Plasma Myo-inositol Concentrations Research Articles

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

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

Alterations in fetal lung phosphatidylinositol metabolism associated with maternal glucose intolerance.

Prior to conception, female rabbits were made hyperglycemic by streptozotocin administration. Fetal hyperglycemia and hyperinsulinemia were documented. Although plasma myoinositol concentration were higher in the fetuses of diabetic mothers, the ratio of lung to plasma myoinositol concentrations in 29-day fetal rabbits were lower than control values. CDP-diglyceride:inositol phosphatidyltransferase was reduced by 70% in the diabetic fetuses and their lung tissue phosphatidylinositol content was decreased.

Dietary myo-inositol intake and peripheral nerve function in diabetic neuropathy

The effect of variations in dietary myo-inositol intake upon plasma myo-inositol concentrations, urinary myo-inositol excretion, motor nerve conduction velocities in the median and peroneal nerves, and sensory nerve conduction velocities in the median and sural nerves was studied in six nondiabetic subjects and in twenty patients with symptomatic distal symmetrical diabetic polyneuropathy. Diets were developed which provided either a low, a normal, or a high intake of myo-inositol. In control subjects, the low- myo-inositol diet was found to decrease, while the high- myo-inositol diet increased both the preprandial plasma myo-inositol concentrations and the daily urinary excretion of myo-inositol. These diets had little effect upon measured nerve function in the control subjects, although the high- myo-inositol diet appeared to slightly reduce the median sensory nerve conduction velocity in this group. In the neuropathic diabetics, the low- and high- myo-inositol diets were found to have similar effects upon the plasma myo-inositol concentrations and urinary myo-inositol excretion, but did not affect the plasma glucose concentrations. When analyzed by groups, no statistically significant changes were observed in any of the measured nerve conduction velocities in the diabetic patients. However, when the change in nerve conduction velocity was analyzed, it was found that the ingestion of the high- myo-inositol diet resulted in a statistically significant increase in the median sensory (+1.92 m/sec, p < 0.001) and the sural sensory nerve conduction velocity (+6.67 m/sec, p < 0.001). In contrast, ingestion of the low- myo-inositol diet produced a statistically significant decrease in the median motor (−2.35 m/sec, p < 0.001) and the peroneal motor nerve conduction velocity (−1.18 m/sec, p < 0.001). Thus, ingestion of a diet enriched in myo-inositol may have a salutory effect upon peripheral nerve function in the patient with symptomatic diabetic neuropathy and appears to be without significant side effects in this patient group.

Rapid improvement in nerve conduction velocity following renal transplantation

In 12 patients with chronic renal failure who received kidney transplants from either cadavers (6) or related living donors (6), rapid improvement in median sensory and motor nerve conduction velocities (NCVs) was observed within a few days after transplantation. The postoperative improvement in median sensory NCV was found to bear a statistically significant negative correlation with creatinine and myo-inositol concentrations. We suggest that metabolic phenomena are responsible for the rapid improvement in median sensory NCV following renal transplantation. The close relationship between myo-inositol and the median sensory NCV following transplantation suggests that elevated plasma myo-inositol concentrations may be related to nerve conduction abnormalities in uremic polyneuropathy.

Myoinositol--a uremic neurotoxin?

In 28 patients predialysis plasma myoinositol was significantly elevated to 10.8 +/- 2.5 versus 0.75 +/- 0.15 mg/100 ml in normals (mean +/- 1 SD), and was weakly correlated with plasma creatinine concentrations (r = 0.42, p less than 0.05). Dialysis decreased plasma myoinositol concentrations to 3.5 +/- 1.1 mg/100 ml. In 16 patients studied more extensively plasma myoinositol was similarly elevated to 10.6 +/- 3.4 mg/100 ml, and spinal fluid myoinositol was increased to 9.4 +/- 2.3 mg/100 ml (versus 2.7 +/- 0.7 in normals, p less than 0.001). Nerve conduction velocities were reduced in 15 and EEG tracings were abnormal in 12 of the 16 patients. However, neither spinal fluid nor plasma myoinositol showed any correlation with nerve conduction velocities or EEG changes (r = 0.05-0.20, NS) Myoinositol is one of the substances retained in renal insufficiency but no indication was found that it is a toxin causing uremic neurological disturbances.

Myoinositol metabolism in diabetes mellitus. Effect of insulin treatment.

The metabolism of myoinositol has been studied in 10 nondiabetic subjects and in six patients with diabetes mellitus before and after insulin therapy. While dietary myoinositol intake and fecal myoinositol excretion were similar in both groups, urinary myoinositol excretion was increased 10-fold in the untreated diabetic and accounted for a significant fraction of his dietary myoinositol intake. Insulin treatment restored the urinary myoinositol excretion toward normal. Despite increased myoinositol excretion, plasma myoinositol concentrations were significantly higher in the diabetics following the ingestion of a standard diet or of a 3.0-gm. myoinositol load. This abnormality in oral myoinositol tolerance was also corrected by insulin treatment. The size of the rapidly equilibrating myoinositol pool was significantly decreased in the untreated diabetic and returned to normal following a brief period of insulin treatment. The elevated plasma myoinositol concentrations observed following myoinositol ingestion in the uncontrolled diabetic presumably represents a combination of enhanced gastrointestinal absorption and impaired intracellular transport of myoinositol. The decreased space of distribution of myoinositol also suggests an impairment of intracellular myoinositol transport in the untreated diabetic. These observations are consistent with the speculation that hyperglycemia may condition a widespread relative intracellular myoinositol deficiency in man and suggest that restoration of normal intracellular myoinositol concentrations might prove to be of benefit in the prevention and treatment of certain of the complications associated with human diabetes mellitus.

PLASMA-MYOINOSITOL CONCENTRATIONS IN URÆMIC NEUROPATHY

In a series of patients with chronic renal failure managed conservatively, the rise in the plasma-myo-inositol (myoinositol) concentration has been found to be related to depression of sural-nerve conduction velocity. There was no correlation with motor-nerve conduction velocity in the peroneal nerve, or with either of these variables in a series of patients receiving chronic hæmodialysis. Despite the negative correlation with sural-nerve conduction velocity, there was no correlation between the plasma-myoinositol concentration and the presence of peripheral neuropathy as assessed clinically. It is concluded that hypermyoinositolæmia may depress nerve conduction velocity, but there is no evidence that it is responsible for the development of uræmic polyneuropathy.

Effects of insulin and dietary myoinositol on impaired peripheral motor nerve conduction velocity in acute streptozotocin diabetes.

The factors influencing the development of impaired sciatic motor nerve conduction velocity (MNCV) in acute experimental diabetes were examined. Decreased MNCV developed by the 14th day after streptozotocin administration but only in rats which became hyperglycemic. Insulin treatment, begun on day 3, failed to prevent imparied MNCV in diabetic rats in which improved or normal weight gain and a decreased degree of hyperglycemia was induced. However, insulin treatment prevented the development of impaired MNCV in a group of diabetic rats in which the tail vein plasma glucose concentration was never found to exceed 160 mg/dl during days 6 through 14, andin which the mean plus or minus SEM of the average plasma glucose concentration for each animal during the same period was 75 plus or minus 18 mg/dl. In normal rats fed diets containing 0.011% or 0.069% free myoinositol (a presumably normal range), sciatic nerve free myoinositol concentrations were 90- and 60-fold higher than those in plasma. On these diets the development of impaired MNCV in the diabetics was associated with a decrease in nerve free myoinositol as compared with nerves from normals fed the same diet, despite similar plasma levels in the normals and diabetics. Plasma and nerve free myoinositol increased with increasing dietary myoinositol content in both normals and diabetics, and nerve myoinositol content could be acutely increased by an i.p. myoinositol load. By supplementing the diets with 1.0% myoinositol, the difference in nerve myoinositol in normal and diabetic rats on day 14 was abolished; on this diet the development of impaired MNCV in the diabetics was moderated or totally prevented, despite persistent hyperglycemia and elevated nerve sorbitol and fructose concentrations. Insulin treatment that prevented impaired MNCV prevented a decrease in nerve myoinositol in diabetics. These studies suggest that insulin deficiency, and possibly hyperglycemia, are primary factors in the development of imparied MNCV in acute experimental diabetes. However, the development of impaired MNCV appears to be related in some manner to a derangement in the regulation of nerve free myoinositol content, which appears to be subject to modification by increases in plasma myoinositol concentration over a critical range.