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Murao, N. ; Takahashi, H.* ; Yokoi, N.* ; Okano, K.* ; Oduori, O.S.* ; Carmean, C.M.* ; Ogawa, W.* ; Sugawara, K.*

A novel small-molecule secretagogue, MDC134, amplifies glucose-dependent insulin secretion in pancreatic β-cells.

Biochem. Biophys. Res. Commun. 823:153962 (2026)
DOI PMC
Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
Insulin secretion from pancreatic β-cells is controlled by multiple mechanisms, including metabolic, electrophysiological, and second-messenger pathways. To identify insulinotropic small molecules, we performed in silico similarity screening using zatebradine, an HCN-channel ligand, as a structural query and functionally evaluated 26 hit compounds. Compound 2 showed the strongest insulinotropic activity and was used to synthesize the novel compound MDC134. MDC134 enhanced insulin secretion in MIN6-K8 cells and isolated mouse islets under stimulatory glucose conditions. MDC134 enhanced insulin secretion in isolated mouse islets and showed a tendency to increase insulin secretion in isolated non-diabetic human islets. Under high-glucose conditions, MDC134 increased intracellular Ca2+ levels, and nifedipine abolished its insulinotropic effect, indicating the involvement of voltage-dependent L-type Ca2+ channel-mediated Ca2+ influx. MDC134 also increased cellular cAMP content, although less potently than GLP-1. MDC134 treatment did not clearly affect glucose tolerance in C57BL/6J or ob/ob mice but significantly suppressed glucose elevation in β-cell-specific Kcnj11 knockout mice. These findings identify MDC134 as a novel glucose-dependent insulinotropic small molecule that enhances β-cell insulin secretion through Ca2+ influx and cAMP-associated amplification, and suggest that it may be useful for therapeutic strategies for diabetes characterized by impaired insulin secretion.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Secretion ; Insulin ; Pancreatic Hormone ; Diabetes Mellitus ; Glucagon-like Peptide-1; Nucleotide-gated Channels; Beta-cell
ISSN (print) / ISBN 0006-291X
e-ISSN 1090-2104
Zeitschrift Biochemical and Biophysical Research Communications
Quellenangaben Band: 823, Heft: , Seiten: , Artikelnummer: 153962 Supplement: ,
Verlag Elsevier
Verlagsort 525 B St, Ste 1900, San Diego, Ca 92101-4495 Usa
Begutachtungsstatus Peer reviewed
Institut(e) Institute for Diabetes und Organoid Technology (IDOT)