Dietary myo-inositol intake and peripheral nerve function in diabetic neuropathy.
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Biomedical subjects
Publications and source records attributed to R S Clements.
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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.
A new strain of obese mouse, the PBB/Ld, has been studied in terms of fat pad cellularity, serum insulin and blood glucose levels, and response to gold thioglucose injections. Age-matched C57B1/6J mice were used as controls. Adipocyte size and number in the major fat depots were determined at various ages from weanling to maturity in the PBB/Ld and C57B1/6J strains. Results indicated that obesity in the PBB/Ld was due to hypertrophy of adipocytes in retroperitoneal and subcutaneous fat depots and to hypertrophy and hyperplasia in the epididymal fat pad. PBB/Ld mice also developed hyperinsulinemia and hyperglycemia and these findings have been discussed in terms of the developmental changes in fat pad cellularity. The injection of gold thioglucose led to increased food intake in both PBB/Ld and C57B1/6J mice. Hyperphagia was also present in the PBB/LD control group, but increased efficiency of converting calories to body weight was not observed in this group when compared to control C57B1/6J mice. The characteristics of obesity seen in the PBB/Ld mouse are discussed and comparisons are made to similar studies in other rodent models of obesity.
The subcellular localization of the incorporation of 2-(3H)-myoinositol into lipids has been studied in isolated pancreatic islets of the rat. The recovery of lipid-bound myoinositol increased with time in the nuclear, mitochondrial, microsomal, and secretory granule fractions. The utilization of a filtration technique for the more complete separation of mitochondrial and secretory granule elements permitted us to show that the recovery of lipid-bound 2-(3H)-myoinositol increased most rapidly in the secretory granule fraction. A 30-minute exposure of prelabeled islets to a stimulatory concentration of D-glucose (3.0 mg./ml.) resulted in a statistically significant decrease in the amount of lipid-bound 2-(3H)-myoinositol that was recovered from the secretory granule fraction (p less than 0.001). In contrast, exposure of islets to the elevated glucose concentration had no statistically significant effect on the recovery of lipid-bound radioactivity from other subcellular fractions. Since the majority of lipid-bound radioactivity associated with the secretory granule fraction could be recovered with the presumptive secretory granule membranes, these data suggest that the hydrolysis of phosphatidylinositol that accompanies glucose-induced insulin secretion from the rat pancreatic islet may be localized to the beta granule and, in particular, to its limiting membrane.
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.
Since many cell types have been shown to respond to extracellular stimulation with a rapid increase in phosphatidylinositol turnover, the present studies were undertaken to determine whether carbohydrate-stimulated insulin secretion from the isolated rat pancreatic islet is accompanied by detectable alterations in the phosphatidylinositol metabolism of this tissue. We have demonstrated that rat pancreatic islets incubated with tritiated myo-inositol rapidly incorporate radioactivity into islet phosphatidylinositol. Incubation of prelabeled islets with elevated concentrations of carbohydrates which stimulate insulin secretion (D-glucose and D-mannose) results in a decrease in the recovery of lipid-bound radioactivity, whereas incubation with carbohydrates which do not stimulate insulin secretion (D-galactose and myo-inositol) has no effect upon the recovery of lipid-bound radioactivity. Within 2 min of exposure of prelabeled islets to elevated concentrations of D-glucose, a decrease in the recovery of [2-3H]myo-inositol-derived radioactivity in islet phosphatidylinositol can be demonstrated. When islets prelabeled with [2-3H]myo-inositol are perifused with elevated concentrations of D-glucose or D-mannose (but not D-galactose or myoinositol) a rapid and transient increase in the rate of extracellular release of water-soluble radioactivity is observed. Since a significant fraction of the radioactivity released under these conditions is in the form of myo-inositol phosphate, cyclic myo-inositol-1,2-phosphate, and glycerophosphorylmyo-inositol, it is presumably derived from the cleavage of labeled islet phosphatidylinositol. It is speculated that alterations in the metabolism of myo-inositol-containing phospholipids may have a functional role in the process of insulin secretion from the pancreatic beta cell.
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The effects of elevated glucose concentrations on the metabolism of the aortic wall were examined in a preparation of tubular segments of rabbit descending thoracic aorta comprised of intima and media only. Increased medium glucose concentrations (20-50 mm) resulted in increased aortic sorbitol and fructose concentrations and an increased rate of fructose release into the medium. This increased flux through the polyol pathway can be explained as a consequence both of an increased free intracellular glucose concentration and of the kinetic characteristics of the alditol: NADP oxidoreductase and the l-iditol: NAD oxidoreductase isolated and partially purified from rabbit thoracic aorta. Incubation with elevated glucose concentrations for 2 or more hr was also associated with a significant increase in the water content of the tissue without a significant increase in the inulin space. The oxygen uptake of the tissues incubated with elevated glucose concentrations was significantly reduced; this appears to result from a limitation imposed by oxygen diffusion at physiological oxygen tensions. A compensatory increase in glycolysis and an increase in the aortic lactate/pyruvate concentration ratio were also observed. The oxygen uptake and lactate production of tissue incubated with 50 mm glucose could be preserved at rates observed in tissue incubated with a physiological glucose concentration by the addition of 40 mm mannitol to the medium. Aortic intima and media from alloxan-diabetic rabbits also exhibit an increased water content and a decreased rate of oxygen uptake. These observations suggest that elevated ambient glucose concentrations result in significant alterations in the metabolism of aortic intima and media.