Abstract
Acidic fibroblast growth factor (aFGF) is a promising regulator of glucose with no adverse effects of hypoglycemia. Previous researches revealed that aFGF mediated adipose tissue remodeling and insulin sensitivity. These findings supported rh-aFGF135 would be used as a new candidate for the treatment of insulin resistance and type 2 diabetes. In this study, we aimed to investigate the hypoglycemic efficacy of recombinant human acidic fibroblast growth factor 135 (rh-aFGF135) with low mitogenic in type 2 diabetic ZDF rats. ZDF rats were treated with rh-aFGF135 at a daily dosage of 0.25 and 0.50 mg/kg by tail intravenous injection for 5 weeks. The blood glucose levels, oral glucose tolerance test, insulin tolerance test, HOMA-IR for insulin resistance, serum biochemical parameters, and the histopathological changes of adipose tissue, liver and other organs were detected at designed time point. The glucose uptake activity and anti-insulin resistance effect of rh-aFGF135 were also detected in HepG2 cells. Results revealed that rh-aFGF135 exhibited a better hypoglycemic effect compared with vehicle group and without the adverse effect of hypoglycemia in ZDF rats. Compared with vehicle group, rh-aFGF135 significantly improved the situation of hyperglycemia and insulin resistance. Rh-aFGF135 decreased ALT, AST, GSP, and FFA levels noticeably compared with vehicle control group (P < 0.01 or P < 0.001). After 5 weeks of treatment, high-dosage rh-aFGF135 could remodel adipose tissue, and has no influence on other organs. H&E staining showed that rh-aFGF135 reduced the size of adipocytes. In addition, rh-aFGF135 may improve insulin resistance partly by increasing the protein expression of p-IRS-1 (human Ser 307). As a hypoglycemic drug for long-term treatment, rh-aFGF135 would be a potentially safe candidate for the therapy of type 2 diabetes.
Highlights
In modern society, type 2 diabetes mellitus (T2DM) has turned into a major health problem worldwide as a common metabolic disorder characterized by insulin resistance (Roden, 2012; Canivell and Gomis, 2014; Guariguata et al, 2014)
There is an array of anti-diabetic drugs to cure T2DM but most of them are accompanied by side effects such as weight gain, hypoglycemia, and so on
We used diabetic ZDF rats to investigate the pharmacological effects of rh-aFGF135 in the treatment of type 2 diabetes
Summary
Type 2 diabetes mellitus (T2DM) has turned into a major health problem worldwide as a common metabolic disorder characterized by insulin resistance (Roden, 2012; Canivell and Gomis, 2014; Guariguata et al, 2014). Compared with thiazolidinediones traditional sensitizers, rats treated with aFGF by subcutaneous injection have not yet been observed any side effects, such as weight gain or liver steatosis (Chang et al, 2013). Our previous 28-day long-term rh-aFGF135 toxicity study on the New Zealand rabbits’ damaged skin using Carbomer 940 hydrogel demonstrated that the rh-aFGF135 long-term treatment had no obvious adverse effects (Zhang et al, 2020). All of these researches suggest that aFGF would become a potential therapeutic drug to treat type 2 diabetes
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