These studies of a rat model for non-insulin-dependent diabetes mellitus (NIDDM) were performed to determine whether hyperglycemia occurs when capacity to synthesize insulin is exceeded. The neonatal streptozocin (STZ)-treated rat has acute hyperglycemia with marked destruction of pancreatic β-cells, followed by gradual regeneration of 50-70% normal β-cell number. At age 4 wk, fed serum glucose concentration is only mildly elevated relative to controls. With age, the rats become progressively hyperglycemic, and by 12 wk they have marked impairment of glucose-stimulated insulin release. In these studies, dexamethasone (0.125 mg/kg/day for 4 days) was administered to control and to STZ-treated animals to produce insulin resistance. The relationship between insulin biosynthesis and serum glucose concentrations was assessed. In control rats, response to dexamethasone was similar at both 4 and 12 wk. Serum glucose levels and pancreatic insulin concentration remained unchanged. Both insulin biosynthetic rates (as measured by 3H-leucine incorporation into proinsulin) and proinsulin mRNA levels increased twofold. STZ-treated rats at age 4 wk demonstrated mild hyperglycemia. Dexamethasone injection resulted in an increase in insulin biosynthesis and proinsulin mRNA in these animals, while serum glucose did not increase. STZ-treated rats at 12 wk showed more profound hyperglycemia (serum glucose 315 ± 38 mg/dl versus control, 187 ± 12 mg/dl). A marked rise in serum glucose (to 519 ± 42 mg/dl) was observed after 4 days of dexamethasone injection. Pancreatic insulin content became severely depleted relative to saline-injected, STZ-treated animals, and there was no response to levels of proinsulin mRNA. These studies demonstrate a significant correlation between mean insulin biosynthetic rates and mean proinsulin mRNA levels in 4-wk-old rats. In these rats with mild glucose intolerance related to a decrease in insulin synthesis, the rate of biosynthesis can still increase if demand for insulin is acutely increased by induction of an insulin-resistant state. If the correlation between proinsulin mRNA and biosynthesis exists in 12-wk-old animals, the data suggest that older, more hyperglycemic animals lose the capacity to increase rates of insulin biosynthesis and secretion; severe hyperglycemia ensues when capacity to synthesize insulin is exceeded.