Apparent involvement of protein kinase C in the central glucoregulatory action of insulin.
We have studied the possible involvement of the calcium- and phospholipid/diacylglycerol-dependent enzyme, protein kinase C (PKC) in mediating insulin action in the central nervous system (CNS) by testing the effect of direct activation or blockade of the CNS PKC system on the plasma glucose responses to central insulin injection in mice. Insulin (0.1-1 microgram), injected into the CNS, produced rapid transient hypoglycemia. This effect appeared to involve interaction of insulin with specific receptors, since insulin analogs exhibiting diminished receptor binding affinity and peripheral bioactivity compared to the native hormone were much less active (i.e., insulin much greater than acetyl 3 insulin greater than proinsulin greater than IGF-I) or not active at all (i.e., insulin chain A and chain B). Central injection of the specific PKC activator, 12-O-tetradecanoylphorbol-13-acetate (TPA) (0.01-0.5 microgram), but not the inactive TPA analog, 4-alpha-phorbol or the unstable synthetic diacylglycerol analog, 1-oleoyl-2-acetyl-sn-glycerol (OAG), significantly enhanced the hypoglycemic response to co-administered insulin (0.5 microgram) or the insulin derivative, acetyl 3 insulin (2.5 micrograms). Central TPA had no effect on basal glucose levels. Furthermore, central administration of the selective PKC blockers, polymyxin B (PMB, 1-25 micrograms) or 1-beta-galactosylsphingosine (psychosine, 0.5-10 micrograms) but not their respective inactive analogs, polymyxin E and sphingomyelin, strongly inhibited the hypoglycemic response to insulin (1 microgram) or acetyl 3 insulin (5 micrograms). PMB and psychosine, injected alone had no effect on basal glucose levels.(ABSTRACT TRUNCATED AT 250 WORDS)
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D007276:Injections, Intraventricular; D007328:Insulin / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D011112:Polymyxin B / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism / Q000502:physiology*; D011609:Psychosine / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000031:analogs & derivatives / Q000494:pharmacology
D001786:Blood Glucose; D007328:Insulin; D011609:Psychosine; C032975:12-O-tetradeca-2,4,6,8-tetranoylphorbol-13-acetate; D011493:Protein Kinase C; D011112:Polymyxin B; D013755:Tetradecanoylphorbol Acetate