Insulin mediators in man: effects of glucose ingestion and insulin resistance

Abstract

Insulin generates/releases chemical substances that alter the activities of purified enzymes [1,2] and the metabolism of intact cells [3,4] in an insulin mimetic fashion. These substances have therefore been termed mediators or second messengers of insulin [5]. Two different insulin mediators have been separated from rat liver [6]. These mediators have been identified as inositol phosphoglycans (IPGs), containing inositol, non-acetylated amino sugars, neutral sugars, ethanolamine, phosphate and, possibly, amino acids [5]. One contains d -chiro-inositol and activates pyruvate dehydrogenase (PDH) phosphatase, whereas another contains myo-inositol and inhibits cyclic AMP-dependent protein kinase (PKA). Injection of each of these IPGs into low-dose streptozotocin-diabetic rats lowers blood glucose [7].Body fluids of patients with non-insulin-dependent diabetes mellitus (NIDDM) have abnormally low levels of Summary Insulin mediators (inositol phosphoglycans) have been shown to mimic insulin action in vitro and in intact mammals, but it is not known which mediator is involved in insulin action under physiological conditions, nor is it known whether insulin resistance alters the mediator profile under such conditions. We therefore investigated the effects of glucose ingestion on changes in the bioactivity of serum inositol phosphoglycan-like substances (IPG) in healthy men and insulin resistant (obese, non-insulin-dependent diabetic) men. Two classes of mediators were partially purified from serum before and after glucose ingestion. The first was eluted from an anion exchange resin with HCl pH 2.0, and bioactivity was determined by activation of pyruvate dehydrogenase in vitro. The second was eluted with HCl pH 1.3, and bioactivity was determined by inhibition of cyclic AMP-dependent protein kinase. In healthy men, the bioactivity of the pH 1.3 IPG was not altered by glucose ingestion, whereas bioactivity of the pH 2.0 IPG increased to approximately 120 % of the pre-glucose ingestion value at 60-240 min post-glucose ingestion (p < 0.05 vs pre-glucose). There was no change in either IPG after glucose ingestion in the insulin-resistant group. These data suggest that the pH 2.0 IPG plays an important role in mediating insulin's effect on peripheral glucose utilization in man under physiological conditions. The data further show, for the first time, a defective change in the bioactivity of an insulin mediator isolated from insulin-resistant humans after hyperinsulinaemia, suggesting that inadequate generation/release of IPGs is associated with insulin resistance. [Diabetologia (1997) 40: 557-563] Keywords Inositol phosphoglycans, non-insulin dependent diabetes mellitus, pyruvate dehydrogenase, cyclic AMP dependent protein kinase.

D-Chiro-Inositol Glycans in Insulin Signaling and Insulin Resistance

“…They further found that in women with PCOS during a glucose tolerance test there was a three-fold decrease in the release of the chiro-inositol glycan compared with control subjects. Similar findings were reported by Shashkin et al in type II diabetic patients compared with control subjects (61). Scoscia et al studied placental membranes from women with preeclampsia, a disease with insulin resistance, compared with controls (60).…”

Decreased myo-inositol to chiro-inositol (M/C) ratios and increased M/C epimerase activity in PCOS theca cells demonstrate increased insulin sensitivity compared to controls

“…Extensive examination of CYP17A1 and CYP11A1 gene expression in normal and PCOS theca cells has revealed that increased CYP17 and myo-inositol to chiro-inositol epimerase activity and a decreased myo-inositol to chiro-inositol ratio. In all previous papers, we have provided evidence for decreased epimerase activity and increased myo-inositol to chiro-inositol ratios in cases of insulin resistance [7][8][9][10][11][12][13][14][15][16]. Our experiments do not shed light on the continuing enigma of the primacy of increased testosterone versus the peripheral insulin resistance as the initiating event in PCOS.…”

“…In addition, deficiency of chiro-inositol in urine of Japanese subjects has been demonstrated to be linearly related to insulin resistance in type 2 diabetics, subjects with impaired glucose tolerance and normal subjects [10]. Further, lack of appearance of chiro-inositol glycan bioactivity (measured as PDH phosphatase (PDHP) activity) in blood of type 2 diabetic subjects during a glucose tolerance test, lack of chiro-inositol glycan bioactivity in women with PCOS during an insulin clamp, and lack of appearance of chiro-inositol glycan bioactivity release from placental membranes with insulin administration in vitro in women with preeclampsia have also been shown [11][12][13]. One glycan isolated from beef liver, named INS-2, has been identified, structure determined and chemically synthesized.…”

Inositol Phosphoglycan P-Type in Preeclampsia

“…18 P-IPG seems to play an important role in mediating the insulin effects on peripheral glucose use under physiological conditions, whereas a lack in generation/release of this molecule has been suggested to underlie insulin resistance in noninsulin-dependent diabetic men. 19 We have reported recently an increased urinary excretion of this molecule during pregnancy compared with nonpregnant women with a particularly high concentration in the amniotic fluid in healthy pregnancies. 20 P-IPG production was enhanced by active PE as demonstrated by an increased content or release of this molecule in placentas or fluids (amniotic fluid and urine) of women with this syndrome.…”