Biomedical subjects

D A Greene

Publications and source records attributed to D A Greene.

At least 19 recordsLinked to original sources

PubMed1992

The reproducibility and sensitivity of sural nerve morphometry in the assessment of diabetic peripheral polyneuropathy.

The nerve fibre loss, atrophy and injury of diabetic peripheral polyneuropathy and their responses to metabolic intervention have been studied by morphometric analysis of sural nerve biopsies. The magnitudes and sources of intra- and inter-individual variation in these morphometric measures have not been investigated previously in a systematic manner. Morphometric parameters of nerve fibre damage were measured in four separate fascicles from bilateral sural nerve specimens obtained post-mortem from 13 diabetic and 13 non-diabetic subjects. Intra- and inter-individual coefficients of variation were computed and compared to the magnitude of the differences between normal and diabetic subjects. Several morphometric variables emerged as highly sensitive and reproducible measures of nerve fibre damage suitable for clinical studies of diabetic peripheral polyneuropathy. These observations provide a rational basis for the design of future clinical trials employing morphometric end-points.

Autopsy↗

PubMed1992

Inhibition of phosphatidylinositol synthase by glucose in human retinal pigment epithelial cells.

A series of interrelated biochemical and functional defects, induced by hyperglycemia, associated with intracellular depletion of D-myo-inositol, and corrected by aldose reductase inhibitors, have been ascribed to abnormal phosphoinositide metabolism in several tissues prone to diabetic complications. However, reductions in tissue D-myo-inositol content are not universally found in complications-prone diabetic tissues, and direct mass-action effects of cellular D-myo-inositol depletion on the critical CDPdiacylglycerol-inositol 3-phosphatidyltransferase (PI synthase; EC 2.7.8.11) step have never been shown conclusively in relevant cells. The studies reported here simultaneously estimated the chemical mass of CDP diglyceride by equilibrium labeling with 5-[3H]cytidine and phosphoinositide biosynthesis by the incorporation of [32P]orthophosphate into phosphoinositide. This was done to assess the degree of inhibition of PI synthase under various degrees of D-myo-inositol depletion and sorbitol accumulation induced by glucose and other metabolic manipulations in cultured human retinal pigment epithelial cells, a new in vitro model for diabetic complications. The results suggest that sorbitol accumulation limits the PI synthase reaction in these cells by selectively depleting specific intracellular pools of D-myo-inositol and/or by possible independent effects of sorbitol on PI synthase.

Aldehyde Reductase↗

PubMed1992

Complications: neuropathy, pathogenetic considerations.

The most common form of neuropathy associated with diabetes mellitus is distal symmetric sensorimotor polyneuropathy, often accompanied by autonomic neuropathy. This disorder is characterized by striking atrophy and loss of myelinated and unmyelinated fibers accompanied by Wallerian degeneration, segmental, and paranodal demyelination and blunted nerve fiber regeneration. In both humans and laboratory animals, this progressive nerve fiber damage and loss parallels the degree and/or duration of hyperglycemia. Several metabolic mechanisms have been proposed to explain the relationship between the extent and severity of hyperglycemia and the development of diabetic neuropathy. One mechanism, activation of the polyol pathway by glucose via AR, is a prominent metabolic feature of diabetic rat peripheral nerve, where it promotes sorbitol and fructose accumulation, myo-inositol depletion, and slowing of nerve conduction by alteration of neural Na(+)-K(+)-ATPase activity or perturbation of normal physiological osmoregulatory mechanisms. ARIs, which normalize nerve myo-inositol and nerve conduction slowing, are currently the focus of clinical trials. Other specific metabolic abnormalities that may play a role in the pathogenesis of diabetic neuropathy include abnormal lipid or amino acid metabolism, superoxide radical formation, protein glycation, or potential blunting of normal neurotrophic responses. Metabolic dysfunction in diabetic nerve is accompanied by vascular insufficiency and nerve hypoxia that may contribute to nerve fiber loss and damage. Although major questions about the pathogenesis of diabetic neuropathy remain unanswered and require further intense investigation, significant recent progress is pushing us into the future and likely constitutes only the first of many therapies directed against one or more elements of the complex pathogenetic process responsible for diabetic neuropathy.

Animals↗

PubMed1992

Pittsburgh Epidemiology of Diabetes Complications Study. Measuring diabetic neuropathy follow-up study results.

OBJECTIVE: This project evaluated the utility of quantitative sensory techniques in predicting the development of neuropathy for subjects participating in a prospective study. RESEARCH DESIGN AND METHODS: Distal symmetric polyneuropathy was evaluated in 77 insulin-dependent diabetes mellitus individuals via quantitative sensory testing, nerve conduction studies, and clinical examination. RESULTS: Although the specificity and positive predictive value were low for the quantitative sensory techniques as predictors of neuropathy diagnosed on clinical exam approximately 2 yr later, the sensitivity for vibratory thresholds was high (100%). Variability over the 2-yr interval was shown on follow-up testing for each of the objective assessment modalities and it was not explained by differences for potential risk factors measured at baseline. CONCLUSION: Despite a cross-sectional relationship between the assessment modalities and clinically overt neuropathy at baseline, these follow-up data suggest that the potential for the objective modalities as predictors of clinically diagnosed neuropathy may be limited.

Adult↗

PubMed1991

Peripheral nerve repair following ARI treatment.

In this placebo-controlled double-blind clinical trial, ARI-treatment was accompanied by small but statistically significant improvements in clinical and electrophysiological indices. These improvements were associated with a lowering of nerve sorbitol levels and significant improvements in quantitative structural parameters. These data suggest that an activated polyol-pathway plays a continuous pathogenetic role even in advanced clinically overt diabetic neuropathy, and that the metabolic abnormalities mediated by the polyol pathway are intimately associated with structural and functional changes and ultimately clinical symptoms. The regenerative and reparative responses to a potent ARI like sorbinil suggest that advanced neuroanatomical changes believed to underlie overt clinic polyneuropathy are at least partly reversible, and that extrapolated over longer treatment periods ARI's may substantially ameliorate the structural changes and the clinical symptoms associated with diabetic neuropathy. As indicated by animal studies ARI's may become valuable adjuncts to the therapeutical arsenal not only in the treatment of diabetic neuropathy and other chronic diabetic complications, but also as a prophylactic regimen, provided that safe compounds can be developed.

Aldehyde Reductase↗

PubMed1991

Receptor-coupled phosphoinositide hydrolysis in human retinal pigment epithelium.

Carbachol and histamine stimulated phosphoinositide (PPI) hydrolysis in cultured human retinal pigment epithelium (RPE), as reflected by an accumulation of 3H-inositol phosphates in the presence of 10 mM Li+. Carbachol increased PPI hydrolysis to greater than 600% of basal with an EC50 of 60 microM; stimulation was linear up to 60 min. This activation likely occurred via the M3 muscarinic cholinergic receptor based on the IC50 values for 4-diphenylacetoxy-N-methylpiperidine methiodide (0.47 nM), pirenzepine (280 nM), and 11-[[2-[(diethylamino)methyl]-1-piperidinyl]-acetyl]-5,11- dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one (1.4 microM). Carbachol-mediated PPI hydrolysis was decreased by 80% in the absence of extracellular Ca2+. Histamine stimulated PPI turnover in a linear manner by 180% with an EC50 of 20 microM by the H1 histaminergic receptor. Serotonin, glutamate, norepinephrine, and dopamine were inactive. In human RPE, the resting cytoplasmic Ca2+ concentration, as determined by fura-2 fluorescence, was 138 +/- 24 nM. On the addition of carbachol, there was a 180% increase in peak intracellular Ca2+; addition of histamine increased intracellular Ca2+ by 187%. These results suggest receptor-mediated, inositol lipid hydrolysis is coupled to intracellular Ca2+ flux in human RPE.

Calcium↗

PubMed1991

Diminished specific activity of cytosolic protein kinase C in sciatic nerve of streptozocin-induced diabetic rats and its correction by dietary myo-inositol.

The impaired Na(+)-K(+)-ATPase activity in peripheral nerve from diabetic rats is prevented by dietary myo-inositol (MI) supplementation in vivo and corrected by protein kinase C (PKC) agonists in vitro, suggesting that PKC may mediate the effects of nerve MI depletion on Na(+)-K(+)-ATPase activity. However, little is known about the effect of diabetes on PKC activity or peptide in rat peripheral nerve. Therefore, the effect of streptozocin-induced diabetes and dietary MI supplementation on the activity and distribution of PKC in rat sciatic nerve homogenates and cytosolic and particulate fractions was explored with histone phosphorylation assay and Western-blot analysis. PKC activity but not peptide was selectively decreased in the cytosolic fraction by streptozocin-induced diabetes, and this abnormality was partially corrected by dietary MI supplementation. These results suggest that altered MI metabolism may affect nerve PKC specific activity, and this alteration may play a role in reduced Na(+)-K(+)-ATPase activity and blunted regenerative response in diabetic nerve.

Administration, Oral↗

PubMed1991

Normalization of Na(+)-K(+)-ATPase activity in isolated membrane fraction from sciatic nerves of streptozocin-induced diabetic rats by dietary myo-inositol supplementation in vivo or protein kinase C agonists in vitro.

A myo-inositol-related defect in nerve Na(+)-K(+)-ATPase in experimental diabetes has been invoked in the pathogenesis of diabetic neuropathy, but the mechanism linking altered myo-inositol metabolism and Na(+)-K(+)-ATPase regulation in diabetic nerve is uncertain. Decreased Na(+)-K(+)-ATPase in diabetic rat nerve is normalized by aldose reductase inhibitors or dietary myo-inositol, which preserve normal nerve myo-inositol content in vivo. Decreased Na(+)-K(+)-ATPase in diabetic rabbit nerve is acutely reversed by exposure to protein kinase C agonists in vitro. This study explored the relationship between the myo-inositol-sensitive and protein kinase C-agonist-sensitive Na(+)-K(+)-ATPase defects in diabetic rat nerve. Ouabain-sensitive ATPase activity was measured in an enriched membrane fraction isolated from nondiabetic, streptozocin-induced diabetic, and myo-inositol-supplemented streptozocin-induced diabetic rats before and after the membranes were exposed to protein kinase C agonists in vitro. The decreased ouabain-sensitive ATPase activity in plasma membranes from untreated diabetic rats was increased after exposure to two structurally unrelated protein kinase C agonists; the normal ouabain-sensitive ATPase in plasma membranes from myo-inositol-supplemented diabetic rats was unaffected by protein kinase C agonists. The nonadditivity and implied equivalence of the Na(+)-K(+)-ATPase defect corrected by myo-inositol in vivo and by protein kinase C agonists in vitro are consistent with the postulated existence of a deficient myo-inositol-dependent phospholipid-derived protein kinase C agonist (presumably diacylglycerol) in diabetic nerve that regulates nerve Na(+)-K(+)-ATPase either directly or via a protein kinase C mechanism.

Animals↗

PubMed1991

Endoneurial microvessels in human diabetic neuropathy. Endothelial cell dysjunction and lack of treatment effect by aldose reductase inhibitor.

Endoneurial microvascular abnormalities have been invoked in the pathogenesis of diabetic distal symmetric polyneuropathy. Detailed morphometric analysis of the endoneurial microvasculature was correlated with previously published data on nerve fiber morphometry and teased fiber analysis obtained from the same sural nerve biopsies. Biopsy specimens from neuropathic diabetic patients were obtained before and after 12 mo of aldose reductase inhibitor (ARI) treatment and compared to 15 carefully age-matched control subjects. Diabetic microvessels showed basement membrane thickening and loss of endothelial cell tight junctions. Microvascular density and the frequency of microvessels closed by endothelial cells increased with age in diabetic and control nerves and were unaffected by diabetes. The density of microvessels showing patent lumina did not differ between control and diabetic subjects and was not related to age or diabetes. Closed microvessels were composed of postcapillary venules that were otherwise devoid of ultrastructural abnormalities. We suggest that microvascular closure by endothelial cells may be a physiological condition and is unlikely to have any pathogenetic significance in diabetic neuropathy. Based on the current limited biopsy material, we conclude that 12 mo of ARI treatment that induced significant fiber repair and regeneration had no detectable effect on endoneurial microvascular abnormalities. These data suggest that endoneurial vascular pathology is not a rate-limiting factor in fiber damage or repair at this stage of diabetic neuropathy.

Adult↗

PubMed1991

Sorbitol, myo-inositol, and rod outer segment phagocytosis in cultured hRPE cells exposed to glucose. In vitro model of myo-inositol depletion hypothesis of diabetic complications.

The "myo-inositol depletion hypothesis" remains a leading but still controversial contender among proposed pathogenetic mechanisms for the chronic complications of diabetes. The multifaceted interrelationships among altered tissue myo-inositol content and metabolism and tissue function have been difficult to elucidate in diabetic animal models due in part to the complex, heterogeneous nature of tissues prone to diabetic complications. The retinal pigment epithelium consists of a homogenous cell monolayer that exhibits related alterations in myo-inositol metabolism and function in diabetic animals. Nontransformed human retinal pigment epithelial (hRPE) cells, which retain their general phenotypic and morphological characteristics during monolayer culture in vitro, were examined for parallel alterations in myoinositol metabolism and cell function when grown under carefully controlled conditions in medium containing hyperglycemic concentrations of glucose. Exposure of hRPE cells to 20-40 mM glucose produced time- and dose-dependent increases in sorbitol content and decreases in myo-inositol content that were partially blocked by the aldose reductase inhibitor sorbinil. myo-Inositol was taken up by two Na-dependent transport systems, at least one of which was competitively inhibited by glucose. Exposure to 20 mM glucose impaired the ability of hRPE cells to take up human retinal rod outer segments, an important physiological function of these cells. The impairment of rod outer segment uptake by high glucose levels was prevented by an aldose reductase inhibitor or elevated medium myo-inositol that corrected the fall in myo-inositol content. Thus, hRPE cells provide a new in vitro model in which to examine the biochemical-functional interrelationships of the myo-inositol depletion hypothesis.

Adult↗

PubMed1990

Diabetic neuropathy.

Diabetic neuropathy, the most common peripheral neuropathy in the Western world, is responsible for most limb amputations and considerable morbidity in diabetic patients. Although it is a sequela to insulin deficiency and/or hyperglycemia, its exact pathogenetic mechanism remains unclear. Therapy is directed at early diagnosis, exclusion of other neuropathic disorders, prudent glucose control, and avoidance of secondary complications of neuropathy such as foot ulceration by aggressive foot care, hygiene, and patient education.

Diabetic Neuropathies↗

PubMed1990

Preventive effect of long-term aldose reductase inhibition (ponalrestat) on nerve conduction and sural nerve structure in the spontaneously diabetic Bio-Breeding rat.

To test the hypothesis that aldose reductase inhibition may prevent or delay the development of functional and structural neuropathy in the insulin-deficient diabetic Bio-Breeding rat (BB-rat), hyperglycemic rats were begun on the aldose reductase inhibitor (ARI) ponalrestat 25 mg/kg body wt soon after the onset of diabetes and followed for 4 or 6 mo. Ponalrestat treatment completely prevented the characteristic nerve conduction slowing and structural abnormalities of the node of Ranvier for 4 mo despite only partial preservation of axonal integrity. Ponalrestat treatment for 6 mo achieved a partial but significant prevention of nerve conduction slowing, axoglial dysjunction, and axonal degenerative changes. This incomplete but significant prevention of neuropathy by ponalrestat suggests that additional mechanisms besides polyol-pathway activation may be of importance in the pathogenesis of diabetic neuropathy. Alternatively, the dosage used in the present study may not have been sufficient to achieve a complete prevention. Despite the only partial protective effect of ARI treatment on degenerative peripheral nerve changes in hyperglycemic BB-rats, 6 mo of treatment resulted in a more than threefold increase in regenerating nerve fibers. These data suggest that prophylactic ARI treatment may be efficacious in delaying the development of diabetic neuropathy.

Aldehyde Reductase↗

PubMed1990

A defect in sodium-dependent amino acid uptake in diabetic rabbit peripheral nerve. Correction by an aldose reductase inhibitor or myo-inositol administration.

A myo-inositol-related defect in nerve sodium-potassium ATPase activity in experimental diabetes has been suggested as a possible pathogenetic factor in diabetic neuropathy. Because the sodium-potassium ATPase is essential for other sodium-cotransport systems, and because myo-inositol-derived phosphoinositide metabolites regulate multiple membrane transport processes, sodium gradient-dependent amino acid uptake was examined in vitro in endoneurial preparations derived from nondiabetic and 14-d alloxan diabetic rabbits. Untreated alloxan diabetes reduced endoneurial sodium-gradient dependent uptake of the nonmetabolized amino acid 2-aminoisobutyric acid by greater than 50%. Administration of an aldose reductase inhibitor prevented reductions in both nerve myo-inositol content and endoneurial sodium-dependent 2-aminoisobutyric acid uptake. Myo-inositol supplementation that produced a transient pharmacological elevation in plasma myo-inositol concentration, but did not raise nerve myo-inositol content, reproduced the effect of the aldose reductase inhibitor on endoneurial sodium-dependent 2-aminoisobutyric acid uptake. Phorbol myristate acetate, which acutely normalizes sodium-potassium ATPase activity in diabetic nerve, did not acutely correct 2-aminoisobutyric uptake when added in vitro. These data suggest that depletion of a small myo-inositol pool may be implicated in the pathogenesis of defects in amino acid uptake in diabetic nerve and that rapid correction of sodium-potassium ATPase activity with protein kinase C agonists in vitro does not acutely normalize sodium-dependent 2-aminoisobutyric acid uptake.

Amino Acids↗

PubMed1990

Diabetic autonomic neuropathy in BB rats and effect of ARI treatment on heart-rate variability and vagus nerve structure.

The preventive effect of the aldose reductase inhibitor (ARI) ponalrestat on heart-rate variability and the development of autonomic neuropathy in the vagus nerve was investigated in the spontaneously diabetic BB rat. ARI treatment completely prevented the characteristic decrease in heart-rate variability and axonal atrophy of the vagus nerve for 4 mo in hyperglycemic BB rats. After 6 mo of treatment, the preventive effect on heart-rate variability was partial, and the vagus nerve demonstrated an increase in regenerating myelinated and unmyelinated fibers. These data suggest that autonomic neuropathy involving the vagus nerve is metabolically induced by demonstrating that inhibition of the polyol pathway significantly delays the occurrence of functional and structural autonomic neuropathy despite the presence of hyperglycemia.

Aldehyde Reductase↗

PubMed1989

Diabetic and hypoglycemic neuropathy--a comparison in the BB rat.

Functional and structural neuropathy was examined in hyperglycemic (diabetic) BB rats maintained on small maintenance doses of insulin, hyperglycemic BB rats receiving no insulin, and BB rats in whom hypoglycemia was induced by the administration of excessive insulin doses. The data were compared with those of non-diabetic age- and sex-matched BB rats. Functional deficits and structural abnormalities were comparable in diabetic rats with and without insulin supplementation, suggesting that the generally necessary insulin dosing in this model does not per se account for the neuropathy. Hypoglycemic neuropathy was characterized by slowing of nerve conduction velocity, marked loss of anterior horn motoneurons and Wallerian degeneration, as well as loss of large myelinated fibers, suggesting a neuropathy involving predominantly motoneurons. Diabetic neuropathy was not associated with nerve cell loss but showed marked axonal atrophy involving predominantly sensory fibers. Thus, diabetic and hypoglycemic neuropathies are two distinguishable entities under strict experimental conditions, but may overlap in human diabetic subjects in whom tight insulin control is desirable.

Animals↗

PubMed1989

In vitro correction of impaired Na+-K+-ATPase in diabetic nerve by protein kinase C agonists.

Diminished Na+-K+-ATPase activity in diabetic peripheral nerve plays a central role in the early electrophysiological, metabolic, and morphological abnormalities of experimental diabetic neuropathy. The defect in Na+-K+-adenosinetriphosphatase (ATPase) regulation in diabetic nerve is linked experimentally to glucose- and sorbitol-induced depletion of nerve myo-inositol but is not fully understood at a molecular level. Therefore, regulation of nerve Na+-K+-ATPase activity by phosphoinositide-derived diacylglycerol was explored as the putative link between myo-inositol depletion and the Na+-K+-ATPase impairment responsible for slowed saltatory conduction in diabetic animal models. In vitro exposure of endoneurial preparations from alloxan-diabetic rabbits to two protein kinase C agonists, 4 beta-phorbol 12 beta-myristate 13 alpha-acetate and 1,2-(but not 1,3-) dioctanoyl-sn-glycerol, for as little as 1 min completely and specifically corrected the 40% decreased enzymatically measured ouabain-sensitive ATPase activity. Neither of these agonists affected ouabain-sensitive ATPase activity in endoneurial preparations derived from nondiabetic controls. These observations are compatible with the hypothesis that metabolites of electrically stimulated phosphoinositide turnover such as diacylglycerol acutely regulate nerve Na+-K+-ATPase activity, probably via protein kinase C, thereby tightly coupling energy-dependent Na+-K+-antiport with impulse conduction in peripheral nerve. Glucose-induced depletion of myo-inositol presumably limits phosphoinositide turnover and diacylglycerol production, thereby disrupting this putative regulatory mechanism for Na+-K+-ATPase in diabetic peripheral nerve.

Animals↗

PubMed1989

Epidemiological correlates of diabetic neuropathy. Report from Pittsburgh Epidemiology of Diabetes Complications Study.

The natural history of diabetic neuropathy and its risk factors are not well understood, apart from the recognition that prevalence increases with duration and, in many studies, degree of glycemia. The role of potential risk factors was therefore evaluated in a cross-sectional analysis from the baseline examination of the Pittsburgh Epidemiology of Diabetes Complications Study. We present results from the first 400 subjects seen at baseline examination. Neuropathy was determined by a trained internist with a standardized examination and was defined as the presence of at least two of three criteria: abnormal sensory or motor signs, symptoms consistent with neuropathy, and decreased tendon reflexes. The prevalence of neuropathy in this cohort was 34% (18%, 18-29 yr old, 58% greater than or equal to 30 yr old) with no difference by sex. By focusing on subjects greater than or equal to 18 yr old, all significant univariate variables (e.g., duration, glycosylated hemoglobin [HbA1]) were analyzed in 3 multiple logistic regression models: all subjects greater than or equal to 18 yr old and separating the same subjects into two groups based on age (18-29 and greater than or equal to 30 yr). Duration, HbA1, smoking status, and high-density lipoprotein cholesterol were found to be associated with neuropathy in the models for the greater than or equal to 18-yr-old group and the greater than or equal to 30-yr-old group. In the 18- to 29-yr-old group, duration, HbA1, and hypertension status were found to be significantly associated with neuropathy.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1989

Pathogenesis of diabetic neuropathy: role of altered phosphoinositide metabolism.

A unifying metabolic hypothesis completely accounting for the development of one or more of the chronic complications of diabetes on the basis of a single aspect of disturbed glucose metabolism resulting from insulin deficiency and/or hyperglycemia has been sought by clinical and basic scientists for decades. A growing body of loosely related but internally consistent scientific data obtained from cultured cells, incubated tissue preparations, animal models, and man implicate sorbitol- and glucose-induced myo-inositol depletion and altered phosphoinositide metabolism in a series of secondary biochemical, functional, and architectural abnormalities in the PNS in diabetes. These early metabolically based functional and structural changes simulate those that characterize human diabetic neuropathy. Can abnormal phosphoinositide metabolism in diabetic nerve thereby by itself explain the development of chronic diabetic neuropathy with all of its clinical complexity and heterogeneity? Almost certainly not. Even if the entire contribution of hyperglycemia to the development of diabetic neuropathy were mediated by secondary abnormalities in phosphoinositide metabolism, other factors must also play a role. Witness the differences in the histopathological picture of neuropathy in patients with IDDM and NIDDM despite similar durations and severity of diabetes, the apparent influence of age and gender on the appearance of early neuropathy in patients with IDDM, and the association of alcohol consumption with diabetic neuropathy. While early metabolic and functional disturbances in diabetic nerve such as impaired (Na,K)-ATPase function and paranodal swelling are empirically attributable to abnormal myo-inositol and phosphoinositide metabolism, more advanced abnormalities such as axo-glial dysjunction may reflect superimposed independent biochemical and/or hormonal defects (although, as mentioned previously, aldose reductase inhibition decreases axo-glial dysjunction in diabetic humans). The PNS has only a limited repertoire of responses to a variety of insults, so that Wallerian degeneration, axonal atrophy, impaired axonal transport, and dystrophic changes in diabetic neuropathy may represent multiple factors. On the other hand, the increasingly recognized importance of the phosphoinositide cascade in neuromodulation may attribute a progressively wider range of disturbances in the diabetic PNS to myo-inositol depletion and associated defects in phosphoinositide metabolism. Thus, while all effects of aldose reductase inhibitors in the PNS of diabetic rats have been reproduced by myo-inositol supplementation when this alternative intervention has been tested, the exact role of phosphoinositide metabolism in most of these responses is not well understood.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗