Abolishing ß-arrestin recruitment is necessary for the full metabolic benefits of G protein-biased glucagon-like peptide-1 receptor agonists.

AIM: Earlier studies have shown that peptide glucagon-like peptide-1 receptor (GLP-1R) agonists with reduced ß-arrestin recruitment show enhanced anti-hyperglycaemic efficacy through avoidance of GLP-1R desensitization. However, the ligand modifications needed to decrease ß-arrestin recruitment usually also reduces GLP-1R affinity, therefore higher doses are needed. Here we aimed to develop new, long-acting, G protein-biased GLP-1R agonists with acute signalling potency comparable with semaglutide, to provide insights into specific experimental and therapeutic scenarios. MATERIALS AND METHODS: New GLP-1R agonist peptides were assessed using a variety of in vitro and in vivo assays. RESULTS: First, we show that very substantial reductions in ß-arrestin recruitment efficacy are required to realize fully the benefits of GLP-1R agonism on blood glucose lowering in mice, with more moderate reductions being less effective. Secondly, our lead compound (SRB107) performs substantially better than semaglutide for effects on blood glucose and weight loss, which may be jointly attributable to its biased agonist action and protracted pharmacokinetics. Thirdly, we show that biased agonist-specific GLP-1R internalization profiles occur at clinically relevant pharmacological concentrations. Finally, we show that SRB107 cAMP signalling is differentially modulated by single and double GLP1R coding variants seen in human populations, with implications for GLP-1R agonist pharmacogenomics. CONCLUSIONS: Completely abolishing ß-arrestin recruitment improves the anti-hyperglycaemic effects of GLP-1R agonists in mice.

Adaptive infusion of a glucagon-like peptide-1/glucagon receptor co-agonist G3215, in adults with overweight or obesity: Results from a phase 1 randomized clinical trial.

AIMS: To determine whether a continuous infusion of a glucagon-like peptide receptor (GLP-1R)/glucagon receptor (GCGR) co-agonist, G3215 is safe and well tolerated in adults with overweight or obesity. METHODS: A phase 1 randomized, double blind, placebo-controlled trial of G3215 in overweight or obese participants, with or without type 2 diabetes. RESULTS: Twenty-six participants were recruited and randomized with 23 completing a 14-day subcutaneous infusion of G3215 or placebo. The most common adverse events were nausea or vomiting, which were mild in most cases and mitigated by real-time adjustment of drug infusion. There were no cardiovascular concerns with G3215 infusion. The pharmacokinetic characteristics were in keeping with a continuous infusion over 14 days. A least-squares mean body weight loss of 2.39 kg was achieved with a 14-day infusion of G3215, compared with 0.84 kg with placebo infusion (p < .05). A reduction in food consumption was also observed in participants receiving G3215 and there was no deterioration in glycaemia. An improved lipid profile was seen in G3215-treated participants and consistent with GCGR activation, a broad reduction in circulating amino acids was seen during the infusion period. CONCLUSION: An adaptive continuous infusion of the GLP-1/GCGR co-agonist, G3215, is safe and well tolerated offering a unique strategy to control drug exposure. By allowing rapid, response-directed titration, this strategy may allow for mitigation of adverse effects and afford significant weight loss within shorter time horizons than is presently possible with weekly GLP-1R and multi-agonists. These results support ongoing development of G3215 for the treatment of obesity and metabolic disease.

Sleeve gastrectomy causes weight-loss independent improvements in hepatic steatosis.

BACKGROUND AND AIMS: Sleeve gastrectomy (VSG) leads to improvement in hepatic steatosis, associated with weight loss. The aims of this study were to investigate whether VSG leads to weight-loss independent improvements in liver steatosis in mice with diet-induced obesity (DIO); and to metabolically and transcriptomically profile hepatic changes in mice undergoing VSG. METHODS: Mice with DIO were treated with VSG, sham surgery with subsequent food restriction to weight-match to the VSG group (Sham-WM), or sham surgery with return to unrestricted diet (Sham-Ad lib). Hepatic steatosis, glucose tolerance, insulin and glucagon resistance, and hepatic transcriptomics were investigated at the end of the study period and treatment groups were compared with mice undergoing sham surgery only (Sham-Ad lib). RESULTS: VSG led to much greater improvement in liver steatosis than Sham-WM (liver triglyceride mg/mg 2.5 ± 0.1, 2.1 ± 0.2, 1.6 ± 0.1 for Sham-AL, Sham-WM and VSG respectively; p = 0.003). Homeostatic model assessment of insulin resistance was improved following VSG only (51.2 ± 8.8, 36.3 ± 5.3, 22.3 ± 6.1 for Sham-AL, Sham-WM and VSG respectively; p = 0.03). The glucagon-alanine index, a measure of glucagon resistance, fell with VSG but was significantly increased in Sham-WM (9.8 ± 1.7, 25.8 ± 4.6 and 5.2 ± 1.2 in Sham Ad-lib, Sham-WM and VSG respectively; p = 0.0003). Genes downstream of glucagon receptor signalling which govern fatty acid synthesis (Acaca, Acacb, Me1, Acly, Fasn and Elovl6) were downregulated following VSG but upregulated in Sham-WM. CONCLUSIONS: Changes in glucagon sensitivity may contribute to weight-loss independent improvements in hepatic steatosis following VSG.

Chronic treatment with glucagon-like peptide-1 and glucagon receptor co-agonist causes weight loss-independent improvements in hepatic steatosis in mice with diet-induced obesity.

OBJECTIVES: Co-agonists at the glucagon-like peptide-1 and glucagon receptors (GLP1R/GCGR) show promise as treatments for metabolic dysfunction-associated steatotic liver disease (MASLD). Although most co-agonists to date have been heavily GLP1R-biased, glucagon directly acts on the liver to reduce fat content. The aims of this study were to investigate a GCGR-biased co-agonist as treatment for hepatic steatosis in mice. METHODS: Mice with diet-induced obesity (DIO) were treated with Dicretin, a GLP1/GCGR co-agonist with high potency at the GCGR, Semaglutide (GLP1R monoagonist) or food restriction over 24 days, such that their weight loss was matched. Hepatic steatosis, glucose tolerance, hepatic transcriptomics, metabolomics and lipidomics at the end of the study were compared with Vehicle-treated mice. RESULTS: Dicretin lead to superior reduction of hepatic lipid content when compared to Semaglutide or equivalent weight loss by calorie restriction. Markers of glucose tolerance and insulin resistance improved in all treatment groups. Hepatic transcriptomic and metabolomic profiling demonstrated many changes that were unique to Dicretin-treated mice. These include some known targets of glucagon signaling and others with as yet unclear physiological significance. CONCLUSIONS: Our study supports the development of GCGR-biased GLP1/GCGR co-agonists for treatment of MASLD and related conditions.

Design of novel therapeutics targeting the glucose-dependent insulinotropic polypeptide receptor (GIPR) to aid weight loss.

INTRODUCTION: With obesity rates growing globally, there is a paramount need for new obesity pharmacotherapies to tackle this pandemic. AREAS COVERED: This review focuses on the design of therapeutics that target the glucose-dependent insulinotropic polypeptide receptor (GIPR) to aid weight loss. The authors highlight the paradoxical observation that both GIPR agonism and antagonism appear to provide metabolic benefits when combined with glucagon-like peptide-1 receptor (GLP-1 R) agonism. The therapeutic potential of compounds that target the GIPR alongside the GLP-1 R and the glucagon receptor are discussed, and the impressive clinical findings of such compounds are reviewed. EXPERT OPINION: In this area, the translation of pre-clinical findings to clinical studies appears to be particularly difficult. Well-designed physiological studies in man are required to answer the paradox highlighted above, and to support the safe future development of a combination of GLP-1 R/GIPR targeting therapies.

Hypoaminoacidemia underpins glucagon-mediated energy expenditure and weight loss.

Glucagon analogs show promise as components of next-generation, multi-target, anti-obesity therapeutics. The biology of chronic glucagon treatment, in particular, its ability to induce energy expenditure and weight loss, remains poorly understood. Using a long-acting glucagon analog, G108, we demonstrate that glucagon-mediated body weight loss is intrinsically linked to the hypoaminoacidemia associated with its known amino acid catabolic action. Mechanistic studies reveal an energy-consuming response to low plasma amino acids in G108-treated mice, prevented by dietary amino acid supplementation and mimicked by a rationally designed low amino acid diet. Therefore, low plasma amino acids are a pre-requisite for G108-mediated energy expenditure and weight loss. However, preventing hypoaminoacidemia with additional dietary protein does not affect the ability of G108 to improve glycemia or hepatic steatosis in obese mice. These studies provide a mechanism for glucagon-mediated weight loss and confirm the hepatic glucagon receptor as an attractive molecular target for metabolic disease therapeutics.

Evaluation of cardiovascular risk in a lung cancer screening cohort: what value does it bring?

There is a significant opportunity to improve cardiovascular disease (CVD) outcomes in lung cancer screening cohorts with a low-cost, noninvasive assessment of CVD risk, alongside existing assessments https://bit.ly/3a6Ha41.