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Inhibition of dynamin-related protein 1-filamin interaction improves systemic glucose metabolism
Yuri Kato1, Kohei Ariyoshi1, Yasunobu Nohara2
1Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
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.
Insights
Cilnidipine effectively lowers blood sugar and improves mitochondrial function in diabetic models by inhibiting the Drp1-filamin complex. This suggests a novel therapeutic strategy for type 2 diabetes treatment.
Area of Science:
- Mitochondrial biology
- Cardiovascular research
- Diabetes mellitus
Background:
- Mitochondrial quality is crucial for managing diabetes and its complications.
- Cilnidipine, an L/N-type Ca2+ channel blocker, previously showed efficacy in heart failure by inhibiting the dynamin-related protein 1 (Drp1)-filamin complex.
- The study explores cilnidipine's potential to improve hyperglycemia in diabetic models.
Purpose of the Study:
- To investigate the efficacy of cilnidipine in improving hyperglycemia in various diabetic mouse models.
- To evaluate the role of the Drp1-filamin complex in diabetes and its potential as a therapeutic target.
- To assess cilnidipine's effect on mitochondrial morphology and function in diabetes.
Main Methods:
- Retrospective analysis of HbA1c in patients treated with cilnidipine versus amlodipine.
- Induction of diabetes in mice using streptozotocin (STZ) and evaluation of cilnidipine's effects on blood glucose and mitochondrial morphology.
- Synthesis and pharmacological evaluation of a Ca2+ channel-insensitive cilnidipine derivative (1,4-DHP) in obese, high-fat diet-fed mice.
- Assessment of oxygen consumption in HepG2 cells under high glucose conditions.
Main Results:
- Cilnidipine demonstrated a superior HbA1c lowering effect compared to amlodipine in patients.
- Cilnidipine improved hyperglycemia and mitochondrial abnormalities in STZ-induced diabetic mice without affecting blood pressure.
- Cilnidipine did not improve hyperglycemia in obese mice and suppressed insulin secretion; however, the 1,4-DHP derivative ameliorated hyperglycemia and mitochondrial issues.
- Both cilnidipine and 1,4-DHP enhanced basal oxygen consumption in HepG2 cells.
Conclusions:
- Inhibition of the Drp1-filamin protein complex represents a promising new therapeutic strategy for type 2 diabetes.
- Cilnidipine's beneficial effects on hyperglycemia and mitochondrial function may be mediated through mechanisms beyond its Ca2+ channel blocking activity.
- Targeting mitochondrial dynamics offers a novel approach for managing diabetes and its associated complications.
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