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.

Redefining ITT cortisol thresholds on Abbott platforms to prevent misdiagnosis of adrenal insufficiency.

BACKGROUND: Adrenal insufficiency (AI) is a life-threatening condition which requires long term glucocorticoid replacement. The insulin tolerance test (ITT) is the current gold standard test for diagnosis of secondary AI, but the widely accepted cut-off value of a peak cortisol of less than 500 nmol/L assumes that anyone who does not reach this value has AI and thus requires full replacement. The cut-off used to diagnose AI is also founded on outdated assays. Use of this cut-off in an era of more specific immunoassays therefore risks misdiagnosis, subsequent unnecessary glucocorticoid exposure and associated adverse effects with increased mortality risk. DESIGN, PATIENTS AND MEASUREMENTS: This retrospective analysis assessed 300 ITT cortisol responses using the Abbott Architect and Alinity analyser platforms in patients with suspected AI over a period of 12 years (August 2010 to January 2022), at a tertiary centre. RESULTS: Patients were classified as having AI or not, based on a comprehensive clinical review of electronic patient records from the point of test to the present day by a panel of pituitary and adrenal specialists. Using the current institutional cut-off value of 500 nmol/L, receiver operating characteristic analysis identified a 100.0% sensitivity and 43.6% specificity (area under the curve 0.979). Using a lower cortisol threshold value of 416 nmol/L on the Abbott analyser platform maintained a sensitivity of 100.0% and improved the specificity to 86.7%. CONCLUSION: This data supports lowering the Abbott analyser ITT peak cortisol threshold to 416 nmol/L. Use of this improved cut-off avoids unnecessary glucocorticoid replacement therapy in 104 (34.7%) of individuals in this study. All patients remained well with at least 1 year longitudinal follow up of glucocorticoid replacement.

Glucagon resistance and metabolic-associated steatotic liver disease: a review of the evidence.

Metabolic-associated steatotic liver disease (MASLD) is closely associated with obesity. MASLD affects over 1 billion adults globally but there are few treatment options available. Glucagon is a key metabolic regulator, and its actions include the reduction of liver fat through direct and indirect means. Chronic glucagon signalling deficiency is associated with hyperaminoacidaemia, hyperglucagonaemia and increased circulating levels of glucagon-like peptide 1 (GLP-1) and fibroblast growth factor 21 (FGF-21). Reduction in glucagon activity decreases hepatic amino acid and triglyceride catabolism; metabolic effects include improved glucose tolerance, increased plasma cholesterol and increased liver fat. Conversely, glucagon infusion in healthy volunteers leads to increased hepatic glucose output, decreased levels of plasma amino acids and increased urea production, decreased plasma cholesterol and increased energy expenditure. Patients with MASLD share many hormonal and metabolic characteristics with models of glucagon signalling deficiency, suggesting that they could be resistant to glucagon. Although there are few studies of the effects of glucagon infusion in patients with obesity and/or MASLD, there is some evidence that the expected effect of glucagon on amino acid catabolism may be attenuated. Taken together, this evidence supports the notion that glucagon resistance exists in patients with MASLD and may contribute to the pathogenesis of MASLD. Further studies are warranted to investigate the direct effects of glucagon on metabolism in patients with MASLD.

Glucagon-based therapy for people with diabetes and obesity: What is the sweet spot?

People with obesity and type 2 diabetes have a high prevalence of metabolic-associated steatotic liver disease, hyperlipidemia and cardiovascular disease. Glucagon increases hepatic glucose production; it also decreases hepatic fat accumulation, improves lipidemia and increases energy expenditure. Pharmaceutical strategies to antagonize the glucagon receptor improve glycemic outcomes in people with diabetes and obesity, but they increase hepatic steatosis and worsen dyslipidemia. Co-agonism of the glucagon and glucagon-like peptide-1 (GLP-1) receptors has emerged as a promising strategy to improve glycemia in people with diabetes and obesity. Addition of glucagon receptor agonism enhances weight loss, reduces liver fat and ameliorates dyslipidemia. Prior to clinical use, however, further studies are needed to investigate the safety and efficacy of glucagon and GLP-1 receptor co-agonists in people with diabetes and obesity and related conditions, with specific concerns regarding a higher prevalence of gastrointestinal side effects, loss of muscle mass and increases in heart rate. Furthermore, co-agonists with differing ratios of glucagon:GLP-1 receptor activity vary in their clinical effect; the optimum balance is yet to be identified.

Society for Endocrinology guidelines for the diagnosis and management of post-bariatric hypoglycaemia.

Post bariatric hypoglycaemia (PBH) is typically a post-prandial hypoglycaemia occurring about 2-4 hours after eating in people who have undergone bariatric surgery. PBH develops relatively late after surgery and often after discharge from post-surgical follow-up by bariatric teams, leading to variability in diagnosis and management in non-specialist centres. AIM: to improve and standardise clinical practice in the diagnosis and management of PBH. OBJECTIVES: (1) to undertake an up-to-date review of the current literature; (2) to formulate practical and evidence-based guidance with regards on the diagnosis and treatment of PBH; (3) to recommend future avenues for research in this condition. METHOD: A scoping review was undertaken after an extensive literature search. A consensus on the guidance and confidence in the recommendations was reached by the steering group authors prior to review by key stakeholders. OUTCOME: We make pragmatic recommendations for the practical diagnosis and management of PBH including criteria for diagnosis and recognition, as well as recommendations for research areas that should be explored.

The cardiovascular effects of GLP-1 receptor agonists beyond obesity and type 2 diabetes: An anti-atherosclerotic action.

Obesity and overweight affect almost one third of the European population. Obesity and its associated conditions, including type 2 diabetes, significantly impact healthcare systems, life expectancy and quality of life. The emergence of glucagon-like peptide-1 (GLP-1) receptor agonists for the treatment of obesity, with or without diabetes, has provided an effective alternative to metabolic surgery and dietary interventions. We are now beginning to understand their pleiotropic effects beyond weight loss, such as their favourable impact on cardiovascular profiles. The aim of this review is to summarize available preclinical and clinical data on the beneficial effects of GLP-1 receptor agonists on atherosclerosis and cardiovascular disease which has the potential to substantially broaden the scope of their clinical applications.

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.

Increased glycemic variability in pregnant women with Roux-en-Y gastric bypass compared with sleeve gastrectomy.

INTRODUCTION: Bariatric surgery is associated with adverse pregnancy outcomes such as reduced birth weight and premature birth. One possible mechanism for this is increased glycemic variability (GV) which occurs after bariatric surgery. The objective of this study was to compare the effect of Roux-en-Y gastric bypass (RYGB) versus vertical sleeve gastrectomy (SG) on GV during pregnancy and to investigate the relationships of GV, type of bariatric surgery and maternal and neonatal outcomes. RESEARCH DESIGN AND METHODS: Fourteen pregnant women after RYGB and 14 after SG were investigated with continuous glucose monitoring in their second or third trimester in this observational study carried out as part of routine clinical care. RESULTS: Pregnant women with RYGB had similar mean interstitial glucose values but significantly increased indices of GV and a lower %time in range 3.9-7.8 mmol/L (70-140 mg/dL), compared with SG. CONCLUSIONS: Pregnant women who have undergone RYGB have greater GV during pregnancy compared with those who have undergone SG. Further research is needed to establish the relationship between GV and pregnancy outcomes to determine the preferred bariatric operation in women of reproductive age, and whether interventions to reduce GV might improve outcomes.