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The Insulin Sensitizer KBP-336 Prevents Diabetes-Induced Cognitive decline in ZDF Rats

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Abstract

Background and Objectives

Diabetes and especially insulin resistance are associated with an increased risk of developing cognitive dysfunction, making anti-diabetic drugs an interesting therapeutic option for the treatment of neurodegenerative disorders. Dual amylin and calcitonin receptor agonists (DACRAs) elicit beneficial effects on glycemic control and insulin sensitivity. However, whether DACRAs affect cognition is unknown.

Design and Intervention

Zucker Diabetic Fatty rats were treated with either the DACRA KBP-336 (4.5 nmol/kg Q3D), the amylin analog AM1213 (25 nmol/kg QD), or vehicle for 18 weeks. Further, the efficacy of a late KBP-336 intervention was evaluated by including a group starting treatment on day 30. Glucose control and tolerance were evaluated throughout the study and spatial learning and memory were evaluated by Morris Water Maze after 17 weeks of treatment.

Results

When evaluating spatial learning, rats receiving KBP-336 throughout the study performed significantly better than AM1213, vehicle, and late intervention KBP-336. Both KBP-336 and AM1213 treatments improved spatial memory compared to the vehicle. The overall performance in the cognitive tests was reflected in the treatment efficacy on glycemic control, where KBP-336 was superior to AM1213.

Conclusion

In summary, the DACRA KBP-336 ameliorates diabetes-induced spatial learning and memory impairment in diabetic rats. Further, KBP-336 improves long-term glycemic control superior to the amylin analog AM1213. Taken together, KBP-336 is, due to its anti-diabetic and insulin-sensitizing properties, a promising candidate for the treatment of cognitive impairments.

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Availability of data: The data supporting the findings of this manuscript are available from the corresponding author upon reasonable request.

Abbreviations

DACRA:

Dual amylin and calcitonin receptor agonist

GLP-1:

Glucagon-like peptide 1

KBP:

KeyBioscience Peptide

OGTT:

Oral glucose tolerance test

PPARγ:

Peroxisome proliferator-activated receptor gamma

SGLT2:

Sodium-glucose co-transporter 2

ZDF:

Zucker diabetic Fatty

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Acknowledgements

We would like to thank Christina Hansen and Majbrith Sprankel for their technical assistance.

Funding

Funding: We acknowledge the Innovation Fund Denmark for the funding.

Author information

Authors and Affiliations

  1. Nordic Bioscience A/S, Herlev Hovedgade 207, DK-2730, Herlev, Denmark

    Anna Thorsø Larsen, K. E. Mohamed, E. A. Petersen, M. A. Karsdal & K. Henriksen

  2. KeyBioscience AG, Stans, Switzerland

    M. A. Karsdal & K. Henriksen

  3. Department of Science and Environment, Roskilde University, Roskilde, Denmark

    K. Henriksen

Authors
  1. Anna Thorsø Larsen
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  2. K. E. Mohamed
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  3. E. A. Petersen
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  4. M. A. Karsdal
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Contributions

Authors’ contributions: ATL designed the study, performed the experiments, analyzed and interpreted the data, and wrote the manuscript. KEM performed some experiments, assisted with data analysis and interpretation, and manuscript preparation. EAP assisted with some experiments and data analysis. KH and MAK assisted with data analysis and manuscript preparation. All authors have read and approved the final version of the manuscript.

Corresponding author

Correspondence to Anna Thorsø Larsen.

Ethics declarations

Ethics approval: All animal procedures were performed in accordance with guidelines from the Animal Welfare Division of the Danish Ministry of Justice under the institutional licenses issued to Nordic Bioscience (2021–15–0201–00886) and were carried out in accordance with the ARRIVE guidelines.

Conflicts of interests: MAK and KH own stock in Nordic Bioscience A/S. All authors are employed by Nordic Bioscience A/S.

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Larsen, A.T., Mohamed, K.E., Petersen, E.A. et al. The Insulin Sensitizer KBP-336 Prevents Diabetes-Induced Cognitive decline in ZDF Rats. J Prev Alzheimers Dis (2024). https://doi.org/10.14283/jpad.2024.74

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