Targeting the Incretin/Glucagon System With Triagonists to Treat Diabetes

Abstract Glucagonlike peptide 1 (GLP-1) receptor agonists have been efficacious for the treatment of type 2 diabetes due to their ability to reduce weight and attenuate hyperglycemia. However, the activity of glucagonlike peptide 1 receptor–directed strategies is submaximal, and the only potent, sustainable treatment of metabolic dysfunction is bariatric surgery, necessitating the development of unique therapeutics. GLP-1 is structurally related to glucagon and glucose-dependent insulinotropic peptide (GIP), allowing for the development of intermixed, unimolecular peptides with activity at each of their respective receptors. In this review, we discuss the range of tissue targets and added benefits afforded by the inclusion of each of GIP and glucagon. We discuss considerations for the development of sequence-intermixed dual agonists and triagonists, highlighting the importance of evaluating balanced signaling at the targeted receptors. Several multireceptor agonist peptides have been developed and evaluated, and the key preclinical and clinical findings are reviewed in detail. The biological activity of these multireceptor agonists are founded in the success of GLP-1-directed strategies; by including GIP and glucagon components, these multireceptor agonists are thought to enhance GLP-1’s activities by broadening the tissue targets and synergizing at tissues that express multiple receptors, such at the brain and pancreatic isletβ cells. The development and utility of balanced, unimolecular multireceptor agonists provide both a useful tool for querying the actions of incretins and glucagon during metabolic disease and a unique drug class to treat type 2 diabetes with unprecedented efficacy.

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Metabolic Effects of Bariatric Surgery

Clinical Chemistry ◽

10.1373/clinchem.2017.272336 ◽

2018 ◽

Vol 64 (1) ◽

pp. 72-81 ◽

Cited By ~ 12

Author(s):

Piriyah Sinclair ◽

Neil Docherty ◽

Carel W le Roux

Keyword(s):

Type 2 Diabetes ◽

Bariatric Surgery ◽

Metabolic Surgery ◽

Positive Impact ◽

Metabolic Effects ◽

Beneficial Effects ◽

Treatment Of Obesity ◽

The Impact ◽

The Brain

Abstract BACKGROUND Obesity can be defined as a chronic subcortical brain disease, as there is an important neurophysiological component to its etiology based on changes in the functioning of those areas of the brain controlling food intake and reward. Extensive metabolic changes accompany bariatric surgery-based treatment of obesity. Consequently, the term “metabolic” surgery is being increasingly adopted in relation to the beneficial effects these procedures have on chronic diseases like type 2 diabetes. CONTENT In the present review, we focus on the key biochemical and physiological changes induced by metabolic surgery and highlight the beneficial effects accrued systemically with the use of an organ-based approach. Understanding the impact on and interactions between the gut, brain, adipose tissue, liver, muscle, pancreas, and kidney is key to understanding the sum of the metabolic effects of these operations. SUMMARY Further mechanistic studies are essential to assess the true potential of metabolic surgery to treat metabolic comorbidities of obesity beyond type 2 diabetes. Approaches that may mitigate the metabolic side effects of surgery also require attention. Understanding the positive impact of metabolic surgery on metabolic health may result in a wider acceptance of this intervention as treatment for metabolic, comorbid conditions.

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Proceedings from the 2018 Association for Chemoreception Annual Meeting Symposium: Bariatric Surgery and Its Effects on Taste and Food Selection

Chemical Senses ◽

10.1093/chemse/bjy076 ◽

2018 ◽

Vol 44 (3) ◽

pp. 155-163 ◽

Cited By ~ 3

Author(s):

Alan C Spector ◽

Natasha Kapoor ◽

Ruth K Price ◽

M Yanina Pepino ◽

M Barbara E Livingstone ◽

...

Keyword(s):

Type 2 Diabetes ◽

Bariatric Surgery ◽

Weight Loss ◽

Gastric Bypass ◽

Annual Meeting ◽

Food Selection ◽

Food Preferences ◽

Empirical Support ◽

Clinical Findings

Abstract This article provides a summary of the topics discussed at the symposium titled “Bariatric Surgery and Its Effects on Taste and Food Selection,” which was held at the Fortieth Annual Meeting of the Association for Chemoreception Sciences. Bariatric surgery such as Roux-en-Y gastric bypass (RYGB) is currently one of the most effective treatments available for weight loss and Type 2 diabetes. For this reason, it is of great interest to clinicians as well as to basic scientists studying the controls of feeding and energy balance. Despite the commonly held view by clinicians that RYGB patients change their food preferences away from fats and sugars in favor of less energy dense alternatives such as vegetables, the empirical support for this claim is equivocal. It is currently thought that the taste and palatability of fats and sugars are affected by the surgery. Some key preclinical and clinical findings addressing these issues were evaluated in this symposium.

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Using multimodal MRI to investigate alterations in brain structure and function in rats with type 2 diabetes.

10.21203/rs.3.rs-17165/v1 ◽

2020 ◽

Author(s):

Christopher M Lawson ◽

Kilian FG Rentrup ◽

Xuezhu Cai ◽

Praveen P Kulkarni ◽

Craig Ferris

Keyword(s):

Type 2 Diabetes ◽

Gray Matter ◽

Brain Structure ◽

Clinical Findings ◽

Structure And Function ◽

Functional Coupling ◽

Brain Structure And Function ◽

And Function ◽

The Brain

Abstract Objectives This is an exploratory study using multimodal magnetic resonance imaging (MRI) to interrogate the brain of rats with type 2 diabetes (T2DM) as compared to controls. It was assumed there would be changes in brain structure and function that reflected the human disorder, thus providing a model system by which to follow disease progression with non-invasive MRI. Methods The transgenic BBZDR/Wor rat, an animal model of T2MD, and age-matched controls were studied for changes in brain structure using voxel-based morphometry, alteration in white and gray matter microarchitecture using diffusion weighted imaging with indices of anisotropy, and functional coupling using resting state BOLD functional connectivity. Images from each modality were registered to, and analyzed, using a 3D MRI rat atlas providing site-specific data on over 168 different brain areas. Results There was an overall reduction in brain volume focused primarily on somatosensory cortex, cerebellum and white matter tracts. The putative changes in white and gray matter microarchitecture were pervasive affecting much of the brain and not localized to any region. There was a general increase in connectivity in T2DM rats as compared to controls. The cerebellum presented with strong functional coupling to pons and brainstem in T2DM rats but negative connectivity to hippocampus. Conclusion Are the neuroradiological measures collected in BBBKZ/Wor rats using multimodal imaging methods common to the clinic, similar to those reported in T2DM patents? In comparison to the clinical findings, the data would suggest the BBBKZ/Wor rat is not an appropriate imaging model for T2DM.

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