Effects of transplantation and resection of a radiation-induced rat insulinoma on glucose homeostasis and the endocrine pancreas

Abstract

Summary Twenty-one days after s.c. subscapular transplantation of a radiation-induced insulinoma, male NEDH rats exhibited hyperinsulinaemia and hypoglycaemia. These features were associated with islet atrophy, degenerative changes in pancreatic A and B cells, and decreases in the pancreatic contents of insulin, glucagon and somatostatin. The immunoreactive glucagon and somatostatin contents of extrapancreatic tissues of insulinoma-bearing rats were unchanged. Surgical resection of the tumour resulted in an immediate fall of plasma insulin, attaining concentrations similar to those of anaesthetised control rats by 0 min. The estimated half-life of insulin was 3.5 min. Hypoglycaemia persisted until 60 min after resection, followed by hyperglycaemia of 1-2 days duration. Glucose tolerance was impaired 1 day after tumour resection despite the coexistence of raised insulin concentrations. Evidence for abnormal pancreatic B cell function was gained by injection of arginine which failed to evoke a plasma insulin response in the resected rats. Two days after resection, plasma glucose and insulin concentrations were similar to those of control rats. Plasma glucose and insulin responses to glucose and arginine were suggestive of tumour recurrence by 12 days. A single large encapsulated tumour was eventually observed in each rat, with resection giving a 17-56 day prolongation of life.

Gα i/o -coupled receptor signaling restricts pancreatic β-cell expansion

“…As in many biologic processes, this negative regulation is at least as important as positive regulation, and defects in negative regulation can have dire pathologic consequences. Limiting cell numbers may be particularly important for the β cell, as evidenced by the contraction in β-cell mass seen in settings such as starvation, insulinoma, or in maternal islets in the postpartum period (25)(26)(27). Our data demonstrate that Gα i/o -coupled signaling restricts β-cell replication, titrating cell number to provide for the organism's metabolic needs.…”

Proliferation, Hyperplasia, Neogenesis, and Neoplasia in the Islets of Langerhans

“…31,33,42Y44 From a physiological standpoint, it seems reasonable that during a period of increased insulin demand, insulin itself could stimulate A-cell growth, creating a positive feedback loop. Rats with insulinomas resulting in hyperinsulinemia and hypoglycemia have smaller A cells, reduced A-cell numbers, and increased rates of A-cell apoptosis, 45,46 and A-cell mass regenerates within days after tumor excision. 47 This demonstrates that excess insulin will inhibit A-cell growth, having a negative feedback effect as do other hormones in their respective endocrine axes.…”

Tumour formation and insulin secretion by clonal RINm5F cells following repeated subcutaneous transplantation in NEDH rats

“…The origin, maintenance and transplantation of tumours in these rats have been described elsewhere (Flatt, Tan, Bailey et al 1986;Flatt, Tan, Swanston-Flatt et al 1987c). …”

“…Crystalline rat insulin (Novo Industria, Copenhagen) was used as the standard in the radioimmunoassay of insulin. Further details of in-vivo methodology are given elsewhere (Flatt et al 1986;Flatt et al 1987c). …”