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Glucagon-like peptide-1 (GLP-1) and its analogs are widely used for diabetes treatment. The paraventricular nucleus (PVN) is crucial for regulating cardiovascular activity. This study aims to determine the roles of GLP-1 and its receptors (GLP-1R) in the PVN in regulating sympathetic outflow and blood pressure. Experiments were carried out in male normotensive rats and spontaneously hypertensive rats (SHR). Renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) were recorded. GLP-1 and GLP-1R expressions were present in the PVN. PVN microinjection of GLP-1R agonist recombinant human GLP-1 (rhGLP-1) or EX-4 increased RSNA and MAP, which were prevented by GLP-1R antagonist exendin 9-39 (EX9-39) or GLP-1R antagonist 1, superoxide scavenger tempol, antioxidant N-acetylcysteine, NADPH oxidase (NOX) inhibitor apocynin, adenylyl cyclase (AC) inhibitor SQ22536 or protein kinase A (PKA) inhibitor H89. PVN microinjection of rhGLP-1 increased superoxide production, NADPH oxidase activity, cAMP level, AC, and PKA activity, which were prevented by SQ22536 or H89. GLP-1 and GLP-1R were upregulated in the PVN of SHR. PVN microinjection of GLP-1 agonist increased RSNA and MAP in both WKY and SHR, but GLP-1 antagonists caused greater effects in reducing RSNA and MAP in SHR than in WKY. The increased superoxide production and NADPH oxidase activity in the PVN of SHR were augmented by GLP-1R agonists but attenuated by GLP-1R antagonists. These results indicate that activation of GLP-1R in the PVN increased sympathetic outflow and blood pressure via cAMP-PKA-mediated NADPH oxidase activation and subsequent superoxide production. GLP-1 and GLP-1R upregulation in the PVN partially contributes to sympathetic overactivity and hypertension., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 the authors.)

Obesity is a major public health crisis. Multi-specific peptides have emerged as promising therapeutic strategies for clinical weight loss. Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are endogenous incretins that regulate weight through their receptors (R). AMG 133 (maridebart cafraglutide) is a bispecific molecule engineered by conjugating a fully human monoclonal anti-human GIPR antagonist antibody to two GLP-1 analogue agonist peptides using amino acid linkers. Here, we confirm the GIPR antagonist and GLP-1R agonist activities in cell-based systems and report the ability of AMG 133 to reduce body weight and improve metabolic markers in male obese mice and cynomolgus monkeys. In a phase 1, randomized, double-blind, placebo-controlled clinical study in participants with obesity ( NCT04478708 ), AMG 133 had an acceptable safety and tolerability profile along with pronounced dose-dependent weight loss. In the multiple ascending dose cohorts, weight loss was maintained for up to 150 days after the last dose. These findings support continued clinical evaluation of AMG 133., (© 2024. The Author(s).)

Aims: To describe the effect of three classes of GLP1 analogues on HbA1c and weight over one year in a homogenous group of patients at the Dubai Diabetes Center in Dubai, United Arab Emirates. The specific objectives are to study the extent of change in HbA1c and weight loss on these medications as well as the sustainability of change over one year., Methods: A retrospective audit of patients diagnosed Type 2 diabetes receiving one of the three following GLP-1 agonists (Exenatide LA 2 mg weekly, liraglutide 1.8 mg once daily, Dulaglutide 1.5 mg) over one year and documenting changes in HbA1c and weight at 3-, 6-, 9-, and 12-months intervals., Results: The study shows that while there was significant reduction in HbA1c and weight in the first 3 months, this change was not clinically significant. Also, the change was not maintained at the end of the year. By the final quarter, the effect of the medication diminishes, accompanied by a partial regain of weight., Conclusion: GLP1 agonists favorable initial effect on HbA1c and weight may not be sustainable beyond a certain period. The exact reason and factors contributing to this need further exploration., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Introduction: Metabolic dysfunction-associated steatohepatitis (MASH) is highly prevalent in type 2 diabetes (T2D). Pioglitazone and glucagon-like peptide-1 receptor agonists (GLP-1RA) are medications used in T2D that can resolve MASH and should be considered in all patients with T2D and MASH. We assessed prescription rates of evidence-based T2D pharmacotherapy (EBP) in MASH, and ascertained racial/ethnic disparities in prescribing., Research Design and Methods: We conducted a cross-sectional study on patients in Duke University Health System with diagnosis codes for T2D and MASH between January 2019 and January 2021. Only patients with ≥1 primary care or endocrinology encounter were included. The primary outcome was EBP, defined as ≥1 prescription for pioglitazone and/or a GLP-1RA during the study period. A multivariable logistic regression model was used to examine the primary outcome., Results: A total of 847 patients with T2D and MASH were identified; mean age was 59.7 (SD 12) years, 61.9% (n=524) were female, and 11.9% (n=101) and 4.6% (n=39) were of Black race and Latino/a/x ethnicity, respectively. EBP was prescribed in 34.8% (n=295). No significant differences were noted in the rates of EBP use across racial/ethnic groups (Latino/a/x vs White patients: adjusted OR (aOR) 1.82, 95% CI 0.78 to 4.28; Black vs White patients: aOR 0.76, 95% CI 0.44 to 1.33, p=0.20)., Conclusions: EBP prescriptions, especially pioglitazone, are low in patients with T2D and MASH, regardless of race/ethnicity. These data underscore the need for interventions to close the gap between current and evidence-based care., Competing Interests: Competing interests: CM has consulted for NovoNordisk and has served on the advisory board for Boehringer Ingelheim, Inc. CM has also received grants from GlaxoSmithKline, Exact Sciences and Madrigal to conduct research at Duke University. All other authors declare no competing interests with this work., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Congenital hyperinsulinism (HI) is a genetic disorder in which pancreatic β-cell insulin secretion is excessive and results in hypoglycemia that, without treatment, can cause brain damage or death. Most patients with loss-of-function mutations in ABCC8 and KCNJ11, the genes encoding the β-cell ATP-sensitive potassium channel (KATP), are unresponsive to diazoxide, the only U.S. Food and Drug Administration-approved medical therapy and require pancreatectomy. The glucagon-like peptide 1 receptor (GLP-1R) antagonist exendin-(9-39) is an effective therapeutic agent that inhibits insulin secretion in both HI and acquired hyperinsulinism. Previously, we identified a highly potent antagonist antibody, TB-001-003, which was derived from our synthetic antibody libraries that were designed to target G protein-coupled receptors. Here, we designed a combinatorial variant antibody library to optimize the activity of TB-001-003 against GLP-1R and performed phage display on cells overexpressing GLP-1R. One antagonist, TB-222-023, is more potent than exendin-(9-39), also known as avexitide. TB-222-023 effectively decreased insulin secretion in primary isolated pancreatic islets from a mouse model of hyperinsulinism, Sur1-/- mice, and in islets from an infant with HI, and increased plasma glucose levels and decreased the insulin to glucose ratio in Sur1-/- mice. These findings demonstrate that targeting GLP-1R with an antibody antagonist is an effective and innovative strategy for treatment of hyperinsulinism., Article Highlights: Patients with the most common and severe form of diazoxide-unresponsive congenital hyperinsulinism (HI) require a pancreatectomy. Other second-line therapies are limited in their use because of severe side effects and short half-lives. Therefore, there is a critical need for better therapies. Studies with the glucagon-like peptide 1 receptor (GLP-1R) antagonist, avexitide (exendin-(9-39)), have demonstrated that GLP-1R antagonism is effective at lowering insulin secretion and increasing plasma glucose levels. We have optimized a GLP-1R antagonist antibody with more potent blocking of GLP-1R than avexitide. This antibody therapy is a potential novel and effective treatment for HI., (© 2023 by the American Diabetes Association.)

Aims: Injectable medicines are increasingly used to manage risk factors for cardiovascular (CV) events, such as dyslipidaemia and diabetes. These include proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists. Little is known about perceptions of injectable therapies among CV healthcare professionals (HCPs). This study explores their views to identify relevant facilitators and barriers to the use of injectables with CV benefit., Methods and Results: A 22-question survey was distributed internationally via online channels. In total, 192 anonymous responses were received (43.7% physicians, 32.6% nurses, 16.8% pharmacists, 6.8% others). Among respondents with experience of these medicines, 69.1% had used an injectable PCSK9 inhibitor and 67.0% had used an injectable GLP-1 receptor agonist. Commonly raised issues were resource problems (36.5%), lack of knowledge among colleagues (32.3%), paperwork (32.3%), and lack of patient knowledge (28.1%). Key barriers respondents felt made patients decline these treatments were fear of injection (56.6%), lack of awareness or education (26.4%), and administration issues (15.1%); potential reasons for discontinuation included side effects (46.4%), perceived lack of benefit (28.6%), and local reactions (21.4%). The main topics around injectables requiring further support included managing non-adherent patients (16.2%), troubleshooting with patients (16.2%), and educating colleagues about injectables (12.2%). Preferred educational methods to support HCPs were face-to-face training (43.5%) and online learning (26.1%); favoured formats were based on role playing and case studies., Conclusion: Healthcare professionals highlighted various potential barriers to initiation, continuation, and adherence with injectable therapies in CV medicine. Although some require healthcare system changes, many could be addressed through simple measures based primarily on enhanced training and support for patients and HCPs., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

An absolute or relative deficiency of pancreatic β-cells mass and functionality is a crucial pathological feature common to type 1 diabetes mellitus and type 2 diabetes mellitus. Glucagon-like-peptide-1 receptor (GLP1R) agonists have been the focus of considerable research attention for their ability to protect β-cell mass and augment insulin secretion with no risk of hypoglycemia. Presently commercially available GLP1R agonists are peptides that limit their use due to cost, stability, and mode of administration. To address this drawback, strategically designed distinct sets of small molecules were docked on GLP1R ectodomain and compared with previously known small molecule GLP1R agonists. One of the small molecule PK2 (6-((1-(4-nitrobenzyl)-1H-1,2,3-triazol-4-yl)methyl)-6H-indolo[2,3-b]quinoxaline) displays stable binding with GLP1R ectodomain and induces GLP1R internalization and increasing cAMP levels. PK2 also increases insulin secretion in the INS-1 cells. The oral administration of PK2 protects against diabetes induced by multiple low-dose streptozotocin administration by lowering high blood glucose levels. Similar to GLP1R peptidic agonists, treatment of PK2 induces β-cell replication and attenuate β-cell apoptosis in STZ-treated mice. Mechanistically, this protection was associated with decreased thioredoxin-interacting protein expression, a potent inducer of diabetic β-cell apoptosis and dysfunction. Together, this report describes a small molecule, PK2, as an orally active nonpeptidic GLP1R agonist that has efficacy to preserve or restore functional β-cell mass., Competing Interests: Conflict of interest No potential conflicts of interest relevant to this article were reported., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Whether the cardiorenal benefits of sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide 1 receptor agonists (GLP-1RAs) are comparable between White and Asian populations remains unclear., Purpose: To compare the cardiorenal benefits of SGLT2 inhibitors and GLP-1RAs between White and Asian populations and to compare the cardiorenal benefits between the two agents in Asian patients., Data Sources: Electronic databases were searched up to 28 March 2021., Study Selection: We included the cardiovascular (CV) and renal outcome trials of SGLT2 inhibitors and GLP-1RAs where investigators reported major adverse CV events (MACE), CV death/hospitalization for heart failure (HHF), or composite renal outcomes with stratification by race., Data Extraction: We extracted the hazard ratio of each outcome stratified by race (Asian vs. White populations)., Data Synthesis: In 10 SGLT2 inhibitor trials, there was no significant difference between Asian and White populations for MACE (P = 0.55), CV death/HHF (P = 0.87), or composite renal outcomes (P = 0.97). In seven GLP-1RA trials, we observed a similar MACE benefit between Asian and White populations (P = 0.10). In our networkmeta-analysis we found a comparable benefit for MACE between SGLT2 inhibitors and GLP-1RAs in Asian patients., Limitations: The data were from stratified analyses., Conclusions: There appear to be comparable cardiorenal benefits of SGLT2 inhibitors and GLP-1RAs between Asian and White participants enrolled in CV and renal outcome trials; the two therapies seem to have similar CV benefits for Asian participants., (© 2022 by the American Diabetes Association.)

Aims: Glucagon-like peptide-1 alleviates the deleterious effects of advanced glycation end products (AGEs), but the underlying mechanisms are not fully understood. In this study, we investigated the protective mechanism using liraglutide, a glucagon-like peptide-1 receptor agonist, in cultured human aortic endothelial cells (HAECs)., Main Methods: Following liraglutide treatment in HAECs, the receptor for AGEs (RAGE) was measured in both cell lysate and culture supernatant, the cytosolic free Ca 2+ level was monitored using Fluo-4 AM, the phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) was analyzed, and immunofluorescence staining was used to visualize a disintegrin and metalloprotease 10 (ADAM10) on the cell surface., Key Findings: Liraglutide (100 nM) induced ectodomain shedding of RAGE within 30 min and inhibited the expression of intercellular adhesion molecule-1 (ICAM-1) induced by AGEs of bovine serum albumin (AGE-BSA). Further experiments revealed that liraglutide rapidly increases extracellular Ca 2+ influx through L-type calcium channels and activates AMPK, resulting in the translocation of ADAM10 to the cell surface, whereas siRNA-mediated ADAM10 depletion prevents liraglutide-induced ectodomain shedding of RAGE and eliminates liraglutide's inhibitory effect on AGE-BSA-induced ICAM-1 expression. Moreover, compound C-mediated AMPK inhibition and siRNA-mediated AMPK depletion both prevented ADAM10 translocation to the cell surface and ADAM10-mediated ectodomain shedding of RAGE., Significance: Liraglutide reduces the number of intact RAGE on the cell surface by inducing ADAM10-mediated ectodomain shedding, which decreases the inflammatory effects of AGEs. AMPK activated by extracellular Ca 2+ influx is critically involved in the translocation of ADAM10 to the cell surface, where it cleaves RAGE., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background/objectives: The weight loss following Semaglutide treatment, a GLP-1 receptor agonist, might be responsible for some effects observed on the nonalcoholic fatty liver disease of obese mice., Subjects/methods: Two groups of C57BL/6 male mice (n = 30/group) were fed the diets Control (C) or high-fat (HF) for 16 weeks. Then, separated into six new groups for an additional four weeks (n = 10/group) and treated with Semaglutide (S, 40 µg/kg) or paired feeding (PF) with S groups (C; C-S; C-PF; HF; HF-S; HF-PF)., Results: Semaglutide reduced energy consumption leading to weight loss. Simultaneously it improved glucose intolerance, glycated hemoglobin, insulin resistance/sensitivity, plasma lipids, and gastric inhibitory polypeptide. Semaglutide and paired feeding mitigated liver steatosis and adipose differentiation-related protein (Plin2) expression. Semaglutide also improved hormones and adipokines, reduced lipogenesis and inflammation, and increased beta-oxidation. Semaglutide lessened liver glucose uptake and endoplasmic reticulum (ER) stress. Among the 14 genes analyzed, 13 were modified by Semaglutide (93 %, six genes were changed exclusively by Semaglutide, and seven other genes were affected by the combination of Semaglutide and paired feeding). In seven genes, the paired diet showed no effect (50% of the genes tested). No marker was affected exclusively by paired feeding., Conclusions: Semaglutide and the consequent weight loss reduced obese mice liver inflammation, insulin resistance, and ER stress. However, weight loss alone did show few or no action on some significant study findings, like liver steatosis, leptin, insulin, resistin, and amylin. Furthermore, hepatic inflammation mediated by MCP-1 and partially by TNF-alpha and IL6 were also not reduced by weight loss. Furthermore, weight loss alone did not lessen hepatic lipogenesis as determined by the findings of SREBP-1c, CHREBP, PPAR-alpha, and SIRT1. Semaglutide was implicated in improving glucose uptake and lessening ER stress by reducing GADD45, independent of weight loss., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: In 2017, an estimated 7.4 million Americans used insulin to treat diabetes. Insulin is proven to lower A1c but can result in hypoglycemia and weight gain. Combining insulin with a glucagon-like peptide-1 receptor agonist (GLP-1-RA) may provide additional blood glucose control while limiting undesirable effects including weight gain., Objective: To characterize the clinical impact of adding a GLP-1-RA to a basal-bolus insulin regimen in patients with type 2 diabetes., Methods: This retrospective observational study used national Veteran's Health Administration data to identify patients with an existing basal-bolus insulin regimen who initiated a GLP-1-RA between January 1, 2005 and December 31, 2017. A1c, insulin total daily dose (TDD), and weight were collected at GLP-1-RA initiation (baseline), 3-, 6-, and 12-month time points and then analyzed using an intent-to-treat approach with the last observation carried forward. Decreases in A1c ≥ 0.5% and weight ≥2 kg were deemed clinically significant., Results: Among 7651 patients initiating GLP-1-RA therapy, mean A1c had a clinically significant decline at 3, 6, and 12 months by -0.5%, -0.7%, and -0.7%, respectively, from a mean baseline of 9%. Patients with lower baseline A1c levels did not have clinically significant changes in A1c, whereas patients with baseline A1c ≥9% had more clinically significant declines. Insulin TDD decreased by -32, -38, and -42 units/day at 3, 6, and 12 months, respectively, where the mean decrease in insulin TDD at 12 months was 79 units/day among patients who discontinued bolus insulin (52.3%) compared with a mean decrease of 2 units/day among those who continued bolus insulin. Mean weight reductions at 3, 6, and 12 months were -1.2, -2.3, and -2.9 kg, respectively, from a mean baseline of 120.6 kg., Conclusion: Combining a GLP-1-RA with basal-bolus insulin had a clinically significant improvement on blood glucose control, lowered insulin TDD, and reduced weight. These outcomes were achieved within 3 to 6 months following GLP-1-RA initiation and were maintained through 1 year., (© 2021 Pharmacotherapy Publications, Inc.)

Background/aim: Given their widespread use and their notorious effects on the lining of gut cells, including the enteroendocrine cells, we explored if chronic exposure to non-steroidal anti-inflammatory drugs (NSAIDs) affects metabolic balance in a mouse model of NSAID-induced enteropathy., Method: We administered variable NSAIDs to C57Blk/6J mice through intragastric gavage and measured their energy balance, glucose hemostasis, and GLP-1 levels. We treated them with Exendin-9 and Exendin-4 and ran a euglycemic-hyperinsulinemic clamp., Results: Chronic administration of multiple NSAIDs to C57Blk/6J mice induces ileal ulcerations and weight loss in animals consuming a high-fat diet. Despite losing weight, NSAID-treated mice exhibit no improvement in their glucose tolerance. Furthermore, glucose-stimulated (glucagon-like peptide -1) GLP-1 is significantly attenuated in the NSAID-treated groups. In addition, Exendin-9-a GLP-1 receptor antagonist-worsens glucose tolerance in the control group but not in the NSAID-treated group. Finally, the hyper-insulinemic euglycemic clamp study shows that endogenous glucose production, total glucose disposal, and their associated insulin levels were similar among an ibuprofen-treated group and its control. Exendin-4, a GLP-1 receptor agonist, reduces insulin levels in the ibuprofen group compared to their controls for the same glucose exchange rates., Conclusions: Chronic NSAID use can induce small intestinal ulcerations, which can affect intestinal GLP-1 production, hepatic insulin sensitivity, and consequently, hepatic glucose production.

In subjects with type 2 diabetes mellitus (T2DM), pancreatic β-cell mass decreases; however, it is unknown to what extent this decrease contributes to the pathophysiology of T2DM. Therefore, the development of a method for noninvasive detection of β-cell mass is underway. We previously reported that glucagon-like peptide-1 receptor (GLP-1R) is a promising target molecule for β-cell imaging. In this study, we attempted to develop a probe targeting GLP-1R for β-cell imaging using single-photon emission computed tomography (SPECT). For this purpose, we selected exendin-4 as the lead compound and radiolabeled lysine at residue 12 in exendin-4 or additional lysine at the C-terminus using [ 123 I]iodobenzoylation. To evaluate in vitro receptor specificity, binding assay was performed using dispersed mouse islet cells. Biodistribution study was performed in normal ddY mice. Ex vivo autoradiography was performed in transgenic mice expressing green fluorescent protein under control of the mouse insulin I gene promoter. Additionally, SPECT imaging was performed in normal ddY mice. The affinity of novel synthesized derivatives toward pancreatic β-cells was not affected by iodobenzoylation. The derivatives accumulated in the pancreas after intravenous administration specifically via GLP-1R expressed on the pancreatic β-cells. Extremely high signal-to-noise ratio was observed during evaluation of biodistribution of [ 123 I]IB12-Ex4. SPECT images using normal mice showed that [ 123 I]IB12-Ex4 accumulated in the pancreas with high contrast between the pancreas and background. These results indicate that [ 123 I]IB12-Ex4 for SPECT is useful for clinical applications because of its preferable kinetics in vivo., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Glucagon-like peptide-1 (GLP-1), a well-known insulin secretagogue, is released from enteroendocrine L cells both luminally and basolaterally to exert different effects. Basolaterally released GLP-1 increases epithelial ion transport by activating CGRP-containing enteric afferent neurons. Although bath-applied GLP-1 reduced the contractility of colonic segments, GLP-1-induced stimulation of afferent neurons could also accelerate peristaltic contractions. Here, the roles of endogenous GLP-1 in regulating colonic peristalsis were investigated using isolated colonic segments. Isolated segments of rat proximal colon were placed in an organ bath, serosally perfused with oxygenated physiological salt solution, and luminally perfused with degassed 0.9% saline. Colonic wall motion was recorded using a video camera and converted into spatiotemporal maps. Intraluminal administration of GLP-1 (100 nM) stimulating the secretion of GLP-1 from L cells increased the frequency of oro-aboral propagating peristaltic contractions. The acceleratory effect of GLP-1 was blocked by luminally applied exendin-3 (9-39) (100 nM), a GLP-1 receptor antagonist. GLP-1-induced acceleration of peristaltic contractions was also prevented by bath-applied BIBN4069 (1 μM), a CGRP receptor antagonist. In colonic segments that had been exposed to bath-applied capsaicin (100 nM) that desensitizes extrinsic afferents, GLP-1 was still capable of exerting its prokinetic effect. Stimulation of endogenous GLP-1 secretion with a luminally applied cocktail of short-chain fatty acids (1 mM) increased the frequency of peristaltic waves in an exendin-3 (9-39)-sensitive manner. Thus, GLP-1 activates CGRP-expressing intrinsic afferents to accelerate peristalsis in the proximal colon. Short-chain fatty acids appear to stimulate endogenous GLP-1 secretion from L cells resulting in the acceleration of colonic peristalsis. NEW & NOTEWORTHY Glucagon-like peptide-1 (GLP-1) activates CGRP-containing intrinsic afferent neurons resulting in the acceleration of colonic peristalsis. Short-chain fatty acids stimulate the secretion of endogenous GLP-1 from L cells that accelerates colonic peristalsis. Thus, besides the well-known humoral insulinotropic action, GLP-1 exerts a local action via the activation of the enteric nervous system to accelerate colonic motility. Such a prokinetic action of GLP-1 could underlie the mechanisms causing diarrhea in patients with type-2 diabetes treated with GLP-1 analogs.

Patients with type 2 diabetes mellitus (T2DM) show an increased risk of cardiovascular diseases (CVD) and mortality. Many factors are implicated in the pathogenesis of CVD in patients with T2DM. Among the factors involved, chronic hyperglycemia and the cluster of CVD risk factors, such as dyslipidemia, hypertension, and obesity, play a major role. For many years, the control of hyperglycemia has been complicated by the fact that the use of many available drugs was associated with an increased risk of hypoglycemia. Paradoxically, hypoglycemia per se represents a risk factor for CVD. Recently, new drugs for the control of hyperglycemia have become available: many of them can determine a good control of hyperglycemia with minor risks of hypoglycemia. Among these new classes of drugs, glucagon-like peptide-1 receptor agonists (GLP-1RAs) offer many advantages. In addition to a strong anti-hyperglycemic action, they possess the ability to act on body weight and other relevant risk factors for CVD. Consistently, some of the GLP-1RAs have demonstrated, in RCT designed to assess their safety, to reduce the risk of major adverse cardiovascular events. Furthermore, GLP-1RAs possess properties useful to treat additional conditions, as the capability of improving liver damage in patients with NAFLD or NASH, highly prevalent conditions in people with T2DM. In this document, written by experts of the Italian diabetes society (SID), we will focus our attention on the therapy with GLP-1RAs in patients with T2DM, particularly on the effects on hyperglycemia, cardiovascular disease risk factors, NAFLD/NASH and CVD prevention., Competing Interests: Declaration of competing interest The authors have nothing to disclose., (Copyright © 2021 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Aims: Metabolic dysfunction-associated fatty liver disease (MAFLD) is common in people with type 2 diabetes (T2D) and can progress to advanced fibrosis and cirrhosis. In this retrospective study, we explored the longitudinal changes in markers of hepatic steatosis and fibrosis during T2D treatment with glucagon-like peptide-1 receptor agonists (GLP-1RAs)., Methods: We analysed observational data from six diabetes outpatient clinics. In the whole T2D population, we calculated the hepatic steatosis index (HSI), which we previously validated against liver ultrasonography, and the Fibrosis (Fib)-4 index. We then identified patients who initiated a GLP-1RA from 2010 to 2018 and for whom data were available to evaluate changes in both HSI and Fib-4 scores over 24 months., Results: From 83,116 outpatients with T2D, 41,302 (49.7%) had complete data for calculating HSI and Fib-4. Most of these T2D patients (∼70%) had MAFLD (defined as HSI>36), 9.7% of whom had advanced fibrosis based on Fib-4 thresholds. Patients with low compared to high risk of advanced fibrosis were 5-times more likely to be treated with GLP-1RA. In 535 patients who initiated a GLP-1RA, the prevalence of MAFLD based on HSI declined significantly at 6 and 24 months, but Fib-4 categories did not. HSI improved significantly only in patients receiving human-based but not exendin-based GLP-1RA, while patients concomitantly receiving metformin had less worsening in Fib-4 categories., Conclusions: MAFLD is very common among outpatients with T2D (∼70%) and the estimated prevalence of advanced fibrosis was ∼10%. Treatment with GLP-1RAs significantly improved MAFLD, but not MAFLD-associated advanced fibrosis., Competing Interests: Declaration of competing interest MLM received grant support, lecture fees, or advisory board fees from Servier, Eli Lilly, Novo Nordisk, Merck Sharp & Dohme, Amryt, and Mylan. MR received lecture and advisory board fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Mundipharma, Novo Nordisk. VF served as consultant for NovoNordisk. NS received lecture or consultancy fees from Astra-Zeneca, Boehringer-Lilly, Novartis, NovoNordisk, Sanofi-Aventis, Takeda, Merck Sharp & Dohme, and Abbott and research support from NovoNordisk. AL received grant support, lecture or advisory board fees from Novo Nordisk, Sanofi, Abbott, and Eli Lilly. AA received research grants, lecture fees, or advisory board fees from Merck Sharp & Dome, AstraZeneca, Novartis, Boehringer Ingelheim, Sanofi, Mediolanum, Janssen, Novo Nordisk, Eli Lilly, Servier, and Takeda. GPF. received grant support, lecture fees, or advisory board fees from Abbott, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Novartis, Novo Nordisk, Sanofi, Genzyme, Servier, and Merck Sharp & Dohme. The remaining authors have nothing to disclose., (Copyright © 2021 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and dipeptidyl peptidase-4 inhibitors (DPP4is) exert their effects via the incretin system, which augments glucose-dependent insulin secretion in response to nutrient intake (the 'incretin effect'). Both classes are well-established pharmacologic options for the management of glycemic control in individuals with type 2 diabetes (T2D) after failure of first-line metformin; however, they have inherent differences in their mechanisms of action that are reflected in their clinical safety and efficacy profiles. GLP-1RAs have high glycemic efficacy and are associated with weight loss and, in some cases, cardioprotective effects, with a side-effect profile of predominantly transient gastrointestinal adverse events. Most GLP-1RAs are administered as subcutaneous injection, although an oral formulation of one GLP-1RA, semaglutide, has recently become available. DPP4is provide moderate glycemic control, are weight-neutral, and do not offer any cardiovascular benefits, but are generally well tolerated. DPP4is are all administered orally. This narrative review aims to provide guidance for a primary care audience on the similarities and differences between GLP-1RA and DPP4i therapies, with a focus on their mechanism of action, clinical safety, efficacy, and real-world effectiveness. The role of incretin-based therapies in the T2D treatment paradigm, including key considerations for guiding treatment decisions, will also be discussed.

Introduction: Sodium Glucose Co-transporter 2 inhibitors and glucagon-like peptide 1 receptor agonists (GLP-1RAs) were associated with a reduction in cardiovascular disease events in cardiovascular outcomes trials (CVOTs) in type 2 diabetes. Most of the patients included in these trials received metformin as background therapy., Aim: To evaluate the effect of glucagon-like peptide 1 receptor agonists on major cardiovascular events (MACE) and mortality in metformin-naïve patients with type 2 diabetes., Methods: A systematic review and meta-analysis of randomized controlled clinical trials of GLP-1RAs on type 2 diabetes population was performed, after searching the PubMed/MEDLINE, Embase, Scielo, Google Scholar and Cochrane Controlled Trials databases. The primary endpoint was MACE. The secondary endpoints were cardiovascular death and all-cause mortality. A meta-analysis of time-to-event outcomes was performed. This meta-analysis was registered in PROSPERO (CRD42021260040) RESULTS: Seven trials, including 11510 patients, were identified and considered eligible for the analyses. GLP-1RAs were associated with a significant reduction in MACE incidence (HR: 0.86, 95% confidence interval: 0.79-0.94; I 2 : 0%). The secondary endpoints analysis showed a non-significant reduction in all-cause mortality (HR: 0.86, 95% confidence interval: 0.73-1.00 I 2 : 0%) and cardiovascular mortality (HR: 0.81, 95% confidence interval: 0.63-1.05; I 2 : 0%)., Conclusions: In this meta-analysis, GLP-1RAs reduced the incidence of MACE in patients with type 2 diabetes without metformin at baseline, without significant reduction in all-cause mortality and cardiovascular mortality. These results support the fact that when a GLP-1RAs is administered, the benefit on cardiovascular outcomes is independent of the use of metformin., (© 2021. Italian Society of Hypertension.)

Background: In international trials, glucagon-like protein-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2Is) were effective in improving cardiovascular (CV) outcomes., Methods: We assessed the effect of GLP-1RAs and SGLT2Is treatment effect on CV endpoints by geographical region in multiple international trials using random effects weighted least squares meta-regressions., Results: The estimated effects of both SGLT2Is and GLP-1RAs on major adverse CV events (MACE) in North America (SGLT2Is n = 12,399, HR 0.90, 95% CI 0.81-1.01; GLP-1RAs n = 12,515, HR 0.95, 95% CI 0.83- 1.09) and in Europe (SGLT2Is n = 19,435, HR 0.93, 95% CI 0.85-1.02; GLP-1RAs n = 22,812, HR 0.88, 95% CI 0.79-0.99) were numerically lower but not statistically different to the rest of the world (ROW) (SGLT2Is n = 15,127, HR 0.83, 95% CI 0.75-0.92, p-value for interaction 0.26; GLP-1RAs n = 17,494, HR 0.82, 95% CI 0.73-0.92, p-value for interaction 0.28). Effects of SGLT2Is on heart failure readmission or CV death varied significantly by region (P = 0.0094). The effect of SGLT2Is was significantly smaller in Europe (n = 18,653, HR 0.86, 95% CI 0.78-0.95) than in the ROW (n = 12,463, HR 0.68, 95% CI 0.61-0.76, P = 0.0024). The smaller effect in North America (n = 9776, HR 0.76, 95% CI 0.66-0.87) did not differ significantly from that in the ROW (P = 0.2370)., Conclusion: The effects of SGLT2Is on HF events are larger in the ROW. Further analyses and studies are needed to better elucidate the differential effects of SGLTIs and GLP-1RAs by geographical regions., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Incretin-potentiated glucose-stimulated insulin secretion (GSIS) is critical to maintaining euglycemia, of which GLP-1 receptor (GLP-1R) on β-cells plays an indispensable role. Recently, α-cell-derived glucagon but not intestine-derived GLP-1 has been proposed as the critical hormone that potentiates GSIS via GLP-1R. However, the function of glucagon receptors (GCGR) on β-cells remains elusive. Here, using GCGR or GLP-1R antagonists, in combination with glucagon, to treat single β-cells, α-β cell clusters and isolated islets, we found that glucagon potentiates insulin secretion via β-cell GCGR at physiological but not high concentrations of glucose. Furthermore, we transfected primary mouse β-cells with RAB-ICUE (a genetically encoded cAMP fluorescence indicator) to monitor cAMP level after glucose stimulation and GCGR activation. Using specific inhibitors of different adenylyl cyclase (AC) family members, we revealed that high glucose concentration or GCGR activation independently evoked cAMP elevation via AC5 in β-cells, thus high glucose stimulation bypassed GCGR in promoting insulin secretion. Additionally, we generated β-cell-specific GCGR knockout mice which glucose intolerance was more severe when fed a high-fat diet (HFD). We further found that β-cell GCGR activation promoted GSIS more than GLP-1R in HFD, indicating the critical role of GCGR in maintaining glucose homeostasis during nutrient overload.

Objectives: Chronic inflammation has been identified as an important driver of cardiovascular disease in type 2 diabetes (T2D) and can lead to a higher risk of cardiovascular events and rehospitalization. Empagliflozin or liraglutide represent 2 classes of drugs with proven efficacy in the treatment of T2D to reduce macrovascular complications; however, the exact mechanism behind their cardioprotective properties remains incompletely understood. The nucleotide-binding and oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is implicated in the progression of cardiovascular disease and linked to the progression of cardiovascular risk factors, such as T2D., Methods: We set out to determine whether the sodium-glucose cotransporter-2 inhibitor, empagliflozin, or the glucagon-like peptide-1 receptor antagonist, liraglutide, modified components of NLRP3 in a rodent model of T2D, which recapitulates many of the features of humans with T2D. Empagliflozin and liraglutide were used for 8 weeks in a 32-week-old rat model of T2D and compared with an age- and sex-matched control. After treatment, left ventricular tissue samples and blood plasma were obtained for immunoblotting and an interleukin-1β enzyme-linked immunossay. NLRP3, apoptosis-associated speck-like protein, pro-caspase-1 as well as the cleaved caspase-1 subunits p12 and p10 were assessed by Western blot., Results: Goto-Kakizaki rats demonstrated increased NLRP3 inflammasome activation, but neither empagliflozin nor liraglutide demonstrated any impact across the NLRP3 inflammasome pathways or interleukin-1β levels., Conclusions: The data suggest that the cardioprotective benefits demonstrated by sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor antagonists occur independently of the NLRP3 inflammasome., (Copyright © 2020 Canadian Diabetes Association. Published by Elsevier Inc. All rights reserved.)

Background: Sodium glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide 1 receptor agonists (GLP-1 RAs) have been demonstrated to be able to improve the cardiovascular and renal prognosis in patients with type 2 diabetes (T2D). However, the relative efficacy of various SGLT2 inhibitors and GLP-1 RAs on cardiorenal outcomes is unestablished., Methods: We searched PubMed and Embase for relevant cardiovascular or renal outcome trials (CVOTs). Endpoints of interest were major adverse cardiovascular events (MACE), stroke, myocardial infarction (MI), cardiovascular death (CVD), all-cause death (ACD), kidney function progression (KFP), and hospitalization for heart failure (HHF). Bayesian network meta-analysis was conducted to produce pooled hazard ratio (HR) and 95% confidence interval (CI). We calculated the probability values of surface under the cumulative ranking curve to rank active and placebo interventions., Results: Fourteen COVTs were included in analysis. Sotagliflozin (HR 0.76, 95% CI 0.61-0.94), subcutaneous semaglutide, and albiglutide lowered MACE versus lixisenatide among others. Sotagliflozin (HR 0.59, 95% CI 0.40-0.89), canagliflozin, and empagliflozin lowered HHF versus subcutaneous semaglutide among others. Dapagliflozin and empagliflozin lowered KFP versus exenatide among others. Empagliflozin and oral semaglutide lowered CVD versus dapagliflozin among others. Sotagliflozin (HR 0.65, 95% CI 0.47-0.91) and albiglutide lowered MI versus ertugliflozin among others. Sotagliflozin (HR 0.56, 95% CI 0.37-0.85) and subcutaneous semaglutide lowered stroke versus empagliflozin among others. Oral semaglutide and empagliflozin lowered ACD versus subcutaneous semaglutide among others. The maximum surface under the cumulative ranking curve values followed sotagliflozin, subcutaneous semaglutide, and albiglutide in lowering MACE; sotagliflozin, canagliflozin, and empagliflozin in lowering HHF; dapagliflozin and empagliflozin in lowering KFP; empagliflozin and oral semaglutide in lowering CVD; sotagliflozin and albiglutide in lowering MI; sotagliflozin and subcutaneous semaglutide in lowering stroke; and oral semaglutide and empagliflozin in lowering ACD., Conclusions: This updated network meta-analysis reproduced the findings in the first network meta-analysis, and moreover revealed that sotagliflozin was one of the most effective drugs as for lowering MI, stroke, MACE, and HHF, whereas ertugliflozin was not. These findings will provide the according evidence regarding the usage of specific SGLT2 inhibitors and GLP-1 RAs in T2D patients for prevention of specific cardiorenal endpoints., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Growing evidences indicate that neuropathic pain is frequently accompanied with cognitive impairments, which aggravate the decrease in the quality of life of chronic pain patients. Furthermore, it has been shown that the activation of Glucagon-like-peptide-1receptor (GLP-1R) improved memory deficit in multiple diseases, including Alzheimer's disease (AD), stroke. However, whether GLP-1R activation could improve memory impairment induced by neuropathic pain and the mechanisms underlying the effect of the activation of GLP-1R on memory protection have not yet been established. The spared nerve injury (SNI) model was established as a kind of neuropathic pain. And novel-object recognition memory (hippocampus-dependent memory) was tested by the novel object recognition test (NORT). The expression levels of GLP-1, GLP-1R, adenosine monophosphate-activated protein kinase (AMPK), p-AMPKThr172, nuclear factor κ B p65 (NF-κB p65), interleukin-1beta (IL-1β), IL-1β p17 (mature IL-1β), tumor necrosis factor-alpha (TNF-α) and the synaptic proteins were tested in the murine hippocampus with memory deficits caused by neuropathic pain. Then, exenatide acetate (Ex-4, a GLP-1R agonist), exendin (9-39) (Ex(9-39), a GLP-1R antagonist) and Compound C dihydrochloride (CC, an AMPK inhibitor) were used to test the effects of the activation of GLP-1R in the mice with neuropathic pain. First, we uncovered that neuropathic pain could inhibit GLP-1/GLP-R axis, disturb inflammatory signaling pathway, increase the expression of IL-1β, IL-1β p17 and TNF-α, downregulate the synaptic proteins (postsynaptic density protein 95 (PSD95) and Arc). Subsequently, we reported that Ex-4 treatment could improve recognition memory impairment, increase the ratio of p-AMPKThr172/AMPK, inhibit the phosphorylation NF-κB p65 and decrease the expression of IL-1β, IL-1β p17 and TNF-α, upregulate the levels of PSD95 and Arc. Moreover, we found that Ex(9-39) and CC treatment could abrogate the memory protection of activation of GLP-1R in mice with neuropathic pain. The results indicated that the activation of GLP-1R could improve recognition memory impairment via regulating AMPK/NF-κB pathway, improving neuroinflammation, reversing the decreased level of synaptic proteins in neuropathic pain mice., (Copyright © 2021. Published by Elsevier Inc.)

[Figure: see text].

Antagonism of glucagon's biological action is a proven strategy for decreasing glucose in diabetic animals and patients. To achieve full, potent, and selective suppression, we chemically optimized N-terminally truncated glucagon fragments for the identification and establishment of the minimum sequence peptide, [Glu9]glucagon(6-29) amide ( 11 ) as a full antagonist in cellular signaling and receptor binding (IC 50 = 36 nM). Substitution of Phe6 with l-3-phenyllactic acid (Pla) produced [Pla6, Glu9]glucagon(6-29) amide ( 21 ), resulting in a 3-fold improvement in receptor binding (IC 50 = 12 nM) and enhanced antagonist potency. Further substitution of Glu9 and Asn28 with aspartic acid yielded [Pla6, Asp28]glucagon amide ( 26 ), which demonstrated a further increase in inhibitory potency (IC 50 = 9 nM), and improved aqueous solubility. Peptide 26 and a palmitoylated analogue, [Pla6, Lys10(γGluγGlu-C16), Asp28]glucagon(6-29) amide ( 31 ), displayed sustained duration in vivo action that successfully reversed glucagon-induced glucose elevation in mice.

The large amount of data that has been collected so far for G protein-coupled receptors requires machine learning (ML) approaches to fully exploit its potential. Our previous ML model based on gradient boosting used for prediction of drug affinity and selectivity for a receptor subtype was compared with explicit information on ligand-receptor interactions from induced-fit docking. Both methods have proved their usefulness in drug response predictions. Yet, their successful combination still requires allosteric/orthosteric assignment of ligands from datasets. Our ligand datasets included activities of two members of the secretin receptor family: GCGR and GLP-1R. Simultaneous activation of two or three receptors of this family by dual or triple agonists is not a typical kind of information included in compound databases. A precise allosteric/orthosteric ligand assignment requires a continuous update based on new structural and biological data. This data incompleteness remains the main obstacle for current ML methods applied to class B GPCR drug discovery. Even so, for these two class B receptors, our ligand-based ML model demonstrated high accuracy (5-fold cross-validation Q 2 > 0.63 and Q 2 > 0.67 for GLP-1R and GCGR, respectively). In addition, we performed a ligand annotation using recent cryogenic-electron microscopy (cryo-EM) and X-ray crystallographic data on small-molecule complexes of GCGR and GLP-1R. As a result, we assigned GLP-1R and GCGR actives deposited in ChEMBL to four small-molecule binding sites occupied by positive and negative allosteric modulators and a full agonist. Annotated compounds were added to our recently released repository of GPCR data.

Hyocholic acid (HCA) and its derivatives are found in trace amounts in human blood but constitute approximately 76% of the bile acid (BA) pool in pigs, a species known for its exceptional resistance to type 2 diabetes. Here, we show that BA depletion in pigs suppressed secretion of glucagon-like peptide-1 (GLP-1) and increased blood glucose levels. HCA administration in diabetic mouse models improved serum fasting GLP-1 secretion and glucose homeostasis to a greater extent than tauroursodeoxycholic acid. HCA upregulated GLP-1 production and secretion in enteroendocrine cells via simultaneously activating G-protein-coupled BA receptor, TGR5, and inhibiting farnesoid X receptor (FXR), a unique mechanism that is not found in other BA species. We verified the findings in TGR5 knockout, intestinal FXR activation, and GLP-1 receptor inhibition mouse models. Finally, we confirmed in a clinical cohort, that lower serum concentrations of HCA species were associated with diabetes and closely related to glycemic markers., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Different countries have their own systems for evaluating new medicines, and they make decisions as to when and how each new medicine is adopted., Purpose: To compare the rate of uptake of new diabetes medicines (dipeptidyl peptidase-4 inhibitors [DPP-4Is], glucagon-like peptide-1 receptor agonists [GLP1-RAs], and sodium-glucose co-transporter-2 inhibitors [SGLT2Is]) in the five most populated European countries., Methods: The monthly volume of sales of antidiabetic drugs was extracted for each country from the IQVIA™ MIDAS® database for the period 2007 to 2016 and the defined daily doses (DDDs) were calculated. For each new drug, market shares were expressed as a percentage of the total market of non-insulin antidiabetic agents., Results: Sharp differences were observed between the countries. Overall, the highest and fastest rates of uptake were seen for Germany and Spain, compared to lower rates for the UK and Italy. This was especially marked for DPP-4Is, where the market share reached over 30% of non-insulin antidiabetic drugs in Germany and Spain, compared to around 10% in the UK and Italy. In France, there was an initial rapid uptake, which stabilized at around 20% after three years. Rates of uptake were lower for the other drugs, with the GLP1-RAs reaching a market share of 2.5-4.5% in Germany, Spain and France, compared to less than 2.5% in the UK and Italy. The SGLT2Is reached a market share of 5-8% in Spain and Germany, compared to less than 4% in the UK and Italy, and they were not launched at all in France in March 2020., Conclusion: The differences in the uptake of new antidiabetic drugs may reflect different methods for assessing and introducing new medicines, as well as cultural factors. The uptake of the new medicines would appear to be more cautious in the UK and Italy, perhaps due to concerns about cost-effectiveness, whereas in Germany and Spain, and possibly also France, a new medicine's potential benefits may be prioritized., (Copyright © 2021 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)

The brainstem dorsal vagal complex (DVC) is known to regulate energy balance and is the target of appetite-suppressing hormones, such as glucagon-like peptide 1 (GLP-1). Here we provide a comprehensive genetic map of the DVC and identify neuronal populations that control feeding. Combining bulk and single-nucleus gene expression and chromatin profiling of DVC cells, we reveal 25 neuronal populations with unique transcriptional and chromatin accessibility landscapes and peptide receptor expression profiles. GLP-1 receptor (GLP-1R) agonist administration induces gene expression alterations specific to two distinct sets of Glp1r neurons-one population in the area postrema and one in the nucleus of the solitary tract that also expresses calcitonin receptor (Calcr). Transcripts and regions of accessible chromatin near obesity-associated genetic variants are enriched in the area postrema and the nucleus of the solitary tract neurons that express Glp1r and/or Calcr, and activating several of these neuronal populations decreases feeding in rodents. Thus, DVC neuronal populations associated with obesity predisposition suppress feeding and may represent therapeutic targets for obesity.

Combinatorial gut hormone therapy is one of the more promising strategies for identifying improved treatments for metabolic disease. Many approaches combine the established benefits of glucagon-like peptide-1 (GLP-1) agonism with one or more additional molecules with the aim of improving metabolic outcomes. Recent attention has been drawn to the glucose-dependent insulinotropic polypeptide (GIP) system due to compelling pre-clinical evidence describing the metabolic benefits of antagonising the GIP receptor (GIPR). We rationalised that benefit might be accrued from combining GIPR antagonism with GLP-1 agonism. Two GIPR peptide antagonists, GIPA-1 (mouse GIP(3-30)NH2) and GIPA-2 (NαAc-K10[γEγE-C16]-Arg18-hGIP(5-42)), were pharmacologically characterised and both exhibited potent antagonist properties. Acute in vivo administration of GIPA-1 during an oral glucose tolerance test (OGTT) had negligible effects on glucose tolerance and insulin in lean mice. In contrast, GIPA-2 impaired glucose tolerance and attenuated circulating insulin levels. A mouse model of diet-induced obesity (DIO) was used to investigate the potential metabolic benefits of chronic dosing of each antagonist, alone or in combination with liraglutide. Chronic administration studies showed expected effects of liraglutide, lowering food intake, body weight, fasting blood glucose and plasma insulin concentrations while improving glucose sensitivity, whereas delivery of either GIPR antagonist alone had negligible effects on these parameters. Interestingly, chronic dual therapy augmented insulin sensitizing effects and lowered plasma triglycerides and free-fatty acids, with more notable effects observed with GIPA-1 compared to GIPA-2. Thus, the co-administration of both a GIPR antagonist with a GLP1 agonist uncovers interesting beneficial effects on measures of insulin sensitivity, circulating lipids and certain adipose stores that seem influenced by the degree or nature of GIP receptor antagonism., Competing Interests: The authors have read the journal’s policy and have the following competing interests: J.A.W. and H.R. are employees and shareholders of Fractyl Laboratories Inc. A.T. has received funding/grant support from the Juvenile Diabetes Research Foundation (JDRF). S.S.G. is an employee of Doon Associates and has received honorariums for consultancy from Fractyl Laboratories Inc. D.G.P. is an employee of DPB Scientific and has received honorariums for consultancy from Fractyl Laboratories Inc R.V.G. and P.J.P. are employees of Gubra ApS. D.M. is an ex-employee of Fractyl Laboratories Inc., is a current shareholder, and has received honorarium for consultancy from Fractyl Laboratories Inc. G.A.B. has received funding/grant support from the European Foundation for the Study of Diabetes and JDRF and honorarium for consultancy from Fractyl Laboratories Inc. This does not alter our adherence to PLOS ONE policies on the sharing of data and materials. There are no patents, products in development or marketed products associated with this research to declare.

Aims: Trial evidence indicates that glucagon-like peptide-1 receptor agonists (GLP-1 RAs) may reduce the risk of cardiovascular (CV) events in patients with diabetes and myocardial infarction (MI). We aimed to expand this observation to routine care settings., Methods and Results: Prospective observational study including all patients with diabetes surviving an MI and registered in the nationwide SWEDEHEART registry during 2010-17. Multivariable Cox regression analyses were used to estimate the association between GLP-1 RAs use and the study outcome, which was a composite of stroke, heart failure, Re-infarction, or CV death. Covariates included demographics, comorbidities, presentation at admission, and use of secondary CV prevention therapies. In total, 17 868 patients with diabetes were discharged alive after a first event of MI. Their median age was 71 years, 36% were women and their median estimated glomerular filtration rate was 75 mL/min/1.73m2. Of those, 365 (2%) were using GLP-1 RAs. During median 3 years of follow-up, 7005 patients experienced the primary composite outcome. Compared with standard of diabetes care, use of GLP-1 RAs was associated with a lower event risk [adjusted hazard ratio (HR) 0.72; 95% confidence interval (CI): 0.56-0.92], mainly attributed to a lower rate of re-infarction and stroke. Results were similar after propensity score matching or when compared with users of sulfonylurea. There was no suggestion of heterogeneity across subgroups of age, sex, chronic kidney disease, and STEMI., Conclusion: GLP-1 RAs use, compared with standard of diabetes care, was associated with lower risk for major CV events in healthcare-managed survivors of an MI., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Diabetes mellitus (DM) is an independent risk factor for atrial fibrillation (AF), which is the most common sustained arrhythmia and is associated with substantial morbidity and mortality. Advanced glycation end product and its receptor activation, cardiac energy dysmetabolism, structural and electrical remodeling, and autonomic dysfunction are implicated in AF pathophysiology in diabetic hearts. Antidiabetic drugs have been demonstrated to possess therapeutic potential for AF. However, clinical investigations of AF in patients with DM have been scant and inconclusive. This article provides a comprehensive review of research findings on the association between DM and AF and critically analyzes the effect of different pharmacological classes of antidiabetic drugs on AF.

The risk of cardiovascular disease (CVD) (myocardial infarction, stroke, peripheral vascular disease) is twice in type 2 diabetes (T2D) patients compared to non-diabetic subjects. Furthermore, cardiovascular disease (CV) is the leading cause of death in patients with T2D.In the last years several clinical intervention studies with new anti-hyperglycaemic drugs have been published, and they have shown a positive effect on the reduction of mortality and cardiovascular risk in T2D patients. In particular, these studies evaluated sodium/glucose-2 cotransporter inhibitors (SGLT2i) and Glucagon-like peptide-1 receptor agonists (GLP-1RA).In secondary prevention, it was clearly demonstrated that SGLT2i and GLP-1RA drugs reduce CV events and mortality, and new guidelines consider now these drugs as first choice (after metformin) in the treatment of T2D; there are also some signs that they may be effective also in primary prevention of CVD. However, the mechanisms involved in cardiovascular protection are not yet fully understood, but they appear to be both "glycaemic" and "extra-glycaemic".In this review, we will examine the fundamental results of the clinical trials on SGLT2i and GLP-1RA, their clinical relevance in term of treatment of T2D, and we will discuss the mechanisms that may explain how these drugs exert their cardiovascular protective effects.

The number of people living with diabetes, the number of deaths attributable to it, and the cost of treating the disease and its complications are increasing exponentially. Centuries of research led to the discovery of insulin and other drugs based on pathophysiology from "the triumvirate to ominous octet". The agonists of the glucagon-like peptide-1 (GLP-1) receptor, and the inhibitors of the sodium-glucose transport protein 2 (SGLT2) are the new drugs that improve cardiovascular outcomes and provide renal protection, and they are being used increasingly for evidence-based treatment of type 2 diabetes. Bariatric surgery, when indicated, results in excellent weight- and metabolic-control, and in many instances even remission of diabetes. Technological advances like Flash glucose monitoring, continuous subcutaneous insulin infusion (CSII), and continuous glucose monitoring (CGM) have improved glycemic control, reduced episodes of severe hypoglycemia, and improved quality of life. For the treatment of diabetic macular edema intravitreal injection of several anti-VEGF agents are being used. Numerous people living in the middle- and low-income countries cannot afford the costs of care of diabetes. Institutions like the World Health Organization, the World Bank and the International Monetary Fund should roll out plans to convince the politicians to invest more in improving the diabetes care facilities.

G protein-coupled receptors (GPCRs) are a group of seven-transmembrane receptor proteins that have proven to be successful drug targets. Antibodies are becoming an increasingly promising modality to target these receptors due to their unique properties, such as exquisite specificity, long half-life, and fewer side effects, and their improved pharmacokinetic and pharmacodynamic profiles compared to peptides and small molecules, which results from their more favorable biodistribution. To date, there are only two US Food and Drug Administration-approved GPCR antibody drugs, namely erenumab and mogamulizumab, and this highlights the challenges encountered in identifying functional antibodies against GPCRs. Utilizing Twist's precision DNA writing technologies, we have created a GPCR-focused phage display library with 1 × 10 10 diversity. Specifically, we mined endogenous GPCR binding ligand and peptide sequences and incorporated these binding motifs into the heavy chain complementarity-determining region 3 in a synthetic antibody library. Glucagon-like peptide-1 receptor (GLP-1 R) is a class B GPCR that acts as the receptor for the incretin GLP-1, which is released to regulate insulin levels in response to food intake. GLP-1 R agonists have been widely used to increase insulin secretion to lower blood glucose levels for the treatment of type 1 and type 2 diabetes, whereas GLP-1 R antagonists have applications in the treatment of severe hypoglycemia associated with bariatric surgery and hyperinsulinomic hypoglycemia. Here we present the discovery and creation of both antagonistic and agonistic GLP-1 R antibodies by panning this GPCR-focused phage display library on a GLP-1 R-overexpressing Chinese hamster ovary cell line and demonstrate their in vitro and in vivo functional activity.

This chapter gives an overview of present knowledge and clinical aspects of antidiabetic drugs according to the recently available research evidence and clinical expertise.Many agents are acting on eight groups of pathophysiological mechanisms, which is commonly called as "Ominous Octet" by DeFronzo. The muscle, liver and β-cell, the fat cell, gastrointestinal tract, α-cell, kidney, and brain play essential roles in the development of glucose intolerance in type 2 diabetic individuals (Defronzo, Diabetes 58:773-795, 2009).A treatment paradigm shift is seen in the initiation of anti-hyperglycemic agents from old friends (meglitinides or sulphonylürea) to newer agents effecting on GLP-1 RA or SGLT-2 inhibitors. It is mostly about the other protective positive effects of these agents for kidney, heart, etc. Although there are concerns for the long term safety profiles; they are used widely around the World. The delivery of patient-centered care, facilitating medication adherence, the importance of weight loss in obese patients, the importance of co-morbid conditions are the mainstays of selecting the optimal agent.

Neuropeptides and peptide hormones affect food-directed motivation, in part, through actions on brain regions associated with reward processing. For instance, previous reports have shown that stimulating glucagon-like peptide-1 (GLP-1) receptors in the nucleus accumbens (NAc), an area that directs motivational processes towards food and drugs of abuse, has an anorectic effect. In contrast, µ-opioid receptor activation of the NAc increases feeding, particularly on highly palatable diets. While both neurotransmitters act within the NAc to impact food intake, it is not clear if and how they might interact to affect feeding. Therefore, these experiments tested the effects of NAc injections of the GLP-1 receptor agonist Exendin 4 (EX4) or antagonist Exendin 9 (EX9) on the consumption of a sweetened fat diet, with and without simultaneous µ-opioid receptor stimulation. Male Sprague-Dawley rats (n = 8/group, EX4 or EX9) underwent surgery to place bilateral cannula above the NAc core. After recovery, animals were tested following NAc injections of saline or the µ-opioid agonist [D-Ala, N-MePhe, Gly-ol]-enkephalin (DAMGO) (0.025 µg/side), combined with varying doses of EX4 (0, 0.05, or 0.10 µg/side) or EX9 (0, 2.5, 5.0 µg/side), counterbalanced across 6 testing days. Food and water intake, along with locomotor activity, was monitored for 2 h. Mu-opioid receptor stimulation significantly increased feeding, and this effect was reduced by GLP-1 receptor stimulation. In contrast, GLP-1 antagonism with EX9 altered the dynamics of DAMGO-induced binge-like feeding, extending µ-opioid-induced binging, and increasing food consumption. These findings are the first to demonstrate an interaction between NAc µ-opioid and GLP-1 receptors on palatable food intake.

Description: The American Diabetes Association (ADA) updates the Standards of Medical Care in Diabetes annually to provide clinicians, patients, researchers, payers, and other interested parties with evidence-based recommendations for the diagnosis and management of diabetes., Methods: To develop the 2020 Standards, the ADA Professional Practice Committee, comprising physicians, adult and pediatric endocrinologists, diabetes educators, registered dietitians, epidemiologists, pharmacists, and public health experts, continuously searched MEDLINE (English language only) from 15 October 2018 through August-September 2019 for pertinent studies, including high-quality trials that addressed pharmacologic management of type 2 diabetes. The committee selected and reviewed the studies, developed the recommendations, and solicited feedback from the larger clinical community., Recommendations: This synopsis focuses on guidance relating to the pharmacologic treatment of adults with type 2 diabetes. Recommendations address oral and noninsulin injectable therapies, insulin treatment, and combination injectable therapies. Results of recent large trials with cardiovascular and renal outcomes are emphasized.

Glucagon-like peptide-1 receptor agonists (GLP-1RA) not only significantly lower blood glucose but also reduce multiple cardiovascular risk factors. Moreover, some of this class of anti-diabetic drugs have been shown to have beneficial effects in cardiovascular outcome trials. This expert consensus is developed for the optimal use of GLP-1RA in individualized treatment of type 2 diabetes mellitus (T2DM) and includes the timing of GLP-1RA use in the glucose-lowering therapeutic algorithm, the precautions while combined with other anti-diabetic drugs, the therapeutic benefits while preferably added on the anti-diabetic therapies for patients with T2DM and atherosclerotic cardiovascular disease (ASCVD), heart failure (HF), or chronic kidney disease (CKD), and the use of GLP-1RA in special population of patients with T2DM.

Background: Obesity causes significant morbidity and mortality and continues to be a significant public health concern. Unfortunately, lifestyle modification and pharmacotherapy do not produce durable results. This has led to bariatric surgical procedures playing an increasingly prominent role in the management of medically complicated obesity. Roux-en-Y gastric bypass and sleeve gastrectomy are the most commonly performed bariatric surgeries in North America and produce mechanical restriction with accelerated gastrointestinal transit accompanied by increased postprandial secretion of glucagon-like peptide-1 (GLP-1). GLP-1 is a gastrointestinal hormone that delays gastric emptying and causes satiety and weight loss. This raises the possibility that the postprandial rise in GLP-1 might affect feeding behavior over and above the mechanical restriction produced by bariatric surgery. Methods: We, therefore, sought to determine the effects of GLP-1 receptor blockade using exendin-9,39-a competitive antagonist of the actions of GLP-1 at its receptor-on caloric intake and gastrointestinal transit in subjects after sleeve gastrectomy and after Roux-en-Y gastric bypass compared with weight-matched controls. Results: GLP-1 receptor blockade did not alter caloric intake in people after bariatric surgery. However, caloric intake was decreased in age-, weight- and sex-matched control subjects, and the mechanisms require further study. Conclusions: Given the known effects of GLP-1 on gastric accommodation, future studies should ascertain effects of GLP-1 receptor blockade on gastric accommodation, which might be a useful and novel strategy to decrease caloric intake in humans with an intact upper gastrointestinal tract. The Clinical Trial Resigtration number is NCT02779075.

Anxiety disorders are among the most prevalent categories of mental illnesses. The gut-brain axis, along with gastrointestinally-derived neuropeptides, like glucagon-like peptide-1 (GLP-1), are emerging as potential key regulators of emotionality, including anxiety behavior. However, the neuroanatomical substrates from which GLP-1 exerts its anxiogenic effect remain poorly characterized. Here we focus on a relatively new candidate nucleus, the supramammillary nucleus (SuM), located just caudal to the lateral hypothalamus and ventral to the ventral tegmental area. Our focus on the SuM is supported by previous data showing expression of GLP-1R mRNA throughout the SuM and activation of the SuM during anxiety-inducing behaviors in rodents. Data show that chemogenetic activation of neurons in the SuM results in an anxiolytic response in male and female rats. In contrast, selective activation of SuM GLP-1R, by microinjection of a GLP-1R agonist exendin-4 into the SuM resulted in potent anxiety-like behavior, measured in both open field and elevated plus maze tests in male and female rats. This anxiogenic effect of GLP-1R activation persisted after high-fat diet exposure. Importantly, reduction of GLP-1R expression in the SuM, by AAV-shRNA GLP-1R knockdown, resulted in a clear anxiolytic response; an effect only observed in female rats. Our data identify a new neural substrate for GLP-1 control of anxiety-like behavior and indicate that the SuM GLP-1R are sufficient for anxiogenesis in both sexes, but necessary only in females., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The pharmacological administration of GLP-1R (glucagon-like peptide-1 receptor) agonists reduces blood pressure (BP) in type 2 diabetes mellitus and nondiabetic patients. This study tested the hypothesis that endogenous GLP-1R signaling influences the regulation of BP. To this end, SHRs (spontaneously hypertensive rats) and Wistar rats were treated with the GLP-1R antagonist Ex9 (exendin-9) or vehicle for 4 weeks. Rats receiving the GLP-1R agonist Ex4 (exenatide) were used as an additional control. We found that blockade of baseline GLP-1R signaling by Ex9 increased systolic BP in both SHR and Wistar rats, compared with vehicle-treated animals, while Ex4 only reduced systolic BP in SHR. Higher systolic BP induced by Ex9 was accompanied by reduced lithium clearance and lower levels of NHE3 (Na + /H + exchanger isoform 3) phosphorylation at the serine 552, indicative of increased proximal tubule sodium reabsorption. Additionally, urinary AGT (angiotensinogen) and renal cortical concentration of Ang II (angiotensin II) were enhanced by Ex9. Conversely, Ex4 decreased both urinary AGT and cortical Ang II but exclusively in SHRs. Moreover, both SHR and Wistar rats treated with Ex9 displayed hyperinsulinemia as compared with vehicle-treated rats, whereas Ex4 reduced fasting insulin concentration in SHR. Collectively, these results suggest that endogenous GLP-1R signaling exerts a physiologically relevant effect on BP control, which may be attributable, in part, to its tonic actions on the proximal tubule NHE3-mediated sodium reabsorption, intrarenal renin-angiotensin system, and insulin sensitivity. The possible role of impaired GLP-1R signaling in the pathogenesis of hypertension warrants further investigation.

Aims: To investigate the effect of anagliptin (Ana), a dipeptidyl peptidase-4 (DPP-4) inhibitor, on acute ischemia-induced bladder dysfunction in rats., Methods: Eight-week-old female Wistar-ST rats were randomly assigned into four groups: (a) sham; (b) ligation (Lig); (c) Lig + Ana; and (d) Lig + Liraglutide (a glucagon-like peptide-1 [GLP-1] receptor agonist; Lira). Rats in the Lig, Lig + Ana, and Lig + Lira groups underwent ligature of the bilateral internal iliac arteries. Ana was orally administered mixed with the CE-2 diet. Lira was subcutaneously administered once a day. Blood glucose levels, plasma dipeptidyl peptidase 4 (DPP-4) activity, GLP-1 levels, and bladder function were measured in all groups. Bladder blood flow was measured in the sham, Lig, and Lig + Ana groups, 4 weeks postsurgery., Results: No differences in blood glucose levels among the groups were observed. DPP-4 activity decreased in the Lig + Ana group (P < .01). GLP-1 levels in the Lig + Ana and Lig + Lira groups were higher than those in the sham and Lig groups (P < .01). Intercontraction intervals (ICIs) were longer in the Lig and Lig + Lira groups than in the sham group (P < .05), but similar to those observed in the Lig + Ana and sham groups. The Lig group exhibited reduced bladder blood flow relative to the sham group (P < .01); however, this measure improved in the Lig + Ana group (P < .01)., Conclusions: Ana administration improved ICIs and bladder blood flow after acute bladder ischemia through a GLP-1 receptor-independent signaling pathway, without altering the blood glucose levels. Therefore, Ana dosing might be useful to prevent ischemia-induced bladder dysfunctions., (© 2020 Wiley Periodicals LLC.)

The gut-brain peptide glucagon-like peptide-1 (GLP-1) reduces reward from palatable food and drugs of abuse. Recent rodent studies show that activation of GLP-1 receptors (GLP-1R) within the nucleus of the solitary tract (NTS) not only suppresses the motivation and intake of palatable food, but also reduces alcohol-related behaviors. As reward induced by addictive drugs and sexual behaviors involve similar neurocircuits, we hypothesized that activation of GLP-1R suppresses sexual behavior in sexually naïve male mice. We initially identified that systemic administration of the GLP-1R agonist, exendin-4 (Ex4), decreased the frequency and duration of mounting behaviors, but did not alter the preference for females or female bedding. Thereafter infusion of Ex4 into the NTS decreased various behaviors of the sexual interaction chain, namely social, mounting and self-grooming behaviors. In male mice tested in the sexual interaction test, NTS-Ex4 increased dopamine turnover and enhanced serotonin levels in the nucleus accumbens (NAc). In addition, these mice displayed higher corticosterone, but not testosterone, levels in plasma. Finally, GLP-1R antagonist, exendin-3 (9-39) amide (Ex9), infused into the NTS differentially altered the ability of systemic-Ex4 to suppress the various behaviors of the sexual interaction chain, indicating that GLP-1R within the NTS is one of many sub-regions contributing to the GLP-1 dependent sexual behavior link. In these mice NTS-Ex9 partly blocked the systemic-Ex4 enhancement of corticosterone levels. Collectively, these data highlight that activation of GLP-1R, specifically those in the NTS, reduces sexual interaction behaviors in sexually naïve male mice and further provide a link between NTS-GLP-1R activation and reward-related behaviors., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: The adoption of 2 classes of new diabetes medications, glucagon-like peptide 1 receptor agonists (GLP1RA) and sodium-glucose co-transporter-2 inhibitors (SGLT2i), has been slow in the United States despite their cardiovascular benefits in addition to their glucose-lowering effect. The objective of this study was to identify providers' perspectives about prescribing GLP1RA and SGLT2i., Methods: In this survey study, a questionnaire was administered between May 17, 2018, and June 11, 2018, in a large academic health care system. Ninety providers who practice in endocrinology, primary care, or cardiology responded the questionnaire, with a 36.3% response rate. The questionnaire explored knowledge, comfort level, beliefs, perceived barriers, and hypothetical clinical decisions about prescribing GLP1RA and SGLT2i., Results: Findings suggested a division of views from endocrinology and primary care providers versus cardiology providers. More than 88% of endocrinology providers and about 50% of primary care providers prescribed GLP1RA or SGLT2i at least 6 times a year, whereas less than 7% of cardiology providers prescribed either medication. All endocrinology providers, approximately 78% of primary care providers, and only 21% of cardiology providers were very comfortable or comfortable in all 4 knowledge aspects about GLP1RA and SGLT2i. Major barriers to prescribing GLP1RA and SGLT2i for endocrinology and primary care providers were cost and nonapproved prior authorizations, yet the top 3 reported barriers for cardiology providers were lack of knowledge about these medications, concerns of introducing confusion into diabetes care, and discomfort of prescribing diabetes medications., Conclusions: Barriers to prescribing GLP1RA or SGLT2i are unique for endocrinology, primary care, and cardiology providers. Given the cardiovascular benefits of these medications, this study suggests specific areas and potential opportunities for clinicians to improve care for patients with diabetes and cardiovascular disease., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Context: The actions of both endogenous incretin hormones during a meal have not previously been characterized., Objective: Using specific receptor antagonists, we investigated the individual and combined contributions of endogenous glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) to postprandial glucose metabolism, energy expenditure, and gallbladder motility., Design: Randomized, double-blinded, placebo-controlled, crossover design., Setting: On four separate days, four liquid mixed meal tests (1894 kJ) over 270 minutes (min)., Patients or Other Participants: Twelve healthy male volunteers., Interventions: Infusions of the GIP receptor antagonist GIP(3-30)NH2 (800 pmol/kg/min), the GLP-1 receptor antagonist exendin(9-39)NH2 (0-20 min: 1000 pmol/kg/min; 20-270 min: 450 pmol/kg/min), GIP(3-30)NH2+exendin(9-39)NH2, or placebo/saline., Main Outcome Measure: Baseline-subtracted area under the curve (bsAUC) of C-peptide., Results: Infusion of GIP(3-30)NH2+exendin(9-39)NH2 significantly increased plasma glucose excursions (bsAUC: 261 ± 142 mmol/L × min) during the liquid mixed meals compared with GIP(3-30)NH2 (180 ± 141 mmol/L × min; P = 0.048), exendin(9-39)NH2 (171 ± 114 mmol/L × min; P = 0.046), and placebo (116 ± 154 mmol/L × min; P = 0.015). Correspondingly, C-peptide:glucose ratios during GIP(3-30)NH2+exendin(9-39)NH2 infusion were significantly lower than during GIP(3-30)NH2 (P = 0.0057), exendin(9-39)NH2 (P = 0.0038), and placebo infusion (P = 0.014). GIP(3-30)NH2 resulted in significantly lower AUCs for glucagon than exendin(9-39)NH2 (P = 0.0417). Gallbladder ejection fraction was higher during GIP(3-30)NH2 compared with placebo (P = 0.004). For all interventions, energy expenditure and respiratory quotient were similar., Conclusions: Endogenous GIP and GLP-1 lower postprandial plasma glucose excursions and stimulate insulin secretion but only endogenous GIP affects gallbladder motility. The two incretin hormones potentiate each other's effects in the control of postprandial glycemia in healthy men., (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)