D-chiro-inositol in insulin action and insulin resistance-old-fashioned biochemistry still at work.
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Animals↗
Biomedical subjects
J Larner
Publications and source records attributed to J Larner.
Community-based service delivery in rehabilitation: the promise and the paradox.
PURPOSE: According to many researchers, rehabilitation is being prevented from developing as a distinct profession due to two major problems. First, it has been claimed that rehabilitation is in need of a professional identity and a sense of cohesion if it is to emerge as a discipline. Second, it has been recognized that there is a need for a rehabilitation framework to challenge the restorative approach that continues to dominate rehabilitation, linking it back to the medical model from which it has attempted to escape. The model of community-based rehabilitation (CBR) is offered as a model that can provide the impetus for an attitudinal shift from the restorative tradition and unite rehabilitation workers through a cohesive framework. METHOD: Unfortunately, the implementation of community-based rehabilitation in urban societies has been disappointing. The current paper is a conceptual discussion of community-based rehabilitation that explores some potential causes of this poor implementation. RESULTS: To some extent, the implementation failure of community-based rehabilitation can be attributed to the paradoxes that are inherent in its fundamental constructs-empowerment and community inclusion. These paradoxes occur at a conceptual level, a practical level and a contextual level. CONCLUSIONS: Some solutions are offered to enable the paradigm to be implemented more fully. In particular, it is suggested that there is a need to develop useful working definitions of these constructs, favourable attitudes among rehabilitation workers and a focus on community development.
Community Health Services↗
Antihyperglycemic effects of 3-O-methyl-D-chiro-inositol and D-chiro-inositol associated with manganese in streptozotocin diabetic rats.
The acute effects after administration of 3-O-Methyl-D-Chiro-inositol, D-Chiro-inositol and manganese, components of the pH 2.0 putative mediator of insulin action, on plasma glucose were examined in low dose streptozotocin-treated rats. 3-O-Methyl-D-Chiro-inositol at a bolus dose of 5 mg/kg decreased plasma glucose 6% at 120 min (p < 0.05). A higher bolus dose of 3-O-Methyl-D-Chiro-inositol (15 mg/kg) promoted a more persistent hypoglycemic effect of 22% at 120 min (p < 0.05). Infusion of 8.3 microg/min of manganese chloride lowered plasma glucose by 23% (p < 0.05). 3-O-Methyl-D-Chiro-inositol (15 mg/kg) together with manganese chloride (8.3 microg/min) promoted a reduction of 49% in 120 min (p < 0.05). D-Chiro-inositol at a bolus dose of 5 mg/kg had no effect. A single dose of 15 mg/kg produced a reduction of 21% (p < 0.05) in 120 min. D-Chiro-inositol (15 mg/kg) associated with manganese chloride (8.3 microg/min) decreased elevated plasma glucose 47% (p < 0.05) in 120 min. D-Chiro-inositol coadministered with manganese reduced glucose concentrations during the final 60 min (p < 0.05). 3-O-Methyl-D-Chiro-inositol and D-chiro-inositol are components of the mediator structure. Manganese is also a presumed component of the mediator, having an important role in glucose uptake, insulin release and mediator generation. These compounds have also been identified in the literature as hypoglycemic agents.
Animals↗
A model phosphatase 2C --> phosphatase 1 activation cascade via dual control of inhibitor-1 (INH-1) and DARPP-32 dephosphorylation by two inositol glycan putative insulin mediators from beef liver.
Two inositol phosphoglycans (IPG) isolated from beef liver and designated as putative insulin mediators were demonstrated to reciprocally enhance the dephosphorylation of inhibitor-1 (INH-1) and DARPP-32, thus directly activating phosphatase 2C and disinhibiting phosphatase 1 in a potential protein phosphatase 2C --> phosphatase 1 cascade mechanism. One IPG termed pH 2.0, containing Dchiro-inositol and galactosamine, stimulated the dephosphorylation of INH-1 and DARPP-32 in a dose-dependent manner in the low micromolar range. A second, termed pH 1.3, containing myo-inositol glucosamine and mannose acted reciprocally to inhibit the cAMP-dependent protein kinase phosphorylation of INH-1 and DARPP-32 in a dose-dependent manner in the low micromolar range. These model experiments are discussed in terms of the observed dephosphorylation of INH-1 with insulin action documented in the literature and the activation of both phosphatase 1 and 2C described in intact cells and in vivo with insulin action.
Animals↗
In vivo chiro-inositol metabolism in the rat: a defect in chiro-inositol synthesis from myo-inositol and an increased incorporation of chiro-[3H]inositol into phospholipid in the Goto-Kakizaki (G.K) rat.
We report our comparative studies of myo- and chiro-[3H]inositol distribution in control nondiabetic Wistar and spontaneous nonobese insulin-resistant Type II diabetic G.K. rat tissues following 78-h labeling period. From various tissue extracts, free inositols, inositol phosphates, and inositol phospholipids were isolated and analyzed. Our findings demonstrate (1) a significant difference in the metabolism of myo- and chiro-inositol in normal Wistar and G.K. rats, (2) a severe defect in conversion of myo-[3H]inositol to chiro-[3H]inositol at the inositol phospholipid level of insulin-sensitive tissues of the G.K. rat, (3) an increased incorporation of myo-[3H]inositol into purified inositol phospholipids of the G.K. rat consistent with a decreased conversion to chiro-[3H]inositol, (4) the presumed presence of a pathway which incorporates chiro-[3H]inositol into inositol phospholipids, and which is overactive in the G.K. rat compared to the Wistar rat, and (5) no or minimal conversion of chiro-[3H]inositol to myo-[3H]inositol.
Animals↗
A phase I-II trial of lovastatin for anaplastic astrocytoma and glioblastoma multiforme.
Malignant gliomas are thought to be highly dependent on the mevalonate pathway for cell growth. Lovastatin, a cholesterol-lowering drug, inhibits not only the rate-limiting step in the mevalonate pathway (hepatic hydroxymethyl glutaryl coenzyme A reductase), but also the prenylation of several key regulatory proteins including ras and the small guanosine triphosphate binding proteins. Therefore, from August 1994 through March 1996, 18 patients with either anaplastic glioma or glioblastoma multiforme were entered into a trial testing the safety of high-dose lovastatin with or without radiation. Although the response data is too premature to evaluate activity, the fact that high doses of lovastatin are well tolerated with concurrent radiation suggests that central nervous system toxicity will not be a significant limiting toxicity as more selective farnesyltransferase inhibitors are brought into the clinic as radiation sensitizers.
Adult↗
The role of preoperative adjuvant treatment in the management of esthesioneuroblastoma: the University of Virginia experience.
OBJECTIVE: Multidisciplinary management of esthesioneuroblastoma has effected markedly increased survival during the past 20 years. The potential for radical craniofacial surgery for complete en bloc resection, the availability of advanced neuroimaging modalities, and the incorporation of neoadjuvant therapy into treatment strategies for tumor remission have all contributed to this accomplishment. However, a standard protocol for the management of these lesions has not been accepted; preoperative radiation and chemotherapy have been advocated, but neither radiographic nor clinical response has been quantified. METHODS: Thirty-four consecutive patients with biopsy-proven esthesioneuroblastoma treated at one institution from 1976 to 1994 were reviewed to determine the effects of preoperative radiation therapy, with or without chemotherapy, on tumor size and long-term survival. RESULTS: In a multivariate regression analysis, advanced age was predictive of decreased disease-free survival (P=0.008), whereas advanced Kadish stage was associated with a borderline higher rate of disease-related mortality (P=0.056). Two-thirds of the patients showed a significant reduction in tumor burden with adjuvant therapy. Patients with response to neoadjuvant therapy demonstrated a significantly lower rate of disease-related mortality (P=0.050). In this series, the overall 5- and 10-year survival rates were 81.0 and 54.5%, respectively. CONCLUSION: Preoperative neoadjuvant therapy provides a valuable complement to radical craniofacial resection, leading to reduction in tumor burden. Patients experiencing reduction in tumor volume by neoadjuvant therapy demonstrate an improved prognosis.
Adolescent↗
Phosphoinositol glycan derived mediators and insulin resistance. Prospects for diagnosis and therapy.
While much work remains, the evidence has become strong that IPG generation following insulin action is a significant signaling mechanism. A considerable body of data has established IPG release by insulin and other growth factors from cell membranes, cells and in human blood and muscle biopsies in vivo. Two separate IPG species containing D-chiro-inositol and myo-inositol have been separated by ion exchange. These IPGs have separate actions in vitro and are both active as insulin surrogates in vivo. A deficiency of the chiro-inositol system has been demonstrated in urine and tissues in humans and directly related to insulin resistance. Accordingly, D-chiro-inositol was administered to STZ diabetic rats and rhesus monkeys and shown to decrease hyperglycemia and enhance glucose disposal. Two trials in humans with impaired glucose tolerance and women with PCOS have now also proven successful. Thus, the pathophysiology in the chiro-inositol system related to insulin resistance and its reversal by chiro-inositol administration, in addition to the basic work, argues strongly for the physiological significance of this novel signaling system in the control of glucose metabolism.
Animals↗
Insulin unexpectedly increases the glucose 6-phosphate Ka of skeletal muscle glycogen synthase in calorie-restricted monkeys.
In skeletal muscle of normal subjects, the concentration of glucose 6-phosphate (G6P) at which the activity of glycogen synthase (GS) is half maximal (Ka) is decreased by in vivo insulin, and the fractional activity is increased without a change in GS maximal activity (Vmax). We have shown that moderate chronic calorie restriction, previously shown in rodents to be effective in slowing aging, resulted in the prevention of obesity and type 2 diabetes in primates (rhesus monkeys, Macaca mulatta). However, unexpectedly, in a subgroup of calorie-restricted monkeys, insulin during a euglycemic hyperinsulinemic clamp caused an unanticipated decrease in skeletal muscle GS fractional activity. These same monkeys had the lowest whole-body glucose disposal rate (M), the greatest increase in skeletal muscle G6P content and the greatest increase in skeletal muscle glycogen phosphorylase activity during the euglycemic hyperinsulinemic clamp compared to the remaining calorie-restricted monkeys with normal insulin action. To determine whether this highly unusual insulin-mediated decrease in GS fractional activity was due to increased phosphorylation (increased Ka), we measured the activity of skeletal muscle GS at 9 different G6P concentrations before and during the euglycemic hyperinsulinemic clamp in 6 calorie-restricted monkeys. G6P Ka increased (n = 4) and Vmax decreased (n = 5) during the clamp. Basal G6P Ka was inversely related to basal GSfv (r = -0.94, p < 0.002). G6P Ka and skeletal muscle G6P content were positively related under insulin-stimulated conditions (r = 0.93, p < 0.005). The change in G6P Ka (insulin-stimulated minus basal) was inversely related to M (r = -0.94, p < 0.002) and positively related to the change in skeletal muscle G6P content (r = 0.93, p < 0.005). We conclude that moderate calorie restriction results in a reversal of normal insulin action at the skeletal muscle with inactivation of glycogen synthase which is likely to be due to an increase in phosphorylation of GS together with a decrease in Vmax of GS during a euglycemic hyperinsulinemic clamp in most of the calorie-restricted monkeys. These alterations are likely to be involved in the anti-diabetogenic effects of calorie restriction.
Animals↗
Infusion of pH 2.0 D-chiro-inositol glycan insulin putative mediator normalizes plasma glucose in streptozotocin diabetic rats at a dose equivalent to insulin without inducing hypoglycaemia.
We compared the effects of infusing a chemically defined chiro-inositol glycan putative insulin mediator with an equivalent dose of insulin in low-dose (45 mg/kg) streptozotocin diabetic rats. Insulin decreased plasma glucose levels from 17.32 +/- 0.17 to 3.96 +/- 0.064 mmol/l (p < 0.0002) in 120 min, a decrease of 77.13%, while the putative mediator promoted a decrease in plasma glucose from 14.85 +/- 0.084 to 7.22 +/- 0.13 mmol/l (p < 0.007) in 60 min. The putative mediator maintained euglycaemia over the ensuing 60 min with a plasma glucose level of 7.01 +/- 0.10 mmol/l at 120 min. Thus, insulin further reduced the plasma glucose from euglycaemia at 60 min to produce hypoglycaemia at 120 min. The lack of production of hypoglycaemia by the putative mediator can be explained by its inhibition of glucose-stimulated insulin secretion by the islet beta cells, thus providing a potential negative feedback regulatory mechanism; or by its selective action on muscle to increase glycogen synthesis. The significance of these results in terms of future directions in drug design is herein considered.
Animals↗
No change in insulin mediators in human skeletal muscle during isometric contraction or recovery.
The rapid activation of glycogen synthase in human skeletal muscle during recovery from isometric contraction is dependent on an intact circulation, which suggests the requirement of an activating humoral factor. To determine whether the activating factor is insulin, muscle biopsies were obtained from subjects at rest, at fatigue, 3 min postexercise with an intact circulation, and 3 min postexercise during which circulation to the muscle was occluded. Two inositol phosphoglycan mediators of insulin action were isolated from the biopsies, and bioactivity was measured by determining the effects of the isolated mediators on the activities of purified cyclic AMP-dependent protein kinase, pyruvate dehydrogenase phosphatase and glycogen synthase phosphatase in vitro. Bioactivity was not altered by any condition compared with rest. These data suggest that changes in inositol phosphoglycans are not responsible for the circulation-dependent activation of glycogen synthase during recovery from exercise.
Adult↗
Circulating factors and insulin resistance. II. The action of the novel myo-inositol cyclic 1,2-inositol phosphate phosphoglycan insulin antagonist from human plasma in regulating pyruvate dehydrogenase phosphatase.
A novel low mol wt inositol phosphoglycan antagonist of insulin action of oxidative glucose metabolism in isolated rat adipocytes was partially purified from normal human plasma and shown to be increased in type II diabetic plasma. It was characterized chemically as a myo-inositol phosphoglycan containing a cyclic 1,2-phosphate. This antagonist, termed fraction V3, is now shown to inhibit the action of an inositol glycan insulin pH 2.0 mediator that stimulates pyruvate dehydrogenase phosphatase in a similar manner to insulin. In addition, fraction V3 inhibits stimulation of the pyruvate dehydrogenase (PDH) phosphatase by Mg2+, the enzyme's required metal, and by spermine, a polyamine. Fraction V3 does not inhibit active PDH itself. The inhibitory effect is dose dependent and apparently noncompetitive or nonsurmountable for the insulin inositol glycan pH 2.0 mediator, thus comparing kinetically with its insulin antagonistic action on intact adipocytes. Its inhibitory action on PDH phosphatase is dose dependent and competitive for Mg2+ stimulation of the phosphatase. Additionally, fraction V3 is shown to inhibit stimulation by Mg2+ of cloned recombinant PDH phosphatase catalytic subunit. Inhibition by fraction V3 of Mg(2+)-stimulated PDH phosphatase and its cloned catalytic subunit helps explain its mechanism of action to inhibit insulin-stimulated oxidative glucose metabolism in adipocytes and its potential clinical significance in insulin resistance.
Animals↗
Characterization of a nucleotide stimulated aspartic proteinase in rat liver plasma membranes.
Inositol phosphoglycan molecules are believed to mediate multiple intracellular actions of insulin. They are released from plasma membranes in response to insulin binding and are transported into the cell. Release of insulin mediators is stimulated by MnATP and MgATP and is inhibited by p-aminobenzamidine. Inositol phosphoglycan mediators may be released by a poorly characterized mechanism requiring proteolytic cleavage of an attached protein from the mediator and phospholipase cleavage of the mediator from its membrane anchor. We examined rat liver plasma membranes for proteinase activity stimulated by insulin and MnATP. Although we could not demonstrate insulin stimulation, we have found and characterized a nucleotide-stimulated aspartic proteinase bound to rat liver plasma membranes. We also detected and separated a soluble activating factor for the proteinase. The activating factor appears to be a protein with M(r) approximately 70 kDa.
Adenosine Diphosphate↗
Urinary myo-inositol-to-chiro-inositol ratios and insulin resistance.
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Diabetes Mellitus, Type 1↗
Effects of D-chiroinositol added to a meal on plasma glucose and insulin in hyperinsulinemic rhesus monkeys.
We have previously demonstrated that D-chiroinositol, administered intravenously to insulin-resistant monkeys, increases the rate of disappearance of plasma glucose and insulin. The purpose of the present study was to determine whether orally administered D-chiroinositol might also similarly improve the postprandial plasma glucose profile of hyperinsulinemic insulin-resistant monkeys. A complete liquid diet meal (15 ml/kg body weight) was ingested by each of six monkeys on two occasions separated by 10 days, with conditions identical except D-chiroinositol (500 mg/kg body weight) was added to the second meal. At 110 minutes following each meal, the monkeys were anesthetized and blood samples obtained at 120, 150, 180, 210, 240, 270 and 300 minutes. Plasma glucose and insulin concentrations were determined. The mean plasma glucose concentration (120-300 minutes) was significantly lower after the meal containing D-chiroinositol compared to the control meal (7.1 +/- 1.2 vs. 7.8 +/- 1.2 mM) (p < 0.05). Plasma insulin concentrations tended to be lower after the meal containing D-chiroinositol compared to the control meal (3930 +/- 1068 vs. 4518 +/- 1200 pM) (p < 0.15, ns). We conclude that in hyperinsulinemic monkeys, D-chiroinositol added to a meal lowers postprandial plasma glucose without an increase in plasma insulin, and therefore may be a useful agent for reducing meal-induced hyperglycemia without inducing hyperinsulinemia.
Animals↗
Circulating factors and insulin resistance. I. A novel myoinositol 1,2-cyclic phosphate phosphoglycan insulin antagonist from human plasma is elevated in noninsulin-dependent diabetes mellitus.
A novel low mol wt inositol phosphoglycan inhibitor (M tau 1200-1500) of insulin action in rat adipocytes has been partially purified from normal human plasma. This inhibitor, termed fraction V after the first purification step and fraction V3 after the second, is different from other reported serum insulin antagonists. It contains myoinositol, galactosamine, and mannose in approximate molar ratios of 1:1:3.3. The myoinositol has a 1,2-cyclic phosphate substituent, which is essential for the inhibitory activity. Its inhibitory activity is significantly elevated (161%, P < 0.05 for fraction V; 278%, P < 0.05 for fraction V3) in plasma of humans with noninsulin-dependent diabetes mellitus as compared with plasma of nondiabetic controls. These findings represent the first report of a naturally occurring mammalian inositol 1,2-cyclic phosphate containing phosphoglycan related to insulin action.
Adipocytes↗
Estimation of haemoglobin concentrations using spectrophotometric tests.
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False Positive Reactions↗
Insulin stimulates the biosynthesis of chiro-inositol-containing phospholipids in a rat fibroblast line expressing the human insulin receptor.
HIRc-B cells (rat fibroblasts expressing the human insulin receptor) were incubated with myo-[3H]inositol for 48 hr, and the biosynthesis of chiro-[3H]inositol was investigated in the absence and presence of insulin following a time course up to 60 min. After phase separation, treatment with insulin for 15 min caused a 2.2-fold increase in the specific radioactivity of chiro-[3H]inositol-containing phospholipids in contrast to a 1.2-fold increase in the specific radioactivity of myo-[3H]inositol-containing phospholipids. No insulin-mediated change in the specific radioactivity was observed in the inositol phosphates or free inositols. Further detailed analysis of individual [3H]inositol-containing phospholipids demonstrated marked increases in specific activity of the chiro-[3H]inositol phospholipids after 15 min of incubation with insulin: phosphatidylinositol 4-phosphate and 4,5-bisphosphate, 4.2-fold; lysophosphatidylinositol, 1.5-fold; phosphatidylinositol, 3.2-fold. In contrast, myo-[3H]inositol-containing phospholipids demonstrated relatively small increases (1.1- to 1.4-fold) after 5 min of incubation with insulin. These findings indicate that insulin stimulates de novo synthesis of chiro-inositol-containing phospholipids at the inositol phospholipid level.
Animals↗