Inhibition of dynamin‐related protein 1‐filamin interaction improves systemic glucose metabolism

• Published in: British journal of pharmacology Vol. 181; no. 21; pp. 4328 - 4347
• Main Authors: Kato, Yuri, Ariyoshi, Kohei, Nohara, Yasunobu, Matsunaga, Naoya, Shimauchi, Tsukasa, Shindo, Naoya, Nishimura, Akiyuki, Mi, Xinya, Kim, Sang Geon, Ide, Tomomi, Kawanishi, Eiji, Ojida, Akio, Nakashima, Naoki, Mori, Yasuo, Nishida, Motohiro
• Format: Journal Article
• Language: English
• Published: England 01.11.2024
• Subjects: Aged; Amlodipine - pharmacology; Animals; Blood Glucose - drug effects; Blood Glucose - metabolism; Calcium Channel Blockers - pharmacology; Diabetes Mellitus, Experimental - drug therapy; Diabetes Mellitus, Experimental - metabolism; Dihydropyridines - pharmacology; Drp1; Dynamins - antagonists & inhibitors; Dynamins - metabolism; Female; filamin; Glucose - metabolism; Glycated Hemoglobin - metabolism; Humans; Hyperglycemia - drug therapy; Hyperglycemia - metabolism; Hypertension - drug therapy; Hypertension - metabolism; insulin; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Middle Aged; Mitochondria - drug effects; Mitochondria - metabolism; mitochondria quality control; Retrospective Studies; type2 diabetes; filamin; mitochondria quality control; insulin; Drp1; type2 diabetes
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/bph.16487

Background and purpose Maintaining mitochondrial quality is attracting attention as a new strategy to treat diabetes and diabetic complications. We previously reported that mitochondrial hyperfission by forming a protein complex between dynamin‐related protein (Drp) 1 and filamin, mediates chronic heart failure and cilnidipine, initially developed as an L/N‐type Ca2+ channel blocker, improves heart failure by inhibiting Drp1‐filamin protein complex. We investigated whether cilnidipine improves hyperglycaemia of various diabetic mice models. Experimental Approach 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 Ca2+ channel‐insensitive cilnidipine derivative (1,4‐dihydropyridine [DHP]) was synthesized and its pharmacological effect was evaluated using obese (ob/ob) mice fed with high‐fat diet (HFD). Key Results In patients, cilnidipine was superior to amlodipine in HbA1c lowering effect. Cilnidipine treatment improved systemic hyperglycaemia and mitochondrial morphological abnormalities in STZ‐exposed mice, without lowering blood pressure. Cilnidipine failed to improve hyperglycaemia of ob/ob mice, with suppressing insulin secretion. 1,4‐DHP improved hyperglycaemia and mitochondria abnormality in ob/ob mice fed HFD. 1,4‐DHP and cilnidipine improved basal oxygen consumption rate of HepG2 cells cultured under 25 mM glucose. Conclusion and implications Inhibition of Drp1‐filamin protein complex formation becomes a new strategy for type 2 diabetes treatment.