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D A Greene

Publications and source records attributed to D A Greene.

At least 109 records · Page 6Linked to original sources
PubMed1986

Glutathione redox state is not the link between polyol pathway activity and myo-inositol-related Na+-K+-ATPase defect in experimental diabetic neuropathy.

Decreased glutathione levels in the ocular lens have been invoked as a possible cause for the decreased lenticular Na+-K+-ATPase in diabetes because both are corrected by aldose reductase inhibitors, and the Na+-K+-ATPase is known to be susceptible to oxidation inactivation. Because an analogous Na+-K+-ATPase defect that is prevented by aldose reductase inhibitors has been described in diabetic peripheral nerve, we examined the effect of streptozocin (STZ) diabetes and aldose reductase inhibition on reduced (GSH) and oxidized (GSSG) glutathione levels in crude homogenates of rat sciatic nerve. Neither GSSG nor GSH levels were altered by 2 or 8 wk of untreated diabetes or by aldose reductase inhibition. Because the defect in Na+-K+-ATPase is fully expressed by 4 wk of STZ diabetes, we conclude that altered glutathione redox state plays no detectable role in the pathogenesis of this defect in diabetic peripheral nerve.

Aldehyde Reductase↗
PubMed1986

Protein kinase C agonists acutely normalize decreased ouabain-inhibitable respiration in diabetic rabbit nerve. Implications for (Na,K)-ATPase regulation and diabetic complications.

Diminished (Na,K)-ATPase activity in diabetic peripheral nerve is attributed to an underlying depletion of free myo-inositol, but no biochemical mechanism linking myo-inositol metabolism and (Na,K)-ATPase has emerged. Since inositol phospholipid turnover releases inositol-(1,4,5)-tris-phosphate and diacylglycerol, two putative "second messengers" that modulate protein kinase C, the effect of protein kinase C agonists on (Na,K)-ATPase activity was examined in diabetic nerve. Phorbol myristate acetate or the diacylglycerol sn-1,2-dioctanoylglycerol acutely normalized depressed ouabain-inhibitable respiration [a measure of (Na,K)-ATPase activity], suggesting that myo-inositol metabolism modulates (Na,K)-ATPase activity via protein kinase C, and that reduced myo-inositol impairs (Na,K)-ATPase activity in diabetic nerve by this mechanism.

Animals↗
PubMed1985

Recent advances in the therapy of diabetic peripheral neuropathy by means of an aldose reductase inhibitor.

Nerve conduction slowing, a hallmark of both experimental and human diabetic neuropathy, is improved or corrected by administration of aldose reductase inhibitors such as sorbinil. Recent experiments in animals attribute acutely reversible nerve conduction slowing in diabetes to a myo-inositol-related defect in nerve sodium-potassium adenosinetriphosphatase, which generates the transmembrane sodium and potassium potentials necessary for nerve impulse conduction and the sodium gradient necessary for sodium-dependent uptake of substrates. This myo-inositol-related abnormality in sodium-potassium adenosinetriphosphatase function is currently viewed as a cyclic metabolic defect involving sequential alteration of sodium-dependent myo-inositol uptake, myo-inositol content, myo-inositol incorporation into membrane phospholipids, and phospholipid-dependent sodium-potassium adenosinetriphosphatase function in peripheral nerve. Aldose reductase inhibitors have been shown to normalize both nerve myo-inositol content and nerve sodium-potassium adenosinetriphosphatase activity. These observations suggest that the acute effects of aldose reductase inhibitors on nerve conduction in both animals and humans with diabetes may be mediated by correction of an underlying myo-inositol-related nerve sodium-potassium adenosinetriphosphatase defect. Furthermore, this sorbinil-corrected sodium-potassium adenosinetriphosphatase defect in diabetic nerve may contribute to other biochemical, functional, and structural abnormalities present in diabetic peripheral neuropathy.

Aldehyde Reductase↗
PubMed1984

Impaired energy utilization and Na-K-ATPase in diabetic peripheral nerve.

Recent electrophysiological and biochemical evidence implicates altered peripheral nerve Na-K-ATPase activity in the nerve conduction impairment of acute experimental diabetes. Composite in vitro nerve energy utilization is seriously impaired by experimental diabetes, yet is not modulated directly by insulin action on peripheral nerve. Therefore, we hypothesized that the reduction in diabetic nerve energy utilization reflects impaired nerve Na-K-ATPase activity. The reduction in steady-state energy utilization in diabetic peripheral nerve is shown to be quantitatively equal to the ouabain-inhibitable fraction of respiration, a measure of Na-K-ATPase activity in peripheral nerve. Na-K-ATPase activity in diabetic (but not nondiabetic) endoneurial preparations is influenced by medium solute concentration. Furthermore, diabetic nerve Na-K-ATPase activity and sodium-dependent myo-inositol uptake are similarly affected by medium solute changes, suggesting that the nerve sodium gradient may limit intracellular myo-inositol uptake in diabetic nerve. Conversely, because reduced diabetic nerve myo-inositol content impairs nerve Na-K-ATPase, a possible pathophysiological cycle of progressively deranged myo-inositol metabolism and Na-K-ATPase function may exist in diabetic peripheral nerve.

Animals↗
PubMed1984

Nerve Na+-K+-ATPase, conduction, and myo-inositol in the insulin-deficient BB rat.

Nerve conduction slowing in acute diabetes in animals has been associated with both a diminished axolemmal transmembrane Na+ potential and a myo-inositol-related defect in nerve Na+-K+-ATPase activity. The interaction between these two potentially related defects, their reversibility, and their possible role in the nerve conduction slowing and axonopathy of diabetes are not well defined. Therefore, the effects of rigorous insulin replacement on peripheral nerve conduction velocity, myoinositol content, and Na+-K+-ATPase activity were studied in the spontaneously diabetic BB-Wistar rat, an animal model that manifests both conduction slowing and a characteristic progressive axonopathy. Twelve weeks of sustained hyperglycemia reduced both motor conduction velocity and Na+-K+-ATPase activity in sciatic nerve. Six weeks of subsequent vigorous insulin replacement normalized the enzymatic defect but only partially corrected diminished nerve conduction velocity. Hence, nerve conduction slowing in diabetic animals may be partly attributable to reduced nerve Na+-K+-ATPase activity, but a less readily reversible component of conduction slowing probably reflects structural alterations that occur in nerve within the first 3 mo of diabetes.

Adenosine Triphosphatases↗
PubMed1984

Action of sorbinil in diabetic peripheral nerve. Relationship of polyol (sorbitol) pathway inhibition to a myo-inositol-mediated defect in sodium-potassium ATPase activity.

The small, but statistically significant, improvement in nerve conduction after treatment of diabetic patients with the aldose reductase inhibitor, sorbinil, suggests that increased polyol (sorbitol) pathway activity may contribute to diabetic nerve conduction slowing. Although classically viewed solely in terms of sorbitol-induced osmotic swelling, polyol pathway inhibition is now speculated to influence a concomitant myo-inositol-mediated alteration in nerve sodium-potassium ATPase activity in diabetic nerve. Therefore, we directly examined the effect of sorbinil treatment on sodium-potassium ATPase activity in crude homogenates of sciatic nerve from streptozotocin-diabetic and non-diabetic rats. We demonstrate that sorbinil treatment, which preserves normal nerve myo-inositol content, prevents the fall in nerve sodium-potassium ATPase activity that has been linked to conduction slowing in the diabetic rat.

Animals↗
PubMed1984

Pancreaticoduodenal transplantation in humans.

Whole cadaveric pancreata were transplanted to the pelvic extraperitoneal location in four patients with diabetes who previously had undergone successful cadaveric renal transplantation. One graft was lost within a few hours from venous thrombosis but with patient survival. The other three are providing normal endocrine function after two and a half, 11 and 12 months. The exocrine pancreatic secretions were drained into the recipient jejunum through enteric anastomoses. Because mucosal slough of the graft duodenum and jejunum in two patients caused a protein losing enteropathy and necessitated reoperations, we now do the pancreatic transplantation with only a blister of graft duodenum large enough for side-to-side enteroenterostomy. The spleen has been transplanted with the pancreas mainly for technical reasons, and this technique should have further trials in spite of the fact that delayed graft splenectomy became necessary in two recipients to treat graft induced hematologic complications.

Adult↗
PubMed1983

Metabolic abnormalities in diabetic peripheral nerve: relation to impaired function.

An hypothesis is presented relating several well-defined metabolic abnormalities in diabetic peripheral nerve to impaired peripheral nerve function by a sodium-potassium ATPase mechanism. It is proposed that this hypothesis be tested in the most well-defined animal model for human insulin deficiency diabetes currently available--the BB diabetic rat.

Animals↗
PubMed1983

Impaired rat sciatic nerve sodium-potassium adenosine triphosphatase in acute streptozocin diabetes and its correction by dietary myo-inositol supplementation.

Nerve conduction impairment in experimental diabetes has been empirically but not mechanistically linked to altered nerve myo-inositol metabolism. The phospholipid-dependent membrane-bound sodium-potassium ATPase provides a potential mechanism to relate defects in diabetic peripheral nerve myo-inositol-phospholipid metabolism, impulse conduction, and energy utilization. Therefore, the effect of streptozocin-induced diabetes mellitus and dietary myo-inositol supplementation on rat sciatic nerve sodium-potassium ATPase was studied. ATPase activity was measured enzymatically in sciatic nerve homogenates from 4-wk streptozocin diabetic rats and age-matched controls either fed a standard or 1% myo-inositol supplemented diet. The sodium-potassium ATPase components were assessed by ouabain inhibition or the omission of sodium and potassium ions. Diabetes reduced the composite ATPase activity recovered in crude homogenates of sciatic nerve. The 40% reduction in the sodium-potassium ATPase was selectively prevented by 1% myo-inositol supplementation (which preserved normal nerve conduction). Thus, in diabetic peripheral nerve, abnormal myo-inositol metabolism is associated with abnormal sodium-potassium ATPase activity. The mechanism of the effect of dietary myo-inositol to correct diabetic nerve conduction may be through changes in a sodium-potassium ATPase, possibly via changes in myo-inositol-containing phospholipids.

Acute Disease↗
PubMed1983

Polyol pathway activity and myo-inositol metabolism. A suggested relationship in the pathogenesis of diabetic neuropathy.

Two major metabolic perturbations, increased polyol (sorbitol) pathway activity and reduced tissue myo-inositol content, are induced in peripheral nerve by hyperglycemia. Although they are commonly invoked as alternative biochemical pathogenetic mechanisms for diabetic neuropathy, their possible interrelationship has never been adequately explored. Therefore, we studied the effect of polyol pathway blockade with sorbinil, a specific inhibitor of aldose reductase, on nerve myo-inositol content in acutely streptozotocin-diabetic rats. Sorbinil administration completely prevented the fall in nerve myo-inositol, thereby implicating increased polyol pathway activity as a likely factor in the fall in nerve myo-inositol content in experimental diabetes.

Aldehyde Reductase↗
PubMed1982

Sodium- and energy-dependent uptake of myo-inositol by rabbit peripheral nerve. Competitive inhibition by glucose and lack of an insulin effect.

Experimental diabetes consistently reduces the concentration of free myo-inositol in peripheral nerve, which usually exceeds that of plasma by 90-100-fold. This phenomenon has been explicitly linked to the impairment of nerve conduction in the acutely diabetic streptozocin-treated rat. However, the mechanism by which acute experimental diabetes lowers nerve myo-inositol content and presumably alters nerve myo-inositol content and presumably alters nerve myo-inositol metabolism is unknown. Therefore, the effects of insulin and elevated medium glucose concentration of 2-[3H]myo-inositol uptake were studied in a metabolically-defined in vitro peripheral nerve tissue preparation derived from rabbit sciatic nerve, whose free myo-inositol content is reduced by experimental diabetes. The results demonstrate that myo-inositol uptake occurs by at least two distinct transport systems in the normal endoneurial preparation. A sodium- and energy-dependent saturable transport system is responsible for at least 94% of the measured uptake at medium myo-inositol concentrations approximating that present in plasma. This carrier-mediated transport system has a high affinity for myo-inositol (Kt = 63 microM), and is not influenced acutely by physiological concentrations of insulin; it is, however, inhibited by hyperglycemic concentrations of glucose added to the incubation medium in a primarily competitive fashion. Thus, competitive inhibition of peripheral nerve myo-inositol uptake by glucose may constitute a mechanism by which diabetes produces physiologically significant alterations in peripheral nerve myo-inositol metabolism.

Animals↗
PubMed1982

Selective effects of myo-inositol administration on sciatic and tibial motor nerve conduction parameters in the streptozocin-diabetic rat.

Time-dependent effects of experimental diabetes and dietary myo-inositol supplementation on motor nerve conduction velocity (MNCV) were assessed in two populations of motor nerve fibers in the rat hind limb. These two populations of large myelinated motor fibers, which innervate the musculature of the calf and the foot, were differentially affected by growth, experimental diabetes, and dietary myo-inositol. Dietary myo-inositol supplementation ameliorated the diabetes-induced MNCV impairment in both nerve fiber populations but with different time courses. These observations suggest metabolic or physiologic heterogeneity among populations of large myelinated motor fibers which may partially explain published discrepancies regarding the efficacy of dietary myo-inositol supplementation in improving slowed MNCV in the streptozocin-diabetic rat.

Age Factors↗
PubMed1981

Peritonsillitis.

Explore the source record for details and available documents.

Humans↗
PubMed1981

Comparison of clinical couse and sequential electrophysiological tests in diabetics with symptomatic polyneuropathy and its implications for clinical trials.

The use of electrophysiological (EP) tests as the primary basis for determining outcome in clinical trials of therapy for symptomatic diabetic polyneuropathy, and the frequently short duration of such trials, is based on assumptions at variance with the pathology and natural history of this disorder and with the evidence that the commonly employed EP tests predominantly reflect the status of the large myelinated nerve fibers. The course of painful, distal symmetrical, primarily sensory polyneuropathy was studied in nine chronic diabetics, aged 21--59 yr, selected for the absence of other forms of diabetic neuropathy, other causes of neuropathy, and other significant illness. All were treated with modifications of diet, insulin, and a daily multivitamin tablet, and, on a randomized basis, also received either placebo or myo-inositol tablets. Initially, and after 2, 4, and 6 mo, a standardized questionnaire was used to assess symptoms, and a standardized neurological examination and battery of EP tests were performed. A minimum of 6 mo was found necessary to assess the clinical course of this syndrome. Clinical improvement occurred in both legs and arms in four patients, as judged by improvement both in symptoms and in the extent of deficits in pinprick and temperature perception; abnormalities in sensory modalities mediated by large myelinated fibers, however, were generally unaltered after 6 mo. A nonuniform distribution of abnormal EP tests of sensory components of the commonly studied nerves of the leg and arm was demonstrated in the study group at the outset, and clinical improvement was not accompanied by evidence of any consistent pattern of improvement in the initially abnormal EP tests. A significant fraction of chronic diabetics with painful, distal symmetrical, primarily sensory polyneuropathy selected by standard criteria appear to have potential for clinical improvement over 6 mo, but primarily in sensory modalities that make it inappropriate to use the common EP tests as the primary basis of judging outcome.

Achilles Tendon↗
PubMed1980

Distal neuropathy in experimental diabetes mellitus.

Although nerve conduction slowing is a well-accepted abnormality in rats with acute experimental diabetes, reports of neuropathological changes in diabetic rat nerves have been inconsistent. To examine this further, we studied electrophysiological and morphological features of posterior tibial nerves and their distal branches from four-week streptozotocin-induced diabetic rats and matched controls. Diabetic rat posterior tibial motor conduction was slowed (mean +/- 1 SD, 34.8 +/- 3.1 m/sec; controls, 41.2 +/- 2.5 m/sec), and evoked muscle response amplitudes were only half of control values. Using quantitative techniques, we documented a diminution in number of the largest myelinated fibers in otherwise normal mid posterior tibial nerves, with an increase in the smaller sizes, indicating either a degree of axonal atrophy or impaired fiber growth during development. The principal pathological finding was active breakdown of myelinated fibers in the most distal motor twigs of hindfoot muscles supplied by posterior tibial branches, with preservation of fibers in more proximal segments of these nerves. This anatomical lesion in diabetic nerves could account for both oberved conduction slowing and lowered muscle response amplitudes. A consistent feature in both diabetic and control mid lateral plantar nerves was a zone of demyelination that apparently occurs at this natural site of nerve entrapment in rats. Taken together, the pathological abnormalities of peripheral nerve in acute experimental diabetes are best explained as resulting from a distal axonopathy.

Animals↗