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Possible Increase in Serum FABP4 Level Despite Adiposity Reduction by Canagliflozin, an SGLT2 Inhibitor
Masato Furuhashi1, Megumi Matsumoto1, Shinya Hiramitsu2
1Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine, S-1, W-16, Chuo-ku, Sapporo, 060-8543, Japan.
Background:
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.
Methods:
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.
Results:
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.
Conclusions:
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.
Trial Registration:
UMIN-CTR Clinical Trial UMIN000018151.
Insights
Canagliflozin, an SGLT2 inhibitor, unexpectedly increased fatty acid-binding protein 4 (FABP4) levels in type 2 diabetic patients. This rise in FABP4 may counteract glucose improvements and potentially explain increased hepatic glucose production.
Area of Science:
- Endocrinology
- Metabolic Syndrome
- Pharmacology
Background:
- Fatty acid-binding protein 4 (FABP4) is an adipokine linked to obesity, insulin resistance, and atherosclerosis.
- Elevated FABP4 contributes to insulin resistance by increasing hepatic glucose production (HGP).
- Sodium-glucose cotransporter 2 (SGLT2) inhibitors lower blood glucose but can enhance HGP.
Purpose of the Study:
- To investigate the effect of canagliflozin, an SGLT2 inhibitor, on serum FABP4 levels in patients with type 2 diabetes.
- To explore the relationship between changes in FABP4 and metabolic parameters after canagliflozin treatment.
Main Methods:
- A 12-week study involving 39 type 2 diabetic patients treated with canagliflozin (100 mg/day).
- Serum FABP4 levels were measured before and after the treatment period.
- Correlations between FABP4 levels and various clinical parameters (adiposity, renal function, noradrenaline, glucose, HbA1c) were analyzed.
Main Results:
- Canagliflozin treatment significantly reduced adiposity, fasting glucose, and HbA1c.
- Serum FABP4 levels increased by 10.3% on average, with elevations observed in 66.7% of patients.
- Increased FABP4 levels correlated positively with increases in fasting glucose, HbA1c, and noradrenaline.
Conclusions:
- Canagliflozin administration paradoxically elevated serum FABP4 levels in type 2 diabetic patients.
- This FABP4 increase may be linked to catecholamine-induced lipolysis and could potentially offset glucose-lowering effects.
- The rise in FABP4 might represent a mechanism contributing to enhanced HGP observed with SGLT2 inhibition.
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