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March 1996


Alpha Lipoic Acid As An Antioxidant

Alpha Lipoic Acid as a Biological Antioxidant
Packer L; Witt EH; Tritschler HJ
Department of Molecular & Cell Biology, University of California, Berkeley 94720, USA
Free Radic Biol Med (UNITED STATES) Aug 1995, 19 (2) p227-50,

Alpha Lipoic acid, which plays an essential role in mitochondrial dehydrogenase reactions, has recently gained considerable attention as an antioxidant. Lipoate, or its reduced form, dihydrolipoate, reacts with reactive oxygen species such as superoxide radicals, hydroxyl radicals, hypochlorous acid, peroxyl radicals, and singlet oxygen. It also protects membranes by interacting with vitamin C and glutathione, which may in turn recycle vitamin E. In addition to its antioxidant activities, dihydrolipoate may exert prooxidant actions through reduction of iron. alpha-Lipoic acid administration has been shown to be beneficial in a number of oxidative stress models such as ischemia-reperfusion injury, diabetes (both alpha-lipoic acid and dihydrolipoic acid exhibit hydrophobic binding to proteins such as albumin, which can prevent glycation reactions), cataract formation, HIV activation, neurodegeneration, and radiation injury. Furthermore, lipoate can function as a redox regulator of proteins such as myoglobin, prolactin, thioredoxin and NF-kappa B transcription factor. We review the properties of lipoate in terms of (1) reactions with reactive oxygen species; (2) interactions with other antioxidants; (3) beneficial effects in oxidative stress models or clinical conditions. (153 Refs.)

Thioctic (lipoic) acid: a therapeutic metal-chelating antioxidant?
Ou P; Tritschler HJ; Wolff SP
Department of Medicine, University College London Medical School, U.K.
Biochem Pharmacol (ENGLAND) Jun 29 1995, 50 (1) p123-6,

Thioctic (alpha-lipoic) acid (TA) is a drug used for the treatment of diabetic polyneuropathy in Germany. It has been proposed that TA acts as an antioxidant and interferes with the pathogenesis of diabetic polyneuropathy. We suggest that one component of its antioxidant activity requiring study is the direct transition metal-chelating activity of the drug. We found that TA had a profound dose-dependent inhibitory effect upon Cu(2+)-catalysed ascorbic acid oxidation (monitored by O2 uptake and spectrophotometrically at 265 nm) and also increased the partition of Cu2+ into n-octanol from an aqueous solution suggesting that TA forms a lipophilic complex with Cu2+. TA also inhibited Cu(2+)-catalysed liposomal peroxidation. Furthermore, TA inhibited intracellular H2O2 production in erythrocytes challenged with ascorbate, a process thought to be mediated by loosely chelated Cu2+ within the erythrocyte. These data, taken together, suggest that prior intracellular reduction of TA to dihydrolipoic acid is not an obligatory mechanism for an antioxidant effect of the drug, which may also operate via Cu(2+)- chelation. The R-enantiomer and racemic mixture of the drug (alpha-TA) generally seemed more effective than the S-enantiomer in these assays of metal chelation.

Elucidation of antioxidant activity of alpha-lipoic acid toward hydroxyl radical
Matsugo S; Yan LJ; Han D; Trischler HJ; Packer L
Department of Molecular and Cell Biology, University of California at Berkeley 94720-3200
Biochem Biophys Res Commun (UNITED STATES) Mar 8 1995, 208 (1) p161-7,

The photosensitive organic hydroperoxide, NP-III, which produces hydroxyl radicals on illumination by UVA light, was used to examine the antioxidant activity of alpha-lipoic acid and its derivatives toward hydroxyl radical. Apolipoprotein (apo-B) of human low density lipoprotein (LDL) and bovine serum alubumin (BSA) were irradiated with UVA in the presence of NP-III and alpha-lipoic acid. The oxidation of BSA and the apo-B protein of LDL by NP-III was completely suppressed by alpha-lipoic acid. ESR studies using dimethylpyrroline oxide (DMPO) as a spin trapping reagent also revealed that in the presence of alpha-lipoic acid, the DMPO-OH adduct produced from the irradiation of NP-III and DMPO completely disappeared. DMPO-OH quenching experiments were performed in the presence or absence of desferoxamine but no change in the signal intensity was found. Hence, the quenching activity of alpha-lipoic acid is not due to its chelating activity toward transition metals (ferrous ions). The results lead us to conclude that alpha-lipoic acid is an efficient hydroxyl radical quencher owing to the disulfide bond in the dithiolane ring.

Effect of DL alpha-lipoic acid on tissue lipid peroxidation and antioxidant systems in normal and glycollate treated rats
Sumathi R; Jayanthi S; Kalpanadevi V; Varalakshmi P
Department of Medical Biochemistry, Dr. A. L. Mudaliar Post Graduate Institute of Basic Medical Sciences, Taramani, University of Madras, India
Pharmacol Res (ENGLAND) May-Jun 1993, 27 (4) p309-18,

The cytoprotective activity of alpha-lipoic acid against free radical toxicity, manifested during experimental hyperoxaluria, has been investigated. Glycollate was used as the inducer of oxalate hyperoxaluria in rats. The increase in lipid peroxidation and superoxide dismutase (SOD) activity, associated with a decrease in catalase activity and glutathione (GSH) level, are the salient features observed in tissues of hyperoxaluric rats. Free radical toxicity in the glycollate fed rats is effectively counteracted by lipoic acid administration. Lipoic acid administration brought about a significant decrease in peroxidative levels with an increase in catalase activity and glutathione level. These observations highlight the antioxidant property of alpha-lipoic acid and its cytoprotective action against experimental hyperoxaluria.

Boosting Other Antioxidants

Alpha-lipoic acid increases intracellular glutathione in a human T-lymphocyte Jurkat cell line
Han D; Tritschler HJ; Packer L
Department of Molecular and Cell Biology, University of California at Berkeley 94720-3200
Biochem Biophys Res Commun (UNITED STATES) Feb 6 1995, 207 (1) p258-64

The addition of exogenous alpha-lipoic acid to cellular medium causes a rapid increase of intracellular unbound thiols in Jurkat cells, a human T-lymphocyte cell line. The rise of cellular thiols is a result of the cellular uptake and reduction of lipoic acid to dihydrolipoic acid and a rise in intracellular glutathione. Although the level of dihydrolipoic acid is 100-fold lower than glutathione, the cellular concentration of dihydrolipoic acid might be responsible for the modulation of total cellular thiol levels. Rises in glutathione correlate with the levels of intracellular dihydrolipoic acid (p < .01). This increase in glutathione is not the result of expression of new proteins like gamma-glutamylcysteine synthetase, since the rise in glutathione was not inhibited by cycloheximide, a protein synthesis inhibitor. Lipoic acid administration is therefore a potential therapeutic agent in an array of diseases with glutathione anomalies including HIV infection.

Alpha-lipoic acid supplementation prevents symptoms of vitamin E deficiency
Podda M; Tritschler HJ; Ulrich H; Packer L
Department of Molecular and Cell Biology, University of California at Berkeley, 94720-3200
Biochem Biophys Res Commun (UNITED STATES) Oct 14 1994, 204 (1) p98-104,

alpha-Lipoic acid, an essential cofactor in mitochondrial dehydrogenases, has recently been shown to be a potent antioxidant in vitro, as well as being capable of regenerating vitamin E in vitro. In this study, using a new animal model for rapid vitamin E deficiency in adult animals and a new technique for tissue extraction of oxidized and reduced alpha-lipoic acid, we examined the antioxidant action of alpha-lipoic acid in vivo. Vitamin E-deficient adult hairless mice displayed obvious symptoms of deficiency within five weeks, but if the diet was supplemented with alpha-lipoic acid the animals were completely protected. At five weeks on a vitamin E-deficient diet animals exhibited similar decreases in tissue vitamin E levels, whether supplemented or unsupplemented with alpha-lipoic acid: vitamin E levels in liver, kidney, heart, and skin decreased 70 to 85%; levels in brain decreased only 25%. These data show that there was no effect of alpha-lipoic acid supplementation on vitamin E tissue concentrations, arguing against a role for alpha-lipoic acid in regenerating vitamin E in vivo.

Protecting Against Ischemia/Reperfusion Injury

Effect of alpha-lipoic acid and dihydrolipoic acid on ischemia/reperfusion injury of the heart and heart mitochondria
Schonheit K; Gille L; Nohl H
Institute of Pharmacology and Toxicology, Veterinary University of Vienna, Austria
Biochim Biophys Acta (NETH.) Jun 9 1995, 1271 (2-3) p335-42,

The aim of the present study was to evaluate a possible interference of alpha-lipoic acid (LA) or its reduced form (dithiol dihydrolipoic acid = DHLA) in the cardiac ischemia/reperfusion injury both at the level of the intact organ and at the subcellular level of mitochondria. In order to follow the effect of LA on the ischemia/reperfusion injury of the heart the isolated perfused organ was subjected to total global ischemia and reperfusion in the presence and absence of different concentrations of LA. Treatment with 0.5 microM LA improved the recovery of hemodynamic parameters; electrophysiological parameters were not influenced. However, application of 10 microM LA to rat hearts further impaired the recovery of hemodynamic functions and prolonged the duration of severe rhythm disturbances in comparison to reperfusion of control hearts. Treatment of isolated mitochondria with any concentration of DHLA could not prevent the impairment of respiratory-linked energy conservation caused by the exposure of mitochondria to 'reperfusion' conditions. However, DHLA was effective in decreasing the formation and the existence of mitochondrial superoxide radicals (O2.-). Apart from its direct O(2.-)-scavenging activities DHLA was also found to control mitochondrial O2.- formation indirectly by regulating redox-cycling ubiquinone. It is suggested that impairment of this mitochondrial O2.- generator mitigates postischemic oxidative stress which in turn reduces damage to hemodynamic heart function.

Alpha Lipoic Acid Therapy For Diabetes

Enhancement of glucose disposal in patients with type 2 diabetes by alpha-lipoic acid
Jacob S.; Henriksen E.J.; Schiemann A.L.; Simon I.; Clancy D.E.; Tritschler H.J.; Jung W.I.; Augustin H.J.; Dietze G.J.
Abteilung fur Innere Medizin, Stadtklinik,D-76527 Baden-Baden Germany
Arzneimittel-Forschung/Drug Research (Germany) , 1995, 45/8 (872-874)

Insulin resistance of skeletal muscle glucose uptake is a prominent feature of Type II diabetes (NIDDM); therefore pharmacological interventions should aim to improve insulin sensitivity. Alpha-lipoic acid (CAS 62-46-4, thioctic acid, ALA), a natural occurring compound frequently used for treatment of diabetic polyneuropathy, enhances glucose utilization in various experimental models. To see whether this compound also augments insulin mediated glucose disposal in NIDDM, 13 patients received either ALA (1000 mg/Thioctacid (R)/500 ml NaCl, n = 7) or vehicle only (500 ml NaCl, n = 6) during a glucose-clamp study. Both groups were comparable in age, body-mass index and duration of diabetes and had a similar degree of insulin resistance at baseline. Acute parenteral administration of ALA resulted in a significant increase of insulin-stimulated glucose disposal; metabolic clearance rate (MCR) for glucose rose by about 50% (3.76 ml/kg/min = pre vs. 5.82 ml/kg/min = post, p < 0.05), whereas the control group did not show any significant change (3.57 ml/kg/min = pre vs. 3.91 ml/kg/min = post). This is the first clinical study to show that alpha-lipoic acid increases insulin stimulated glucose disposal in NIDDM. The mode of action of ALA and its potential use as an antihyperglycemic agent require further investigation.

Results of adjuvant antioxidant supplementation
Kahler W; Kuklinski B; Ruhlmann C; Plotz C
Klinik fur Innere Medizin, Klinikums Rostock-Sudstadt.
Z Gesamte Inn Med (GERMANY) May 1993, 48 (5) p223-32,

Our investigations carried out in patients with diabetes mellitus revealed oxidative stress loads. The study presented here was to clarify whether a therapy with antioxidants can contribute to an improvement of prognosis. 80 patients affected with a long term diabetic late syndrome were randomised and arranged to 4 groups of n = 20 each. In contrast to a control group these patients received 600 mg of alpha lipoic acid or 100 micrograms of selenium (sodium selenite) daily or 1200 IE of D-alpha-tocopherol respectively for a time of 3 months. In comparison with the control group all groups treated in an antioxidative way showed significantly diminished serum concentrations of thiobarbituric acid reactive substances and of urinary albumin excretion rates. The symptoms of distal symmetric neuropathy measured according to the thermo and vibration sensitivity also improved in a highly significant manner. The results prove that oxidative stress plays a promoting role in developing of long term diabetic late complications and that a therapy with adjuvant antioxidants may lead to a regression of diabetic late complications.

For Diabetic Polyneuropathy

Alternative therapeutic principles in the prevention of microvascular and neuropathic complications Gries F.A.
Diabetesforschungsinstitut, Heinrich-Heine-Universitat, Auf'm Hennekamp 65, D-40225 Dusseldorf Germany
Diabetes Research and Clinical Practice (Ireland) , 1995, 28/SUPPL.

Since the prevention of chronic diabetic complications by near normal metabolic control is not always achievable, alternative therapeutic principles have been developed. The specific intervention at metabolic abnormalities which seem to play a key role in the pathogenesis of complications has been shown to prevent the development of microangiopathy and neuropathy in experimental diabetes, e.g. inhibition of non-enzymatic glycation by aminoguanidine, inhibition of polyol pathway activity by aldose reductase inhibitors, prevention of hypoxia and oxidative stress by vasodilators and radical scavengers such as alpha-lipoic acid. Some of these drugs should soon be available for common clinical use.

Oral alpha lipoic acid preparation proves good bioavailability in diabetic polyneuropathy
Merz P.G.; Rietbrock S.; Schrodter A.; Loew D.; Kirkov V.K.
Abt. der Klinische Pharmakologie, Johann Wolfgang Goethe-Universitat, Theodor-Stern-Kai 7, 60590 Frankfurt am Main Germany
Therapiewoche (Germany) , 1995, 45/23 (1367-1370)

Causal therapy with alpha lipoic acid is capable of getting polyneuropathy, the most frequent concomitant disease of diabetes mellitus, under control or to influence its progression favourably: about half of all German diabetics, hence no less than 2 million people, suffer from that life-threatening disease. Yet a basic condition for the effectiveness of an oral dose of alpha lipoic acid, the per diem doses of which have been raised to 300 to 600 mg in recent years, is its absolute bioavailability. This has been shown to be 71% (arith. Mean) resp. 58% (geom. Mean) in case of Thiogamma 399 oral capsules by an open monocentric study covering 12 probands. Thus, a rational treatment with this preparation is guaranteed.

Diabetic polyneuropathy. Most effective measure: Keep blood sugar close to normal from the start
Mehnert H.; Schmidt K.; Stracke H.; Sachse G.
Institut fur Diabetesforschung, Krankenhaus Schwabing, Kolner Platz 1, 80804 Munchen Germany
Munchener Medizinische Wochenschrift (Germany) , 1995, 137/6 (31-32+35-36)

More than 50% of all type I and II diabetics suffer from diabetic polyneuropathy after 10 years of the disease. Sensory and/or motoric damage can be distinguished from autonomic neuropathies. Of the latter, cardiovascular neuropathy is particularly significant on account of the high mortality. Hyperglycaemia clearly plays a decisive role in various interlinked ways in the pathogenesis of all manifestations of diabetic polyneuropathy. As a result, the treatment of choice lies in normalising metabolism, i.e. in adjusting blood sugar levels close to normal. The often unavoidable adjunctive medicamentous therapy is headed at present by thioctic acid (alpha-lipoic acid), supplemented by the analgesic action of tricyclic antidepressants if required.

Pharmacological prevention of diabetic microangiopathy
Guillausseau P.J.
Service de Medecine B, Hopital Lariboisiere, 2 Rue Ambroise Pare, 75010 Paris France
DIABETE METABOL. (France) , 1994, 20/2 BIS (219-228)

The development of drugs in order to block metabolic pathways of glucose responsible for diabetic vascular dysfunction is in progress. Aldose reductase inhibitors prevent or reduce the different components of vascular dysfunction, cataract, neuropathy and nephropathy in animal models of diabetes. Promising results have been observed in diabetic patients concerning the prevention of neuropathy and of retinopathy. Larger scale studies with the second generation compounds are in progress. Glycation inhibitors, mainly aminoguanidine, have been shown to prevent or reduce vascular dysfunction and microvascular complications in animal models. Trials in diabetic patients with aminoguanidine are just beginning. Anti-oxidant therapy is also at its early stage of development (vitamine E, vitamine C, alpha lipoic acid). Antiplatelet agents (aspirin, ticlopidine) have been demonstrated to reduce the progression of non proliferative diabetic retinopathy. Angiotensin converting enzyme inhibitors are of particular interest in preventing diabetic glomerulopathy.

Preventive treatment of diabetic microangiopathy: blocking the pathogenic mechanisms
Guillausseau PJ
Service de Medecine B, Hopital Lariboisiere, Paris, France
Diabete Metab (FRANCE) 1994, 20 (2 Pt 2) p219-28,

The development of drugs in order to block metabolic pathway of glucose responsible for diabetic vascular dysfunction is in progress. Aldose reductase inhibitors prevent or reduce the different components of vascular dysfunction, cataract, neuropathy and nephropathy in animal models of diabetes. Promising results have been observed in diabetic patients concerning the prevention of neuropathy and of retinopathy. Larger scale studies with the second generation compounds are in progress. Glycation inhibitors, mainly aminoguanidine, have been shown to prevent or reduce vascular dysfunction and microvascular complications in animal models. Trials in diabetic patients with aminoguanidine are just beginning. Anti-oxidant therapy is also at its early stage of development (vitamin E, vitamin C, alpha lipoic acid). Antiplatelet agents (aspirin, ticlopidine) have been demonstrated to reduce the progression of non proliferative diabetic retinopathy. Angiotensin converting enzyme inhibitors are of particular interest in preventing diabetic glomerulopathy. (83 Refs.)

Effects of lipoic acid in hexacarbon-induced neuropathy
Altenkirch H; Stoltenburg-Didinger G; Wagner HM; Herrmann J; Walter G
Department of Neurology, Spandau Hospital, Freie Universitat Berlin
Neurotoxicol Teratol (U.S.) Nov-Dec 1990, 12 (6) p619-22,

The effects of lipoic acid on hexacarbon neurotoxicity in rats were investigated. Rats were exposed by inhalation to n-hexane for 24 hours/day, 7 days/week, up to a total period of 9 weeks. Eight animals were exposed to 700 ppm n-hexane only, and eight animals were exposed to 700 ppm n-hexane and additionally received 100 mumol/kg lipoic acid PO daily. Clinical status of the animals was evaluated by examination of general condition, motor performance tests and neurophysiological measurements of caudal nerve motor conduction velocity. Results showed that animals exposed to 700 ppm n-hexane developed severe motor neuropathy leading to paralysis by the 6th week. Motor distal latencies of these animals were severely prolonged. In contrast, in animals treated with lipoic acid the onset of motor neuropathy was delayed for approximately 3 weeks as could be demonstrated by motor performance tests and measurements of motor distal latencies.

Alpha Lipoic Acid Inhibits Glycation

Lipoate prevents glucose-induced protein modifications
Suzuki YJ; Tsuchiya M; Packer L
Department of Molecular & Cell Biology, University of California, Berkeley 94720
Free Radic Res Commun (SWITZERLAND) 1992, 17 (3) p211-7,

Nonenzymatic glycation has been found to increase in a variety of proteins in diabetic patients. The present study examined a possibility of preventing glycation and subsequent structural modifications of proteins by alpha-lipoic acid (thioctic acid) as lipoate, a substance which has gained attention as a potential therapeutic agent for diabetes-induced complications. Incubation of bovine serum albumin (BSA) at 2 mg/ml with glucose (500 mM) in a sterile condition at 37 degrees C for seven days caused glycation and structural modifications of BSA observed by SDS-PAGE, near UV absorption, tryptophan and nontryptophan fluorescence, and fluorescence of an extrinsic probe, TNS (6-(p-toluidinyl)naphthalene-2-sulfonate). When BSA and glucose were incubated in the presence of lipoate (20 mM), glycation and structural modifications of BSA were significantly prevented. Glycation and inactivation of lysozyme were also prevented by lipoate. These results suggest a potential for the therapeutic use of lipoic acid against diabetes-induced complications.

Alpha Lipoic Acid Prevents Cataracts

Alpha-lipoic acid prevents buthionine sulfoximine-induced cataract formation in newborn rats
Maitra I; Serbinova E; Trischler H; Packer L
Department of Molecular and Cell Biology, University of California, Berkeley 94720, USA
Free Radic Biol Med (UNITED STATES) Apr 1995, 18 (4) p823-9,

We investigated the effect of alpha-lipoic acid, a powerful antioxidant, on cataract formation in L-buthionine(S,R)-sulfoximine (BSO)-treated newborn rats and found that a dose of 25 mg/kg b.w. protected 60% of animals from cataract formation. L-buthionine(S,R)-sulfoximine is an inhibitor of glutathione synthesis, whose administration to newborn animals leads to the development of cataracts; this is a potential model for studying the role of therapeutic antioxidants in protecting animals from cataract formation. Major biochemical changes in the lens associated with the protective effect of alpha-lipoic acid were increases in glutathione, ascorbate, and vitamin E levels, loss of which are effects of BSO administration. Treatment with alpha-lipoic acid also restored the activities of glutathione peroxidase, catalase, and ascorbate free radical reductase in lenses of L-buthionine(S,R)-sulfoximine-treated animals but did not affect glutathione reductase or superoxide dismutase activity. We conclude that alpha-lipoic acid may take over some of the functions of glutathione (e.g., maintaining the higher level of ascorbate, indirect participation in vitamin E recycling); the increase of glutathione level in lens tissue mediated by lipoate could be also due to a direct protection of protein thiols. Thus, alpha-lipoic acid could be of potential therapeutic use in preventing cataracts and their complications.

Protecting Neurons And Improving Memory

The endogenous cofactors, thioctic acid and dihydrolipoic acid, are neuroprotective against NMDA and malonic acid lesions of striatum
Greenamyre JT; Garcia-Osuna M; Greene JG
Department of Neurology, University of Rochester Medical Center, NY 14642
Neurosci Lett (IRELAND) Apr 25 1994, 171 (1-2) p17-20,

Thioctic acid (alpha-lipoic acid) and dihydrolipoic acid are endogenous, interconvertible cofactors of the mitochondrial pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase complexes. These compounds help to maintain glutathione and alpha-tocopherol in their reduced states, and they possess intrinsic free radical scavenging properties. We examined whether systemic treatment with thioctic acid or dihydrolipoic acid is protective against direct- and indirect-acting excitotoxins. Adult rats were treated for 10 days with intraperitoneal injections of vehicle, thioctic acid or dihydrolipoic acid, and on day 7 of treatment animals received unilateral stereotaxic injections of NMDA or malonic acid into the striatum. Histological assessment 3 days after the stereotaxic injections revealed a marked reduction in lesion volume in animals treated with thioctic acid or dihydrolipoic acid. We conclude that thioctic acid and dihydrolipoic acid are neuroprotective against direct and indirect excitotoxic insults.

Prolonged pretreatment with alpha-lipoic acid protects cultured neurons against hypoxic, glutamate, or iron-induced injury
Muller U; Krieglstein J
Institut fur Pharmakologie und Toxikologie, Philipps-Universitat, Marburg, Germany
J Cereb Blood Flow Metab (U.S.) Jul 1995, 15 (4) p624-30

The antioxidant dihydrolipoic acid has been shown to reduce hypoxic and excitotoxic neuronal damage in vitro. In the present study, we tested whether pretreatment with alpha-lipoic acid, which presumably allows endogenous formation of dihydrolipoic acid, can protect cultured neurons against injury caused by cyanide, glutamate, or iron ions, using the trypan blue exclusion method to determine neuronal damage. One hour of preincubation with dihydrolipoic acid (1 microM), but not with alpha-lipoic acid, reduced damage of neurons from chick embryo telencephalon caused by 1 mM sodium cyanide or iron ions. alpha-Lipoic acid (1 microM) reduced cyanide-induced neuronal damage when added 24 h before hypoxia, and pretreatment with alpha-lipoic acid for > 24 h enhanced this neuroprotective effect. Both the R- and the S-enantiomer of alpha-lipoic acid exerted a similar neuroprotective effect. Pretreatment with alpha-lipoic acid (1 microM) from the day of plating onward prevented the degeneration of chick embryo telencephalic neurons that had been exposed to Fe2+/Fe3+. alpha-Lipoic acid (1 microM) added to the culture medium the day of plating also reduced neuronal injury induced by 1 mM L-glutamate in rat hippocampal cultures, whereas 30 min of preincubation with alpha-lipoic acid failed to attenuate glutamate-induced neuronal damage. Our results indicate that neuroprotection by prolonged pretreatment with alpha-lipoic acid is probably due to the radical scavenger properties of endogenously formed dihydrolipoic acid.

The potent free radical scavenger alpha-lipoic acid improves memory in aged mice: putative relationship to NMDA receptor deficits
Stoll S; Hartmann H; Cohen SA; Muller WE
Central Institute for Mental Health, Department of Psychopharmacology, Mannheim, Germany
Pharmacol Biochem Behav (U.S.) Dec 1993, 46 (4) p799-805,

Alpha-Lipoic acid (alpha-LA) improved longer-term memory of aged female NMRI mice in the habituation in the open field test at a dose of 100 mg/kg body weight for 15 days. In a separate experiment, no such effect could be found for young mice. alpha-LA alleviated age-related NMDA receptor deficits (Bmax) without changing muscarinic, benzodiazepine, and alpha 2-adrenergic receptor deficits in aged mice. The carbachol-stimulated accumulation of inositol monophosphates was not changed by the treatment with alpha-LA. These results give tentative support to the hypothesis that alpha-LA improves memory in aged mice, probably by a partial compensation of NMDA receptor deficits. Possible modes of action of alpha-LA based on its free radical scavenger properties are discussed in relation to the membrane hypothesis of aging.

Diabetes And Glucose Metabolism

Glucose metabolism in obesity: influence of body fat distribution
Peiris AN; Struve MF; Mueller RA; Lee MB; Kissebah AH
Department of Medicine, Medical College of Wisconsin, Milwaukee 53226
J Clin Endocrinol Metab (U.S.) Oct 1988, 67 (4) p760-7,

The dose-response relationships between portal venous insulin concentrations and hepatic glucose production and between peripheral insulin concentrations and peripheral glucose utilization were determined in 8 nonobese and 17 obese premenopausal women with either upper or lower body fat localization. The glucose production dose-response curves for the two obese groups were shifted to the right at all levels of portal insulinemia. The upper body obese women had a greater rightward shift compared to the lower body obese women. The peripheral glucose utilization dose-response curve was shifted to the right in the lower body obese women, but maximal glucose utilization was normal. The upper body obese women had both a greater rightward shift and a marked reduction in maximal glucose utilization. The insulin concentrations that had half-maximal effects on glucose production and utilization were similar in each group. These results indicate that the liver is not inherently more sensitive to insulin than peripheral tissues. Obesity is associated with a moderate diminution of hepatic and peripheral insulin sensitivity. Upper body fat localization in obese women is characterized by a greater diminution in insulin sensitivity and decline in peripheral insulin responsivity than is lower body fat localization. The marked peripheral insulin resistance in the former group may account for the increased prevalence of glucose intolerance.

Role of insulin resistance in human disease (syndrome X): an expanded definition Reaven GM
Department of Medicine, Stanford University School of Medicine, California 94305
Annu Rev Med (U.S.) 1993, 44 p121-31

Resistance to insulin-mediated glucose uptake is characteristic of individuals with impaired glucose intolerance or non-insulin-dependent diabetes, and it also occurs commonly in patients with high blood pressure. The physiological response to a decrease in insulin-mediated glucose uptake is an increase in insulin secretion, and as long as a state of compensatory hyperinsulinemia can be maintained, frank decompensation of glucose tolerance can be prevented. However, it is likely that the defect in insulin action and/or the associated hyperinsulinemia will lead to an increase in plasma triglyceride and a decrease in high density lipoprotein-cholesterol concentration, and high blood pressure. It seems likely that the cluster of changes associated with resistance to insulin-mediated glucose uptake comprise a syndrome, which plays an important role in the etiology and clinical course of patients with non-insulin-dependent diabetes, high blood pressure, and coronary heart disease. (56 Refs.)

Glucose and lipid metabolism during long-term lisinopril therapy in hypertensive patients
Shionoiri H; Ueda S; Gotoh E; Ito T; Ogihara T
Second Department of Internal Medicine, Yokohama City University, Japan
J Cardiovasc Pharmacol (U.S.) Dec 1990, 16 (6) p905-9,

The effects of long-term lisinopril therapy on glucose tolerance and serum lipid profiles were investigated prospectively in 30 hypertensive patients: 15 with normal glucose tolerance and the remaining 15 with glucose intolerance. The levels of plasma glucose, serum lipids, and plasma glycosylated hemoglobin A1c were determined before and during long-term (6 months) therapy with lisinopril. A 75 g oral glucose tolerance test was performed before and during long-term lisinopril therapy. Lisinopril produced significant falls in both systolic and diastolic blood pressure in both patient groups during the long-term therapy. Neither fasting nor post-glucose-load venous plasma glucose levels were altered in either group of patients, and no patients with normal glucose tolerance developed diabetes mellitus during the study. There was no significant change in the insulinogenic index (delta IRI/delta BS at 30 min post-glucose load) in both patient groups. No significant changes in fasting levels of serum cholesterol, triglycerides, and HDL-cholesterol were observed in either group during long-term lisinopril therapy. Long-term lisinopril therapy does not compromise glucose or lipid metabolism in hypertensive patients. Lisinopril may have an advantage as an antihypertensive agent that can be given to hypertensive patients without concern that it might alter their serum lipid concentrations or impair glucose tolerance.

Nutrition and Diabetes

Alternative snack system for children and teenagers with diabetes mellitus
Loghmani E; Rickard KA
Department of Nutrition and Dietetics, Indiana University School of Medicine, James Whitcomb Riley Hospital for Children, Indianapolis 46202-5200
J Am Diet Assoc (U.S.) Oct 1994, 94 (10) p1145-8

An alternative snack system facilitates diabetes management and provides a teaching tool for age-appropriate nutrition education of children and teenagers with diabetes mellitus. The system consists of four snack sizes: Mini-7 to 10 g available glucose, Little-15 to 20 g, Big-30 to 35 g, and Super-Big-50 to 55 g. Within each category, several snack patterns are equivalent to each other in terms of available glucose and energy. By using this system, a child or teenager can eat snacks that contain different food groups and still adhere to the overall meal plan. When additional carbohydrate is needed for exercise or the prevention of nighttime hypoglycemia, a snack from the next largest category will increase available glucose by approximately 15 g and energy intake by approximately 100 kcal. Generally, for every hour of extra physical activity, a Little snack is added. When blood glucose concentrations before a nighttime snack are 4.4 to 6.7 mmol/L, a Little Snack is added to the usual bedtime snack, and when levels are less than 4.4 mmol/L, a Big snack is added. Further adjustments are made for children younger than 5 years old. The alternative snack system is a valuable nutrition education tool for the management of diabetes in children and teenagers.

Chromium Therapy For Diabetes

Chromium(III)-insulin derivatives and their implication in glucose metabolism
Govindaraju K; Ramasami T; Ramaswamy D
Central Leather Research Institute, Adyar, Madras, India
J Inorg Biochem (U.S.) Feb 1989, 35 (2) p137-47

Insulin has been reacted with five chromium(III) complexes that are capable of relatively facile substitution of aquo ligands. The new Cr(III) insulin derivatives have been characterized by means of electronic and infrared spectra, and evidence for major changes in the protein structure, including the state of aggregation, has been presented. Supporting evidence for the arguments favoring the beneficiary role of chromium(III) in glucose metabolism has been obtained using in vivo studies, and it has been shown that insulin derived with Cr(salen) (H2O)2+ is capable of reversing the blood sugar, serum cholesterol, and phospholipids levels to those of normal rats. The results emphasize the dependence of biopotency on the structure of Cr(III) complexes used for derivation of insulin and discount the postulates that Cr(III) serves to assemble insulin and receptor units through metal-sulphur bonding. The influence of Cr(III) on the structural stability and state of aggregation of insulin and their possible role in glucose metabolism is discussed.

Chromium metabolism and its role in disease processes in man
Anderson RA
Clin Physiol Biochem (SWITZERLAND) 1986, 4 (1) p31-41,

Chromium is an essential element required for normal carbohydrate and lipid metabolism. Insufficient dietary Cr has been linked to maturity-onset diabetes and cardiovascular diseases. The dietary Cr intake of most individuals is considerably less than the suggested safe and adequate intake. Consumption of refined foods, including simple sugars, exacerbates the problem of insufficient dietary Cr since these foods are not only low in dietary Cr but also enhance additional Cr losses. Chromium losses are also increased due to pregnancy, strenuous exercise, infection, physical trauma and other forms of stress. Supplementation of Cr to normal free-living individuals often leads to significant improvements in glucose tolerance, serum lipids including high-density lipoprotein cholesterol, insulin and insulin binding. Chromium also tends to normalize blood sugar. Chromium supplementation of subjects with elevated blood sugar following a glucose load leads to a decrease in blood sugar while hypoglycemics respond to supplemental Cr by an increase in hypoglycemic glucose values, increased insulin binding and alleviation of hypoglycemic symptoms. In summary, dietary intake of Cr is suboptimal and this is exacerbated by increased Cr losses due to stress and certain refined foods including simple sugars that enhance Cr losses. Supplemental Cr is associated with improvements of risk factors associated with maturity-onset diabetes and cardiovascular diseases. (33 Refs.)