한빛사논문
- 조회343
Jin Wook Lee1,2, Hyun-Oh Gu1,2, Yunshin Jung2, YunJae Jung2,3, Seung-Yong Seo4, Jeong-Hee Hong1, In-Sun Hong5, Dae Ho Lee6, Ok-Hee Kim1 and Byung-Chul Oh1,2
1Department of Physiology, Lee Gil Ya Cancer and Diabetes Institute, Gachon College of Medicine, Incheon 21999, Republic of Korea.
2Department of Health Sciences and Technology (GAIHST), Gachon University, Incheon 21999, Republic of Korea.
3Department of Microbiology, Lee Gil Ya Cancer and Diabetes Institute, Gachon University College of Medicine, Incheon 21999, Republic of Korea.
4College of Pharmacy, Gachon University, Incheon 21936, Republic of Korea.
5Department of Molecular Medicine, Lee Gil Ya Cancer and Diabetes Institute, Gachon University College of Medicine, Incheon 21999, Republic of Korea.
6Department of Internal Medicine, Gachon University Gil Medical Center, Incheon 21565, Republic of Korea.
Corresponding authors : Correspondence to Ok-Hee Kim or Byung-Chul Oh.
Abstract
Insulin resistance is a major contributor to the pathogenesis of several human diseases, including type 2 diabetes, hypertension, and hyperlipidemia. Notably, insulin resistance and hypertension share common abnormalities, including increased oxidative stress, inflammation, and organelle dysfunction. Recently, we showed that excess intracellular Ca2+, a known pathogenic factor in hypertension, acts as a critical negative regulator of insulin signaling by forming Ca2+-phosphoinositides that prevent the membrane localization of AKT, a key serine/threonine kinase signaling molecule. Whether preventing intracellular Ca2+ overload improves insulin sensitivity, however, has not yet been investigated. Here, we show that the antihypertensive agent candesartan, compared with other angiotensin-II receptor blockers, has previously unrecognized beneficial effects on attenuating insulin resistance. We found that candesartan markedly reduced palmitic acid (PA)-induced intracellular Ca2+ overload and lipid accumulation by normalizing dysregulated store-operated channel (SOC)-mediated Ca2+ entry into cells, which alleviated PA-induced insulin resistance by promoting insulin-stimulated AKT membrane localization and increased the phosphorylation of AKT and its downstream substrates. As pharmacological approaches to attenuate intracellular Ca2+ overload in vivo, administering candesartan to obese mice successfully decreased insulin resistance, hepatic steatosis, dyslipidemia, and tissue inflammation by inhibiting dysregulated SOC-mediated Ca2+ entry and ectopic lipid accumulation. The resulting alterations in the phosphorylation of key signaling molecules consequently alleviate impaired insulin signaling by increasing the postprandial membrane localization and phosphorylation of AKT. Thus, our findings provide robust evidence for the pleiotropic contribution of intracellular Ca2+ overload in the pathogenesis of insulin resistance and suggest that there are viable approved drugs that can be repurposed for the treatment of insulin resistance and hypertension.
논문정보
- Research article
- 2023년 05월 (BRIC 등록일 2023-05-18)
- 국내 연구진
- 생명과학 > 생리학
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