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We previously reported that mitochondrial hyperfission by forming a protein complex between dynamin\u2010related protein (Drp) 1 and filamin, mediates chronic heart failure and cilnidipine, initially developed as an L\/N\u2010type Ca<jats:sup>2+<\/jats:sup> channel blocker, improves heart failure by inhibiting Drp1\u2010filamin protein complex. We investigated whether cilnidipine improves hyperglycaemia of various diabetic mice models.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>Retrospective analysis focusing on haemoglobin A1c (HbA1c) was performed in hypertensive and hyperglycaemic patients taking cilnidipine and amlodipine. After developing diabetic mice by streptozotocin (STZ) treatment, an osmotic pump including drug was implanted intraperitoneally, followed by weekly measurements of blood glucose levels. Mitochondrial morphology was analysed by electron microscopy. A Ca<jats:sup>2+<\/jats:sup> channel\u2010insensitive cilnidipine derivative (1,4\u2010dihydropyridine [DHP]) was synthesized and its pharmacological effect was evaluated using obese (<jats:italic>ob\/ob<\/jats:italic>) mice fed with high\u2010fat diet (HFD).<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>In patients, cilnidipine was superior to amlodipine in HbA1c lowering effect. Cilnidipine treatment improved systemic hyperglycaemia and mitochondrial morphological abnormalities in STZ\u2010exposed mice, without lowering blood pressure. Cilnidipine failed to improve hyperglycaemia of <jats:italic>ob\/ob<\/jats:italic> mice, with suppressing insulin secretion. 1,4\u2010DHP improved hyperglycaemia and mitochondria abnormality in <jats:italic>ob\/ob<\/jats:italic> mice fed HFD. 1,4\u2010DHP and cilnidipine improved basal oxygen consumption rate of HepG2 cells cultured under 25\u2009mM glucose.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion and implications<\/jats:title><jats:p>Inhibition of Drp1\u2010filamin protein complex formation becomes a new strategy for type 2 diabetes treatment.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.16487","type":"journal-article","created":{"date-parts":[[2024,7,11]],"date-time":"2024-07-11T00:49:15Z","timestamp":1720658955000},"page":"4328-4347","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Inhibition of dynamin\u2010related protein 1\u2010filamin interaction improves systemic glucose 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