Furuhashi Masato, Matsumoto Megumi, Hiramitsu Shinya, Omori Akina, Tanaka Marenao, Moniwa Norihito, Yoshida Hideaki, Ishii Junnichi, Miura Tetsuji
Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine, S-1, W-16, Chuo-ku, Sapporo, 060-8543, Japan.
Hiramitsu Heart Clinic, Shiroshita-cho 2-35, Minami-ku, Nagoya, 457-0047, Aichi, Japan.
PLoS One. 2016 Apr 28;11(4):e0154482. doi: 10.1371/journal.pone.0154482. eCollection 2016.
Fatty acid-binding protein 4 (FABP4/A-FABP/aP2) is secreted from adipocytes in association with catecholamine-induced lipolysis, and elevated serum FABP4 level is associated with obesity, insulin resistance and atherosclerosis. Secreted FABP4 as a novel adipokine leads to insulin resistance via increased hepatic glucose production (HGP). Sodium-glucose cotransporter 2 (SGLT2) inhibitors decrease blood glucose level via increased urinary glucose excretion, though HGP is enhanced. Here we investigated whether canagliflozin, an SGLT2 inhibitor, modulates serum FABP4 level.
Canagliflozin (100 mg/day) was administered to type 2 diabetic patients (n = 39) for 12 weeks. Serum FABP4 level was measured before and after treatment.
At baseline, serum FABP4 level was correlated with adiposity, renal dysfunction and noradrenaline level. Treatment with canagliflozin significantly decreased adiposity and levels of fasting glucose and HbA1c but increased average serum FABP4 level by 10.3% (18.0 ± 1.0 vs. 19.8 ± 1.2 ng/ml, P = 0.008), though elevation of FABP4 level after treatment was observed in 26 (66.7%) out of 39 patients. Change in FABP4 level was positively correlated with change in levels of fasting glucose (r = 0.329, P = 0.044), HbA1c (r = 0.329, P = 0.044) and noradrenaline (r = 0.329, P = 0.041) but was not significantly correlated with change in adiposity or other variables.
Canagliflozin paradoxically increases serum FABP4 level in some diabetic patients despite amelioration of glucose metabolism and adiposity reduction, possibly via induction of catecholamine-induced lipolysis in adipocytes. Increased FABP4 level by canagliflozin may undermine the improvement of glucose metabolism and might be a possible mechanism of increased HGP by inhibition of SGLT2.
UMIN-CTR Clinical Trial UMIN000018151.
脂肪酸结合蛋白4（FABP4/A-FABP/aP2）与儿茶酚胺诱导的脂肪分解相关，由脂肪细胞分泌，血清FABP4水平升高与肥胖、胰岛素抵抗和动脉粥样硬化有关。分泌型FABP4作为一种新型脂肪因子，通过增加肝脏葡萄糖生成（HGP）导致胰岛素抵抗。钠-葡萄糖协同转运蛋白2（SGLT2）抑制剂通过增加尿糖排泄降低血糖水平，尽管HGP会增强。在此，我们研究了SGLT2抑制剂卡格列净是否能调节血清FABP4水平。
对39例2型糖尿病患者给予卡格列净（100mg/天）治疗12周。在治疗前后测量血清FABP4水平。
在基线时，血清FABP4水平与肥胖、肾功能不全和去甲肾上腺素水平相关。卡格列净治疗显著降低了肥胖程度以及空腹血糖和糖化血红蛋白水平，但平均血清FABP4水平升高了10.3%（从18.0±1.0ng/ml升至19.8±1.2ng/ml，P=0.008），尽管39例患者中有26例（66.7%）在治疗后出现FABP4水平升高。FABP4水平的变化与空腹血糖水平变化（r=0.329，P=0.044）、糖化血红蛋白水平变化（r=0.329，P=0.044）和去甲肾上腺素水平变化（r=0.329，P=0.041）呈正相关，但与肥胖程度变化或其他变量无显著相关性。
尽管卡格列净改善了糖代谢并减轻了肥胖，但在一些糖尿病患者中却反常地增加了血清FABP4水平，这可能是通过诱导脂肪细胞中儿茶酚胺诱导的脂肪分解实现的。卡格列净导致FABP4水平升高可能会削弱糖代谢的改善，并且可能是抑制SGLT2导致HGP增加的一种可能机制。
UMIN-CTR临床试验UMIN000018151。
