HYPOGLYCEMIA IN A DOG WITH A LEIOMYOMA OF THE GASTRIC WALL PRODUCING AN INSULIN-LIKE GROWTH-FACTOR II-LIKE PEPTIDE

A 12-year-old mixed-breed male dog was referred to the Clinica Medica Veterinaria of Bologna University for recurrent episodes of seizures due to hypoglycemia with abnormally low plasma insulin levels (18 pmol/l). Resection of a large leiomyoma (780 g) of the gastric wall resulted in a permanent resolution of the hypoglycemic episodes. Insulin-like growth factors I and II (IGF-I and -II) were measured by RIA in serum before and after surgery and in tumor tissue, Results were compared to the serum concentration of 54 normal and to the tissue concentration observed in eight non-hypoglycemic dog gastric wall extracts, Before surgery, circulating immunoreactive IGF-I was 0.92 nmol/l, which is significantly lower than the control values (16.92+/-8.44 nmol/l, range 3.53-35.03), while IGF-II was 152 nmol/l, which is significantly higher than the control values (42.21+/-3.75, range 31.99-50.74). After surgery, IGF-I increased to 6.80 nmol/l while IGF-II decreased to 45.52 nmol/l. Tumor tissue IGF-II concentration was higher than normal (5.66 nmol/kg tissue as compared to a range in normal gastric wall tissue of 1.14-3.72 nmol/kg), while IGF-I was 0.08 nmol/kg tissue, which is close to the lowest normal value (range in controls, 0.08-1.18 nmol/kg). Partial characterization of IGF-II immunoreactivity extracted from tissue evidenced a molecular weight similar to that of mature IGF-II, thus excluding that peptide released by the tumor is a precursor molecule. In agreement with these data, at variance with samples of normal dog gastric wall, IGF-II immunostaining was positive and in situ hybridization evidenced the expression of IGF-II mRNA in tumor tissue specimen. Evaluation of the molecular distribution of the IGFs in the circulation evidenced that IGF-II immunoreactivity was predominantly in the 35-65 kD region and barely detectable in the other regions. These results show that in dog, non-islet cell tumor hypoglycemia, as demonstrated in humans, can be ascribed to overproduction of IGF-II circulating in a molecular form that can more easily cross the capillary wall, thus exerting its insulin-like effects on target tissues.