The metabolic state of diabetic monkeys is regulated by fibroblast growth factor-21

Kharitonenkov, Alexei; Wroblewski, Victor J.; Koester, Anja; Chen, Yun-Fei; Clutinger, Cathleen K.; Tigno, Xenia T.; Hansen, Barbara C.; Shanafelt, Armen B.; Etgen, Garret J.

doi:10.1210/en.2006-1168

Cited by 738Fibroblast Growth Factor ResearchDiabetes Treatment and ManagementDiabetes Management and Research

The metabolic state of diabetic monkeys is regulated by fibroblast growth factor-21

Kharitonenkov, Alexei, Wroblewski, Victor J., Koester, Anja, Chen, Yun-Fei, Clutinger, Cathleen K., Tigno, Xenia T., Hansen, Barbara C., Shanafelt, Armen B. +1 more·2007·Endocrinology

DOI 10.1210/en.2006-1168

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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.

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FGF21 appears to protect pancreatic β cells from cell death induced by glycotoxicity.
“In addition, FGF21 appears to protect pancreatic β cells from cell death induced by glycotoxicity (Kharitonenkov et al., 2005, 2007).”
From Physical Exercise-Induced Myokines and Muscle-Adipose Tissue Crosstalk: A Review of Current Knowledge and the Implications for Health and Metabolic Diseases (2018) · cites this paper as Kharitonenkov et al., 2007
FGF21 has a short half-life of approximately 0.5-1.5 hours.
“Once secreted, FGF21 has a short half-life of approximately 0.5–1.5 hours (refs. 40,41).”
From Metabolic messengers: FGF21 (2021) · cites this paper as [40]
Prolonged administration of FGF21 or FGF21 analogues decreases body weight in rodents and non-human primates, and has more modest effects on body weight in humans.
“prolonged administration of FGF21 or FGF21 analogues has important metabolic effects, including a marked decrease in body weight in rodents and non-human primates, and more modest effects on body weight in humans3,40,58,77,78.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [40]
Some studies report FGF21-mediated weight loss without effects on food intake; another study using PF-05231023 reports weight loss attributable to significant decreases in food intake.
“whereas some studies have reported FGF21-mediated weight loss without effects on food intake40,86, another study using an FGF21 analogue (PF-05231023) in non-human primates has reported that the weight loss is attributable to significant decreases in food intake81.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [40]
In DIO non-human primates, FGF21 or FGF21-analog administration promotes weight loss.
“In DIO non-human primates, similarly to rodents, FGF21 or FGF21-analog administration also promotes weight loss40,81,86.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [40]

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Authors: Kharitonenkov, A., Wroblewski, V. J., Koester, A., Chen, Y.-F., Clutinger, C. K., Tigno, X. T., Hansen, B. C., Shanafelt, A. B., & Etgen, G. J.
Affiliations: Eli Lilly (United States) (US)
University of South Florida (US)
ORCID: Kharitonenkov, Alexei
Wroblewski, Victor J.
Hansen, Barbara C.
Venue: Endocrinology
Publisher: The Endocrine Society
Published: 2007-02
Volume: 148
Issue: 2
Pages: 774-781
ISSN: 0013-7227 (ISSN-L)
1945-7170
DOI: 10.1210/en.2006-1168
OpenAlex: W2119351413
Cited by: 738
References: 31
Citations by year: 2026: 8 · 2025: 20 · 2024: 39 · 2023: 31 · 2022: 31 · 2021: 39 · 2020: 37 · 2019: 37 · 2018: 62 · 2017: 45 · 2016: 52 · 2015: 57 · 2014: 55 · 2013: 49 · 2012: 57
FWCI: 7.79
Type: journal article
Language: en
Open access: closed
Locations: Endocrinology (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
Keywords: FGF21, type 2 diabetes, rhesus monkeys, non-human primates, plasma glucose, triglycerides, insulin, glucagon, lipoprotein profile, LDL cholesterol, HDL cholesterol, cardiovascular risk markers, weight loss, hypoglycemia, diabetes treatment
MeSH terms: Animals, Blood Glucose, Body Weight, Diabetes Mellitus, Dose-Response Relationship, Drug, Eating, Fibroblast Growth Factors, Humans, Cholesterol, HDL, Cholesterol, LDL, Macaca fascicularis, Male, Mice, Inbred Strains, Mice, Mutant Strains, Obesity, Recombinant Proteins, Triglycerides, Lipid Metabolism, Mice

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The metabolic state of diabetic monkeys is regulated by fibroblast growth factor-21

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