AJP - Endocrinology and Metabolism, Vol 262, Issue 2 E150-E154, Copyright © 1992 by American Physiological Society
Impact of uncoupling glucose stimulus from secretion on B-cell release and biosynthesis
Y. Sako, D. Eizirik and V. Grill
Department of Endocrinology, Karolinska Hospital, Stockholm, Sweden.
We studied the impact of a defined degree of long-term hyperglycemia with
or without blockade of attendant insulin release on subsequent B-cell
secretory responsiveness and biosynthesis. Nondiabetic rats were infused
for 48 h with glucose to produce marked hyperglycemia (21.3 +/- 0.5
mmol/l). Comparable levels of hyperglycemia were upheld when additions were
made to this protocol. Hyperglycemia increased plasma insulin 12-fold but
depressed glucose (27 mmol/l)-induced insulin secretion in vitro (isolated
islets) by 67% compared with saline-infused rats. Addition of diazoxide
infusion during hyperglycemia completely inhibited the
hyperglycemia-induced rise in plasma insulin but enhanced glucose-induced
insulin release in vitro eightfold compared with islets from rats infused
with glucose alone. Addition of insulin (2 U/day) to the diazoxide plus
hyperglycemia protocol inhibited the secretory response to glucose in vitro
by 46% (P less than 0.05). Proinsulin biosynthesis was enhanced by 67% in
islets from rats infused with glucose alone; this effect was paralleled by
a similar increase in preproinsulin mRNA. Diazoxide in vivo did not affect
these stimulatory effects of hyperglycemia on insulin biosynthesis;
however, insulin infusion in vivo abolished the hyperglycemia-induced
increase in proinsulin biosynthesis. We conclude that impairment by
hyperglycemia of glucose-induced insulin secretion occurs concomitant with
stimulation of biosynthesis. Uncoupling of glucose stimulus from secretion
crucially affects subsequent secretory responsiveness but not biosynthesis.
Insulin biosynthesis is depressed by direct or indirect effects of
circulating insulin.
