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

Lilly Research Laboratories, A Division of Eli Lilly and Company (A.K.,V.J.W., A.K., Y.-F.C., C.K.C., A.B.S., G.J.E.), Indianapolis, Indiana 46285; The Obesity, Diabetes and Aging Research Center, Departments of Internal Medicine and Pediatrics (X.T.T., B.C.H.), College of Medicine, University of South Florida, Tampa, Florida 33602

Address all correspondence and requests for reprints to: Alexei Kharitonenkov or Garret J. Etgen, Lilly Research Laboratories, A Division of Eli Lilly and Company, Indianapolis, Indiana 46285. E-mail: a.kharch{at}lilly.com; g.etgen{at}lilly.com.

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.