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Publication
MetAP2 inhibitor treatment of high-fat and -fructose-fed dogs: impact on the
response to oral glucose ingestion and a hyperinsulinemic hyperglycemic clamp.
Authors Moore MC, Coate KC, Scott M, Kraft G, Vath JE, Hughes TE, Farmer B, Cherrington
AD
Submitted By Submitted Externally on 12/3/2021
Status Published
Journal American journal of physiology. Endocrinology and metabolism
Year 2020
Date Published 4/1/2020
Volume : Pages 318 : E514 - E524
PubMed Reference 31990576
Abstract We examined the methionine aminopeptidase 2 inhibitor fumagillin in dogs
consuming a high-fat and -fructose diet (HFFD). In pilot studies (3 dogs that
had consumed HFFD for 3 yr), 8 wk of daily treatment with fumagillin reduced
food intake 29%, weight 6%, and the glycemic excursion during an oral glucose
tolerance test (OGTT) 44%. A second group of dogs consumed the HFFD for 17 wk:
pretreatment (weeks 0-4), treatment with fumagillin (FUM; n = 6), or no drug
(Control, n = 8) (weeks 4-12), washout period (weeks 12-16), and fumagillin or
no drug for 1 wk (week 17). OGTTs were performed at 0, 4, 11, and 16 wk. A
hyperinsulinemic hyperglycemic clamp was performed in week 12; 4 chow-fed dogs
underwent identical clamps. Kilocalories per day intake during the treatment
period was 2,067?±?50 (Control) versus 1,824?±?202 (FUM). Body weights (kg)
increased 1.9?±?0.3 vs. 2.7?±?0.8 (0-4 wk) and 1.2?±?0.2 vs. -0.02?±?0.9 (4-12
wk) in Control versus fumagillin. The OGTT glycemic response was 30% greater in
Control versus fumagillin at 11 wk. Net hepatic glucose uptake (NHGU;
mg·kg-1·min-1) in the Chow, Control, and fumagillin dogs was ~1.5?±?0.6,
-0.1?±?0.1, and 0.3?±?0.4 (with no portal glucose infusion) and 3.1?±?0.6,
0.5?±?0.3, and 1.5?±?0.5 (portal glucose infusion at 4 mg·kg-1·min-1),
respectively. Fumagillin improved glucose tolerance and NHGU in HFFD dogs,
suggesting methionine aminopeptidase 2 (MetAP2) inhibitors have the potential
for improving glycemic control in prediabetes and diabetes.




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