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.

The Hypoglycemic and Hypocholesterolemic Activity of Dioscorea deltoidea, Tribulus terrestris and Panax japonicus Cell Culture Biomass in Rats with High-Fat Diet-Induced Obesity.

Obesity, and its consequences for human health, is a huge and complicated problem that has no simple solution. The constant search for natural and safe compounds with systemic action that can be used for obesity prophylactics and treatment is hampered by the limited availability and variable quality of biomass of wild medicinal plants. Plant cell biotechnology is an alternative approach for the sustainable production of vegetative biomass or individual phytochemicals with high therapeutic potential. In this study, the suspension cell biomass of the medicinal plants, Dioscorea deltoidea Wall., Tribulus terrestris L., and Panax japonicus (T. Nees) C.A. Mey, produced in 20 L and 630 L bioreactors, were tested for therapeutic effects in rat models with alimentary-induced obesity. Three-month intake of water infusions of dry cell biomass (100 mg/g body weight) against the background of a hypercaloric diet reduced weight gain and the proportion of fat mass in the obese animals. In addition, cell biomass preparation reduced the intracellular dehydration and balanced the amounts of intra- and extracellular fluids in the body as determined by bioimpedance spectroscopy. A significant decrease in the glucose and cholesterol levels in the blood was also observed as a result of cell biomass administration for all species. Hypocholesterolemic activity reduced in the line P. japonicus > D. deltoidea > T. terrestris/liraglutide > intact group > control group. By the sum of parameters tested, the cell culture of D. deltoidea was considered the most effective in mitigating diet-induced obesity, with positive effects sometimes exceeding those of the reference drug liraglutide. A safety assessment of D. deltoidea cell phytopreparation showed no toxic effect on the reproductive function of the animals and their offspring. These results support the potential application of the biotechnologically produced cell biomass of medicinal plant species as safe and effective natural remedies for the treatment of obesity and related complications, particularly for the long-term treatment and during pregnancy and lactation periods when conventional treatment is often contraindicated.

Osmoadaptive GLP-1R signalling in hypothalamic neurones inhibits antidiuretic hormone synthesis and release.

OBJECTIVES: The excessive release of the antidiuretic hormone vasopressin is implicated in many diseases including cardiovascular disease, diabetes, obesity, and metabolic syndrome. Once thought to be elevated as a consequence of diseases, data now supports a more causative role. We have previously identified CREB3L1 as a transcription factor that co-ordinates vasopressin synthesis and release in the hypothalamus. The objective here was to identify mechanisms orchestrated by CREB3L1 that co-ordinate vasopressin release. METHODS: We mined Creb3l1 knockdown SON RNA-seq data to identify downstream target genes. We proceeded to investigate the expression of these genes and associated pathways in the supraoptic nucleus of the hypothalamus in response to physiological and pharmacological stimulation. We used viruses to selectively knockdown gene expression in the supraoptic nucleus and assessed physiological and metabolic parameters. We adopted a phosphoproteomics strategy to investigate mechanisms that facilitate hormone release by the pituitary gland. RESULTS: We discovered glucagon like peptide 1 receptor (Glp1r) as a downstream target gene and found increased expression in stimulated vasopressin neurones. Selective knockdown of supraoptic nucleus Glp1rs resulted in decreased food intake and body weight. Treatment with GLP-1R agonist liraglutide decreased vasopressin synthesis and release. Quantitative phosphoproteomics of the pituitary neurointermediate lobe revealed that liraglutide initiates hyperphosphorylation of presynapse active zone proteins that control vasopressin exocytosis. CONCLUSION: In summary, we show that GLP-1R signalling inhibits the vasopressin system. Our data advises that hydration status may influence the pharmacodynamics of GLP-1R agonists so should be considered in current therapeutic strategies.

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.

Tanycytes control hypothalamic liraglutide uptake and its anti-obesity actions.

Liraglutide, an anti-diabetic drug and agonist of the glucagon-like peptide one receptor (GLP1R), has recently been approved to treat obesity in individuals with or without type 2 diabetes. Despite its extensive metabolic benefits, the mechanism and site of action of liraglutide remain unclear. Here, we demonstrate that liraglutide is shuttled to target cells in the mouse hypothalamus by specialized ependymoglial cells called tanycytes, bypassing the blood-brain barrier. Selectively silencing GLP1R in tanycytes or inhibiting tanycytic transcytosis by botulinum neurotoxin expression not only hampers liraglutide transport into the brain and its activation of target hypothalamic neurons, but also blocks its anti-obesity effects on food intake, body weight and fat mass, and fatty acid oxidation. Collectively, these striking data indicate that the liraglutide-induced activation of hypothalamic neurons and its downstream metabolic effects are mediated by its tanycytic transport into the mediobasal hypothalamus, strengthening the notion of tanycytes as key regulators of metabolic homeostasis.

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.

Olfactory dysfunction in type II diabetes: Therapeutic options and lessons learned from other etiologies - A scoping review.

INTRODUCTION: Olfactory dysfunction (OD) is highly prevalent amongst type 2 diabetes mellitus (DM2) patients and has many associated health risks. For example, OD can lead to poor nutrition, safety issues related to diminished hazard detection, and increased mortality rates. While limited research exists about therapeutics for DM2-associated OD, recovery of olfactory function is better studied in other pathologic states. The objectives of this scoping review are to synthesize the existing data on interventions for DM2-associated OD and present the evidence for therapies that have been utilized for non-DM2-associated causes of OD. Additionally, the potential therapeutic opportunities for patients with DM2 are explored. METHODS: A scoping review was conducted with a medical librarian to identify studies investigating treatments of DM2-related OD. 6 databases were searched (Embase, CINAHL, the Cochrane Library, Google Scholar, OVID Medline, and Web of Science). Studies were eligible if the primary discussion involved treatment of olfactory deficits in the context of DM2. All publication dates were included, and studies published in languages other than English were excluded. RESULTS: 3631 articles were identified; 3 articles met inclusion criteria and underwent full text review. Hyperbaric oxygen (HBO), the DPP-4 inhibitor Linagliptin and the GLP-1 agonists Exenatide and Liraglutide are the only therapeutics that have been used in the context of DM2. Only HBO and GLP-1 agonists produced statistically significant improvements in olfactory identification. The literature regarding non-DM2-associated OD supports interventions such as olfactory training, dietary supplements, and intranasal insulin. Specifically, olfactory training was very effective in many contexts such as post-viral and traumatic OD while being affordable and non-invasive. CONCLUSION: This scoping review of olfactory rehabilitation options for DM2-induced OD demonstrates a paucity of prospective investigations of plausible therapeutics. Additionally, treatments for OD related to non-DM2-associated etiologies, such as olfactory training, are well-studied, efficacious, and should be investigated in the context of DM2. Future investigation has the potential to enhance the quality of clinical intervention for OD and improve short- and long-term outcomes for DM2 patients.

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.

Liraglutide Counteracts Endoplasmic Reticulum Stress in Palmitate-Treated Hypothalamic Neurons without Restoring Mitochondrial Homeostasis.

One feature of high-fat diet-induced neurodegeneration in the hypothalamus is an increased level of palmitate, which is associated with endoplasmic reticulum (ER) stress, loss of CoxIV, mitochondrial fragmentation, and decreased abundance of MC4R. To determine whether antidiabetic drugs protect against ER and/or mitochondrial dysfunction by lipid stress, hypothalamic neurons derived from pre-adult mice and neuronal Neuro2A cells were exposed to elevated palmitate. In the hypothalamic neurons, palmitate exposure increased expression of ER resident proteins, including that of SERCA2, indicating ER stress. Liraglutide reverted such altered ER proteostasis, while metformin only normalized SERCA2 expression. In Neuro2A cells liraglutide, but not metformin, also blunted dilation of the ER induced by palmitate treatment, and enhanced abundance and expression of MC4R at the cell surface. Thus, liraglutide counteracts, more effectively than metformin, altered ER proteostasis, morphology, and folding capacity in neurons exposed to fat. In palmitate-treated hypothalamic neurons, mitochondrial fragmentation took place together with loss of CoxIV and decreased mitochondrial membrane potential (MMP). Metformin, but not liraglutide, reverted mitochondrial fragmentation, and both liraglutide and metformin did not protect against either loss of CoxIV abundance or MMP. Thus, ER recovery from lipid stress can take place in hypothalamic neurons in the absence of recovered mitochondrial homeostasis.

Growth Promotion and Increased ATP-Binding Cassette Transporters Expression by Liraglutide in Triple Negative Breast Cancer Cell Line MDA-MB-231.

BACKGROUND: Glucagon-like petide-1 (GLP-1) agonists such as liraglutide are widely employed in type 2 diabetes due to their glucose reducing properties and small risk of hypoglycemia. Recently, it has been shown that GLP-1agonists can inhibit breast cancer cells growth. Nonetheless, concerns are remained about liraglutide tumor promoting effects as stated by population studies. MATERIAL AND METHODS: We evaluated the effects liraglutide on proliferation of MDA-MB-231 cells by MTT assay and then ATP-binding cassette (ABC) transporters expressions assessed by Real time PCR. Statistical comparisons were made using one-way analysis of variance followed by a post hoc Dunnett test. RESULTS: Here, we report that liraglutide can stimulate the growth of highly invasive triple negative cell line MDA-MB-231; which can be attributed to AMPK-dependent epithelial-mesenchymal transition (EMT) happening in MDA-MB-231 context. Toxicity effects were only observed with concentrations far above the serum liraglutide concentration. ATP-binding cassette (ABC) transporters expressions were upregulated, indicating the possible drug resistance and increased EMT. CONCLUSION: In conclusion, these results suggest that liraglutide should be used with caution in patients who are suffering or have the personal history of triple negative breast cancer. However, more detailed studies are required to deepen understanding of liraglutide consequences in triple negative breast cancer. ▶Graphical Abstract.

Roux-en-Y Gastric Bypass and Caloric Restriction but Not Gut Hormone-Based Treatments Profoundly Impact the Hypothalamic Transcriptome in Obese Rats.

BACKGROUND: The hypothalamus is an important brain region for the regulation of energy balance. Roux-en-Y gastric bypass (RYGB) surgery and gut hormone-based treatments are known to reduce body weight, but their effects on hypothalamic gene expression and signaling pathways are poorly studied. METHODS: Diet-induced obese male Wistar rats were randomized into the following groups: RYGB, sham operation, sham + body weight-matched (BWM) to the RYGB group, osmotic minipump delivering PYY3-36 (0.1 mg/kg/day), liraglutide s.c. (0.4 mg/kg/day), PYY3-36 + liraglutide, and saline. All groups (except BWM) were kept on a free choice of high- and low-fat diets. Four weeks after interventions, hypothalami were collected for RNA sequencing. RESULTS: While rats in the RYGB, BWM, and PYY3-36 + liraglutide groups had comparable reductions in body weight, only RYGB and BWM treatment had a major impact on hypothalamic gene expression. In these groups, hypothalamic leptin receptor expression as well as the JAK-STAT, PI3K-Akt, and AMPK signaling pathways were upregulated. No significant changes could be detected in PYY3-36 + liraglutide-, liraglutide-, and PYY-treated groups. CONCLUSIONS: Despite causing similar body weight changes compared to RYGB and BWM, PYY3-36 + liraglutide treatment does not impact hypothalamic gene expression. Whether this striking difference is favorable or unfavorable to metabolic health in the long term requires further investigation.

Glucagon-Like Peptide-1 Analog Liraglutide Attenuates Pressure-Overload Induced Cardiac Hypertrophy and Apoptosis through Activating ATP Sensitive Potassium Channels.

PURPOSE: This study aimed to investigate whether inhibition of glucagon-like peptide-1 (GLP-1) on pressure overload induced cardiac hypertrophy and apoptosis is related to activation of ATP sensitive potassium (KATP) channels. METHODS: Male SD rats were randomly divided into five groups: sham, control (abdominal aortic constriction), GLP-1 analog liraglutide (0.3 mg/kg/twice day), KATP channel blocker glibenclamide (5 mg/kg/day), and liraglutide plus glibenclamide. RESULTS: Relative to the control on week 16, liraglutide upregulated protein and mRNA levels of KATP channel subunits Kir6.2/SUR2 and their expression in the myocardium, vascular smooth muscle, aortic endothelium, and cardiac microvasculature. Consistent with a reduction in aortic wall thickness (61.4 ± 7.6 vs. 75.0 ± 7.6 µm, p < 0.05), liraglutide enhanced maximal aortic endothelium-dependent relaxation in response to acetylcholine (71.9 ± 8.7 vs. 38.6 ± 4.8%, p < 0.05). Along with a reduction in heart to body weight ratio (2.6 ± 0.1 vs. 3.4 ± 0.4, mg/g, p < 0.05) by liraglutide, hypertrophied cardiomyocytes (371.0 ± 34.4 vs. 933.6 ± 156.6 µm2, p < 0.05) and apoptotic cells (17.5 ± 8.2 vs. 44.7 ± 7.9%, p < 0.05) were reduced. Expression of anti-apoptotic protein BCL-2 and contents of myocardial ATP were augmented, and expression of cleaved-caspase 3 and levels of serum Tn-I/-T were reduced. Echocardiography and hemodynamic measurement showed that cardiac systolic function was enhanced as evidenced by increased ejection fraction (88.4 ± 4.8 vs. 73.8 ± 5.1%, p < 0.05) and left ventricular systolic pressure (105.2 ± 10.8 vs. 82.7 ± 7.9 mmHg, p < 0.05), and diastolic function was preserved as shown by a reduction of ventricular end-diastolic pressure (-3.1 ± 2.9 vs. 6.7 ± 2.8 mmHg, p < 0.05). Furthermore, left ventricular internal diameter at end-diastole (5.8 ± 0.5 vs. 7.7 ± 0.6 mm, p < 0.05) and left ventricular internal diameter at end-systole (3.0 ± 0.6 vs. 4.7 ± 0.4 mm, p < 0.05) were improved. Dietary administration of glibenclamide alone did not alter all the parameters measured but significantly blocked liraglutide-exerted cardioprotection. CONCLUSION: Liraglutide ameliorates cardiac hypertrophy and apoptosis, potentially via activating KATP channel-mediated signaling pathway. These data suggest that liraglutide might be considered as an adjuvant therapy to treat patients with heart failure.

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.

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.

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.