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Systemic Metabolic Derangement, Pulmonary Effects, and Insulin Insufficiency following subchronic ozone exposure in rats
Citation:
Miller, D., S. Snow, A. Henriquez, M. Schladweiler, A. Ledbetter, J. Richards, D. Andrews, AND U. Kodavanti. Systemic Metabolic Derangement, Pulmonary Effects, and Insulin Insufficiency following subchronic ozone exposure in rats. TOXICOLOGY AND APPLIED PHARMACOLOGY. Academic Press Incorporated, Orlando, FL, 306:47-57, (2016).
Impact/Purpose:
This study demonstrates that subchronic weekly episodic ozone exposure induces pulmonary injury/inflammation, hyperglycemia, glucose intolerance, and increases cholesterols. We further show that while peripheral insulin resistance did not occur by subchronic ozone, it had a major impact on beta-cell insulin secretion in response to circulating glucose, likely mediated by increased circulating epinephrine levels. Overall, these data provide further insight into the mechanism(s) of how subchronic ozone exposure may contribute to insulin insufficiency and produce other systemic impairments.
Description:
Acute ozone exposure induces a classical stress response with elevated circulating stress hormones along with changes in glucose, protein and lipid metabolism in rats, with similar alterations in ozone-exposed humans. These stress-mediated changes over time have been linked to insulin resistance. We hypothesized that acute ozone-induced stress response and metabolic impairment would persist during subchronic episodic exposure and induce peripheral insulin resistance. Male Wistar Kyoto rats were exposed to air or 0.25 ppm or 1.00 ppm ozone, 5hr/day, 3 consecutive days/week (wk) for 13wks. Pulmonary, metabolic, insulin signaling and stress endpoints were determined immediately after 13wk or following a 1wk recovery period (13wk + 1wk recovery). We show that episodic ozone exposure is associated with persistent pulmonary injury and inflammation, fasting hyperglycemia, glucose intolerance, as well as, elevated circulating adrenaline and cholesterol when measured at 13wk, however, these responses were largely reversible following a 1wk recovery. Moreover, the increases noted acutely after ozone exposure in non-esterified fatty acids and branched chain amino acid levels were not apparent following a subchronic exposure. Neither peripheral or tissue specific insulin resistance nor increased hepatic gluconeogenesis were present after subchronic ozone exposure. Instead, long-term ozone exposure lowered circulating insulin and severely impaired glucose-stimulated beta-cell insulin secretion. Thus, our findings in young-adult rats provide potential insights into epidemiological studies that show a positive association between ozone exposures and type 1 diabetes. Ozone-induced β-cell dysfunction may secondarily contribute to other tissue-specific metabolic alterations following chronic exposure due to impaired regulation of glucose, lipid, and protein metabolism.
