Acetyl-L-carnitine effects on nerve conduction and glycemic regulation in experimental diabetes

Soneru I.L.; Khan T.; Orfalian Z.; Abraira C.
Dr. I.L. Soneru, Hines VA Hospital, Hines, IL 60141 USA
Endocrine Research (USA), 1997, 23/1-2 (27-36)

Acetyl-L-Carnitine (ALC), an activator of carnitine, can accelerate nerve regeneration after experimental surgical injury in rats. In this study, we examined the ability of ALC to improve nerve conduction velocity and its effect on intravenous glucose tolerance test in streptozotocin-induced diabetic rats. Diabetic (blood glucose > 200 mg%) and normal animals were treated intraperitoneally for four weeks with ALC, 50 mg/Kg/d and 150 mg/Kg/d. Nerve conduction velocity was measured by direct exposure of sural nerve. Two-hour IVGTT was studied by measuring plasma glucose, insulin and free fatty acids after intravenous injection of glucose, 1.75 gm/Kg/body weight in animals treated either with ALC 150 mg/Kg/d or saline alone. Six weeks of STZ-induced diabetes resulted in impairment of nerve conduction velocity in animals injected with saline (16.05 plus or minus 1.09 m/s), as compared to saline-treated normals who did not receive streptozotocin (31.9 plus or minus 0.84 m/s, p<0.0005). Diabetic animals treated with ALC, 150 mg/Kg/d, preserved near normal nerve conduction (27.10plus or minus1.42 m/s), compared with the saline-treated diabetic animals (p<0.0005), but diabetic animals treated with ALC, 50 mg/Kg/d, had a non-significant increase in nerve conduction (23.68plus or minus1.6). ALC treatment had no effect on fasting or post-intravenous plasma glucose in normal or diabetic rats, although it moderately reduced baseline and 40 minute insulin levels (p<0.02) in normal rats as compared with their saline- treated counterparts. ALC treatment lowered baseline free fatty acids in normal (p<0.04) and diabetic (p<0.03) animals, and the 60 minute levels in the normal group only (p<0.003). Conclusion: ALC at a dose of 150 mg/Kg/d given for one month, produced near normalization of nerve conduction velocity in streptozotocin-induced diabetes with no adverse effects on glucose, insulin or free fatty acid levels.

Age-related decreases in chromium levels in 51,665 hair, sweat, and serum samples from 40,872 patients - Implications for the prevention of cardiovascular disease and type II diabetes mellitus

Davies S.; Howard J.M.; Hunnisett A.; Howard M.
United Kingdom
Metabolism: Clinical and Experimental (USA), 1997, 46/5 (469-473)

This report shows, for the first time using modern analytical techniques, highly significant age-related decreases in chromium levels in 51,665 hair, sweat, and serum samples obtained from 40,872 patients referred by their physicians to an independent medical research clinic and laboratory (r = -.598 to -.762, P < .0001 for all correlations). Males were found to have significantly lower mean chromium levels than females (P < .05 to .0001). There was good correlation between chromium levels in hair, sweat, and serum (r = 536 to .729, P < .0001 for all correlations), indicating that hair and sweat chromium levels are valid additions to the serum levels in assessing chromium status. Chromium measurements in sweat, hair, and serum were performed using graphite furnace atomic absorption spectrophotometry. The influences that age-related decreases in chromium levels might have on increasing the risk to develop age-related impaired glucose metabolism, disordered lipid metabolism, coronary heart disease, arteriosclerosis, and type II diabetes mellitus are outlined, and the role that refined carbohydrates play in the development of compromised chromium status is presented.

Lipoic acid (thioctic acid): Antioxidant properties and their clinical implications

Packer L.
Prof. L. Packer, Dept. of Molecular and Cell Biology, University of California, 251 LSA, Berkeley, CA 94720 USA
Diabetes und Stoffwechsel (Germany), 1996, 5/3 Suppl. (98-101)

The following article describes the protective effects of alpha-lipoic acid and the enantiomers of alpha-lipoic acid and dihydrolipoic acid on the in vitro cataractogenesis in rat lenses incubated with glucose (55.6 mM). Glucose also leads to a leakage of lactate dehydrogenase into the medium (32 plus or minus 3 units/g lens fresh weight/day). R-lipoic acid inhibited the leakage of LDH (4.34 plus or minus 3.23 units/g lens fresh weight/day, p < 0.001) and lens opacity. In addition, lipoic acid inhibited cataract formation in newborn rats under buthionine sulfoxide (BSO). While 100% of the rats given BSO showed cataract formation, this was observed only in 40 plus or minus 8% of the animals receiving BSO and alpha-lipoic acid (p < 0.005). Further influences of lipoic acid and dihydrolipoic acid on the cataract model are under discussion. The established interactions between dihydrolipoic acid and other antioxidants certainly have implications for both cataractogenesis and the clinical use of alpha-lipoic acid.

Effect of lipoic acid (thioctic acid) on peripheral nerve of experimental diabetic neuropathy

Low P.A.; Nagamatsu M.; Nickander K.; Schmelzer J.D.; Raya A.; Tritschler H.J.
USA Diabetes und Stoffwechsel (Germany), 1996, 5/3 Suppl. (94-97)

Oxidative stress is present in the diabetic state. Our work in streptozotocin-diabetic rats has focussed on its presence in peripheral nerve. Antioxidant enzymes are reduced in peripheral nerve and are further reduced in diabetic nerves. That lipid peroxidation will cause neuropathy is supported by evidence of the development of neuropathy de novo when normal rat nerve is rendered alpha-tocopherol deficient and augmentation of the conduction deficit in diabetic nerves subjected to this insult. The mechanism of oxidative stress appears to be primarily due to the processes of nerve ischemia and hyperglycemia auto-oxidation. The indices of oxidative stress include an increase in nerve, dorsal root and sympathetic ganglia lipid hydroperoxides and conjugated dienes. However the most reliable and sensitive index is a reduction in reduced glutathione. Experimental diabetic neuropathy results in myelinopathy of dorsal roots and a vacuolar neuropathy of dorsal root ganglion. The vacuoles are mitochondrial; we posit that lipid peroxidation causes mitochondrial DNA mutations that increase reduced oxygen species, causing further damage to mitochondrial chain and function, resulting in a sensory neuropathy. alpha-lipoic acid is a potent antioxidant that prevents lipid peroxidation in vitro and in vivo. We evaluated the efficacy of the drug in doses of 20, 50 and 100 mg/kg, administered intraperitoneally to streptozotocin diabetic rats in preventing the biochemical, electrophysiologic and nerve blood flow deficits in peripheral nerve of experimental diabetic neuropathy. alpha-lipoic acid dose- and time-dependently prevented the deficits in nerve conduction, nerve blood flow and biochemical abnormalities of a reduction in reduced glutathione and lipid peroxidation. The nerve blood flow deficit was 50% (p < 0.001). Supplementation dose-dependently prevented the deficit; at the highest concentration, nerve blood flow was not different to control nerves. Digital nerve conduction underwent a dose-dependent improvement at 1 month (p < 0.05). By 3 months, all treated groups had lost their deficit. The antioxidant drug is potentially efficacious for human diabetic sensory neuropathy.

Lipoic acid alpha-potential modulator of insulin sensitivity in patients with non-insulin-dependent diabetes mellitus

Jacob S.; Clancy D.E.; Schiemann A.-L.; Simon I.; Jung W.-I.; Henriksen E.J.; Tritschler H.J.; Augustin H.J.; Dietze G.J.
Germany
Diabetes und Stoffwechsel (Germany), 1996, 5/3 Suppl. (64-70)

Thioctic acid, also known as alpha lipoic acid (ALA), a naturally occuring compound, is frequently used for the treatment of diabetic polyneuropathy and was shown to be a safe and reliable drug. Experimental studies revealed enhanced glucose transport and utilization in different animal models. Therefore, it was of interest to investigate whether ALA is also capable to stimulate glucose disposal in clinical conditions of reduced insulin sensitivity, such as NIDDM. A case report supported the hypothesis, and pilot studies were initiated, in which well controlled Type 2 diabetics received ALA (1.000 mg/500 ml NaCl; or vehicle only) during a hyperinsulinemic glucose-clamp (placebo controlled study) or 500 ml ALA/d over 10 d in an open uncontrolled study. While the acute administration of vehicle had no significant effect on insulin sensitivity (MCR1 3,6 plus or minus 0,21 vs. MCR2 4,01 plus or minus 0,19 ml/kg/min), the infusion of ALA resulted in a marked increase of glucose disposal by about 50% (MCR1 3,91 plus or minus 0,6 vs. MCR2 5,89 plus or minus 0,8 ml/kg/min, p less than or equal to 0,05, Wilcoxon-Rank-Sumtest). The ten day treatment of type II diabetics with ALA enhanced insulin-stimulated whole body glucose disposal by about 30% (MCR1 2,47 plus or minus 0,28 vs. MCR2 3,15 plus or minus 0,35 ml/kg/min, p less than or equal to 0,05, Wilcoxon-Rank-Sumtest). Meanwhile other groups have confirmed these observations. In conclusion, the present data indicate that parenteral administration of thioctic acid enhances insulin-stimulated glucose disposal in NIDDM. Animal studies suggest that the compound increases insulin-stimulated glucose transport activity, non-oxidative glucose disposal and glucose oxidation in peripheral tissues, such as skeletal muscle.

Lipoic acid acutely ameliorates insulin sensitivity in obese subjects with type 2 diabetes

Rett K.; Wicklmayr M.; Ruus P.; Nehrdich D.; Hermann R.; Standl E.
Germany
Diabetes und Stoffwechsel (Germany), 1996, 5/3 Suppl. (59-63)

Background: Alpha-lipoic acid, a natural cofactor of pyruvate-dehydrogenase, has long been suggested to improve glucose oxidation. Recent data from insulin resistant muscle models demonstrate, that glucose transport and hence non-oxidative glucose metabolism are ameliorated with this substance. Corresponding data in man are lacking.

Methods: The effect of an acute infusion of 600 mg alpha-lipoic acid on insulin sensitivity was investigated in a double blind randomised placebo controlled cross-over study using the isoglycemic glucose clamp technique in 12 obese, insulin resistant subjects (4 postmenopausal women, 8 men) aged between 48 and 69 years with poorly controlled type 2 diabetes.

Results: The infusion was well tolerated, only one subject complained of headache. Of the 12 multimorbid subjects, Z (58,3%) responded to the acute infusion of 600 mg alpha-lipoic acid with a clinically relevant increase (> 20%) in insulin sensitivity (metabolic clearance rate >MCR<). The mean relative increase of MCR of all participants (including nonresponders) was 27% (p = 0.002).

Conclusion: For the first time, a single infusion of 600 mg alpha-lipoic acid is shown to improve attenuated insulin sensitivity in a controlled study in a defined insulin resistant group of subjects with type 2 diabetes. The high number of nonresponders gives rise to further studies.

Treatment of symptomatic diabetic peripheral neuropathy with alpha-lipoic acid. A 3-week multicentre randomized controlled trial (ALADIN Study)

Ziegler D.; Hanefeld M.; Ruhnau K.J.; Meissner H.P.; Lobisch M.; Schutte K.; Gries F.A.; Ticinelli E.-C.; Hahnzog B.; Nehrdich D.; Netten C.; Dannehl K.; Peukert M.; Wessel K.; Anders M.; Brauning H.; Brun M.; Brunner E.; V. Bultzingslowen S.; Donaubauer B.; Forchheim W.; Funke K.; Gerlach-Eniyew S.; Hampel T.; Hoche I.; Hunecke I.; Klinkenstein C.; v. Klitzing K.L.; Kluttig G.; Konig I.; Krause I.; Kruger R.; Kunz U.; Mantz S.; Marquardt C.; Meissner H.P.; Mende M.; Myrach-Rahn A.; Richter E.; Ruhnau K.J.; Ruthe W.D.; Sand K.; Schubert R.; Schultz U.; Seebacher M.L.; Simonsohn M.; Stoll M.; Stundel M.; Szilleweit G.; Walch O.; Walz E.; Wittmann N.
Germany
Diabetes und Stoffwechsel (Germany), 1996, 5/3 Suppl. (102-110)

Treatment with anti-oxidants reduces oxidative stress and prevents neuropathy in experimental diabetes. Such a therapeutic approach based on pathogenetic mechanisms may have potential in diabetic patients with neuropathy. The efficacy and safety of the anti-oxidant alpha-lipoic acid (thioctic acid) were studied in a 3-week multicentre, randomized, double-blind placebo-controlled trial (Alpha-Lipoic Acid in Diabetic Neuropathy: ALADIN) in 328 Type 2 diabetic patients with symptomatic peripheral neuropathy who were randomly assigned to treatment with intravenous infusion of alpha-lipoic acid using three doses (ALA 1200 mg/600 mg/100 mg) or placebo (PLAC). Neuropathic symptoms (pain, burning, paraesthesiae, and numbness) were scored at baseline and each visit (days 2-5, 8-12, and 15-19) prior to infusion. In addition, the Hamburg Pain Adjective List (HPAL), a multidimensional specific pain questionnaire, as well as the Neuropathy Symptom Score (NSS) and Neuropathy Disability Score (NDS) were assessed at baseline and day 19. According to the protocol 260 (65/63/66/66) patients completed the study. The total symptom score (TSS) in the feet decreased from baseline to day 19 (mean plus or minus SD;%) by -4.5 plus or minus 3.7 (-58.6%) points in ALA 1200, -5.0 plus or minus 4.1 (-63.5%) points in ALA 600, -3.3 plus or minus 2.8 (-43.2%) points in ALA 100, and -2.6 plus or minus 3.2 (-38.4%) points in PLAC (ALA 1200 vs PLAC: p = 0.003; ALA 600 vs PLAC: p < 0.001). The response rates, defined as an improvement in the TSS of at least 30% after 19 days, were 70.8% in ALA 1200, 82.5% in ALA 600, 65.2% in ALA 100, and 57.6% in PLAC (ALA 600 vs PLAC: p = 0.002). The total scale of the HPAL was significantly reduced in ALA 1200 and ALA 600 as compared with PLAC after 19 days (both p < 0.01). The rates of adverse events were 32.6% in ALA 1200, 18.2% in ALA 600, 13.6% in ALA 100, and 20.7% in PLAC. These findings substantiate the efficacy of intravenous treatment with alpha-lipoic acid using a dose of 600 mg/day over 3 weeks that is superior to placebo in reducing symptoms of diabetic peripheral neuropathy, without causing significant adverse reactions.

Effect of lipoic acid (thioctic acid) on glucose homeostasis and muscle glucose transporters in diabetic rats

Khamaisi M.; Potashnik R.; Tritschler H.; Wessel K.; Bashan N.
Prof. N. Bashan, Clinical Biochemistry Unit, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva Israel
Diabetes und Stoffwechsel (Germany), 1996, 5/3 Suppl. (50-54)

Background: alpha-Lipoic acid (LA), a cofactor of alpha-ketodehydrogenase, is a natural antioxidant. Though clinically used in treating peripheral diabetic polyneuropathy, its mode of action is not clear. In this study we tested whether LA affects glucose homeostasis and muscle glucose transporters.

Methods: LA was administrated to fasting control and streptozotocin diabetic rats either acutely (100 mg/kg, i.v.) or chronically (30 mg/kg, i.p. for 10 days).

Results: Acute administration reduced blood glucose, 76 plus or minus 16 vs. 38 plus or minus 9 mg% (p < 0.01) by 1 hour in control, and 255 plus or minus 22 vs. 185 plus or minus 41 mg% (p < 0.05) by 2 hours in diabetic rats. Chronic treatment reduced blood glucose concentration in diabetic, 341 plus or minus 36 vs. 189 plus or minus 48 mg% (p = 0.001), but not in control rats. Gastrocnemius GLUT4-protein content was increased by LA approximately 2-fold in both control and diabetic rats, resulting in normalization ot muscle GLUT4 content in diabetic rats. Muscle lactate was increased in diabetic rats (19.9 plus or minus 5.5 vs. 10.4 plus or minus 2.8 in control p < 0.05, respectively), and normalized by chronic LA treatment.

Conclusions: Chronic LA treatment improves glycemia of streptozotocin diabetic rats by increasing muscle GLUT4-protein content. This may improve diabetes related muscle glucose metabolism abnormalities.

Altered 14C-deoxyglucose incorporation in rat brain following treatment with alpha-lipoic acid (thioctic acid). Clinical implications for diabetic neuropathy and neurodegenerative disorders

Jenner P.; Seaton T.A.; Marsden C.D.
Prof. Dr. P. Jenner, King's College, University of London, Biomedical Science Division, Manresa Road, London SW3 GLX United Kingdom
Diabetes und Stoffwechsel (Germany), 1996, 5/3 Suppl. (31-35)

The incorporation of 14C-2-deoxyglucose (2DG) into areas of basal ganglia was investigated in rats treated acutely or for 5 days with R- or S-thioctic acid (alpha-lipoic acid). In addition, the effect of animal source and age (up to 30 months) on the ability of R- and S-thioctic acid to alter 14C-2DG incorporation was studied. Following acute administration, R-thioctic acid was more effective than S-thioctic acid in altering 14C-2DG incorporation. For example, in substantia nigra of acute administration R-thioctic acid caused an approximately 40% increase in 14C-2DG incorporation while S-thioctic acid was without effect. However, the effects observed were dependent on basal 14C-DG incorporation in different rat strains. Following subacute administration, the pattern of change in 14C-2DG incorporation was altered and now both isomers were equally effective. The effects of R-thioctic acid were largely maintained with increasing animal age but the ability of the S-isomer to alter 14C-2DG incorporation was lost by 30 months. The data indicate an ability of thioctic acid to alter glucose utilisation in vivo which may be relevant to the treatment of diabetic neuropathy and neurodegenerative disorders, such as Parkinson's disease.

Studies on the bioavailability of alpha lipoic acid in type I and type II diabetics with diabetic neuropathy

Rosak C, Hoffken P, Baltes W, Drinda H, Ulrich H, Tritschler HJ, Elze M, Blume H
Germany
Diabetes und Stoffwechsel (Germany), 1996, 5/3 Suppl. (23-26)

In a controlled randomized cross-over study with two parallel groups 24 type I and type II diabetics with diabetes-induced polyneuropathy were given alpha lipoic acid in two different dosages and methods of administration. Group A (12 patients) was given 600 mg of alpha lipoic acid administered intravenously as a defined short infusion and orally in tablet form. Group B (12 patients) was given 200 mg of alpha lipoic acid administered intravenously as a defined short infusion and orally in tablet form. The extent of the bioavailability (AUC) of free alpha lipoic acid in plasma after intravenously administering 600 mg of alpha lipoic acid was 13.1 microg/ml.h and after 200 mg was 2.2 microg/ml.h. After 600 mg of orally administered alpha lipoic acid the AUC was 2.1 microg/ml.h and after 200 mg it was 0.4 microg/ml.h. The AUC of the single dose of 600 mg administered intravenously and orally was thus about twice as high as the adjusted dosage AUC of 200 mg. This difference was statistically significant. These results support the recommended therapy plan of 600 mg intravenously followed by an oral maintenance therapy of 1 x 600 mg daily.

On the pharmacokinetics of alpha-lipoic acid in patients with diabetic polyneuropathy

Preiss R.; Teichert J.; Preiss C.; Kern J.; Tritschler H.J.; Ulrich H.
Germany
Diabetes und Stoffwechsel (Germany), 1996, 5/3 Suppl. (17-22)

After the administration von 600 mg alpha lipoic acid (alpha-L) per oral (Thioctacid(R) 200 film tablets) or as an intravenous infusion over 20 minutes (Thioctacid(R) T ampules) the kinetics of alpha-L in plasma were investigated in 12 diabetes type II-patients with normal liver and renal function and symptoms of diabetic neuropathy. alpha-L was electrochemically detected as a total fraction of lipoic and dihydrolipoic acid. alpha-L is quickly absorbed. Maximum plasma concentrations were found after 42.9 plus or minus 45.6 minutes. In seven of the 12 patients alpha-L showed alpha second peak behaviour with a mean difference of 89,1 minutes between the first and the second plasma peak. a-L was quickly eliminated from plasma with a mean terminal hallife time of 32.8 plus or minus 9.4 minutes. 7-10 hours after the start of the application of alpha-L its endogenous basic levels in plasma are reached, which are measured in a magnitude of 10 ng/ml. With respect to Thioctacid(R) 200 film tablets a mean absolute oral bioavailability of 20.2% (13.1-26.8%) for alpha-L was estimated. After a dose of 200 mg alpha-L healthy volunteers showed with 29.1% a 44% significantly higher bioavailability of a-L. The reduced bioavailability of alpha-L in patients with diabetic neuropathy is caused by a dose-inadequate, stronger elevation of the plasma levels of alpha-L after its intravenous administration. In patients with diabetic neuropathy the oral absorption behaviour of alpha-L is not different from that of normal persons.

Chromium oligopeptide activates insulin receptor tyrosine kinase activity

Davis C.M.; Vincent J.B.
USA
Biochemistry (USA), 1997, 36/15 (4382-4385)

A possible new mechanism for the amplification of insulin receptor tyrosine kinase activity in response to insulin has been identified. The chromium-containing oligopeptide low molecular weight chromium-binding substance (LMWCr) does not effect the tyrosine protein kinase activity of rat adipocytic membrane fragments in the absence of insulin; however, insulin- stimulated kinase activity in the membrane fragments is increased up to 8- fold by the oligopeptide. Using isolated rat insulin receptor, LMWCr has been shown to bind to insulin-activated insulin receptor with a dissociation constant of circa 250 pM, resulting in the increase of its tyrosine protein kinase activity. The ability of LMWCr to stimulate insulin receptor tyrosine kinase activity is dependent on its chromium content. The results appear to explain the previously poorly understood relationship between chromium and adult-onset diabetes and cardiovascular disease.

Effect of chromium nicotinic acid supplementation on selected cardiovascular disease risk factors

Thomas V.L.K.; Gropper S.S.
S.S. Gropper, Department of Nutrition/Food Science, 328 Spidle Hall, Auburn University, Auburn, AL 36849 USA
Biological Trace Element Research (USA), 1996, 55/3 (297-305)

The effects of daily supplemental chromium (200 microg) complexed with 1.8 mg nicotinic acid on plasma glucose and lipids, including total cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides, were assessed in 14 healthy adults and 5 adults with noninsulin-dependent diabetes mellitus (NIDDM) using a double-blind crossover study with 8-wk experimental periods. Eight of the 14 healthy subjects and all 5 subjects with NIDDM also underwent an oral glucose tolerance test with assessment of 90 min postprandial plasma glucose and insulin concentrations. No statistically significant effects of chromium nicotinic acid supplementation were found on plasma insulin, glucose, or lipid concentrations, although chromium nicotinic acid supplementation slightly lowered fasting plasma total and LDL cholesterol, triglycerides, and glucose concentrations, and 90-min postprandial glucose concentrations in individuals with NIDDM.

Modulation of cellular reducing equivalent homeostasis by alpha-lipoic acid. Mechanisms and implications for diabetes and ischemic injury

Roy S.; Sen C.K.; Tritschler H.J.; Packer L.
Dr. S. Roy, 251 Life Sciences Addition, Dept. of Molecular/Cell Biology, University of California, Berkeley, CA 94720-3200 USA
Biochemical Pharmacology (USA), 1997, 53/3 (393-399)

The therapeutic potential of alpha-lipoic acid (thioctic acid) was evaluated with respect to its influence on cellular reducing equivalent homeostasis. The requirement of NADH and NADPH as cofactors in the cellular reduction of alpha-lipoic acid to dihydrolipoate has been reported in various cells and tissues. However, there is no direct evidence describing the influence of such reduction of alpha-lipoate on the levels of cellular reducing equivalents and homeostasis of the NAD(P)H/NAD(P) ratio. Treatment of the human Wurzburg T-cell line with 0.5 mM alpha-lipoate for 24 hr resulted in a 30% decrease in cellular NADH levels. alpha-Lipoate treatment also decreased cellular NADPH, but this effect was relatively less and slower compared with that of NADH. A concentration-dependent increase in glucose uptake was observed in Wurzburg cells treated with alpha-lipoate. Parallel decreases (30%) in cellular NADH/NAD+ and in lactate/pyruvate -*--ratios were observed in alpha-lipoate-treated cells. Such a decrease in the NADH/NAD+ ratio following treatment with alpha-lipoate may have direct implications in diabetes, ischemia-reperfusion injury, and other pathologies where reductive (high NADH/NAD+ ratio) and oxidant (excess reactive oxygen species) imbalances are considered as major factors contributing to metabolic disorders. Under conditions of reductive stress, alpha-lipoate decreases high NADH levels in the cell by utilizing it as a co-factor for its own reduction process, whereas in oxidative stress both alpha-lipoate and its reduced form, dihydrolipoate, may protect by direct scavenging of free radicals and recycling other antioxidants from their oxidized forms.

Endothelial dysfunction: Clinical implications

Drexler H.
Germany
Progress in Cardiovascular Diseases (USA), 1997, 39/4 (287-324)

The endothelium is involved in the control of vascular tone and homeostasis. Risk factors for arteriosclerosis, as well as other conditions have been shown to be associated with a dysfunctional endothelium. Clinically, endothelial function and dysfunction have been mostly evaluated by the assessment of endothelial dependent relaxation, for example in response to acetylcholine or increase inflow. The functional implications of endothelial dysfunction in cardiovascular disease are not well defined, but recent clinical trials have suggested that endothelial dysfunction may affect vascular tone and organ perfusion particularly during stress situations such as exercise. Moreover, endothelial dysfunction may represent an early event in the development of arteriosclerosis. Therefore, recent clinical studies have been performed to restore normal endothelial function in patients, using interventions such as L-arginine, lipid lowering drugs, vitamin C, other antioxidants, or exercise.

Effects of treatment with the antioxidant alpha-lipoic acid on cardiac autonomic neuropathy in NIDDM patients: A 4-month randomized controlled multicenter trial (DEKAN study)

Ziegler D.; Schatz H.; Conrad F.; Gries F.A.; Ulrich H.; Reichel G.; Schifferdecker E.; Heieck F.; Koeppen S.; Diener H.C.; Richter W.O.; Rolfs H.C.; Scharafinski H.-W.; Schulze-Schleppinghoff B.; Schultz-Venrath U.; Winkelmann W.
Germany
Diabetes Care (USA), 1997, 20/3 (369-373)

OBJECTIVE - To evaluate the efficacy and safety of oral treatment with the antioxidant alpha-lipoic acid (ALA) in NIDDM patients with cardiac autonomic neuropathy (CAN), assessed by heart rate variability (HRV).

RESEARCH DESIGN AND METHODS - In a randomized, double-blind placebo-controlled multicenter trial (Deutsche Kardiale Autonome Neurophatic (DEKAN) Study), NIDDM patients with reduced HRV were randomly assigned to treatment with a daily oral dose of 800 mg ALA (n = 39) or placebo (n = 34) for 4 months. Parameters of HRV at rest included the coeficient of variation (CV), root mean square successive difference (RMSSD), and spectral power in the low-frequency (LF; 0.5-0.15 Hz) and high-frequency (HF; 0.15-0.5 Hz) bands. In addition, cardiovascular autonomic symptoms were assessed.

RESULTS - Seventeen patients dropped out of the study (ALA n= 10; placebo n = 7). Mean blood pressure and HbA1 levels did not differ between the groups at baseline and during the study, but heart rate at baseline was higher in the group treated with ALA (P < 0.05). RMSSD increased from baseline to 4 months by 1.5 ms (-37.6 to 77.1) (median (minimum-maximum)) in the group given ALA and decreased by -0.1 ms (-19.2 to 32.8) in the placebo group (P < 0.05 for ALA vs. placebo). Power spectrum in the LF band incresed by 0.06 bpm2 (-0.09 to 0.62) in ALA, whereas it declined by -0.01 bpm2 (-0.48 to 1.86) in placebo (P < 0.05 for ALA vs. placebo). Furthermore, there was a trend toward a favorable effect of ALA versus placebo for the CV and HF band power spectrum (P = 0.097 and P = 0.094 for ALA vs. placebo. The charges in cardiovascular autonomic symptoms did not differ significantly between the groups during the period studied. No differences between the groups were noted regarding the rates of adverse events.

CONCLUSIONS - These findings suggest that treatment with AlA using a well-tolerated oral dose of 800 mg/day for months may slightly improve CAN in NIDDM patients.

alpha-Lipoic acid corrects neuropeptide deficits in diabetic rats via induction of trophic support

Garrett N.E.; Malcangio M.; Dewhurst M.; Tomlinson D.R.
D.R. Tomlinson, Department of Pharmacology, St.Bartholomew's/Royal Sch. Medicine, Queen Mary/Westfield College, Mile End Road, London E1 4NS United Kingdom
Neuroscience Letters (Ireland), 1997, 222/3 (191-194)

This study compared the effects of treatment of diabetic rats with either alpha-lipoic acid (100 mg/kg/day i.p. 5 days/week) or with recombinant human nerve growth factor (rhNGF; 0.2 mg/kg s.c. 3 days/week) on NGF-like immunoreactivity (NGFLI) and neuropeptide Y-like immunoreactivity (NPYLI) levels in the sciatic nerve and on the release of substance P-like immunoreactivity (SPLI) from the spinal cord in response to electrical stimulation of the dorsal roots In vitro. Diabetic rats showed depletion of NGFLI and NPYLI, together with reduced release of SPLI. Treatment with NGF increased the sciatic nerve NGFLI (to four times that seen in untreated diabetic rats) and normalised stimulus-evoked release of SPLI, but did not affect the sciatic nerve NPYLI. Treatment with alpha-lipoic acid caused a small non-significant increase in sciatic nerve NGFLI, but normalised both NPYLI levels and stimulus;evoked release of SPLI. These findings indicate that alpha-lipoic acid can boost neurotrophic support in diabetic rats, with effects beyond those related to NGF.

Chromium picolinate supplementation improves cardiac metabolism, but not myosin isoenzyme distribution in the diabetic heart

Morris G.S.; Hasten D.L.; Hegsted M.; Guidry K.L.
USA
Journal of Nutritional Biochemistry (USA), 1996, 7/11 (617-622)

Because chromium (Cr) containing compounds are thought to improve glucose homeostasis, we hypothesized that chromium picolinate (CrP) could partially reverse diabetes-induced damage to cardiac tissue. Young, adult female rats were fed either a basal diet (CONT), a basal diet containing no CrP and made diabetic (DIAB-CONT), or a basal diet containing 600 ng/g of CrP (3 times the suggested daily chromium intake) and made diabetic (DIAB-CrP). Diabetes was induced by a single streptozotocin injection, 55 mg/kg i.p. After 8 weeks animals were sacrificed, hearts removed, and spectrophotometrically analyzed for citrate synthase (CS), hexokinase (HK), and beta hydroxyacyl CoA dehydrogenase activity (HOAD). Cardiac myosin isoenzymes were separated from crude myofibril extracts by PAGE electrophoresis. Diabetes did not alter CS activity relative to the CONT group, but did significantly (P < 0.05) reduce HK and HOAD activity and expression of the high ATPase myosin isoenzyme VI. In contrast, DIAB-CrP animals displayed normal HK activity and greater HOAD activity relative to CONT animals. Surprisingly, the addition of CrP to the diet further reduced expression of the VI myosin isoenzyme. These results demonstrate thet dietary CrP supplementation has diverse effects on the subcellular properties of the diabetic heart. The functional impact of these CrP-induced changes remains to be defined.

Dehydroepiandrosterone and diseases of aging

Watson R.R.; Huls A.; Araghinikuam M.; Chung S.
Arizona Prevention Center, University of Arizona, School of Medicine, Tucson, AZ 85724 USA
Drugs and Aging (New Zealand), 1996, 9/4 (274-291)

Dehydroepiandrosterone (DHEA; prasterone) is a major adrenal hormone with no well accepted function. In both animals and humans, low DHEB levels occur with the development of a number of the problems of aging: immunosenesence, increased mortality, increased incidence of several cancers, loss of sleep, decreased feelings of well-being, osteoporosis and atherosclerosis. DHEA replacement in aged mice significantly normalised immunosenescence, suggesting that this hormone plays a key role in aging and immune regulation in mice. Similarly, osteoclasts and lymphoid cells were stimulated by DHEA replacement, an effect that may delay osteoporosis, Recent studies do not support the original suggestion that low serum DHEA levels are associated with Alzheimer's disease and other forms of cognitive dysfunction in the elderly. As DHEA modulates energy metabolism, low levels should affect lipogenesis and gluconeogenesis, increasing the risk of diabetes mellitus and heart disease. Most of the effects of DHEA replacement have been extrapolated from epidemiological or animal model studies, and need to be tested in human trials, Studies that have been conducted in humans show essentially no toxicity of DHEA treatment at dosages that restore serum levels, with evidence of normalisation in some aging physiological systems. Thus, DHEA deficiency may expedite the development of some diseases that are common in the elderly.

Sex hormones and DHEA-SO4 in relation to ischemic heart disease mortality in diabetic subjects: The Wisconsin Epidemiologic Study of Diabetic Retinopathy

Haffner S.M.; Moss S.E.; Klein B.E.K.; Klein R.
Univ. of Texas Hlth. Science Center, 7703 Floyd Curl Dr., San Antonio, TX 78284-7873 USA
Diabetes Care (USA), 1996, 19/10 (1045-1050)

OBJECTIVE - Sex hormones are associated with atherogenic changes in lipoproteins and changes in glucose and insulin metabolism, yet few data are available on the relationship of sex hormones and dehydroepiandrosterone sulfate (DHEA-SO4) to ischemic heart disease (IHD) in diabetic subjects, a group with very high levels of IHD.

RESEARCH DESIGN AND METHODS - We examined the relation of total and free testosterone, sex hormone binding globulin, estrone, estradiol, and DHEA-SO4 to the 5-year IHD mortality in the older- onset diabetic subjects in the Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR) in a matched diabetic subject-control design (two control subjects for every diabetic subject).

RESULTS - In men (n = 123), none of the sex hormones or DHEA-SO4 significantly predicted IHD mortality. In women (n = 120), lower levels of DHEA-SO4 (P < 0.01) and total testosterone (P = 0.07) predicted IHD mortality. These results were essentially unchanged after adjustment for duration of diabetes, GHb, diuretic use, and serum creatinine, which are major predictors of IHD mortality in the WESDR. Finding lower testosterone levels in diabetic subjects of IHD in women is contrary to data on risk factors, which suggests that increased androgen activity may he associated with worse IHD risk factors.

CONCLUSIONS - This study suggests that alterations in sex hormones and DHEA-SO4 are unlikely to explain a major proportion of the variation in IHD mortality in diabetic subjects.

The effects of acetyl-L-carnitine and sorbinil on peripheral nerve structure, chemistry, and function in experimental diabetes

Malone J.I.; Lowitt S.; Salem A.F.; Miranda C.; Korthals J.K.; Carver J.
USF College of Medicine, MDC Box 45, 12901 Bruce B. Downs Blvd, Tampa, FL 33612-4799 USA
Metabolism: Clinical and Experimental (USA), 1996, 45/7 (902-907)

Nerve conduction velocity (NCV) increased with age in nondiabetic male Wistar rats for the first 26 weeks of life. The NCV of animals made hyperglycemic at age 6 weeks by administration of streptozotocin (STZ) also increases, but at a slower rate. Animals with 4 weeks of hyperglycemia and reduced NCV treated with an aldose reductase inhibitor (sorbinil) or a short- chain acyl-carnitine (acetyl-L-carnitine (ALC)) daily for 16 weeks showed an improvement in NCV. Morphometric studies of tibial nerves collected from animals after 20 weeks of hyperglycemia (age 26 weeks) showed a consistent reduction in the width of the myelin sheath and little change in axon area. The number of large myelinated fibers (>6.5 microm) found in nerves collected from hyperglycemic animals was less than the number found in nondiabetic animals. Treatment of hyperglycemic rats with either sorbinil or ALC was associated with increased NCV, myelin width, and large myelinated fibers. The apparent metabolic effect of these agents was similar for fatty acid metabolism, but different for polyol pathway activity. We conclude that in animals hyperglycemic long enough to slow NCV, sorbinil and/or ALC treatment reduces the functional, structural, and biochemical changes associated with hyperglycemia that occur in the myelin sheath.

Acetyl-L-carnitine deficiency as a cause of altered nerve myo-inositol content, Na,K-ATPase activity, and motor conduction velocity in the streptozotocin-diabetic rat

Stevens M.J.; Lattimer S.A.; Feldman E.L.; Helton E.D.; Millington D.S.; Sima A.A.F.; Greene D.A.
5570 MSRB II, Box 0678, 1150 W Medical Center Dr, Ann Arbor, MI 48109-0678 USA
Metabolism: Clinical and Experimental (USA), 1996, 45/7 (865-872)

Defective metabolism of long-chain fatty acids and/or their accumulation in nerve may impair nerve function in diabetes by altering plasma or mitochondrial membrane integrity and perturbing intracellular metabolism and energy production. Carnitine and its acetylated derivatives such as acetyl- L-carnitine (ALC) promote fatty acid beta-oxidation in liver and prevent motor nerve conduction velocity (MNCV) slowing in diabetic rats. Neither the presence nor the possible implications of putative ALC deficiency have been definitively established in diabetic nerve. This study explored sciatic nerve ALC levels and the dose-dependent effects of ALC replacement on sciatic nerve metabolites, Na,K-ATPase, and MNCV after 2 and 4 weeks of streptozotocin- induced diabetes (STZ-D) in the rat. ALC treatment that increased nerve ALC levels delayed (to 4 weeks) but did not prevent nerve myo-inositol (Mf) depletion, but prevented MNCV slowing and decreased ouabain-sensitive (but not-insensitive) ATPase activity in a dose-dependent fashion. However, ouabain-sensitive ATPase activity was also corrected by subtherapeutic doses of ALC that did not increase nerve ALC affect MNCV. These data implicate nerve ALC depletion in diabetes as a factor contributing to alterations in nerve intermediary and energy metabolism and impulse conduction in diabetes, but suggest that these alterations may be differentially affected by various degrees of ALC depletion.

Unrecognized pandemic subclinical diabetes of the affluent nations: Causes, cost and prevention

Ely J.T.A.
Radiation Studies, University of Washington, Box 351560, Seattle, WA 98195 USA
Journal of Orthomolecular Medicine (Canada), 1996, 11/2 (95-99)

Regarding populations on the industrialized 'western affluent diet', arguments are made that:

(1) plasma glucose values commonly seen and accepted as normal are abnormal;
(2) their glucose tolerance is innately unstable;
(3) most of their morbidity and mortality is produced by hyperglycemia far below glycosuria and/or arteriosclerosis which can occur independently or together;
(4) simple low cost methods for preventing and treating both have been in the literature for decades (correction of the sugar, fat and protein excesses; and controlled supplementation of pyridoxine (vitamin B6). Mg, Cr and coenzyme Q10); and
(5) these lessons were missed by main stream medicine because of the vast size of the literature, enforcement of 'treatment of choice', and lack of computer aided diagnosis. Cited as striking evidence of this tragic situation is the failure of mainstream clinical medicine to understand the cause of the remarkable decline in CVD in the 1960s and 1970s that followed U.S. enrichment of cereals with pyridoxine (vitamin B6). Recommendations are made for correction of unnecessary costly delays between publication and implementation of such research findings.

Evidence of a relationship between childhood-onset type I diabetes and low groundwater concentration of zinc

Haglund B.; Ryckenberg K.; Selinus O.; Dahlquist G.
Dept. of Epidemiology/Public Health, Umea University, S-901 85 Umea Sweden
Diabetes Care (USA), 1996, 19/8 (873-875)

OBJECTIVE - Zinc deficiency ha shown to increase the risk for diabetes in diabetes-prone experimental animals. Low concentrations of zinc have also been shown in serum of recent onset cases with IDDM. The present study examines the hypothesis that exposure to a low concentration of zinc in drinking water could increase the risk for future onset of IDDM.

RESEARCH DESIGN AND METHODS - Using the Swedish childhood diabetes registry and data on residence 3 years before the onset of disease, a case-control study was designed comparing cases and control subjects with estimates of groundwater contents of zinc obtained in biogeochemical samples from areas of residence.

RESULTS - A high groundwater concentration of zinc was associated with a significant decrease in risk (odds ration (OR) = 0.8; 95% CI = 0.7-0.9). The same OR was obtained when the model included information of other metals that might act as possible confounders (chromium, vanadium, cobalt selenium, cadmium, lead, and mercury). In small rural areas, in which drinking water is taken from local wells and thus is closely associated with the groundwater content within the area, an even stronger association between zinc and diabetes (OR = 0.6; 95% CI = 0.4-0.9) was found.

CONCLUSIONS - It is concluded that this study for the first time provides evidence that a low groundwater content of zinc, which may reflect long-term exposure through drinking water, is associated with later development of childhood onset diabetes.

Improved pallesthetic sensitivity of pudendal nerve in impotent diabetic patients treated with acetyl-L-carnitine

Giammusso B.; Morgia G.; Spampinato A.; Motta M.
Catania University, Catania Italy
Acta Urologica Italica (Italy), 1996, 10/3 (185-187)

Neurogenic impotence in diabetic patients seems to be largely associated with abnormal sensory nerve conduction of pudendal nerve afferent pathways. This condition accounts for a hypoactivity in the mechanisms of erection reflex and has been described as sensory-deficit impotence. Our study investigates the pharmacological action of acetyl-L-carnitine (ALC) in the treatment of this neurological disorder. Penile biothesiometry was applied to two groups of diabetic patients, whose impotence was principally neurogenic, in order to assess their vibration perception threshold variables. The groups were treated with ALC (1,500 mg/day) and placebo, respectively. The results obtained show a significant improvement in dorsal nerve somatosensory conduction in patients treated with ALC.

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