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  • American Diabetes Association  (2)
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  • American Diabetes Association  (2)
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  • 1
    Online Resource
    Online Resource
    299-OR: Discovery of Long-Acting Unimolecular Peptide Tetra-agonists Targeting GLP-1, GIP, Amylin, and Calcitonin Receptors for Enhanced Metabolic Benefits in Animal Models of Obesity
    American Diabetes Association ; 2024
    In:  Diabetes Vol. 73, No. Supplement_1 ( 2024-06-14)
    Details
    In: Diabetes, American Diabetes Association, Vol. 73, No. Supplement_1 ( 2024-06-14)
    Abstract: Objective: The burgeoning prevalence of obesity and associated co-morbidities necessitates innovative approaches for safe and efficacious therapies. We describe the characterization of PTT-A, a novel long-acting peptide agonist for GLP-1, GIP, Amylin and Calcitonin Receptors, in rodent models and assessed its efficacy against the dual GIPR/GLP-1R agonist Tirzepatide. Methods: In vitro assays used recombinant cell lines expressing individual receptors to assess GLP-1, GIP, Amylin and Calcitonin receptor agonism. Multiple metabolic endpoints were examined in rodents, including acute food intake and calcium regulation effects of PTT-A in lean rats, acute glucose-lowering effects in lean mice, and its chronic effects in diet-induced obesity (DIO) rats compared to Tirzepatide. Results: PTT-A exhibited potent GIP, GIP, Amylin, and Calcitonin receptor agonism in cAMP assays, and induced decreases in blood glucose and calcium levels in acute studies in lean rodents. In lean rats, PTT-A dose-dependently reduced cumulative food intake. Chronic studies in DIO rats revealed significant reduction in cumulative food intake and body weight, driven by decreases in fat mass without loss of muscle mass, unlike that seen with Tirzepatide. PTT-A demonstrated robust efficacy for glucose and plasma lipid lowering, insulin sensitization and liver benefits, as indicated by lowered plasma insulin, alanine aminotransferase and liver triglycerides, while outperforming Tirzepatide at equivalent doses. Conclusion: PTT-A is a novel tetra-receptor agonist, offering superior outcomes for weight loss, glycemic control, insulin sensitization, and liver health compared to Tirzepatide. These findings underscore the promise of such poly-pharmacological agents to tackle the complex challenges associated with obesity-related metabolic disorders. Disclosure S. Ghosh: Consultant; Abvance Therapeutics, Akero Therapeutics, Inc., Fractyl Health, Inc., Takeda Pharmaceutical Company Limited. P. Valdecantos: Research Support; Pep2Tango Therapeutics INC. P. Rada: Research Support; Pep2Tango Therapeutics INC. A.M. Valverde: Research Support; Pep2Tango Therapeutics INC. C.M. Rondinone: Board Member; Pep2tango Therapeutics Inc. Stock/Shareholder; Pep2tango Therapeutics Inc.
    Type of Medium: Online Resource
    ISSN: 0012-1797
    URL: Article
    DOI: 10.2337/db24-299-OR
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2024
    detail.hit.zdb_id: 1501252-9
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  • 2
    Online Resource
    Online Resource
    300-OR: Beneficial Effect of the Combination Therapy of Cagrilintide, a Dual Amylin/Calcitonin Agonist, and Tirzepatide, a Dual GLP-1/GIP Agonist, on Body Weight Loss in Obese Rats
    American Diabetes Association ; 2024
    In:  Diabetes Vol. 73, No. Supplement_1 ( 2024-06-14)
    Details
    In: Diabetes, American Diabetes Association, Vol. 73, No. Supplement_1 ( 2024-06-14)
    Abstract: Introduction & Objective: Combinatorial therapies with incretin receptor agonists targeting multiple pathways that regulate energy balance is a promising strategy for weight loss since it potentially allows dose reduction of each drug and can help to ameliorate the associated gastrointestinal side-effects of the current monotherapies. We evaluated the combination of cagrilintide and tirzepatide on weight loss in obese rats. Methods: Diet-induced obese Sprague Dawley male rats were dosed subcutaneously once-daily for 12 days with 3 and 10 nmol/kg of cagrilintide and tirzepatide alone or in combination at submaximal dose of 3 nmol/kg. Body weight and food intake were measured daily. Biochemical parameters in plasma were analyzed. Results: Relative to vehicle, cagrilintide administered alone presented superior efficacy in body weight reduction (-7.22%±1.80% at 3 nmol/kg and -9.61% ± 0.52% at 10 nmol/kg) compared with tirzepatide (-2.53% ± 0.44% at 3 nmol/kg and -5.81 ± 0.86% at 10 nmol/kg). Peptide combination at submaximal dose of 3 nmol/kg each reduced body weight by -11.0 ± 0.86% (P & lt;0.05 vs cagrilintide and P & lt;0.001 versus tirzepatide) at the same doses, Reductions in cumulative food intake correlated with weight loss. Combination therapy was superior in decreasing ALT than cagrilintide (P & lt;0.001) and tirzepatide (P & lt;0.05) and plasma TGs levels were lower compared to the tirzepatide group (P & lt; 0.001). Conclusion: Combination therapy at submaximal doses of cagrilintide and tirzepatide achieved significantly greater weight loss and higher reduction in food intake compared to the monotherapy, suggesting the potential opportunity of this combination for further clinical development. Disclosure P. Valdecantos: Research Support; Pep2Tango Therapeutics INC. P. Rada: Research Support; Pep2Tango Therapeutics INC. S. Ghosh: Consultant; Abvance Therapeutics, Akero Therapeutics, Inc., Fractyl Health, Inc., Takeda Pharmaceutical Company Limited. C.M. Rondinone: Board Member; Pep2tango Therapeutics Inc. Stock/Shareholder; Pep2tango Therapeutics Inc. A.M. Valverde: Research Support; Pep2Tango Therapeutics INC. Funding Pep2Tango Therapeutics INC
    Type of Medium: Online Resource
    ISSN: 0012-1797
    URL: Article
    DOI: 10.2337/db24-300-OR
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2024
    detail.hit.zdb_id: 1501252-9
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
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