Tolbutamide (25 mg/kg; maximum 1 mg) intravenously (IV) and glucagon (0.03 mg/kg; maximum 1 mg) intramuscularly (IM) were given sequentially to 12 untreated girls with XO-Turner's syndrome (ages 6.5 to 17.0 years) and to ten female siblings (ages 8.0 to 16.7 years) to evaluate blood sugar (BS), plasma free fatty acids (FFA), serum immunoreactive insulin (IRI), and growth hormone (IRGH) responses to these insulinogenic secretagogues in order to appreciate any differences of genotypes on carbohydrate metabolism within identical family backgrounds. Seven of 12 patients with Turner's syndrome (58%) but none of the siblings were 20% or more overweight for height. There was a family history of diabetes mellitus in 7 of 12 patients (58%). The results showed significant elevations of mean FFA levels and decreased mean IRI responses to both fractional areas under insulin curves were also lower inTS than in siblings at 30 to 45 minutes (TS: 1,062 ± 185 pU-min/ml; CS: 2,180 ± 402 pUmin/ ml, P<0.02). Basal salivary immunoreactive insulin (IRI) concentrations were similar in both groups: TS: 4.8 ± 2.1 μU/min; CS: 2.1 ± 0.4 μU/min. Peak salivary IRI concentrations after tolbutamide were 13.8 ± 4.7 μU/min in Turner's syndrome and 8.8 ± 1.8 μU/ml in control siblings. IRI values in Turner's syndrome and in control siblings after glucagon were 26.8 ± 10.1 and 13.4 ± 2.1 μU/min, respectively. While significant differences in insulin secretion in serum were detected in the two patient groups, no differences were noted between groups when salivary insulin concentrations were compared. These data confirm serum insulin deficiency in gonadal dysgenesis, the presence of immunoreactive insulin in parotid saliva, and suggest the possibility that extrapancreatic insulin synthesis could occur in the parotid gland.