Islet Contents of Cyclic 3′,5′-Guanosine Monophosphate Under Conditions Which Affect the Cyclic 3′,5′-Adenosine Monophosphate

Abstract

The sensitivity of the radioimmunoassay for cGMP was considerably increased by previous 2\m='\-O-succinylation of the nucleotide. The basal content of cGMP in \g=b\-cell-richpancreatic islets isolated from ob/ob-mice was similar to that of cAMP, i. e. about 3 \g=m\molesper kg dry weight. Extracellular Ca2+ was a prerequisite for maintaining this amount of cGMP. The islet cGMP differed from cAMP in being only slightly enhanced or not affected at all when the islets were exposed to high concentrations of glucose, the sulphydryl reagents chloromercuribenzene-p-sulphonic acid and iodoacetamide, or the potent phosphodiesterase inhibitor 3-isobutyl-l\x=req-\ methylxanthine. The data obtained suggest that the turnover rate for cGMP is much slower than that for cAMP in the pancreatic \g=b\-cells. The interrelationships between the two cyclic nucleotides do not seem to fit into a simple pattern of antagonism.It is well established that cyclic 3',5'-adenosine monophosphate (cAMP) mo¬ dulates insulin secretion by potentiating the secretory response to glucose and other initiators of insulin release (Montague 8c Howell 1976). In contrast to the extensive studies on cAMP only little is known about the regulation and Presented in part at

Cyclic nucleotide phosphodiesterase of rat pancreatic islets. Effects of Ca2+, calmodulin and trifluoperazine

“…A role for Ca2+ in activation of islet guanylate cyclase is suggested by the observation that removal of extracellular Ca2+ reduced the cyclic GMP content of islets from ob/ob mice (Gagerman & Hellman, 1977) and by direct measurement of islet guanylate cyclase activity (Howell & Montague, 1974). The present study indicates that Ca2+ could also regulate the rate of degradation of cyclic GMP.…”

“…There is evidence that cyclic GMP may affect insulin biosynthesis (Lin et al, 1979;Howell & Montague, 1974). However, there is no evidence that changes in islet cyclic GMP concentration modulate glucose-induced insulin release; thus in the presence of stimulatory concentration of glucose (Howell & Montague, 1974;Gagerman & Hellman, 1977) or glucose plus arginine (Charles et al, 1976) islet content of cyclic GMP was unchanged. An increase in cyclic GMP content of guinea-pig islets stimulated by acetylcholine has been reported (Howell & Montague, 1974) but, in mouse islets, although acetylcholine elicited insulin release and membrane electrical activity no change in cyclic GMP could be detected (Gagerman et al, 1978).…”

The Adenylate cyclase-cyclic AMP system in islets of langerhans and its role in the control of insulin release

“…Thus inadequate intracellular cyclic AMP could be a contributory factor in the starvation-induced decrease in insulin release. That the response to glucose in starved animals could be restored by increasing cyclic AMP levels with inhibitors of phosphodiesterase has been confirmed [41,74] but the data on cyclic AMP content of islets of Langerhans in starvation are contradictory. In a 1973 report, islets from rats fasted for 48-72 h had significantly decreased cyclic AMP levels [76].…”

“…In a 1973 report, islets from rats fasted for 48-72 h had significantly decreased cyclic AMP levels [76]. Since then, four groups have failed to detect significant decreases in cyclic AMP content due to starvation when insulin release was clearly decreased [41,[72][73][74], though changes in cyclic AMP response to raised glucose concentrations were observed. Thus when fed rats were compared with rats starved for 16 and 48 h, it was clear that the first phase of insulin release was preferentially affected by starvation as was the early cyclic AMP response [72].…”

“…Actinomycin D blocked this restoration so that the results could suggest a glucose-inducible enzyme system which is involved in the changed levels of responsiveness. Very high glucose concentrations restore the maximal secretory capacity of islets of starved animals [41,[72][73][74] so that an increase in the Km for glucose stimulation of the release process occurs which could be a consequence of the reduced glucose phosphorylating ability of islets from starved animals [75].…”