The effect of insulin administration on the insulin content of the pancreas1

Abstract

IT has been reported previously that fasting or fat feeding causes a definite reduction in the insulin content of the pancreas of rats [Haist, Ridout & Best, 1939;Best, Haist & Ridout, 1939]. It was thought that the administration of insulin to fasting animals or to those receiving fat might throw some light on the mechanism by which this effect was brought about. Several interesting facts have emerged. Insulin administration produces a decrease in the insulin content of the pancreas in fed rats and augments the fall in fasting or fat-fed animals. METHODSThe procedures employed for the extraction of insulin from the pancreas and the determination of the potency of the insulin solutions were the same as reported previously [Best et al. 1939]. Male rats of the Wistar strain weighing between 200 and 300 g. were used and the pancreatic tissue from ten rats was taken for each test. RESULTS(1) The effect of insulin in fed rats Several experiments were performed to demonstrate the effect of insulin administration in rats fed a balanced diet. The groups injected with insulin received the same diet and the same caloric intake as the controls. In the first experiment a daily subcutaneous injection of 1 unit of protamine zinc insulin was given to each rat. In the second expeximent each rat received 1 unit of protamine zinc insulin daily for the first 2 days, 2 units daily for the following 2 days, 3 units on the next day and 1 A preliminary account of part of this work appeared in Science (1940), 91, 410.

Feedback inhibition of insulin gene expression by insulin.

“…Feedback inhibition ofinsulin secretion by insulin was initially observed in 1941 by Best and Haist (1). These results were verified by isolated islet and pancreas perfusion studies in vitro (2, 3) and later confirmed in man.…”

Insulin Contributes to Fine-Tuning of the Pancreatic Beta-Cell Response to Glucagon-Like Peptide-1

“…As β-cells under a high glucose condition are exposed to insulin concentrations that are higher than those in the periphery (Zawalich et al, 1975), it is likely that glucose exerts a stimulatory effect on the β-cell response to GLP-1 in the initial phase but high concentrations of secreted insulin from β-cells decrease the β-cell response to GLP-1 in the late phase. The concept that insulin inhibits its own secretion has been suggested for a long time (Best and Haist, 1941;Loreti et al, 1974). However, this autocrine effect of secreted insulin on β-cell function has been a matter of debate (Leibiger, 2002).…”

“…However, this autocrine effect of secreted insulin on β-cell function has been a matter of debate (Leibiger, 2002). Chronic administration of insulin or transplantation of insulinomas reduced pancreatic insulin content (Best and Haist, 1941;Koranyi et al, 1992). In contrast to these results, disruption of insulin signaling in the IRS-2 knockout mouse or in the β-cellrestricted IR knockout mouse led to reduction in the pancreatic insulin content in the adult state (Kulkarni et al, 1999;Withers et al, 1998) and selective loss of glucose-stimulated acute insulin secretion (Kulkarni et al, 1999).…”

The Role of the Endocrine Glands in Ketosis. Ii. Ketonemia Following Insulin Hypoglycemia*

“…The abrupt decline in post-hypoglycemic ketonemnia in response to a minute second dose of insulin suggests that an absolute deficiency of endogenous insulin may be more important in the early development of ketonemia than are insulin antagonists. This belief is reinforced by the similar pattern of ketonemia exhibited by the hypophysectomized rat, which is deficient in insulin antagonists, and by direct studies on the pancreas, which demonstrate diminished content and secretion of endogenous insulin after insulin hypoglycemia (13,14).…”

“…Since hypoglycemia suppresses endogenous insulin secretion (13,14) and stimulates secretion of glucagon (15), which has been reported to affect ketosis (16,17), these factors were investigated (Table III).…”