ESSENTIALITY OF CIRCULATING FATTY-ACIDS FOR GLUCOSE-STIMULATED INSULIN-SECRETION IN THE FASTED RAT

We asked whether the well known starvation-induced impairment of gluco se-stimulated insulin secretion (GSIS) seen in isolated rat pancreas p reparations also applies in vivo. Accordingly, fed and 18-24-h-fasted rats were subjected to an intravenous glucose challenge followed by a hyperglycemic clamp protocol, during which the plasma-insulin concentr ation was measured, Surprisingly, the acute (5 min) insulin response w as equally robust in the two groups, However, after infusion of the an tilipolytic agent, nicotinic acid, to ensure low levels of plasma FFA before the glucose load, GSIS was essentially ablated in fasted rats, but unaffected in fed animals,Maintenance of a high plasma FFA concent ration by coadministration of Intralipid plus heparin to nicotinic aci d-treated rats (fed or fasted), or further elevation of the endogenous FFA level in nonnicotinic acid-treated fasted animals by infusion of etomoxir (to block hepatic fatty acid oxidation), resulted in supranor mal GSIS. The in vivo findings were reproduced in studies with the per fused pancreas from fed and fasted rats in which GSIS was examined in the absence and presence of palmitate, The results establish that in t he rat, the high circulating concentration of FFA that accompanies foo d deprivation is a sine qua non for efficient GSIS when a fast is term inated. They also serve to underscore the powerful interaction between glucose and fatty acids in normal beta cell function and raise the po ssibility that imbalances between the two fuels in vivo could have pat hological consequences.