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ABSTRACT: Rats with or without 0.5% tolbutamide in the diet were injected over a 5-day period with growth hormone, ACTH, cortisol, dexamethasone, or various mixtures of these diabetogenic hormones and the daily alterations in blood glucose (BG), serum (SI), and pancreatic insulin (PI) concentrations followed as well as glucosuria. GH (5 mg/day) increased the insulin concentration in the pancreas and serum without affecting blood glucose. ACTH (80 IU/day) decreased PI and increased SI with only a slight increase in BG. Cortisol and dexamethasone decreased PI and increased SI and BG. The severalfold increase in SI with glucocorticoids always preceded the increase in BG by 12–24 hr. Mixtures of GH with the glucocorticoids increased and quickened the rise in BG and SI and the falls in PI, but the rise in SI always preceded the rise in BG by several hours. During multiple hormonal treatment, PI decreased in magnitude usually for 3–4 days but by the fifth day tended to revert toward normal, showing adaptation. In contrast, BG and SI tended to remain elevated and glucosuria persisted. These data suggest that in spite of the high concentrations of diabetogenic agents used compensatory changes were made by the rat with intact pancreas over a period of 5 or more days. This hormonally induced condition of elevated SI and BG but normal PI is characteristic of insulin resistance. Tolbutamide by itself decreased PI without a rise in SI (except for a temporary increase at 4–8 hr after the first injection) and with only a minor decrease in BG. Most of the changes due to the hormones were accentuated in rats with 0.5% tolbutamide in the diet, suggesting that tolbutamide is diabetogenic because it decreases PI.