phosphocreatine and Diabetic-Neuropathies

To identify differences in postexercise phosphocreatine (PCr) recovery, an index of mitochondrial function, in diabetic patients with and without lower extremity complications.. We enrolled healthy control subjects and three groups of patients with type 2 diabetes mellitus: without complications, with peripheral neuropathy, and with both peripheral neuropathy and peripheral arterial disease. We used magnetic resonance spectroscopic measurements to perform continuous measurements of phosphorous metabolites (PCr and inorganic phosphate [Pi]) during a 3-minute graded exercise at the level of the posterior calf muscles (gastrocnemius and soleus muscles). Micro- and macrovascular reactivity measurements also were performed.. The resting Pi/PCr ratio and PCr at baseline and the maximum reached during exercise were similar in all groups. The postexercise time required for recovery of Pi/PCr ratio and PCr levels to resting levels, an assessment of mitochondrial oxidative phosphorylation, was significantly higher in diabetic patients with neuropathy and those with both neuropathy and peripheral arterial disease (P < .01 for both measurements). These two groups also had higher levels of tumor necrosis factor-α (P < .01) and granulocyte colony-stimulating factor (P < .05). Multiple regression analysis showed that only granulocyte colony-stimulating factor, osteoprotegerin, and tumor necrosis factor-α were significant contributing factors in the variation of the Pi/PCr ratio recovery time. No associations were observed between micro- and macrovascular reactivity measurements and Pi/PCr ratio or PCr recovery time.. Mitochondrial oxidative phosphorylation is impaired only in type 2 diabetes mellitus patients with neuropathy whether or not peripheral arterial disease is present and is associated with the increased proinflammatory state observed in these groups.

Topics: Adult; Aged; Aged, 80 and over; Case-Control Studies; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Neuropathies; Exercise; Female; Granulocyte Colony-Stimulating Factor; Humans; Inflammation Mediators; Magnetic Resonance Spectroscopy; Male; Middle Aged; Mitochondria; Muscle Contraction; Muscle, Skeletal; Osteoprotegerin; Oxidative Phosphorylation; Peripheral Arterial Disease; Phosphocreatine; Time Factors; Tumor Necrosis Factor-alpha

OBJECTIVE To investigate changes in the foot muscle energy reserves in diabetic non-neuropathic and neuropathic patients. RESEARCH DESIGN AND METHODS We measured the phosphocreatinine (PCr)/inorganic phosphate (Pi) ratio, total (31)P concentration, and the lipid/water ratio in the muscles in the metatarsal head region using MRI spectroscopy in healthy control subjects and non-neuropathic and neuropathic diabetic patients. RESULTS The PCr/Pi ratio was higher in the control subjects (3.23 +/- 0.43) followed by the non-neuropathic group (2.61 +/- 0.36), whereas it was lowest in the neuropathic group (0.60 +/- 1.02) (P < 0.0001). There were no differences in total (31)P concentration and lipid/water ratio between the control and non-neuropathic groups, but both measurements were different in the neuropathic group (P < 0.0001). CONCLUSIONS Resting foot muscle energy reserves are affected before the development of peripheral diabetic neuropathy and are associated with the endothelial dysfunction and inflammation.

Topics: Diabetes Mellitus; Diabetic Neuropathies; Endothelium, Vascular; Energy Metabolism; Female; Foot; Humans; Inflammation; Magnetic Resonance Imaging; Male; Middle Aged; Muscle, Skeletal; Phosphates; Phosphocreatine; Reference Values

Nitrosative stress, that is, enhanced peroxynitrite formation, has been documented in both experimental and clinical diabetic neuropathy (DN), but its pathogenetic role remains unexplored. This study evaluated the role for nitrosative stress in two animal models of type 1 diabetes: streptozotocin-diabetic mice and diabetic NOD mice. Control (C) and streptozotocin-diabetic (D) mice were treated with and without the potent peroxynitrite decomposition catalyst FP15 (5 mg kg(-1) d(-1)) for 1 wk after 8 wk without treatment. Sciatic nerve nitrotyrosine (a marker of peroxynitrite-induced injury) and poly(ADP-ribose) immunoreactivities were present in D and absent in C and D+FP15. FP15 treatment corrected sciatic motor and hind-limb digital sensory nerve conduction deficits and sciatic nerve energy state in D, without affecting those variables in C. Nerve glucose and sorbitol pathway intermediate concentrations were similarly elevated in D and D+FP15 vs C. In diabetic NOD mice, a 7-day treatment with either 1 or 3 mg kg(-1) d(-1) FP15 reversed increased tail-flick latency (a sign of reduced pain sensitivity); the effect of the higher dose was significant as early as 3 days after beginning of the treatment. In conclusion, nitrosative stress plays a major role in DN in, at least, type 1 diabetes. This provides the rationale for development of agents counteracting peroxynitrite formation and promoting peroxynitrite decomposition, and their evaluation in DN.

Topics: Animals; Blood Glucose; Creatine; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetic Neuropathies; Metalloporphyrins; Mice; Mice, Inbred NOD; Neural Conduction; Neurons, Afferent; Oxidative Stress; Peroxynitrous Acid; Phosphocreatine; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerases; Reactive Nitrogen Species; Sciatic Nerve; Tyrosine; Weight Gain

To address the problem of the pathogenesis of diabetic neuropathy, rats were made diabetic by alloxan administration, and sciatic nerves were sampled for electrolyte and water content and levels of selected carbohydrates and intermediates in energy metabolism at 3, 6, and 26 weeks. Significant increases were seen in the nerve content of glucose, sorbitol, and fructose. Decreases of myo-inositol were not statistically significant. Glucose-6-phosphate was increased at all times; fructose-1,6-bisphosphate was elevated at 6 and 26 weeks. Nerve ATP and phosphocreatine levels were both increased concomitantly, as was the energy charge. Nerve lactate levels increased only at 26 weeks when plasma lactate levels were also high. Plasma ketone bodies were elevated throughout the 26-week experimental interval. It is postulated that ketone bodies were being used as alternative metabolic fuels in diabetic nerve, thereby causing inhibition of pyruvate oxidation and increased aerobic production of lactate. Increased plasma ketone body levels could also inhibit hepatic lactate uptake. There was no other evidence for hypoxia/ischemia. Lactate:pyruvate ratios did not differ from control values at any time in these ketotic hypoinsulinemic animals. Five major hypotheses have been proposed to explain the pathogenesis of diabetic neuropathy: 1) hypoxia/ischemia, 2) hyperglycemic pseudohypoxia, 3) myo-inositol deficiency, 4) fructose and polyol accumulation and osmotic disequilibrium, and 5) nonenzymatic glycation of macromolecules by fructose and glucose. The data obtained in this study seem to fit best with hypotheses 4 and perhaps 5.

Topics: Acute Disease; Adenosine Triphosphate; Animals; Carbohydrate Metabolism; Chronic Disease; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Electrolytes; Energy Metabolism; Fructose; Glucose; Male; Peripheral Nervous System Diseases; Phosphocreatine; Polymers; Rats; Rats, Sprague-Dawley; Sciatic Nerve; Sorbitol

The effect of a newly developed oral agent, prostaglandin E1 (PGE1) analogue TFC 612, on diabetic neuropathy was studied by giving it for 6 wk to streptozocin-induced diabetic rats that had been diabetic for 3 mo and was compared with the effects of aldose reductase inhibitor ONO 2235. Although both compounds improved decreased motor nerve conduction velocity, the effect of TFC 612 continued during the 6 wk of treatment, whereas that of ONO 2235 became weaker from wk 4. The abnormality in sciatic nerve sorbitol and myo-inositol levels was reversed with ONO 2235, whereas it was unchanged with TFC 612. With the laser Doppler flowmetry technique, a decrease in the sciatic nerve blood flow in diabetic rats was shown to improve with both compounds, but TFC 612 had a greater effect than ONO 2235, and the increased lactate level of the diabetic nerve was corrected with both compounds, suggesting that both may be associated with the amelioration of ischemia in the diabetic endoneurium. Both TFC 612 and ONO 2235 partially but significantly normalized decreased fiber size in diabetic rats. On the other hand, TFC 612 completely normalized the dilated lumen area in diabetic rats, whereas ONO 2235 did not. These results suggest that the PGE1 analogue TFC 612 has a significant effect on diabetic neuropathy, possibly via vasotropic action, and may be a potent compound for the treatment of diabetic neuropathy.

Topics: Adenosine Triphosphate; Aldehyde Reductase; Alprostadil; Animals; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Electrophysiology; Inositol; Lactates; Male; Myelin Sheath; Nerve Fibers; Phosphocreatine; Rats; Rats, Inbred Strains; Rhodanine; Sciatic Nerve; Sorbitol; Streptozocin; Sugar Alcohol Dehydrogenases; Thiazoles; Thiazolidines

Topics: Animals; Axons; Diabetic Neuropathies; Humans; Inositol; Phosphocreatine; Sorbitol

Hyperbaric oxygenation is known to affect energy metabolism and endothelial cell structure and function, but its effects on peripheral nerve have not been reported. We investigated whether it would (i) reverse established streptozotocin-induced diabetic neuropathy, a condition in which endoneurial hypoxia exists; (ii) affect energy metabolism in nerve; and (iii) alter the blood-nerve barrier. Sprague-Dawley rats that had been diabetic for 3 months and age-matched controls were used in these studies. One diabetic group and one control group were treated with hyperbaric oxygenation (2 atm for 2 h, 5 days/week) for 4 weeks. Identical groups remained in room air. Sciatic nerve adenosine triphosphate (ATP), creatine phosphate, lactate, and glucose concentrations showed similar changes at rest in both room air and after hyperbaric oxygenation. Nerves of control and diabetic groups exhibited increased lactate production and increased utilization of glucose, ATP, and creatine phosphate after 15 min of anoxia. The albumin blood-nerve barrier index was increased in control and diabetic nerves after hyperbaric treatment. Nerve conduction velocity was reduced in the diabetic-room air group and not improved by hyperbaric oxygenation. Caudal nerve action potential, which was significantly reduced in this group, was normalized after hyperbaric treatment. Resistance to ischemic conduction failure was increased in untreated diabetic nerve but not significantly different from controls after hyperbaric exposure. These findings indicate that treatment with hyperbaric oxygenation will partially reverse the neuropathy encountered in chronic diabetes. The biochemical changes are suggestive of enhanced nerve energy metabolism induced by hyperbaric oxygenation. The altered albumin blood-nerve barrier index presumably results from the action of free radicals on endothelial cells.

Topics: Action Potentials; Adenosine Triphosphate; Animals; Biological Transport, Active; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Energy Metabolism; Glucose; Hyperbaric Oxygenation; Lactates; Lactic Acid; Male; Neural Conduction; Peripheral Nerves; Phosphocreatine; Rats; Rats, Inbred Strains; Sciatic Nerve; Serum Albumin, Radio-Iodinated

We examined the effect of ischemia on nerve conduction in experimental diabetic neuropathy (EDN) and related electrophysiological changes to nerve adenosine triphosphate (ATP), creatine phosphate (CP), and lactate under anoxic conditions. Rats rendered diabetic with streptozotocin had a resistance to ischemic conduction block (RICB). Caudal nerve action potential (NAP) was well maintained for 10 min in controls and for 15 min in EDN, after which time NAP declined in both groups but more rapidly in normal rats. Time to 50% reduction in nerve ATP and CP was 10 and 3 min, respectively, in controls and delayed to 20 and 8 min in EDN. Rate of utilization of high-energy phosphate (approximately P) was linear for 5 min in controls to be followed by a progressive decline. In EDN rate of utilization of approximately P was linear to 15 min to be followed by a more gradual decline than in normal nerves. These findings suggest that the maintenance of nerve transmission in anoxic-ischemic states depends on anaerobic metabolism and that RICB in EDN is due in part to the ability of diabetic nerves to maintain a higher level of anaerobic glycolysis and for a longer time than normal nerves.

Topics: Action Potentials; Adenosine Triphosphate; Animals; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Energy Metabolism; Glycolysis; Ischemia; Lactates; Lactic Acid; Male; Nerve Block; Neural Conduction; Peripheral Nerves; Phosphocreatine; Rats; Rats, Inbred Strains; Time Factors