mechanisms.METHODSEight-week-old male Sprague-Dawley rats were randomly divided into a control group, model group, low-dose liraglutide group, and high-dose liraglutide group. Control rats were fed a standard diet, while model group and intervention group rats were fed high-sugar, high-fat feed for 1 mo and then intraperitoneally injected with 40 mg/kg STZ to induce type 2 diabetes. The low-dose and high-dose intervention groups received 100 µg/kg and 200 µg/kg liraglutide, respectively, once daily by subcutaneous injection. The control and model groups were given an equivalent volume of physiological saline for 8 wk. Pathological changes in renal tissues were observed by hematoxylin and eosin staining and periodic acid-Schiff staining, and GRP78 and caspase-12 expression was detected by Western blot and reverse transcription-polymerase chain reaction (RT-PCR).RESULTSWestern blot analysis showed that GRP78 and caspase-12 protein expression in kidney tissue was significantly higher in model rats than in normal rats and lower in the liraglutide-treated groups than in the model group, with a more significant decrease being observed in the high-dose group than in the low-dose group. RT-PCR showed that the mRNA expression of GRP78 and caspase-12 was higher in model rats than in control rats and lower in the liraglutide-treated groups than in the model group, with the high-dose group exhibiting a more significant decrease than the low-dose group.CONCLUSIONLiraglutide may delay the progression of diabetic nephropathy by reducing endoplasmic reticulum stress and protect the kidneys in a dose-dependent manner.

Glucagon-Like Peptide-1 Receptor Agonist Liraglutide Ameliorates the Development of Periodontitis

Periodontitis is one of the diabetic complications due to its high morbidity and severity in patients with diabetes. The prevention of periodontitis is especially important in diabetic patients because the relationship between diabetes and periodontitis is bidirectional. Here, we evaluated the impacts of glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide on the amelioration of periodontitis. Five-wk-old Male Sprague–Dawley (SD) rats (n = 30) were divided into 3 groups: normal, periodontitis, and periodontitis with liraglutide treatment groups. Periodontitis was induced by ligature around the maxillary second molar in SD rats. Half of the rats were administered liraglutide for 2 weeks. Periodontitis was evaluated by histological staining, gene expressions of inflammatory cytokines in gingiva, and microcomputed tomography. Periodontitis increased inflammatory cell infiltration, macrophage accumulation, and gene expressions of tumor necrosis factor-α and inducible nitric oxide synthase in the gingiva, all of which were ameliorated by liraglutide. Liraglutide decreased M1 macrophages but did not affect M2 macrophages in periodontitis. Moreover, ligature-induced alveolar bone resorption was ameliorated by liraglutide. Liraglutide treatment also reduced osteoclasts on the alveolar bone surface. These results highlight the beyond glucose-lowering effects of liraglutide on the treatment of periodontitis.

The novel GLP-1/GIP dual agonist DA3-CH is more effective than liraglutide in reducing endoplasmic reticulum stress in diabetic rats with cerebral ischemia-reperfusion injury

Background and aimsDiabetes is one of the most important risk factors and comorbidities of ischemic stroke. Endoplasmic reticulum stress (ERS) is considered to be the major injury mechanism of ischemic stroke with diabetes. Studies have found that incretin can inhibit ERS in ischemia-reperfusion injury of the liver and heart. We aimed to explore the effects of GLP-1/GIP double agonist DA3-CH and GLP-1 single agonist liraglutide on ERS and apoptosis in diabetic rats with cerebral ischemia-reperfusion injury. Methods and results72 Sprague–Dawley (SD) male rats were randomly divided into 4 groups: ① blank group (Sham group, n = 18); model group (Saline group, n = 18); DA3 treatment group (DA3 group, n = 18); liraglutide treatment group (Lir group, n = 18). The Sham group was not given any treatment and was only raised in the same environment as the other groups. The remaining 3 groups used STZ-induced diabetes models. After the successful membrane formation of diabetes, DA3-CH and liraglutide (10 mmol/kg, once-daily for 14 days) were injected intraperitoneally. Thereafter, rats were subjected to middle cerebral artery occlusion followed by 24-h reperfusion. Animals were evaluated for neurologic deficit score, infarct volume, and biomarker analyses of the brain after ischemia. The DA3-CH-treated and liraglutide-treated groups showed significantly reduced scores of neurological dysfunction and cerebral infarction size, and reduced the expression of ERS markers GRP78, CHOP and Caspase-12, and the expression of apoptosis marker bax. Anti-apoptotic markers bcl-2 and neuronal numbers increased significantly. ConclusionsDA3-CH and liraglutide have obvious neuroprotective effects in a rat model of cerebral ischemia-reperfusion injury with diabetes, which can reduce the infarct size and the neurological deficit score. Their exert neuroprotective effects in a rat model of cerebral ischemia-reperfusion injury with diabetes by inhibiting endoplasmic reticulum stress and thereby reducing apoptosis. DA3 is better than liraglutide.

A GLP-1 Analog Liraglutide Reduces Intimal Hyperplasia After Coronary Stent Implantation via Regulation of Glycemic Variability and NLRP3 Inflammasome/IL-10 Signaling in Diabetic Swine.

ObjectiveThis study aimed to explore whether treatment with the glucagon-like peptide-1 (GLP-1) analog liraglutide reduces intimal hyperplasia after coronary stent implantation via regulation of glycemic variability, the NLRP3 inflammasome, and IL-10 in diabetic swine.MethodsFifteen pigs were divided into a diabetes mellitus (DM) group (n = 6), a DM + liraglutide treatment group (L group) (n = 6) and a sham group (n = 3). A total of 24 everolimus-eluting stents were implanted in the left anterior descending and right coronary arteries at 3 weeks. A novel continuous glucose monitoring system (GMS) was used for 2 weeks. The means and standard deviations (SDs) were measured and calculated by the GMS. At 22 weeks, the lumen area (LA), neointimal thickness (NIT), neointimal area (NIA), and percent area stenosis (%AS) were analyzed by optical coherence tomography. Plasma tumor necrosis factor-α, interleukin-6, and interleukin-10 were assayed by ELISA. The intima protein expression levels of NLRP3, interleukin-1β, interleukin-18 and interleukin-10 were examined using Western blot analysis. Histology was used to evaluate the healing response. In an in vitro study, THP-1 cells were divided into control, high glucose (HG), HG + liraglutide, and HG + liraglutide + Exe(9–39) (a GLP-1 receptor inhibitor) groups.ResultsThe L group had a lower SD, NIT, NIA, and %AS; a larger LA; reduced inflammation and injury scores; lower expression levels of tumor necrosis factor-α, interleukin-6, NLRP3, interleukin-1β, and interleukin-18; and higher expression of interleukin-10 compared with those of the DM group (p < 0.05). In the in vitro study, similar results were obtained in the HG + liraglutide group, and Exe(9–39) abolished the effect of liraglutide (p < 0.05).ConclusionsLiraglutide treatment reduces intimal hyperplasia after stent implantation via regulation of glycemic variability, the NLRP3 inflammasome, and IL-10 in diabetic pigs in a GLP-1 receptor-dependent manner. Reducing the inflammation induced by glycemic variability may be one of the cardioprotective mechanisms of liraglutide.

Effects of liraglutide on metabolic syndrome in WBN/Kob diabetic fatty rats supplemented with a high-fat diet.

BackgroundLiraglutide, a GLP‐1 receptor agonist, has recently been used to treat metabolic syndrome (MS) because of its anti‐diabetic and anti‐obesity effects. We have previously shown that Wistar Bonn Kobori diabetic and fatty (WBN/Kob‐Leprfa, WBKDF) rats fed a high‐fat diet (HFD) developed MS including marked obesity, hyperglycemia, and dyslipidemia. To obtain further information on WBKDF‐HFD rats as a severe MS model, we performed a pharmacological investigation into the anti‐MS effects of liraglutide in this model.MethodsSeven‐week‐old male WBKDF‐HFD rats were allocated to three groups (N = 8 in each group): a vehicle group, a low‐dose liraglutide group, and a high‐dose liraglutide group. They received subcutaneous injections of either saline or liraglutide at doses of 75 or 300 μg/kg body weight once daily for 4 weeks.ResultsResults showed that liraglutide treatment reduced body weight gain and food intake in a dose‐dependent manner. The marked hyperglycemia and the glucose tolerance were also significantly ameliorated in the liraglutide‐treated groups. Moreover, liraglutide also reduced the plasma triglyceride concentration and liver fat accumulation.ConclusionsThe present study demonstrated that liraglutide could significantly alleviate MS in WBKDF‐HFD rats, and the reaction to liraglutide is similar to human patients with MS. WBKDF‐HFD rats are therefore considered to be a useful model for research on severe human MS.

Liraglutide improved inflammation via mediating IL-23/Th-17 pathway in obese diabetic mice with psoriasiform skin

Objectives The purpose of this study was to investigate the effect of liraglutide on obesity diabetic mice with psoriasiform skin inflammation. Methods Wild-type mice and db/db mice were randomly divided into five groups (n = 6): including the control group which received Vaseline, the imiquimod (IMQ)-induction group and the liraglutide-treatment group. The advanced treatment with liraglutide (0.3 mg/kg/d) for 4 weeks before IMQ induced psoriatic skin inflammation in the db/db + IMQ + Lira group. Basic parameters of diabetes, PASI, histopathology of skin, the expression of IL-17A, IL-23, IL-22, and TNF-α in the skin of back were measured. Results After IMQ induction, the psoriatic skin inflammation and pathological changes in the db/db + IMQ group were more serious than those in the WT + IMQ group. The glucose metabolism and insulin resistance of in the db/db + IMQ + Lira group were significantly improved, Psoriasis Area and Severity Index (PASI) was significantly reduced, and the protein and mRNA expressions of IL-23, IL-17, IL-22, and TNF-α in the back skin tissues were decreased. Conclusions Liraglutide can improve psoriasis skin lesions of obese diabetic mice, and the mechanism may be related to the inhibition of the expression of IL-23, IL-17, IL-22, and TNF-α through the IL-23/Th-17 pathway.

Effects of Liraglutide and Behavioral Weight Loss on Food Cravings, Eating Behaviors, and Eating Disorder Psychopathology.

This exploratory analysis examined the effects of intensive behavioral therapy (IBT) for obesity ("IBT-alone"), IBT plus liraglutide 3.0 mg/d ("IBT-liraglutide"), and IBT plus liraglutide 3.0 mg/d plus 12 weeks of a portion-controlled diet that provided 1,000 to 1,200 kcal/d ("Multicomponent") on changes in food cravings, eating behaviors, and eating disorder psychopathology at 24 and 52 weeks post randomization. Adults with obesity (mean age = 47.6 ± 11.8 years and BMI = 38.4 ± 4.9 kg/m2 ; 79.3% female; 54.0% non-Hispanic white; 44.7% black) were randomized to IBT-alone (n = 50), IBT-liraglutide (n = 50), or Multicomponent (n = 50). At weeks 24 and 52, liraglutide-treated groups reported significantly larger declines in weight concern relative to the IBT-alone group. At week 24, compared with IBT-alone, liraglutide-treated groups reported significantly greater reductions in dietary disinhibition, global eating disorder psychopathology, and shape concern. TheMulticomponent grouphad significantly greater reductions in binge eating at week 24 relative tothe IBT-alonegroup. However, differences among groups were no longer significant at week 52. Groups did not differ in total food cravings at week 24 or 52. The combination of liraglutide and IBT was associated with greater short-term improvements in dietary disinhibition, global eating disorder psychopathology, and shape concern than IBT alone.

Changes in health-related quality of life with intensive behavioural therapy combined with liraglutide 3.0 mg per day.

This study examined the effects of intensive behavioural therapy (IBT) for obesity (IBT-alone), IBT plus liraglutide 3.0 mg/day (IBT-liraglutide), and IBT-liraglutide combined with 12 weeks of a portion-controlled diet (Multicomponent) on changes in general health-related (HR) quality of life (QoL) and weight-related QoL. Adults with obesity (79.3% female; 54.0% white; 44.7% black; mean age = 47.6 ± 11.8 years and body mass index = 38.4 ± 4.9 kg/m2 ) were randomized to IBT-alone (n = 50), IBT-liraglutide (n = 50) or Multicomponent (n = 50). General HRQoL was measured with the Short Form-36 (SF-36), and weight-related QoL was assessed with the Impact of Weight on Quality of Life-Lite scale. At week 52, participants in the three groups lost 6.1 ± 1.3%, 11.5 ± 1.3% and 11.8 ± 1.3% of initial body weight, respectively. Both liraglutide-treated groups were significantly more likely than IBT-alone to achieve clinically meaningful improvements in total weight-related QoL. They also both achieved greater improvements than IBT-alone in weight-related public distress and in general mental health, as measured by the SF-36 mental component summary score. Independent of treatment group, greater categorical weight loss was associated with greater improvements in several domains of both general and weight-related QoL. The addition of liraglutide to IBT appeared to improve aspects of both general HRQoL and weight-related QoL.

618-P: Effect of Liraglutide Combined with Human Umbilical Cord Mesenchymal Stem Cells on Liver Injury of T2DM with NAFLD Rats by Mediating Toll-Like Receptor 4/Nuclear Factor-kappa B Signaling Pathway and Oxidative Stress

Objective: To observe the effect of liraglutide combined with human umbilical cord mesenchymal stem cells on type 2 diabetes mellitus with nonalcoholic fatty liver disease rats liver injury. And then to investigate relation of the effect on the liver injury between the toll-like receptor 4/nuclear factor-kappa B inflammatory signal pathway and oxidative stress mechanism. Methods: Animal model establishment and experimental grouping and intervention: The rats were randomly selected and divided into the following four groups: T2DM with NAFLD model group, hUC-MSCs treatment group, Liraglutide treatment group, Liraglutide combined with hUC-MSCs treatment group. Results: 1. Rat serum levels of TNF-α, IL-6, 8-OHdG and SOD: Compared with MC+LIRA group, the levels of TNF-α, IL-6 and 8-OHdG were decreased in MC+LIRA+hUC-MSCs group (P &amp;lt;0.05), SOD was increased (P&amp;lt;0.05). 2. Pathological changes of rats liver tissue:Compared with MC+LIRA group, the NAS score were decreased in MC+LIRA+hUC-MSCs group (P &amp;lt;0.05).3. Expression of TLR4 and NF-κB mRNA in rat liver tissue: Compared with MC+hUC-MSCs group, the expression of TLR4 and NF-κB mRNA were significantly decreased in MC+LIRA group and MC+LIRA+hUC-MSCs group (P&amp;lt;0.05). Compared with MC+LIRA group, the expression of TLR4 and NF-κB mRNA were decreased in MC+LIRA+hUC-MSCs group (P &amp;lt;0.05). Conclusion: The mechanism of liraglutide combined with human umbilical cord mesenchymal stem cells on type 2 diabetes mellitus with nonalcoholic fatty liver disease is closely related to the down-regulation of TLR4/NF-κB inflammation pathway and oxidative stress. Disclosure P. Chen: None.

The key role of a glucagon-like peptide-1 receptor agonist in body fat redistribution

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are an ideal therapy for type 2 diabetes and, as of recently, for obesity. In contrast to visceral fat, subcutaneous fat appears to be protective against metabolic diseases. Here, we aimed to explore whether liraglutide, a GLP-1RA, could redistribute body fat via regulating lipid metabolism in different fat depots. After being fed a high-fat diet for 8 weeks, 50 male Wistar and Goto-Kakizaki rats were randomly divided into a normal control group, a diabetic control group, low- and high-dose liraglutide-treated groups and a diet-control group. Different doses of liraglutide (400 μg/kg/day or 1200 μg/kg/day) or an equal volume of normal saline were administered to the rats subcutaneously once a day for 12 weeks. Body composition and body fat deposition were measured by dual-energy X-ray absorptiometry and MRI. Isotope tracers were infused to explore lipid metabolism in different fat depots. Quantitative real-time PCR and Western blot analyses were conducted to evaluate the expression of adipose-related genes. The results showed that liraglutide decreased visceral fat and relatively increased subcutaneous fat. Lipogenesis was reduced in visceral white adipose tissue (WAT) but was elevated in subcutaneous WAT. Lipolysis was also attenuated, and fatty acid oxidation was enhanced. The mRNA expression levels of adipose-related genes in different tissues displayed similar trends after liraglutide treatment. In addition, the expression of browning-related genes was upregulated in subcutaneous WAT. Taken together, the results suggested that liraglutide potentially redistributes body fat and promotes browning remodeling in subcutaneous WAT to improve metabolic disorders.

Intensive Behavioral Therapy for Obesity Combined with Liraglutide 3.0 mg: A Randomized Controlled Trial.

The Centers for Medicare and Medicaid Services (CMS) covers intensive behavioral therapy (IBT) for obesity. The efficacy, however, of the specific approach has never been evaluated in a randomized trial, as described here. The 1-year trial also assessed whether the addition to IBT of liraglutide 3.0 mg would significantly increase weight loss and whether the provision of meal replacements would add further benefit. A total of 150 adults with obesity were randomly assigned to: IBT (IBT-alone), providing 21 counseling visits; IBT combined with liraglutide (IBT-liraglutide); or IBT-liraglutide combined for 12 weeks with a 1,000- to 1,200-kcal/d meal-replacement diet (Multicomponent). All participants received weekly IBT visits in month 1, every-other-week visits in months 2 to 6, and monthly sessions thereafter. Ninety-one percent of participants completed 1 year, at which time mean (± SEM) losses for IBT-alone, IBT-liraglutide, and Muticomponent participants were 6.1±1.3%, 11.5±1.3%, and 11.8±1.3% of baseline weight, respectively. Fully 44.0%, 70.0%, and 74.0% of these participants lost ≥ 5% of weight, respectively. The liraglutide-treated groups were superior to IBT-alone on both outcomes. Weight loss in all three groups was associated with clinically meaningful improvements in cardiometabolic risk factors. The findings demonstrate the efficacy of IBT for obesity and the potential benefit of adding pharmacotherapy to this approach.

Bone Protective Effect of a Novel Long-Acting GLP-1/GIP/Glucagon Triple Agonist (HM15211) in an Animal Model

Severe weight loss is often associated with reduction of bone mineral density (BMD) and an imbalance between bone formation and reabsorption in obese people. As a consequence, there can be an increased risk of bone fractures with body weight loss. Several studies have proposed that the gut hormones, GIP and GLP-1, might be modulators of bone growth and remodeling. HM15211 is a novel long-acting GLP-1/GIP/Glucagon agonist that is being developed for the treatment of obesity. In this study, we investigated whether treatment with HM15211 prevents bone loss under a severe weight loss condition, and the underlying mechanism of action. First, the bone protective effect of HM15211 was evaluated using diet induced obesity ovariectomized osteoporosis rat model. After 4 weeks subcutaneous treatment of HM15211 (120 µg/kg/Q3D), lower levels of serum decarboxylated osteocalcin (42.2 ng/mL) and higher serum P1NP (procollagen type I pro-peptide, 53.2 ng/mL) were observed compared with those of vehicle- (156.4 ng/mL for osteocalcin, 28.6 ng/mL for PINP) and liraglutide-treated groups (94 µg/kg/BID, 120.6 ng/mL for osteocalcin, 29.4 ng/mL for PINP). Furthermore, HM15211 showed comparable BMD of femur bones and lumbar spine with vehicle group while weight loss was greater (-26.0% vs. vehicle) compared to liraglutide (-11.5% vs. vehicle). These results suggest that treatment with HM15211 effectively prevents bone loss even after potent body weight loss in high fat dieted ovariectomized obese rats. Second, to elucidate the underlying molecular mechanism, related marker gene expression was investigated using the SaOS2 cell, human osteogenic cell. In line with the bone protective effect in vivo, HM15211 led to significant increases in type 1 collagen-α1, -α2, and carboxylated osteocalcin expression, which were blunted by inhibition of GIPR-mediated signaling. In conclusion, these results suggest that HM15211 might provide potent weight loss without the otherwise inevitable bone loss. Disclosure S. Lee: Employee; Self; Hanmi Pharmaceutical. Y. Kim: None. J. Lee: Employee; Self; Hanmi Pharmaceutical. Stock/Shareholder; Self; Hanmi Pharmaceutical. S. Lee: Employee; Self; Hanmi Pharmaceutical. Y. Kim: Employee; Self; Hanmi Pharmaceutical. I. Choi: Employee; Self; Hanmi Pharmaceutical. Stock/Shareholder; Self; Hanmi Pharmaceutical. S. Kim: Employee; Self; Hanmi Pharmaceutical. Stock/Shareholder; Self; Hanmi Pharmaceutical.

Evaluating the Sub-chronic Effects of MEDI0382, a GLP-1/Glucagon Receptor Dual Agonist, on Weight Loss in Male ob/ob Mice

MEDI0382, a balanced GLP-1/glucagon dual receptor agonist, is under development for the treatment of type 2 diabetes (T2DM). MEDI0382 reduces food intake and improves glucose control in lean and obese mice. Here, we determined the effects of MEDI0382 on body weight in leptin-deficient ob/ob mice. MEDI0382 (10, 20 or 30 nmol/kg), liraglutide (30 nmol/kg; a GLP-1 analog), or G1437 (30 nmol/kg; a lipidated glucagon receptor agonist) was administered to ob/ob mice for 21 days. Body weight was reduced by MEDI0382 treatment compared to vehicle controls, with 15% weight loss observed in the highest dose group. In comparison, liraglutide reduced body weight by 8% and G1437 by 29% (both p&amp;lt;0.0001 vs. vehicle and high-dose MEDI0382). Glucose tolerance was improved by MEDI0382 (30 nmol/kg), similar to liraglutide, whereas G1437 worsened glucose tolerance. Additionally, 4-h fasted glucose on day 7 and 14 in high-dose MEDI0382- and liraglutide-treated groups was lower than vehicle, whereas G1437-treated mice exhibited higher glucose levels. Overnight fasting glucose was also reduced in all groups relative to vehicle except G1437. Liver fat was reduced in a dose-dependent manner (11%, 14% and 22%, respectively) by MEDI0382 compared to vehicle. Both liraglutide (12%) and G1437 (10%) also reduced liver fat (both p&amp;lt;0.vs. vehicle and MEDI0382 30 nmol/kg dose). Serum ALT levels were also dose-dependently reduced by MEDI0382 and liraglutide, but not G1437. Expression of thermogenic genes (Ucp1, Ppargc1a and/or Adrb3) tended to be increased in brown and white adipose tissue by MEDI0382 administration, whereas negligible effects were observed following liraglutide or G1437 administration. In summary, these data indicate that high-dose MEDI0382 produced superior body weight loss and improved liver health compared to liraglutide but the improved glucose homeostasis was similar to liraglutide. Disclosure S. Oldham: Stock/Shareholder; Self; AstraZeneca. Employee; Self; MedImmune. C.D. Church: Employee; Self; MedImmune. S. Will: Employee; Self; MedImmune. Stock/Shareholder; Self; AstraZeneca. A. Konkar: Employee; Self; Sanofi. Other Relationship; Self; MedImmune. J. Trevaskis: Employee; Self; MedImmune. Stock/Shareholder; Self; AstraZeneca. G.R. Davies: Employee; Self; MedImmune.