Hepatosplanchnic insulin kinetics in awake endotoxemic Yucatan minipigs: the "misinformed B-cell" hypothesis revisited.

Increased pancreatic insulin secretion may be one of the factors associated with the insulinlike activity (ILA) of endotoxemia. While there is little doubt that the prominent hypoglycemia of endotoxicosis is often preceded by systemic hyperinsulinemia, the cause of this increased secretion and its cause-and-effect relationship to the glucose deficit is less obvious. Recently, a "misinformed B-cell" hypothesis was proposed in which it was suggested that increased glucose flux across the pancreatic B-cell early in endotoxemia might lead to a misinterpretation of the existing glycemic state, resulting in increased insulin release. This possibility was based in part on the observation that increased 6-3H-glucose-derived rates of glucose disappearance (Rd) in endotoxic Yucatan minipigs preceded the onset of systemic hyperinsulinemia. Examination herein of the chronological order of events in this group of pigs and three other groups treated with lidocaine, naloxone, or captopril reveals an increase in pancreatic insulin secretory rate most often before increases in systemic Rd. Each of the three therapies were administered as a primed continuous intravenous infusion, 1 hour after the initiation of a continuous intravenous infusion of Difco 055:B5 E. coli lipopolysaccharide at an LD67 dose of 15 micrograms/kg/hr. In those pigs receiving no therapy, lidocaine, or naloxone, significant increases in pancreatic insulin secretion recurred at 40, 40, and 60 min following the onset of endotoxemia respectively. This was followed in 20 min by the first significant increase in relative glucose disappearance rates (%Rd). Captopril-treated pigs experienced a significant increase in %Rd at 60 min, which was followed in 20 min by a significant increase in pancreatic insulin secretion. In all groups, a significant hyperinsulinemia occurred transiently at 80 min postendotoxin, followed in 20 min by the onset of significant hypoglycemia. These observations suggest that increases in %Rd and transient increases in insulin secretion may be simultaneous events at best, and that along with significant increases in absolute levels of hepatic insulin extraction (observed in all groups at 60 or 80 min postendotoxin) may indicate some local effect of insulin release on hepatic glucose.