FP02-4 Olanzapine Modulation of Metabolic Status in a Non-Human Primate

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: FP02-Obesity and Diabetes: Drugs & Interventions
Saturday, June 15, 2013: 11:00 AM-11:30 AM
Presentation Start Time: 11:15 AM
Room 303 (Moscone Center)

Poster Board SAT-788
Cynthia L Bethea*1, Oleg Varlamov2, Paul Kievit3 and Charles T Roberts Jr.2
1OR Regional Primate Res Ctr, Beaverton, OR, 2Oregon Natl Primate Rsrch Ctr, Beaverton, OR, 3Oregon National Primate Research Center, Beaverton, OR
Clinical and animal data suggest that atypical antipsychotics such as (OLZ) induce significant metabolic changes that are serious side effects of their primary use. Since controlled human studies are problematic and rodent data may be poorly translatable, we have started to develop a macaque model of OLZ-induced metabolic disease. A female Japanese macaque was administered OLZ (5 mg/kg/day) for 6 months, with dietary changes instituted at 2-month intervals; i.e., OLZ+restricted chow, OLZ+unrestricted chow, OLZ+western-style diet (WSD), and placebo+WSD. Weight was accessed weekly, with glucose tolerance tests and Dexa scans performed at baseline and every 2 months. On OLZ+restricted chow, weight increased 14% over baseline; on OLZ+unrestricted chow, weight increased further and stabilized at 26% over baseline; on OLZ+WSD, the animal found the diet unpalatable and weight returned to 14% over baseline, and remained similar on placebo+WSD. Body fat increased from 14% at baseline to 22%, 31%, 28% and 19% at 2, 4, 6 and 8 mo, respectively, indicating that body fat was elevated on OLZ regardless of diet and declined upon OLZ removal. OLZ alone induced partial glucose intolerance, while subsequent access to unlimited chow resulted in increased post-prandial hyperglycemia and loss of first-phase and decreased second-phase insulin secretion, which was exacerbated upon addition of WSD. After removal of OLZ but continued WSD, a more normal insulin secretory pattern was seen and hyperglycemia was reduced, although this was achieved through hyperinsulinemia, suggesting continued insulin resistance. There was no evidence for elevated fasting glucose. To evaluate adipose-specific effects, visceral (V) and subcutaneous (SC) adipose tissue biopsies were obtained at baseline and after OLZ+unrestricted chow and OLZ+WSD to evaluate adipocyte size, and lipolysis and insulin-stimulated fatty acid uptake. Adipocyte diameter was increased in SQ and, to a lesser degree, in V fat by OLZ alone. Basal lipolysis was unaffected by OLZ or diet, but isoproterenol-stimulated lipolysis was increased by OLZ in V and SQ fat, and subsequently reduced by addition of WSD. Insulin-stimulated fatty acid uptake was inhibited in both depots by OLZ alone and not further influenced by diet. We conclude that OLZ can exert metabolic effects that are independent of diet but that can be exacerbated by dietary excess, and that these changes involve alteration of both islet and adipose function.

Nothing to Disclose: CLB, OV, PK, CTR Jr.

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