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【Endocrinology】FGF21通过调节肝脏葡萄糖变化及胰
Fibroblast growth factor 21 (FGF21) is a potent metabolic regulator shown to improve glucose and lipid metabolism as well as to reduce overall body weight and adipose mass (1, 2, 3, 4, 5, 6, 7, 8). Importantly, beneficial effects associated with therapeutic administration and/or transgenic overexpression of FGF21 occurred without concomitant hypoglycemia or mitogenicity characteristic of several current antidiabetic drugs (9). Accordingly, FGF21 is now considered a potential therapeutic agent to treat a variety of metabolic diseases including hyperglycemia and dyslipidemia (9).
Based on evidence that chronic FGF21 administration lowers plasma insulin and improves glucose tolerance in diabetic rodents and nonhuman primates (2, 4, 5, 6, 8), it is likely that FGF21 ameliorates insulin resistance, and this outcome contributes to the striking anti-hyperglycemic effects of FGF21. This concept may be important considering that insulin resistance is a hallmark of numerous metabolic diseases and critically associated with defects in glucose flux. Indeed, several current therapies aim to treat hyperglycemia through modulation of insulin signaling (10). The link between FGF21 treatment and insulin sensitivity has been recently strengthened by findings that insulin sensitivity is improved in chronically treated high-fat-fed mice (11). This notion is further supported by recent evidence of insulin-FGF21 cross talk as well as a functional interplay between FGF21- and peroxisome proliferator-activated receptor (PPAR)-dependent mechanisms because PPAR agonists, which are potent insulin sensitizers, to a certain extent signal through changes in either FGF21 expression or action (8, 12, 13, 14).
In the present studies, FGF21 was administered sc to obese, diabetic ob/ob mice for 8 d and compared with vehicle-treated ob/ob and ob/+ mice to test whether, and to what extent, FGF21 improves insulin sensitivity and glucose flux in a mouse model of severe insulin resistance. This was examined in catheterized, conscious animals using hyperinsulinemic-euglycemic clamp techniques. In subsequent experiments, ob/+ and ob/ob mice were infused with FGF21 for 6 h, and blood glucose was clamped to assess the direct metabolic effects of FGF21 on glucose fluxes. In both experiments, isotopic tracer techniques were used to quantify whole-body and tissue-specific glucose fluxes. The present studies clearly demonstrate that FGF21 treatment improves insulin sensitivity in the liver.
Fibroblast growth factor 21 (FGF21) is a novel metabolic regulator shown to improve glycemic control. However, the molecular and functional mechanisms underlying FGF21-mediated improvements in glycemic control are not completely understood. We examined FGF21 effects on insulin sensitivity and glucose fluxes upon chronic (daily injection for 8 d) and acute (6 h infusion) administration in ob/+ and ob/ob mice. Results show that chronic FGF21 ameliorated fasting hyperglycemia in ob/ob mice via increased glucose disposal and improved hepatic insulin sensitivity. Acute FGF21 suppressed hepatic glucose production, increased liver glycogen, lowered glucagon, and improved glucose clearance in ob/+ mice. These effects were blunted in ob/ob mice. Neither chronic nor acute FGF21 altered skeletal muscle or adipose tissue glucose uptake in either genotype. In conclusion, FGF21 has potent glycemic effects caused by hepatic changes in glucose flux and improved insulin sensitivity. Thus, these studies define mechanisms underlying anti-hyperglycemic actions of FGF21 and support its therapeutic potential. Fibroblast Growth Factor 21 Controls Glycemia via Regulation of Hepatic Glucose Flux and Insulin Sensitivity
FGF21通过调节肝脏葡萄糖变化及胰岛素敏感性来调控血糖
Fibroblast growth factor 21 (FGF21) is a potent metabolic regulator shown to improve glucose and lipid metabolism as well as to reduce overall body weight and adipose mass (1, 2, 3, 4, 5, 6, 7, 8). Importantly, beneficial effects associated with therapeutic administration and/or transgenic overexpression of FGF21 occurred without concomitant hypoglycemia or mitogenicity characteristic of several current antidiabetic drugs (9). Accordingly, FGF21 is now considered a potential therapeutic agent to treat a variety of metabolic diseases including hyperglycemia and dyslipidemia (9).
成纤维细胞生长因子-21（FGF21）具有很强的调节代谢的作用。已被证明其可以促进糖及脂肪的代谢、降低体重及脂肪含量。重要的是，治疗性服用和/或用转基因的方法促进FGF21的过度表达不会像目前使用的抗糖尿病药物一样有易造成低血糖或影响有丝分裂的副作用。因此，FGF21现在被认为是有潜力应用于治疗各种代谢性疾病包括高血糖和脂质代谢紊乱。
Based on evidence that chronic FGF21 administration lowers plasma insulin and improves glucose tolerance in diabetic rodents and nonhuman primates (2, 4, 5, 6, 8), it is likely that FGF21 ameliorates insulin resistance, and this outcome contributes to the striking anti-hyperglycemic effects of FGF21. This concept may be important considering that insulin resistance is a hallmark of numerous metabolic diseases and critically associated with defects in glucose flux. Indeed, several current therapies aim to treat hyperglycemia through modulation of insulin signaling (10). The link between FGF21 treatment and insulin sensitivity has been recently strengthened by findings that insulin sensitivity is improved in chronically treated high-fat-fed mice (11). This notion is further supported by recent evidence of insulin-FGF21 cross talk as well as a functional interplay between FGF21- and peroxisome proliferator-activated receptor (PPAR)-dependent mechanisms because PPAR agonists, which are potent insulin sensitizers, to a certain extent signal through changes in either FGF21 expression or action (8, 12, 13, 14).
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作者:admin@医学,生命科学 2010-11-21 05:11
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