A new glucagon and GLP-1 co-agonist eliminates obesity in rodents

Day, Jonathan W.; Ottaway, Nickki; Patterson, James T.; Gelfanov, Vasily; Smiley, David L.; Gidda, Jas; Findeisen, Hannes M.; Bruemmer, Dennis; Drucker, Daniel J.; Chaudhary, Nilika; Holland, Jenna; Hembree, Jazzminn; Abplanalp, William; Grant, Erin; Ruehl, Jennifer; Wilson, Hilary; Kirchner, Henriette; Lockie, Sarah H.; Hofmann, Susanna M.; Woods, Stephen C.; Nogueiras, Rubén; Pfluger, Paul T.; Pérez-Tilve, Diego; DiMarchi, Richard D.; Tschöp, Matthias H.

doi:10.1038/nchembio.209

Cited by 524 publications

(498 citation statements)

References 33 publications

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“…Fibroblast growth factor 21 has broad metabolic effects, including enhancing insulin sensitivity, decreasing triglyceride concentrations, and inducing weight loss, and this activity acts additively with GLP-1 (107,108). By combining two peptides with different effects, GLP-1R/glucagon coagonism may normalize adiposity and glucose tolerance through fat loss, decreased food intake, and increased energy expenditure, while minimizing hypoglycemic risk (109).…”

Section: Potential Therapeutic Targetsmentioning

confidence: 99%

Weight Management in Type 2 Diabetes: Current and Emerging Approaches to Treatment

2015

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Diabetes is a growing global health concern, as is obesity. Diabetes and obesity are intrinsically linked: obesity increases the risk of diabetes and also contributes to disease progression and cardiovascular disease. Although the benefits of weight loss in the prevention of diabetes and as a critical component of managing the condition are well established, weight reduction remains challenging for individuals with type 2 diabetes due to a host of metabolic and psychological factors. For many patients, lifestyle intervention is not enough to achieve weight loss, and alternative options, such as pharmacotherapy, need to be considered. However, many traditional glucose-lowering medications may lead to weight gain. This article focuses on the potential of currently available pharmacological strategies and on emerging approaches in development to support the glycemic and weight-loss goals of individuals with type 2 diabetes. Two pharmacotherapy types are considered: those developed primarily for blood glucose control that have a favorable effect on body weight and those developed primarily to induce weight loss that have a favorable effect on blood glucose control. Finally, the potential of combination therapies for the management of obese patients with type 2 diabetes is discussed.

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Section: Potential Therapeutic Targetsmentioning

confidence: 99%

Weight Management in Type 2 Diabetes: Current and Emerging Approaches to Treatment

2015

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“…The antagonism of glucagon action on the liver also partly mediates the glucose-lowering effect of biguanides (196) . It has been recently demonstrated that the design of peptides with dual agonism for both the glucagon and the GLP-1 receptors is useful to fight against obesity in mice without any apparent adverse effects (197,198) . This is mainly the result of the antihyperglycaemic, lipolytic, satiating and energy expenditure actions of this combined treatment.…”

Section: Therapeutic Potential Of Modulating Glucagon Secretion and Amentioning

confidence: 99%

Nutrient regulation of glucagon secretion: involvement in metabolism and diabetes

et al. 2014

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Glucose homeostasis is precisely regulated by glucagon and insulin, which are released by pancreatic a-and b-cells, respectively. While b-cells have been the focus of intense research, less is known about a-cell function and the actions of glucagon. In recent years, the study of this endocrine cell type has experienced a renewed drive. The present review contains a summary of established concepts as well as new information about the regulation of a-cells by glucose, amino acids, fatty acids and other nutrients, focusing especially on glucagon release, glucagon synthesis and a-cell survival. We have also discussed the role of glucagon in glucose homeostasis and in energy and lipid metabolism as well as its potential as a modulator of food intake and body weight. In addition to the well-established action on the liver, we discuss the effects of glucagon in other organs, where the glucagon receptor is expressed. These tissues include the heart, kidneys, adipose tissue, brain, small intestine and the gustatory epithelium. Alterations in a-cell function and abnormal glucagon concentrations are present in diabetes and are thought to aggravate the hyperglycaemic state of diabetic patients. In this respect, several experimental approaches in diabetic models have shown important beneficial results in improving hyperglycaemia after the modulation of glucagon secretion or action. Moreover, glucagon receptor agonism has also been used as a therapeutic strategy to treat obesity.

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“…Further studies are required before a definitive conclusion can be made with regard to the mechanism of action of OXM6421. Interestingly, it has recently been shown that GLP-1 and glucagon receptors' dual agonism can reverse obesity in rodents, 31,32 which further highlights the important role of the peptides from the pre-proglucagon family in the modulation of energy balance.…”

Section: Discussionmentioning

confidence: 99%

Subcutaneous oxyntomodulin analogue administration reduces body weight in lean and obese rodents

et al. 2010

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Objective: To determine the efficacy of a long-acting oxyntomodulin (OXM) analogue, OXM6421, in inhibiting food intake and decreasing body weight in lean and diet-induced obese (DIO) rodents. Research design and methods: The glucagon-like peptide-1 (GLP-1) receptor binding affinity and efficacy, sensitivity to enzymatic degradation in vitro and persistence in the circulation after peripheral administration were investigated for OXM6421 and compared with native OXM. The chronic effect of OXM6421 on food intake, body weight and energy expenditure was examined in lean rats, and its anti-obesity potential was evaluated in DIO mice. Results: OXM6421 showed enhanced GLP-1 receptor binding affinity and cyclic adenosine monophosphate (cAMP) stimulation, and higher resistance to enzymatic degradation by dipeptidyl peptidase IV (DPP-IV) and neutral endopeptidase (NEP) compared with native OXM. OXM6421 persisted longer in the circulation than OXM after peripheral administration. Acute administration of OXM6421 potently inhibited food intake in lean rodents, with cumulative effects lasting up to 24 h. In lean rats, daily subcutaneous (s.c.) administration of OXM6421 caused greater weight loss than the pair-fed animals, and a higher rate of oxygen consumption than both the pair-fed and the saline controls. In DIO mice, continuous s.c. infusion of OXM6421 resulted in a significant weight loss, accompanied by an improvement in glucose homeostasis and an increase in circulating adiponectin levels. Once-daily s.c. administration of OXM6421 for 21 days caused sustained weight loss in DIO mice. Conclusion: OXM6421 induces negative energy balance in both lean and obese rodents, suggesting that long-acting OXM analogues may represent a potential therapy for obesity.

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A new glucagon and GLP-1 co-agonist eliminates obesity in rodents

Cited by 524 publications

References 33 publications

Weight Management in Type 2 Diabetes: Current and Emerging Approaches to Treatment

Weight Management in Type 2 Diabetes: Current and Emerging Approaches to Treatment

Nutrient regulation of glucagon secretion: involvement in metabolism and diabetes

Subcutaneous oxyntomodulin analogue administration reduces body weight in lean and obese rodents

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