Impact of uncoupling glucose stimulus from secretion on B-cell release and biosynthesis.
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.
Sako
Y
Y
Department of Endocrinology, Karolinska Hospital, Stockholm, Sweden.
Eizirik
D
D
Grill
V
V
D000818:Animals; D003981:Diazoxide / Q000494:pharmacology; D005947:Glucose / Q000494:pharmacology*; D006943:Hyperglycemia / Q000378:metabolism; D066298:In Vitro Techniques; D007328:Insulin / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains
D007328:Insulin; D012333:RNA, Messenger; D005947:Glucose; D003981:Diazoxide