The effect and mechanism of short-chain fatty acid regulate tacrolimus-related hyperglycemia in mice
10.3760/cma.j.cn112330-20200720-00549
- VernacularTitle:短链脂肪酸对他克莫司相关高血糖的影响及相关机制研究
- Author:
Zijian ZHANG
1
;
Wenjiao JIAO
;
Yue XU
;
Lian GONG
;
Weixun ZHANG
;
Xiaopeng HU
Author Information
1. 首都医科大学附属北京朝阳医院泌尿外科，北京 100020
- Keywords:
Transplantation;
Diabetes mellitus;
Tacrolimus;
Short-chain fatty acids;
Gut microbiota
- From:
Chinese Journal of Urology
2021;42(11):856-861
- CountryChina
- Language:Chinese
-
Abstract:
Objective:To investigate the effect and mechanism of short-chain fatty acids (SCFAs) on the side-effect of tacrolimus on blood glucose.Methods:The C57BL/6 mice were treated with tacrolimus orally (10 mg/kg, tacrolimus group), tacrolimus plus 150 mmol/L sodium butyrate and isovalerate mixed solution (SCFAs group), broad-spectrum antibiotics (antibiotic group), and tacrolimus plus broad-spectrum antibiotics (tac&abx group). After 8 weeks intervention, the fasting blood glucose (FBG), oral glucose tolerance test (OGTT), hemoglobin A1C (HbA1c) were tested as indicators of glucose metabolism, and the gut microbiota, SCFAs concentration in the ileocecal, serum glucagon-like peptide-1 (GLP-1), fasting serum insulin, and GLP-1 expression in intestinal mucosa were performed for intestinal-glucose metabolism mechanism.Results:The FBG and HbA1c were significantly increased in tacrolimus group[(7.31±0.97)mmol/L, (8.34±1.12)%] than control group [(5.23±0.30)mmol/L, (4.32±0.80)%, all P<0.05], which remained normal in antibiotic group [(4.92±0.31)mmol/L, (5.61±0.98)%)], tac&abx group[(5.95±0.37)mmol/L, (4.56±0.26)%] and SCFAs groups [(5.87±0.68)mmol/L, (5.07±1.79)%]. The OGTT in the tacrolimus group showed glucose tolerance impairment, while other groups remained normal. The ileocecal butyric acid and isovaleric acid concentrations in the tacrolimus group were (722.3±262.2) μg/g and (10.0±5.1)μg/g, lower than the control group[ (1 321.3±165.5) μg/g, (19.7±3.6)μg/g, P<0.05]. The above acids in the SCFAs group remained normal as in the control group [(1 375.7±451.6) μg/g, (24.5±11.5)μg/g)]. The fasting serum insulin in the tacrolimus group decreased significantly to (3.2 ± 0.6)mIU/L, compared with control[ (4.4±0.9) mIU/L]and SCFAs groups [(7.0±1.1) mIU/L]. The GLP-1 test indicated a significant decrease in the tacrolimus group[ (4.7±2.9)pg/ml, P<0.05] compared with the SCFAs group and control group [(42.5±19.9) pg/ml, (33.1±9.1) pg/ml]. Conclusions:Tacrolimus affects glucose metabolism through the SCFAs-associated GLP-1 pathway in the intestine, and oral supplementation with mixed SCFAs provides a new insight for the prevention and treatment of tacrolimus-induced hyperglycemia in transplant recipients.
