The effect of water deprivation was studied in rats fasted twenty-four, forty-eight and seventy-two hours. Glucose tolerance was impaired and insulin levels were lower one hour after an intraperitoneal glucose load. Ketone bodies (KB) and free fatty acid (FFA) levels were significantly lower. FFA rise after epinephrine was reduced. Hypertonic mannitol (3 M) administered subcutaneously to fasted rats also resulted in glucose intolerance and decreased levels of FFA and KB. In vitro hyperosmolarity(50, 100 mOsm. per liter mannitol) reduced FFA release from rat epididymal fat pads and impaired pancreatic insulin response to glucose. No effect on ketone body production by perfused rat liver was found. It is postulated that the above metabolic effects of dehydration and hyperosmolarity may be involved in the pathogenesis of hyperosmolar nonketotic coma in patients.

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