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GLP-1/glucagon receptor co-agonism for treatment of obesity.

ABSTRACT: Over a relatively short period, obesity and type 2 diabetes have come to represent a large medical and economic burden to global societies. The epidemic rise in the prevalence of obesity has metabolic consequences and is paralleled by an increased occurrence of other diseases, such as diabetes, cancer and cardiovascular complications. Together, obesity and type 2 diabetes constitute one of the more preventable causes of premature death and the identification of novel, safe and effective anti-obesity drugs is of utmost importance. Pharmacological attempts to treat obesity have had limited success, with notable adverse effects, rendering bariatric surgery as the only current therapy for substantially improving body weight. Novel unimolecular, multifunctional peptides have emerged as one of the most promising medicinal approaches to enhance metabolic efficacy and restore normal body weight. In this review, we will mainly focus on the discovery and translational relevance of dual agonists that pharmacologically function at the receptors for glucagon and glucagon-like peptide-1. Such peptides have advanced to clinical evaluation and inspired the pursuit of multiple related approaches to achieving polypharmacy within single molecules.

SUBMITTER: Sanchez-Garrido MA

PROVIDER: S-EPMC6448809 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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GLP-1/glucagon receptor co-agonism for treatment of obesity.

Sánchez-Garrido Miguel A MA Brandt Sara J SJ Clemmensen Christoffer C Müller Timo D TD DiMarchi Richard D RD Tschöp Matthias H MH

Diabetologia 20170721 10

Over a relatively short period, obesity and type 2 diabetes have come to represent a large medical and economic burden to global societies. The epidemic rise in the prevalence of obesity has metabolic consequences and is paralleled by an increased occurrence of other diseases, such as diabetes, cancer and cardiovascular complications. Together, obesity and type 2 diabetes constitute one of the more preventable causes of premature death and the identification of novel, safe and effective anti-obe ...[more]

PMID: 28733905

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Project description:ObjectiveTreatment with glucagon receptor antagonists (GRAs) reduces blood glucose but causes dyslipidemia and accumulation of fat in the liver. We investigated the acute and chronic effects of glucagon on lipid metabolism in mice.MethodsChronic effects of glucagon receptor signaling on lipid metabolism were studied using oral lipid tolerance tests (OLTTs) in overnight fasted glucagon receptor knockout (Gcgr-/-) mice, and in C57Bl/6JRj mice treated with a glucagon receptor antibody (GCGR Ab) or a long-acting glucagon analogue (GCGA) for eight weeks. Following treatment, liver tissue was harvested for RNA-sequencing and triglyceride measurements. Acute effects were studied in C57Bl/6JRj mice treated with a GRA or GCGA 1 h or immediately before OLTTs, respectively. Direct effects of glucagon on hepatic lipolysis were studied using isolated perfused mouse liver preparations. To investigate potential effects of GCGA and GRA on gastric emptying, paracetamol was, in separate experiments, administered immediately before OLTTs.ResultsPlasma triglyceride concentrations increased 2-fold in Gcgr-/- mice compared to their wild-type littermates during the OLTT (P = 0.001). Chronic treatment with GCGR Ab increased, whereas GCGA treatment decreased, plasma triglyceride concentrations during OLTTs (P < 0.05). Genes involved in lipid metabolism were upregulated upon GCGR Ab treatment while GCGA treatment had opposite effects. Acute GRA and GCGA treatment, respectively, increased (P = 0.02) and decreased (P = 0.003) plasma triglyceride concentrations during OLTTs. Glucagon stimulated hepatic lipolysis, evident by an increase in free fatty acid concentrations in the effluent from perfused mouse livers. In line with this, GCGR Ab treatment increased, while GCGA treatment decreased, liver triglyceride concentrations. The effects of glucagon appeared independent of changes in gastric emptying of paracetamol.ConclusionsGlucagon receptor signaling regulates triglyceride metabolism, both chronically and acutely, in mice. These data expand glucagon´s biological role and implicate that intact glucagon signaling is important for lipid metabolism. Glucagon agonism may have beneficial effects on hepatic and peripheral triglyceride metabolism.

Project description:During recent years combining GLP-1 and glucagon receptor agonism with the purpose of achieving superior weight loss and metabolic control compared to GLP-1 alone has received much attention. The superior efficacy has been shown by several in preclinical models but has been difficult to reproduce in humans. In this paper, we present the pre-clinical evaluation of NN1177, a long-acting GLP-1/glucagon receptor co-agonist previously tested in clinical trials. To further investigate the contribution from the respective receptors, two other co-agonists (NN1151, NN1359) with different GLP-1-to-glucagon receptor ratios were evaluated in parallel. In the process of characterizing NN1177, species differences and pitfalls in traditional pre-clinical evaluation methods were identified, highlighting the translational challenges in predicting the optimal receptor balance in humans. In diet-induced obese (DIO) mice, NN1177 induced a dose-dependent body weight loss, primarily due to loss of fat mass, and improvement in glucose tolerance. In DIO rats, NN1177 induced a comparable total body weight reduction, which was in contrast mainly caused by loss of lean mass, and glucose tolerance was impaired. Furthermore, despite long half-lives of the three co-agonists, glucose control during steady state was seen to depend on compound exposure at time of evaluation. When evaluated at higher compound exposure, glucose tolerance was similarly improved for all three co-agonists, independent of receptor balance. However, at lower compound exposure, glucose tolerance was gradually impaired with higher glucagon receptor preference. In addition, glucose tolerance was found to depend on study duration where the effect of glucagon on glucose control became more evident with time. To conclude, the pharmacodynamic effects at a given GLP-1-to-glucagon ratio differs between species, depends on compound exposure and study length, complicating the identification of an optimally balanced clinical candidate. The present findings could partly explain the low number of clinical successes for this dual agonism.

Project description:Diet induced obesity in swine was associated with altered cardiovascular functional, miR transcriptome, and proteomic response to ischemia-reperfusion. Furthermore, the GLP-1 mimetic exendin-4 altered functional, miR and protein responses differently in obese versus lean swine, demonstrating the pervasive effect of obesity on modulating cardiac response to pathophysiologies and therapeutics. This study tested the hypothesis that obesity alters the left ventricular microRNA (miR) transcriptome, proteome and functional cardiac response to ischemia-reperfusion (I/R) injury and to glucagon like peptide-1 (GLP-1) receptor activation. Ossabaw swine were fed normal chow or obesogenic diet for 6 months followed by IV infusion of either saline (vehicle) or the GLP-1 mimetic exendin-4 (Ex-4). Left ventricular pressure volume relationships were assessed under baseline conditions, during a 30-minute occlusion of the circumflex artery and during a 2 hour reperfusion period. Cardiac biopsies were obtained from normally-perfused and ischemia-reperfusion territories, and analyzed using Affymetrix 3.0 miR microarray and protein mass spectrometry. I/R was found to depress global cardiac function in lean swine (systolic pressure, end-diastolic volume). In contrast, Ex-4 therapies did not affect blood pressure in obese animals, but significantly reduced end-diastolic volume following the reperfusion period. These divergent physiologic response to regional I/R in obese vs lean hearts were associated with significantly different protein and miRNA changes. Obesity was associated with altered abundance of proteins associated with calcium handling and contractility, and with changes in miRs relating to metabolism, hypertrophy, and cell death, including the miR-15 and miR-30 families, miR-199a, and miR-214. These effects were modified differently by EX-4 treatment in lean vs obese swine. These findings suggest specific miR and proteomic differences contribute to differences in functional cardiac responses to ischemia-reperfusion injury and pharmacologic activation of GLP-1 signaling in the setting of obesity, volume, stroke volume and ejection fraction) with partial amelioration seen in Ex-4 treated animals.

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GLP-1/glucagon receptor co-agonism for treatment of obesity.

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GLP-1/glucagon receptor co-agonism for treatment of obesity.

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