The response of peripheral tissues to insulin is reduced in fasting and diabetes mellitus. The experiments described herein were designed to determine whether insulin-stimulated glucose oxidation is affected by the free–fatty acid–derived plasma metabolites acetone, acetol, and propylene glycol (1,2-propanediol [1,2-PD]), concentrations of which are elevated in both starvation and diabetic ketosis. In epididymal adipose tissue from fed and 48-h–fasted rats given 3% acetone drinking water for 7 days, insulin-stimulated glucose oxidation was reduced by ∼30–40%. After ingestion of 2% acetol for 7 days, basal and insulin-stimulated glucose oxidation was lowered ∼30%, whereas the consumption of 1,2-PD had no influence on either basal or insulin-stimulated glucose oxidation. Similar effects on glucose oxidation were observed in isolated adipocytes from fed rats after ingestion of 3% acetone and 2% acetol for 7 days. The reduction in insulin-stimulated glucose oxidation in adipose tissue in vitro required the consumption of 3% acetone water for >3 days. In 48-h–fasted rats that ingested 3% acetone for 5 days, insulin-stimulated glucose oxidation remained depressed 4 days after withdrawal of acetone from the drinking water. These studies imply that at least part of the insulin resistance indigenous to fasting and diabetic ketosis may be attributed to the metabolic influence of acetone and/or acetol in body fluids. In rats consuming drinking water containing 0.5–5.0% (vol/vol) acetone for 7 days, both acetol and 1,2-PD were found in plasma at concentrations related to the acetone content of the drinking water and to the degree of acetonemia, which ranged from 0.520 ± 0.076 to 15.90 ± 1.43 mM. The concentrations of acetol and 1,2-PD but not acetone were elevated in the plasma of rats given acetol in the drinking water, and only the concentration of 1,2-PD was elevated in the plasma of rats that consumed 1,2-PD. These results indicate that acetone is converted sequentially and irreversibly to acetol and 1,2-PD.

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