The Metabolic State of Diabetic Monkeys Is Regulated by Fibroblast Growth Factor-21

Abstract

Fibroblast growth factor (FGF)-21 has been recently characterized as a potent metabolic regulator. Systemic administration of FGF-21 reduced plasma glucose and triglycerides to near normal levels in genetically compromised diabetic rodents. Importantly, these effects were durable and did not come at the expense of weight gain, hypoglycemia, or mitogenicity. To explore the therapeutic properties of FGF-21 in a nongenetically modified primate species, and thus demonstrate the potential for efficacy in humans, we evaluated its bioactivity in diabetic nonhuman primates. When administered daily for 6 wk to diabetic rhesus monkeys, FGF-21 caused a dramatic decline in fasting plasma glucose, fructosamine, triglycerides, insulin, and glucagon. Of significant importance in regard to safety, hypoglycemia was not observed at any point during the study. FGF-21 administration also led to significant improvements in lipoprotein profiles, including lowering of low-density lipoprotein cholesterol and raising of high-density lipoprotein cholesterol, beneficial changes in the circulating levels of several cardiovascular risk markers/factors, and the induction of a small but significant weight loss. These data support the development of FGF-21 for the treatment of diabetes and other metabolic diseases.

Myokines in insulin resistance and type 2 diabetes

“…FGF21 administration improves metabolic phenotypes such as increased fasting glucose, insulin and triacylglycerol levels in different obese mice models and diabetic rhesus monkeys [123][124][125][126]. Additionally, experiments on FGF21-treated mice indicated that this protein regulates whole body insulin responsiveness by enhanced glucose uptake in skeletal muscle, WAT and BAT and improved suppression of WAT lipolysis [99].…”

Functional evolutionary history of the mouse Fgf gene family

“…In addition, acidic glycosaminoglycans in the form of heparan sulfate proteoglycans function to retain these FGFs in the vicinity of FGF-producing sites, such that they primarily act in a paracrine manner. By contrast, the hFGFs have low-affinity heparin-binding sites and have been found to act in an endocrine manner (Tomlinson et al, 2002;Lundasen et al, 2006;Kharitonenkov et al, 2005Kharitonenkov et al, , 2007Fukumoto and Yamashita, 2007;Liu and Quarles, 2007).…”

“…In addition, acidic glycosaminoglycans limit the diffusion of FGFs, localizing their activity to the vicinity of FGF-producing cells (Flaumenhaft et al, 1990). In contrast, hFGFs have poor heparin-binding affinity and act on target cells far from their site of production in an endocrine manner (Tomlinson et al, 2002;Lundasen et al, 2006;Kharitonenkov et al, 2005Kharitonenkov et al, , 2007Fukumoto et al, 2007;Liu et al, 2007). In addition, FGF15, FGF21, and FGF23 require co-receptors, Klotho or ␤Klotho, to activate FGFRs (Ogawa et al, 2007;Urakawa et al, 2006).…”

FGF21 Alleviates Hepatic Endoplasmic Reticulum Stress under Physiological Conditions

“…When FGF21 expression was strongly induced in response to chemical ER stress inducers, such as tunicamycin, a rapid decline in increased FGF21 expression was observed even in the presence of these chemical inducers (data not shown). In addition, it is well known that circulating FGF21 protein is labile and has a short halflife (20,21). In contrast, adenovirus-mediated expression is thought to keep its circulating concentration steady at relatively high levels.…”