MetAP2 inhibitor treatment of high-fat and -fructose-fed dogs: impact on the response to oral glucose ingestion and a hyperinsulinemic hyperglycemic clamp

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 similar to 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.