Insulin resistance, a result of reduced synthesis of prostaglandylinositol cyclic phosphate, a mediator of insulin action?

Abstract

Reduced ability or failure to stimulate cyclic adenosinemonophosphate (AMP) synthesis on a second addition of hormone 30 min after a first stimulation was taken as an indirect indication of the synthesis of the cyclic AMP antagonist prostaglandylinositol cyclic phosphate (cyclic PIP). In diabetic rats, because of an increased possibility of restimulating cyclic AMP synthesis, the formation of cyclic PIP should be reduced. Additionally, severalfold increased basal cyclic AMP synthesis can be observed in diabetic hepatocytes in comparison with controls. Upon measuring cyclic PIP levels after hormonal stimulation in all organs of diabetic rats, it was found that stimulation of cyclic PIP synthesis by insulin decreased gradually in a time-dependent manner. Plasma membranes were prepared from diabetic Ksj db/db mice and from spontaneously hypertensive rats (SHR), and in a subsequent assay for cyclic PIP synthetase, an up to 60% decrease of enzyme activity was found. Cyclic PIP synthetase can be completely inhibited by preincubation with protein kinase A. It is most likely that this serine phosphorylation reaction by which the enzyme is inhibited also in vivo is a result of increased cyclic AMP levels. The addition of 10(-5)-10(-4) M sulfonylureas to the enzyme assay of liver plasma membrane causes full inhibition, and the addition of 10(-5)-10(-4) M biguanides, a two- to fourfold activation of the enzyme. Activation of cyclic PIP synthetase by biguanides can also be demonstrated in intact cells. It is a fast reaction and additive with respect to the activation by fluoride or guanylyl-imidodiphosphate (GMP-PNP), and it is most likely the effect with which the biguanides produce the correcting changes in metabolism. Furthermore, antihypertensive drugs like captopril, guanethidine, and dihydralazine also activate cyclic PIP synthetase. In contrast to the activation by the biguanides, this effect is not additive to the activation by fluoride. It appears that essential hypertension and type 2 diabetes are connected with or may be the result of a reduction in synthesis of the intracellular messenger cyclic PIP, whose synthesis is stimulated by hormones like insulin and noradrenaline (alpha-adrenergic action).

Prostaglandylinositol cyclic phosphate (cPIP): a novel second messenger of insulin action. Comparative analysis of two kinds of ‘insulin mediators’

“…This finding was not surprising because higher levels of glucagon could promote higher levels of cAMP, leading to enhanced activity of cAMPdependent PKA. cPIP was initially described as a cAMP antagonist and its synthesis is completely inhibited by incubation with PKA [36]; higher amounts of glucagon could significantly counteract stimulation of cPIP synthase by in vivo insulin.…”

“…Similarly, tyrosine-phosphorylated cPIP synthase is likely to be the most active form whereas a serinephosphorylated enzyme is likely to be the least active form. Thus, low activity of cPIP synthase in insulinresistant states could be connected with decreased tyrosine phosphorylation and/or increased serine phosphorylation of this enzyme [32,36]. One more intriguing parallel between cPIP synthase and IRS-1 is that IRS-1 tyrosine phosphorylation appears to be reduced and serine/threonine phosphorylation increased in diabetesrelated events.…”

“…It has been proposed that cPIP synthase may be closely related to or identical to IRS-1 [31,36]. This was based on the observation that anti-IRS-1 antibodies bind solubilized cPIP synthase [31,36].…”

“…Phospholipase A 2 and phospholipase C, activated by tyrosine phosphorylation of the insulin receptor upon insulin binding to its receptor, liberate either unsaturated fatty acids (FAs) or inositol phosphates, which are transformed to prostaglandins (PG) and novel inositol phosphate (n-IP) with an energy-rich bond. The prostaglandylinositol cyclic phosphate synthase, which may be similar to IRS-1, combines these 2 substrates (PG and n-IP) to cPIP [31,34,36].…”

Prostaglandylinositol cyclic phosphate, the natural antagonist of cyclic AMP

“…In hepatocytes of diabetic rats, less inhibition of cyclic AMP synthesis was observed than with non-diabetic rats. 3,4 This suggests that the diabetic state correlates with a reduced ability to synthesize this inhibitor. Furthermore, inhibition of prostaglandin synthesis by non-steroidal-anti-inflammatory drugs (as aspirin and indomethacin) caused a considerable increase in adrenaline-stimulated cyclic AMP synthesis.…”