Effect of Liraglutide combined with Jinlida granules on glycolipid metabolism and islet function of type 2 diabetes mellitus.

To investigate whether Liraglutide combined with Jinlida granules affects glycolipid metabolism and islet function in the treatment of type 2 diabetes mellitus (T2DM), a control group and an observation group were established with 90 T2DM patients. The control group was given Jinlida treatment and the observation group was given liraglutide combined treatment for 12 weeks. The clinical efficacy, glycolipid metabolism, bone metabolism, islet function, and endothelial function. The curative effect of the observation group was better than that of the control group. After treatment, FBG, 2hPG, HbAlc, TC, TG, and LDL-C in the observation group were lower and HDL-C was higher than those in the control group (P < 0.05). After treatment, the observation group showed higher bone mineral density, osteocalcin, FINS, and HOMA-ß and lower HOMA-IR than the control group (P < 0.05). After treatment, endothelin-1 level in the observation group was lower than that in the control group, and the NO level was higher (P < 0.05). No significant difference was found in the incidence of adverse reactions between the two groups (P > 0.05). Liraglutide combined with Jinlida in T2DM can improve glucose, lipid, and bone metabolism, promote the recovery of islet function, and enhance vascular endothelial function.

Clinical Efficacy and Safety of Liraglutide and Dapagliflozin on Glucose and Lipid Metabolism and Insulin Function in Patients with Type 2 Diabetes Mellitus.

Objective: Observe the changes in clinical indicators of patients with early diabetic nephropathy treated with liraglutide or dapagliflozin, evaluate their clinical efficacy, and provide new ideas for the treatment of diabetic patients. Methods: In this study, from January 2020 to January 2022, a total of 120 patients with early-stage type 2 diabetic nephropathy who met the inclusion criteria were selected. According to the order of treatment, the patients were randomly divided into traditional group, liraglutide group and dapagliflozin group, with 40 cases in each group. All patients continued their previous conventional hypoglycemic treatment, and the traditional group did not need to adjust the treatment plan; the liraglutide group: added liraglutide (average dose was 1.2 mg daily); the dapagliflozin group: added dapagliflozin (average dose was 10 mg daily). At the same time, all patients received dietary guidance and appropriate exercise intervention for a total of 12 weeks. The changes in blood sugar, blood lipids, pancreatic islet function, liver function, weight, body mass index (BMI) and other indicators before and after treatment were compared, and the adverse reactions that occurred during the medication of the three groups of patients were recorded. Standard doses of liraglutide and dapagliflozin were used in the treatment groups, 0.6 mg daily and 10 mg daily, respectively. These standard doses have been shown to be effective in a wide range of clinical practices and were therefore chosen in this study to ensure consistency and comparability. This helps readers better understand the study methods and results to evaluate these specific dosing options. Results: Prior to treatment, there were no significant differences in the general data and indicators among the three groups, including FPG, 2hPG, HbA1c, TC, TG, HDL-C, LDL-C, ALT, AST, HOMA-IR, FINS, and HOMA-ß (all P > .05). In the conventional group, significant changes were observed in FPG, 2hPG, HbA1c, body weight, BMI, HDL-C, LDL-C, ALT, AST, HOMA-IR, FINS, and HOMA-ß compared to the pre-treatment period, and these differences were statistically significant (all P < .05).Both the liraglutide and dagliflozin groups exhibited significant changes in FPG, 2hPG, HbA1c, TC, TG, LDL-C, HOMA-IR, FINS, HOMA-ß, body weight, BMI, HDL-C, ALT, and AST when compared to the post-treatment period, and these changes were statistically significant (all P < .05). Post-treatment analysis revealed that in terms of blood glucose, FPG, 2hPG, and HbA1c decreased more significantly in the liraglutide and dagliflozin groups compared to the conventional group (all P < .05). Regarding lipids, TC, TG, and LDL-C decreased more significantly in the liraglutide and dagliflozin groups compared to the conventional group (all P < .05). For pancreatic islet function, HOMA-IR and HOMA-ß decreased more significantly compared to the conventional group (all P < .05). Weight and BMI decreased more significantly in the liraglutide and dagliflozin groups compared to the conventional group (all P < .05). However, there were no significant differences in hepatic function among the three groups after treatment.Post-treatment comparisons between the liraglutide and dagliflozin groups revealed significant differences in FPG, HbA1c, body weight, and BMI (all P < .05). No adverse events occurred during the treatment period in any of the three groups, and there were no reported deaths. Conclusion: The addition of liraglutide or dagliflozin to conventional hypoglycaemic drug therapy in early diabetic patients can not only bring blood glucose to a safe and faster standard, but also regulate blood lipids and glucose, and the therapeutic effect of liraglutide is obvious than that of dagliflozin in terms of blood glucose regulation. Study limitations include small sample size, short study duration, unspecified exclusion criteria, unclear randomization method, and the impact of patient compliance.

Seladelpar combined with complementary therapies improves fibrosis, inflammation, and liver injury in a mouse model of nonalcoholic steatohepatitis.

Seladelpar, a selective peroxisome proliferator-activated receptor δ (PPARδ) agonist, improves markers of hepatic injury in human liver diseases, but histological improvement of nonalcoholic steatohepatitis (NASH) and liver fibrosis has been challenging with any single agent. To discover how complementary agents could work with seladelpar to achieve optimal outcomes, this study evaluated a variety of therapeutics (alone and in combination) in a mouse model of NASH. Mice on a high-fat amylin liver NASH (AMLN) diet were treated for 12 wk with seladelpar, GLP-1-R (glucagon-like peptide-1 receptor) agonist liraglutide, apoptosis signal-regulating kinase 1 (ASK1) inhibitor selonsertib, farnesoid X receptor (FXR) agonist obeticholic acid, and with seladelpar in combination with liraglutide or selonsertib. Seladelpar treatment markedly improved plasma markers of liver function. Seladelpar alone or in combination resulted in stark reductions in liver fibrosis (hydroxyproline, new collagen synthesis rate, mRNA indices of fibrosis, and fibrosis staining) compared with vehicle and the other single agents. Robust reductions in liver steatosis were also observed. Seladelpar produced a reorganization of metabolic gene expression, particularly for those genes promoting peroxisomal and mitochondrial lipid oxidation. In summary, substantial improvements in NASH and NASH-induced fibrosis were observed with seladelpar alone and in combination with liraglutide in this model. Broad gene expression analysis suggests seladelpar should be effective in concert with diverse mechanisms of action.NEW & NOTEWORTHY NASH is a chronic, progressive, and increasingly problematic liver disease that has been resistant to treatment with individual therapeutics. In this study using a diet-induced mouse model of NASH, we found that the PPARδ agonist seladelpar reduced fibrosis and NASH pathology alone and in combinations with a GLP-1-R agonist (liraglutide) or an ASK1 inhibitor (selonsertib). Liver transcriptome analysis comparing each agent and coadministration suggests seladelpar should be effective in combination with a variety of therapeutics.

Independent and combined effects of liraglutide and aerobic interval training on glycemic control and cardiac protection in diabetic cardiomyopathy rats.

OBJECTIVE: This study intended to explore the hypoglycemic and cardioprotective effects of 8-week aerobic interval training combined with liraglutide and elucidate the underlying mechanisms. METHOD: Male Wistar rats were randomly divided into 5 groups - normal control group (CON), diabetic cardiomyopathy group (DCM), high-dose liraglutide group (DH), low-dose liraglutide group (DL), and aerobic interval training combined with liraglutide group (DLE). High-fat diet and streptozotocin (STZ) were used to induce the DCM model, and both the liraglutide administration group and combination therapy group allocated to 8 weeks of either liraglutide or liraglutide and exercise intervention. Cardiac functions were analyzed by electrocardiography. Blood biochemical parameters were measured to judge glycemic control conditions. Hematoxylin and eosin (HE) staining and Sirus red staining was used to identify cardiac morphology and collagen accumulation, respectively. Advanced glycation end products (AGEs) were determined by enzymatic methods. The mRNA expression of myocardial remodeling genes (BNP, GSK3ß, α-MHC, ß-MHC and PPARα) and the protein expression of GLP-1, GLP-1R were analyzed. RESULTS: DCM rats developed hyperglycemia, impaired cardiac function with accumulation of AGEs and collagen (P < 0.05). The development of hyperglycemia and cardiac dysfunction was significantly attenuated with all interventions, as reduced cardiac fibrosis and improved cardiac function (P < 0.05). Cardiac remodeling genes were normalized after all interventions, these positive modifications were due to increased GLP-1 and GLP-1R expression in DCM heart (P < 0.05). Liraglutide combined with AIT significantly increased the diameters of cardiomyocytes, increased the α-MHC expressionx, reduced PPARαexpression and reduced the fluctuation of blood glucose level, which showed the safety and effective of medicine combined with exercise. CONCLUSION: Liraglutide combined with AIT intervention normalized blood glucose alleviates myocardial fibrosis and improves cardiac contractile function in DCM rats, supporting the efficacy and safety of the combination therapy.

Liraglutide chronic treatment prevents development of tolerance to antiseizure effects of diazepam in genetically epilepsy prone rats.

Glucagon-like peptide-1 (GLP-1) is a hormone that can regulate several neuronal functions. The modulation of GLP-1 receptors emerged as a potential target to treat several neurological diseases, such as epilepsy. Here, we studied the effects of acute and chronic treatment with liraglutide (LIRA), in genetically epilepsy prone rats (GEPR-9s). We have also investigated the possible development of tolerance to antiseizure effects of diazepam, and how LIRA could affect this phenomenon over the same period of treatment. The present data indicate that an acute treatment with LIRA did not diminish the severity score of audiogenic seizures (AGS) in GEPR-9s. By contrast, a chronic treatment with LIRA has shown only a modest antiseizure effect that was maintained until the end of treatment, in GEPR-9s. Not surprisingly, acute administration of diazepam reduced, in a dose dependent manner, the severity of the AGS in GEPR-9s. However, when diazepam was chronically administered, an evident development of tolerance to its antiseizure effects was detected. Interestingly, following an add-on treatment with LIRA, a reduced development of tolerance and an enhanced diazepam antiseizure effect was observed in GEPR-9s. Overall, an add-on therapy with LIRA demonstrate benefits superior to single antiseizure medications and could be utilized to treat epilepsy as well as associated issues. Therefore, the potential use of GLP1 analogs for the treatment of epilepsy in combination with existing antiseizure medications could thus add a new and long-awaited dimension to its management.

Liraglutide Plus Dapagliflozin for High Uric Acid and Microalbuminuria in Diabetes Mellitus Complicated With Metabolic Syndrome.

Context: Diabetes mellitus (DM) represents an emerging epidemic, poses serious threats to human health, and can seriously compromise patients' quality of life (QoL). Currently, no cure exists for DM. Some studies have found that both liraglutide and dapagliflozin have great therapeutic potential in preventing and treating DM and its complications. Objective: The study aimed to examine the impact of liraglutide plus dapagliflozin on high uric acid (UA) and microalbuminuria (MAU) in patients with diabetes mellitus (DM) complicated with metabolic syndrome (MS). Design: The research team designed a randomized controlled trial. Setting: The study took place at the Second Affiliated Hospital of Nanjing Medical University in Nanjing, Jiangsu, China. Participants: Participants were 125 patients with DM complicated with MS who were treated in the outpatient clinic of the endocrinology department at the hospital between January 1, 2020 and December 31, 2021, with 68 in the intervention group and 57 in the control group. Intervention: The intervention and control groups both received 0.6 mg of liraglutide. The intervention group also received 5 mg of dapagliflozin once a day. The dosages were increased at one week after baseline based on the participant's condition. Outcome Measures: Therapeutic effects, glycolipid metabolism, inflammation, uric acid (UA), microalbuminuria (MAU), cardiac function, and quality of life (QoL) were compared between the two groups. Results: Postintervention, the clinical efficacy was significantly higher in the intervention group than in the control group. The intervention group had significantly lower glycolipid metabolism and inflammatory-factor levels than the control group UA and MAU had declined in both groups but were significantly lower in the intervention group. The left ventricular ejection fraction (LVEF) increased and the left ventricular end diastolic diameter (LVEDd) decreased in both groups, but the intervention group had significantly greater changes as compared with those in the control group. The intervention group was also superior to the control group in patients' QoL. Conclusions: Liraglutide plus dapagliflozin has highly therapeutic effect for patients with DM complicated with MS and can effectively reduce UA and MAU levels. The current research team will launch a more comprehensive analysis as soon as possible to obtain the most accurate results.

Liraglutide Attenuates Restenosis After Vascular Injury in Rabbits With Diabetes Via the TGF-ß/Smad3 Signaling Pathway.

Background: Lower limb ischemia due to arterial stenosis is a major complication in patients with diabetes mellitus (DM). Liraglutide is a long-acting analogue of a glucagon-like peptide 1 (GLP-1) receptor agonist used for lowering blood glucose in patients with DM, and is believed to possess cardiovascular protective effects. The aim of this study was to investigate whether liraglutide has a protective effect on blood vessels and alleviates vascular intimal hyperplasia in streptozotocin (STZ)-induced rabbits with DM and its molecular mechanism. Methods: Rabbits with DM were induced by STZ, and a lower limb ischemia model was established. The animals were divided into a control group, DM-injury group and liraglutide treatment group. Pathological staining was used to observe the intimal growth, analyze the oxidation levels of malondialdehyde (MDA), superoxide dismutase (SOD) and plasma glutathione peroxidase (GSH-Px), and analyze the changes in expression of marker proteins and signaling pathway proteins by Western blotting. A hyperglycemia (HG)-injured vascular smooth muscle cells (VSMCs) model was established to analyze reactive oxygen species (ROS) levels, Cell-Counting Kit-8 (CCK-8) was used to analyze cell proliferation, scratch assay and Transwell Migration Assay to analyze cell migration, flow cytometry to analyze apoptosis and Western blotting was used to analyze changes in the expression of marker and signaling pathway proteins. Results: The results of pathological staining showed that intimal hyperplasia was severe after diabetes-induced lower limb ischemia in rabbits at 4 weeks, and liraglutide treatment reduced symptoms. Liraglutide treatment significantly decreased MDA content, increased SOD, GSH-Px content, and augmented total antioxidant capacity levels in tissues. The results of Western blotting analysis showed that E-cadherin, mitochondrial membrane potential 9 (MMP-9), proliferating cell nuclear antigen (PCNA), and type I collagen protein expression levels were significantly decreased after liraglutide treatment compared with the DM injury group. The results indicated that liraglutide inhibited epithelial-mesenchymal transition (EMT) progression, vascular cell proliferation and migration and collagen production. Liraglutide inhibits transforming growth factor beta 1 (TGF-ß1)/Smad3 signaling pathway protein expression. In vitro assays have shown that liraglutide reduces cellular ROS levels, inhibits cell proliferation and migration and promotes apoptosis. Liraglutide down-regulated the expression of E-cadherin, MMP-9, PCNA, type I collagen protein as well as the TGF-ß1/Smad3 signaling pathway, but this effect could be reversed by tumor necrosis factor alpha (TNF-α). Conclusion: Liraglutide can significantly improve tissue antioxidant capacity, reduce vascular cell proliferation and migration via the TGF-ß1/Smad3 signaling pathway, inhibit the EMT and collagen production processes, and alleviate hyperglycemia(HG)-induced lower limb ischemia and intimal hyperplasia.

Incidence and Predictors of Primary Nonadherence to Sodium Glucose Co-transporter 2 Inhibitors and Glucagon-Like Peptide 1 Agonists in a Large Integrated Healthcare System.

BACKGROUND: Newer glucose-lowering drugs, including sodium glucose co-transporter 2 inhibitors (SGLT2i) and GLP-1 agonists, have a key role in the pharmacologic management of type 2 diabetes. No studies have measured primary nonadherence for these two drug classes, defined as when a medication is prescribed for a patient but ultimately not dispensed to them. OBJECTIVE: To describe the incidence and predictors of primary nonadherence to SGLT2i (canagliflozin, empagliflozin) or GLP-1 agonists (dulaglutide, liraglutide, semaglutide) using a dataset that links electronic prescribing with health insurance claims. DESIGN AND PARTICIPANTS: A retrospective cohort design using data of adult patients from a large health system who had at least one prescription order for a SGLT2i or GLP-1 agonist between 2012 and 2019. We used mixed-effects multivariable logistic regression to determine associations between sociodemographic, clinical, and provider variables and primary nonadherence. MAIN MEASURES: Primary medication nonadherence, defined as no dispensed claim within 30 days of an electronic prescription order for any drug within each medication class. KEY RESULTS: The cohort included 5146 patients newly prescribed a SGLT2i or GLP-1 agonist. The overall incidence of 30-day primary medication nonadherence was 31.8% (1637/5146). This incidence rate was 29.8% (n = 726) and 33.6% (n = 911) among those initiating a GLP-1 agonist and SGLT2i, respectively. Age ≥ 65 (aOR 1.37 (95% CI 1.09 to 1.72)), Black race vs White (aOR 1.29 (95% CI 1.02 to 1.62)), diabetic nephropathy (aOR 1.31 (95% CI 1.02 to 1.68)), and hyperlipidemia (aOR 1.18 (95% CI 1.01 to 1.39)) were associated with a higher odds of primary nonadherence. Female sex (aOR 0.86 (95% CI 0.75 to 0.99)), peripheral artery disease (aOR 0.73 (95% CI 0.56 to 0.94)), and having the index prescription ordered by an endocrinologist vs a primary care provider (aOR 0.76 (95% CI 0.61 to 0.95)) were associated with lower odds of primary nonadherence. CONCLUSIONS: One third of patients prescribed SGLT2i or GLP-1 agonists in this sample did not fill their prescription within 30 days. Black race, male sex, older age, having greater baseline comorbidities, and having a primary care provider vs endocrinologist prescribe the index drug were associated with higher odds of primary nonadherence. Interventions targeting medication adherence for these newer drugs must consider primary nonadherence as a barrier to optimal clinical care.

A GLP-2 Analogue Protects SH-SY5Y and Neuro-2a Cells Against Mitochondrial Damage, Autophagy Impairments and Apoptosis in a Parkinson Model.

Glucagon-like peptide-2 (GLP-2) is a peptide hormone that belongs to the glucagon-derived peptide family. We have previously shown that analogues of the sister hormone Glucagon-like peptide-1 (GLP-1) showed neuroprotective effects. Here we investigated the effect of a GLP-2 agonist in a cell model of Parkinson's disease (PD) created by treating SH-SY5Y or Neuro-2a cells with 1-Methyl-4-phenyl-pyridine ion (MPP+). Cell viability and cell cytotoxicity was detected by MTT and LDH assays, respectively. The protein expression levels of mitochondrial, autophagy and apoptotic biomarkers including PGC-1α, Mfn2, IRE1, ATG7, LC3B, Beclin1 and Bcl-2 were detected by western blot. Mitochondrial superoxide was detected by MitoSOX Red. In addition, mitochondrial morphology, autophagosome and apoptotic corpuscles were observed by transmission electron microscope (TEM). We found that the GLP-1 and the GLP-2 agonists both protect cells against mitochondrial damage, autophagy impairments and apoptosis induced by MPP+both in SH-SY5Y and Neuro-2a cells. Cell signaling for mitogenesis was enhanced, and oxidative stress levels much reduced by the drugs. This demonstrates for the first time the neuroprotective effects of a GLP-2 analogue in PD cellular models, in which oxidative stress, autophagy and apoptosis play crucial roles. The protective effects were comparable to those seen with the GLP-1 analogue liraglutide. The results suggest that not only GLP-1, but also GLP-2 has neuroprotective properties and may be useful as a novel treatment of PD.

New-generation anti-obesity drugs: naltrexone/bupropion and liraglutide. An update for endocrinologists and nutritionists.

The prevalence of obesity increases worldwide and has a significant economic impact on health care systems. A comprehensive program of lifestyle modification, including diet, exercise, and behavior therapy is considered the first option for achieving the significant weight loss. However, the intrinsic difficulties associated with maintenance of lifestyle changes contribute to the unsatisfactory long-term outcomes reported and weight regain in the obesity management. In this context, pharmacological approaches are useful to maximize non-pharmacological interventions in the long-term management of obesity. As add-on to lifestyle modification, pharmacological interventions are useful to facilitate clinically weight loss. In the past, anti-obesity drugs were limited. To date, the landscape has changed and naltrexone/bupropion and liraglutide have been recently added as new-generation anti-obesity drugs on obesity treatment and could represent important tools to manage of obesity. Liraglutide is a glucagon-like peptide 1 (GLP-1) receptor agonist that shares 97% homology to native GLP-1 with effects on the limbic system. The treatment with liraglutide 3.0 mg, in combination with a hypocaloric diet and increased physical activity, provides a clinically meaningful weight loss. The combination of naltrexone 32 mg and bupropion 360 mg acts on the mesolimbic reward pathway and the hypothalamic hunger system, two areas of the central nervous system. The combination of naltrexone/bupropion, an adjunct to a hypocaloric diet and increased physical activity, is approved for chronic weight management in adults with obesity or overweight and ≥1 weight-related comorbidity. In the present review, we have focused on the current evidence on two new-generation anti-obesity drugs, naltrexone/bupropion and liraglutide 3.0 mg addressing the main studies that investigated these two new drugs for obesity treatment. Furthermore, evidence on semaglutide, currently in the pipeline for potential future therapeutic use for weight loss, are reported.

LEADER Trial Eligibility and Preventable Cardiovascular Events in US Adults with Diabetes: the National Health and Nutrition Examination Surveys 2007-2016.

PURPOSE: The Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial showed the cardiovascular disease (CVD) benefits of liraglutide therapy among patients with type 2 diabetes mellitus (T2DM). We applied this trial to US adults with T2DM in terms of eligibility and preventable CVD events. METHODS: We included US adults with T2DM from the National Health and Nutrition Examination Survey (NHANES) 2007-2016. Eligibility criteria from LEADER primary and secondary prevention cohorts were applied to determine potentially eligible US adults. We estimated the number of primary composite and secondary CVD endpoints that would occur based on LEADER treated and placebo published event rates, with the difference indicating the number of preventable events. RESULTS: Among 4672 (projected to 27.3 million [M]) adults we identified with T2DM, we estimated 800 (4.2 million) (15.4%) to fit LEADER eligibility criteria, including 205 (0.9 M) primary prevention 595 (3.3 M) secondary prevention subjects. Compared to LEADER trial participants, our sample had higher proportions of women and minorities, prior angina, chronic kidney disease, and lipid-lowering medication use. We estimated 21,209 primary composite CVD events, 29,691 extended CVD composite outcomes, 16,967 all-cause deaths, 16,967 cardiovascular deaths, 12,725 myocardial infarctions, and 12,725 microvascular events would be prevented annually if our eligible T2DM subjects were on liraglutide. CONCLUSION: Liraglutide may prevent many fatal and non-fatal CVD events if provided to US adults meeting LEADER eligibility criteria. More efforts are needed to educate the healthcare providers on the CVD benefits from newer diabetes therapies, including liraglutide.

Liraglutide Lowers Body Weight Set Point in DIO Rats and its Relationship with Hypothalamic Microglia Activation.

OBJECTIVE: This study aimed to investigate the effects of liraglutide on the body weight set point (BWSP) in diet-induced obese rats and to determine the relationship between BWSP and hypothalamic arcuate nucleus (ARC) microglial activation. METHODS: Diet-induced obesity (DIO) rats were divided into three groups: continuous high-fat diet (HFD) plus saline, HFD with liraglutide, and HFD with liraglutide pair feeding. Body weight, BWSP, inflammatory cytokines, suppressor of cytokine signaling 3, orexigenic/anorexigenic proteins, apoptosis, and microglia in the ARC were assessed. The effect of liraglutide on the Notch-1 signaling pathway and its relationships with  nuclear factor-κB and p38 mitogen-activated protein kinase were also investigated in a lipopolysaccharide (LPS)-induced microglia activation model. RESULTS: Liraglutide reduced BWSP; reversed adverse changes in hypothalamic inflammation, suppressor of cytokine signaling 3, and apoptosis; and diminished microgliosis in DIO rats. The BWSP showed a linear correlation with ARC microglial density. Liraglutide inhibited LPS-induced M1 microglial polarization and promoted microglial polarization to the M2 phenotype, diminishing inflammatory cytokine expression. Liraglutide inhibited Notch-1 signaling pathway activation and decreased nuclear factor-κB and p38 mitogen-activated protein kinase pathway activation in LPS-stimulated microglia. CONCLUSIONS: Liraglutide can reduce BWSP in DIO rats. There is a linear correlation between hypothalamic microgliosis and BWSP. Liraglutide reduces excessive microglial activation and inflammation, which may contribute to BWSP reduction.

Effect of GLP-1 Receptor Agonists in the Cardiometabolic Complications in a Rat Model of Postmenopausal PCOS.

Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism and ovulatory dysfunction. Women with PCOS have an elevated prevalence of cardiometabolic risk factors that worsen after menopause. Liraglutide (Lira), a glucagon-like peptide-1 receptor agonist, has shown beneficial metabolic effects in small clinic trials in reproductive-age women with PCOS. We have shown that chronic hyperandrogenemia in an experimental model of postmenopausal PCOS is associated with an adverse cardiometabolic profile and upregulation of the intrarenal renin-angiotensin system (RAS). We analyzed the effect of Lira in the cardiometabolic profile, intrarenal RAS, and blood pressure (BP) in postmenopausal PCOS. Four-week-old female Sprague Dawley rats were treated with DHT or placebo for 17 months. Lira administration during the last 3 weeks caused a bigger reduction in food intake, body weight, fat mass, and homeostasis model assessment of insulin resistance index in PCOS than in control rats. Moreover, Lira improved dyslipidemia and elevated leptin levels in PCOS. In contrast, Lira decreased intrarenal expression of RAS components only in the control group. Lira transiently increased heart rate and decreased BP in control rats. However, Lira did not modify BP but increased heart rate in PCOS. The angiotensin-converting-enzyme inhibitor enalapril abolished the BP differences between PCOS and control rats. However, Lira coadministration with enalapril further reduced BP only in control rats. In summary, Lira has beneficial effects for several cardiometabolic risk factors in postmenopausal PCOS. However, hyperandrogenemia blunted the BP-lowering effect of Lira in postmenopausal PCOS. Androgen-induced activation of intrarenal RAS may play a major role mediating increases in BP in postmenopausal PCOS.

Effects of glucagon-like peptide-1 analog liraglutide on the systemic inflammation in high-fat-diet-induced mice.

OBJECTIVE: Metabolic syndrome is a chronic-metabolic disease caused by a variety of factors, including high peripheral blood insulin levels and insulin resistance. It has been reported that GLP-1 could regulate insulin resistance. It is not known whether and how GLP-1 protects from fat-induced inflammation and immune changes. We investigated if GLP-1 alters the populations of fat-induced inflammation and immune cells and the related mechanism. METHODS: We obtained obese C57BL/6J mice by feeding them high-fat food, then treated the obese mice with GLP-1+ high-fat diet (G + Hi), normal chow diet (Nor), or high-fat diet (Hi) (n = 20 for each group) for 8 weeks. The GLP-1 receptor-/- B6 group were fed with HFD for 8 weeks (GLP-1R KO + Hi). In vivo and in vitro experiments were conducted on mice immune cells to investigate the effects of GLP-1 on the changes of the immune components and functions in obesity. RESULTS: We found that GLP-1 could efficiently change the CD4+ T subsets and level of cytokines in high-fat-induced mice by GLP-1 receptor. Further, these changes were correlated with a reduction in fat content and serum lipid level. Interestingly, GLP-1 could enhance the function of Tregs in vitro. CONCLUSION: Our data showed that GLP-1 has an important role in shaping the CD4+ T population in high-fat-diet-induced mice by GLP-1 receptor, possibly providing a new target for the treatment of metabolic syndrome.

Postprandial hypoglycaemia after Roux-en-Y gastric bypass and the effects of acarbose, sitagliptin, verapamil, liraglutide and pasireotide.

AIM: To investigate the effects of acarbose, sitagliptin, verapamil, liraglutide and pasireotide on post-bariatric hypoglycaemia (PBH) after Roux-en-Y gastric bypass. MATERIALS AND METHODS: In a randomized crossover study, 11 women who had undergone Roux-en-Y gastric bypass and had documented hypoglycaemia were each evaluated during a baseline period without treatment and during five treatment periods with the following interventions: acarbose 50 mg for 1 week, sitagliptin 100 mg for 1 week, verapamil 120 mg for 1 week, liraglutide 1.2 mg for 3 weeks and pasireotide 300 µg as a single dose. Treatment effects were evaluated by a mixed-meal tolerance test (MMTT) and, for all treatment periods except pasireotide, by 6 days of continuous glucose monitoring (CGM). RESULTS: Treatment with acarbose and treatment with pasireotide both significantly lifted nadir glucose levels (mean ± SEM 3.9 ± 0.2 and 7.9 ± 0.4 vs 3.4 ± 0.2; P < .03) and reduced time in hypoglycaemia during the MMTTs. Acarbose reduced peak glucose levels and time in hyperglycaemia, whereas pasireotide greatly increased both variables. Acarbose and pasireotide reduced insulin and C-peptide levels, and pasireotide also diminished glucagon-like peptide-1 levels. Sitagliptin lowered nadir glucose values, while verapamil and liraglutide had no effect on hypoglycaemia. During the CGM periods, the treatments had no impact on hypoglycaemia, whereas acarbose and liraglutide reduced hyperglycaemia and glycaemic variability. CONCLUSIONS: In an experimental setting, treatment with acarbose and pasireotide reduced PBH. Acarbose appears to have an overall glucose-stabilizing effect, whereas pasireotide leads to increased and sustained hyperglycaemia.

The effect of liraglutide on the proliferation, migration, and osteogenic differentiation of human periodontal ligament cells.

OBJECTIVE: Liraglutide (LIRA) is a novel antidiabetic therapy that may have anti-inflammatory and bone protective effects. Thus, we studied the potential therapeutic effect of LIRA on periodontitis by assessing the effects of LIRA on the proliferation, migration, inflammation, and osteogenic differentiation of human periodontal ligament cells (hPDLCs) after LPS stimulation. MATERIAL AND METHODS: The expression of glucagon like-peptide 1 receptor (GLP-1R) was measured using qRT-PCR. HPDLCs proliferation after LIRA were analyzed using MTT assays. Cell migration was quantified using a wound-healing assay. The expression of inflammatory (IL-6 and TNF-α) was measured by qRT-PCR and ELISA in hPDLCs. The effect of LIRA on the mineralization potential of hPDLCs was assessed by alizarin red S staining. Furthermore, the expression of Runx2 and ALP was measured by qRT-PCR and Western blot in hPDLCs. RESULTS: GLP-1R mRNA was present on hPDLCs, and LIRA increased the expression of GLP-1R mRNA. When cultured with 25, 50, 75, 100 and 125 nM LIRA for 24 h, hPDLCs proliferation was enhanced in a dose-dependent manner (P < 0.05), and 100 nM was optimal. LIRA promoted hPDLCs migration in a time-dependent manner. LPS significantly increased the expression of IL-6 and TNF-α (P < 0.01), decreased the formation of mineralization nodes (P < 0.01), and inhibited the expression of ALP and Runx2 (P < 0.05). LIRA treatment blocked the expression of IL-6 and TNF-α (P < 0.01), increased the formation of mineralization nodes (P < 0.01), and enhanced the expression of ALP and Runx2 (P < 0.05). CONCLUSION: LIRA can enhance the proliferation, migration, and osteogenic differentiation of hPDLCs and inhibit the inflammatory response. Thus, LIRA may have potential therapeutic use as an adjuvant treatment for human periodontitis, and this effect is independent of hypoglycemic activity.

[Treatment of non-alcoholic fatty liver disease].

Non-alcoholic fatty liver disease and especially non-alcoholic steatohepatitis (NASH) and fibrosis are associated with severe liver disease and increased cardiovascular risk. It is therefore important to identify patients with NASH fibrosis. Therapeutical options include life style intervention and pharmacological treatment with vitamin E and pioglitazone; however, evidence of effect is scarce for all options. New treatments are under investigation and include glucagon-like peptide-1, farnesoid receptor as well as peroxisome proliferator-activated receptor-α/δ agonists. Bariatric surgery may be an option in selected patients.

[Obesity treatment with liraglutide in a patient with Prader-Willi syndrome: a case report]. / Tratamiento de obesidad con liraglutida en un paciente con síndrome de Prader-Willi: reporte de un caso.

BACKGROUND: Prader-Willi syndrome (PWS) is a major cause of syndromic obesity, caused by deletions on chromosome 15q11-q13. It is characterized by neonatal hypotonia, difficulty in feeding with low birth-weight and subsequent development of hyperphagia, behavioral disorders and obesity. Treatment options for weight control in those patients is limited and there are controversies for a surgical approach. CASE REPORT: we present the case of a patient with PWS who achieved weight loss and control through the use of liraglutide, nutritional therapy and physical activity. DISCUSSION: the treatment of obesity in patients with PWS is challenging and requires an adequate nutritional approach combined with psychological therapy. In those patients that persist with uncontrolled appetite, medications such as metformin or GLP-1 analogs can be used.

WEIGHT LOSS IN A YOUNG PATIENT WITH TYPE 2 DIABETES: CHALLENGES OF DIABETES MANAGEMENT USING ONLINE PROGRAM OF GOOD NUTRITION (CASE REPORT).

A 31-year-old male with a history of obesity, type 2 diabetes mellitus (T2DM) and hypercholesterolemia came to our clinic for medical weight-loss management. According to his initial anthropometric measurements (weight - 193 kg, height - 181 cm, and body mass index (BMI) - 58 kg/m2) patient had morbid obesity. In order to educate our patient about good nutrition, physical activity and the need of sun exposure we used an online system based on the video lessons, full of humor, pictures, and cartoons. Even one month of watching the short educational movies was sufficient for the patient to form the habits of healthy eating, including restriction of fat and digestible carbohydrates and increase in daily consumption of low-fat dairy products, slow carbohydrates, protein and fiber. Endocrinologist was regularly available for any questions and inquiries that the patient might have had. In addition to the dietary recommendations subcutaneous liraglutide 2.4 mg daily was initiated. After 8 months of treatment the patient has lost 58 kg and reached the body weight of 135 kg; moreover, he had motivation to continue losing weight.