Roles of fibroblast growth factors in the treatment of diabetes

Table 1 The effects of fibroblast growth factors on diabetes and diabetes-associated diseases

Diabetes	FGFs	Functions	Ref.
Type 2 diabetes	FGF-1	A single parenteral treatment of recombinant FGF-1 can decrease glucose levels in diabetic ob/ob mice and DIO mice that mimic human type 2 diabetes	Suh et al[25]
Diabetic nephropathy	FGF-2	In mice with diabetic nephropathy, Klotho (a co-receptor for FGF-23) can inhibit renal injury and fibrosis by suppressing FGF-2 expression that is negatively associated with E-cadherin expression	Dong et al[27]
Diabetic retinopathy	FGF-3	FGF-3 and its receptor have been found to be downregulated in diabetic retinopathy	Ljubimov et al[30], Saghizadeh et al[31]
Type 2 diabetes	FGF-4	Intracerebroventricular administration of FGF-4 shows an anti-diabetic function in male db/db mice and DIO mice by activating glucose-excited neurons via FGFR1, while it can also deactivate glucose-inhibited neurons	Sun et al[33]
Type 2 diabetes	FGF-5	Knockdown of lncRNA TUG1 can inhibit glucose-induced proliferation of islet cell line MIN6 cells and promote cell apoptosis by increasing expression miR-188-3p to suppress the expression of FGF-5	Zhang et al[35]
Obesity and insulin resistance	FGF-6	Overexpression of FGF-6 in inguinal white adipose tissue can inhibit HFD–induced obesity and insulin resistance in lean mice, while overexpression of FGF-6 in mouse skeletal muscle tissues can also suppress HFD-induced insulin resistance and bodyweight increase	Liu et al[37], Xu et al[38]
Type 1 diabetes	FGF-7	Treatment with FGF-7-loaded galactosylated poly (DL-lactide-co-glycolic acid) particles can improve the islet engraftment into the liver and normalize blood glucose levels in mice with diabetes	Alwahsh et al[39]
Neuron differentiation	FGF-8	FGF-8 plays a key role in brain development and neuron differentiation by interacting with its receptors such as FGFR1	Yellapragada et al[42]
Non-alcoholic steatohepatitis (NASH)-associated hepatocellular carcinoma (HCC)	FGF-9	A study also shows that the expression of FGF-9 was increased in patients with NASH-HCC, which regulated the expression of extracellular matrix components by regulating the β-catenin signaling pathway	Zhang et al[44]
Pancreas organogenesis	FGF-10	FGF-10 is required for the development of the pancreas during early organogenesis	Bhushan et al[46], Norgaard et al[47]
Diabetic nephropathy	FGF-11	FGF-11 knockdown can significantly reduce mesangial cell proliferation and fibrosis in the progression of diabetic nephropathy	Liu et al[50]
Cardiac dysfunction	FGF-12	FGF-12 upregulation can improve cardiac dysfunction in mice with myocardial infarction by reducing the production of extracellular matrix components in cardiac fibroblasts induced by angiotensin II, including fibronectin and collagen I and III	Liu et al[53]
Type 2 diabetes	FGF-13	The serum level of FGF-13 was decreased in patients with impaired glucose tolerance and T2DM compared to that in the healthy controls, suggesting that it could serve as a diagnostic marker for T2DM	Che et al[55]
Cancers	FGF-14	FGF-14 plays a pivotal role in cancer progression and prognosis	Turkowski et al[58], Raja et al[59]
Diabetes, obesity, insulin resistance, and non-alcoholic fatty liver disease	FGF-15	Mouse FGF-15 is the homolog of human FGF-19. Overexpression or activation of FGF-15 or FGF-19 can decrease the levels of fasting blood glucose, free fatty acids, triglycerides, and insulin resistance, which also displays anti-diabetic effects and inhibits hepatic lipogenesis	Zhao et al[60], Hu et al[61], Kim et al[62]
Diabetic nephropathy and diabetic retinopathy	FGF-16	FGF-16 is a target of microRNAs such as miR-372-3p and miR-144-3p, which can regulate high glucose-induced glomerular endothelial cell dysfunction in patients with diabetic nephropathy and suppress high-glucose-induced proliferation of human umbilical vein endothelial cells and human retinal endothelial cells to potentially suppress diabetic retinopathy	Meng et al[63], Chen et al[64]
Cancers	FGF-17	FGF-17 plays a key role in cancer diagnosis (e.g., acute myeloid leukemia) and cancer cell survival (e.g., hepatocellular carcinoma)	Ling and Du[66], Gauglhofer et al[67]
Liver fibrosis	FGF-18	Overexpression of FGF-18 in mouse liver can promote liver fibrosis development	Tsuchiya et al[73]
Type 1 and type 2 diabetes	FGF-19	Serum levels of FGF-19 were significantly decreased in patients with T1DM and T2DM	Barutcuoglu et al[76], Hu et al[77]
Diabetic renal diseases	FGF-20	Increased plasma FGF-20 protein could delay the progression of diabetic renal diseases at the end stage	Md Dom et al[79]
Type 2 diabetes	FGF-21	Treatment with recombinant human FGF-21 can ameliorate insulin resistance, hyperglycemia, and endothelial dysfunction in T2DM mice induced by HFD-STZ treatment by activating the CaMKK2/AMP-AMPKα signaling pathway	Ying et al[82]
Spinal cord injury	FGF-22	FGF-22 plays an essential role in the recovery process of spinal cord injury, which can inhibit endoplasmic reticulum stress-induced apoptosis	Aljović et al[84], Zhu et al[85]
Diabetic nephropathy	FGF-23	FGF-23 could be implicated in proteinuria and endothelial dysfunction in patients with diabetic nephropathy	Yilmaz et al[88]

DIO: Diet-induced obese; HCC: Hepatocellular carcinoma; HFD: High-fat diet; lncRNA: Long non-coding RNA; NASH: Nonalcoholic steatohepatitis; STZ: Streptozotocin.