Review
The role of fibroblast growth factor 21 in diabetes and its complications: A review from clinical perspective

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Highlights

  • Circulating FGF21 level is increased in patients with type 2 diabetes (T2DM).

  • Increased level of FGF21 in patients with T2DM may be attributable to FGF21 resistance.

  • Circulating FGF21 level is associated with both micro- and macro-vascular complications in patients with T2DM.

  • FGF21 may be a mediator of anti-diabetic drugs.

  • FGF21 signaling pathway is a potential therapeutic target for treatment of T2DM and its complications.

Abstract

Fibroblast growth factor 21 (FGF21) has been well-recognized as a metabolic hormone and a promising target for treatment of metabolic diseases. The level of endogenous FGF21 is elevated in patients with impaired glucose tolerance and progressively increased from patients with overt type 2 diabetes to those with micro- and macro-vascular complications, presumably as a compensation or response to the deterioration of metabolic imbalance. A few exploratory in vivo studies, including a recent clinical trial, showed that exogenous FGF21 mimetics targeting FGF21 signaling can attain beneficial metabolic effects not with-standing the already elevated ambient FGF21 levels. In addition, some clinically available pharmacologic agents such as fenofibrates and metformin may modulate energy and macronutrients metabolism by acting through FGF21. This review mainly focuses on the role of FGF21 in development, progression and treatment of type 2 diabetes from a clinical perspective.

Introduction

Fibroblast growth factor 21 (FGF21) belongs to the fibroblast growth factor (FGF) superfamily but it lacks the conventional heparin-binding domain of other FGF members. Together with FGF19 and FGF23, these three FGF members are often classified as “endocrine” FGFs [1]. Human FGF21 is a 181 amino acid protein well conserved across species and it shares 75% homology to mouse FGF21 [2]. FGF21 is primarily secreted by the liver. Moreover, it is also expressed by adipose tissue, thymus, skeletal muscle and pancreas [3].

The metabolic action of FGF21 was first discovered when it was found to activate 3T3-L1 adipocytes glucose uptake in a high throughput screening [4]. Knowledge of the physiological function of FGF21 was mainly obtained by administration of recombinant FGF21 into animal models and from gain-of-function transgenic mouse [4], [5]. FGF21 has now been well-recognized as a metabolic hormone and a promising target for treatment of metabolic diseases [1], [6]. The role of FGF21 as a regulator of lipids and glucose metabolism and the mechanisms of its actions on energy metabolism have been reviewed extensively elsewhere [1], [3], [7]. This review focuses on the role of FGF21 in diabetes and its complications from a clinical perspective. We will also discuss recent preclinical and clinical studies suggesting FGF21 as a therapeutic target for treatment of type 2 diabetes and its associated cardiometabolic risk factors.

Section snippets

Association of FGF21 with type 2 diabetes

A hallmark of type 2 diabetes is insulin resistance, namely impaired response to the normal actions of insulin to control glucose and lipids homeostasis in insulin-sensitive organs including liver, fat tissue, and muscle. Insulin resistance also contributes to the progressive failure of the pancreatic islet beta cells insulin production [8]. The pathogenesis of type 2 diabetes involves dysregulation of multiple pathways of energy metabolism. The cardio-metabolic risk factors associated with

Changes of FGF21 in patients with type 1 diabetes and LADA

Although the level of circulating FGF21 in patients with type 2 diabetes is higher than that in controls without diabetes, the level of FGF21 in type 1 diabetes is significantly lower compared with those in age- and sex-matched controls [16]. Similarly but to a lesser extent, the level of circulating FGF21 is also lower in patients with LADA compared to that in age- and sex-matched controls [16]. These findings lead to the inference that circulating FGF21 may be explored as a biomarker for

Mechanisms of FGF21 resistance in patients with type 2 diabetes

The concept of “FGF21 resistance” is derived from the following observations: (1) the level of circulating FGF21 in animal and human with metabolic imbalance is higher than that in metabolically healthy controls; (2) The changes of metabolic indicators including glucose and free fatty acids in response to exogenous FGF21 mimetics is significantly attenuated in animals with dysmetabolism [1], [21]. In corollary, a very high pharmacologic dose of FGF21 mimetic is needed to attain overt changes in

FGF21 and vascular complications in patients with type 2 diabetes

Microvascular and macrovascular complications are the leading causes of morbidity and mortality in patients with diabetes [27]. Circulating FGF21 is positively correlated with urinary albumin excretion, an indicator of microangiopathy which is also an established predictor of cardiovascular events in patients with diabetes [28]. Notably, the level of circulating FGF21 is significantly increased in patients with microalbuminuria compared with those with normoalbuminuria, suggesting that the

FGF21 as a mediator of anti-diabetic drugs

Some commonly used anti-diabetic drugs may modulate metabolic dysregulations in patients with diabetes by acting on FGF21 signaling pathway. Metform is recommended as the first line treatment for type 2 diabetes because of its proven efficacy, safety and body weight neutral property [40]. Metformin inhibits respiratory complex I in mitochondria and leads to reduced liver gluconeogenesis in an AMP kinase (AMPK)-dependent pathway. The glucose lowering effect of metformin also attributes to its

FGF21 signaling pathway as a therapeutic target for treatment of type 2 diabetes

Several preclinical studies have shown that administration of FGF21 mimetics to obese diabetes rodent and nonhuman primates improves dyslipidemia, hyperglycemia and reduces body weight [7]. These remarkable beneficial metabolic effects of FGF21 mimetics attained in animal models prompted mounting efforts to explore FGF21 signaling pathway as a therapeutic target [49]. Various formats of FGF21 mimetics are now in the pipeline awaiting clinical trials. These creative efforts include coupling

Pharmacologic FGF21, bone loss and growth inhibition

Uncommon but severe adverse effects may become apparent only when the drug is used in a large population or for a long period [60]. Activation of PPAR-γ signaling in the bone inhibits osteoblastogenesis and accelerates bone loss [61]. FGF21 is regulated by PPAR-γ and it also up-regulates the activity of PPAR-γ signaling in a feed-forward loop [47]. In preclinical studies, FGF21 causes massive bone loss in both pharmacologic and genetic gain-of-function studies in rodents [5], [62]. Therefore,

Perspective for future studies

To date, most of the clinical studies of FGF21 are cross-sectional in nature. Large prospective studies are needed to elucidate the role of FGF21 in development and progression of diabetes and the associated vascular complications.

Although FGF21 mimetics showed promising therapeutic effects on metabolic dysregulation in patients with diabetes, the dosage needed to attain the clinically meaningful change in metabolic indicators is rather high, presumably due to FGF21 resistance in the obese with

Summary

A complex network of transcriptional regulators converges on FGF21 and modulates its expression in response to a wide range of physiological and pathological stimuli. In addition, many pharmacologic agents modulate energy and macronutrients metabolism by acting through FGF21 [66]. Therefore, FGF21 signaling pathway constitutes a promising therapeutic target for prevention and treatment of metabolic diseases. With more FGF21-targeted therapeutics entering clinical trials, we will gain in-depth

Conflict of interests

The authors have no potential conflict of interest to declare.

Acknowledgement

The work is in part supported by Alexandra Health Singapore Small Innovation Grant SIG/14035.

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