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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Diabetes, with only mild ketosis, was induced in male rats by a single injection of streptozotocin. After 12 weeks the specific activities of enzymes concerned with the metabolism of inositol and of inositol lipids were measured in various tissues. Inositol 1-phosphate synthase (EC 5.5.1.4) was most active in testis and the activity was significantly less in diabetic rats than in controls on a similar diet. Inositol oxygenase (EC 1.13.99.1), which converts myo-inositol into glucuronic acid, was also less active in kidney from diabetic animals. CDP-diacylglycerol-inositol phosphatidyltransferase (EC 2.7.8.11) and phosphatidylinositol 4-phosphate kinase (EC 2.7.1.68) showed decreased specific activities in brain and sciatic nerve of diabetic rats. By contrast the diabetic state did not affect the specific activities of phosphatidylinositol kinase (EC 2.7.1.67) or phosphatidylinositol 4,5-bisphosphate phosphatase (EC 3.1.3.36) in these tissues. The results are discussed in relation to diabetic neuropathy.
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PMID:Enzymes of myo-inositol and inositol lipid metabolism in rats with streptozotocin-induced diabetes. 22 62

The changes in the concentration profile of free carbohydrates (glucose, sorbitol, fructose and myo-inositol) in rat lens and retina were studied in the first 5 days following induction of diabetes with streptozotocin. In both tissues, the total concentration of free carbohydrate increased markedly in this period. In the lens, the major component was sorbitol, whereas in the retina the major component was glucose. Myoinositol loss occurred only in the lens. The significance of these early changes in carbohydrate concentrations are discussed in relation to the development of subsequent metabolic derangements.
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PMID:Initial changes in the free carbohydrate profile of rat lens and retina following streptozotocin-induced diabetes. 53 Feb 67

Changes in cerebrospinal fluid (CSF) concentrations of sorbitol and myoinositol in 21 patients with diabetic polyneuropathy were studied with gas-liquid chromatography. The sorbitol concentration was significantly increased in diabetic patients with elevated plasma glucose. Myoinositol concentration was significantly decreased in patients with polyneuropathy compared with the controls. Both alterations in polyol concentrations of the CSF were present already two months from onset of symptoms of diabetes. Patients with peripheral polyneuropathy receiving oral hypoglycemic drugs did not have elevated plasma glucose and CSF sorbitol levels, but showed significantly decreased CSF myoinositol concentrations compared with the controls. These observations suggest that myoinositol concentration may be decreased in the central nervous system in adult onset mild diabetes with normal plasma glucose and that the decrease in the myoinositol in CSF possibly is connected with the development of neuropathy.
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PMID:Cerebrospinal fluid sorbitol and myoinositol in diabetic polyneuropathy. 92 Feb 49

Although inhibition of Na(+)-K+ ATPase has been described in the diabetic heart, K+ loss from myocardium has not been observed in a canine model of mild diabetes. The finding of tissue Na+ accumulation and a potential relation to alteration of left ventricular inositol as observed in other tissues in diabetes form the basis of this investigation. Diabetes was induced with alloxan in three groups of male mongrel dogs who were studied after 1 yr. In the initial experiment the tissue compartment volumes, determined with intravenous 51Cr EDTA as a marker, were found to be normal. Calculated cell sodium was increased to 32.8 +/- 2.6 mEq/kg cell H2O vs 18.7 +/- 1.1 in controls (p < 0.01). Cell potassium in diabetes was normal. In the second group, myocardial polyols were analyzed by gas-liquid chromatography. Inositol was diminished in diabetes to 0.61 +/- 23 microM/g of left ventricle, vs the respective control levels of 1.9 +/- 0.57 microM/g (p < 0.02). Sorbitol concentration was unaltered. Left ventricular sodium increments were not associated with altered tissue calcium. In group III the hypothesis that inhibition of Na(+)-K+ ATPase in diabetes might not elicit the expected alteration of K+ transport was assessed during intracoronary infusion of acetyl strophanthidin. No difference in cation responses from control was observed. It is postulated that a change in the conformation of Na(+)-K+ ATPase, with high affinity sodium binding sites facing the intracellular compartment, may render sodium less releasable from cell membrane.
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PMID:Myocardial inositol and sodium in diabetes. 133 48

Attenuation of both the active transport of myo-inositol and Na(+)-K(+)-ATPase pumping activity has been implicated in the onset of sugar cataract and other diabetic complications in cell culture and animal models of the disease. Cultured bovine lens epithelial cells (BLECs) maintained in galactose-free Eagle's minimal essential medium (MEM) or 40 mM galactose with and without sorbinil for up to 5 days were examined to determine the temporal effects of hypergalactosemia on Na(+)-K(+)-ATPase and myo-inositol uptake. The Na(+)-K(+)-ATPase pumping activity after 5 days of continuous exposure to galactose did not change, as demonstrated by 86Rb uptake. The uptake of myo-[3H]inositol was lowered after 20 h of incubation in galactose and remained significantly below that of the control throughout the 5-day exposure period. The coadministration of sorbinil to the galactose medium normalized the myo-[3H]inositol uptake. No significant difference in the rates of passive efflux of myo-[3H]inositol or 86Rb from preloaded galactose-treated and control cultures was observed. Culture-media reversal studies were also carried out to determine whether the galactose-induced dysfunction in myo-inositol uptake could be corrected. BLECs were incubated in galactose for 5 days, then changed to galactose-free physiological medium with and without sorbinil for a 1-day recovery period. myo-Inositol uptake was reduced to 34% of control after 6 days of continuous exposure to galactose. Within 24 h of media reversal, myo-inositol uptake returned to or exceeded control values in BLECs switched to either MEM or MEM with sorbinil.2+ reversible and occurred independently of changes in Na(+)-K(+)-ATPase pumping activity in cultured lens epithelium, indicating that the two parameters are not strictly associated and that the deficit in myo-inositol uptake occurs rapidly during hypergalactosemia.
Diabetes 1991 Jun
PMID:Uncoupling of attenuated myo-[3H]inositol uptake and dysfunction in Na(+)-K(+)-ATPase pumping activity in hypergalactosemic cultured bovine lens epithelial cells. 164 82

myo-Inositol uptake by culture neuroblastoma cells at a concentration of myo-inositol less than 50 microM was largely Na+ dependent. Exposing neuroblastoma cells to media supplemented with increasing concentrations of myo-inositol resulted in an increase in myo-inositol accumulation and intracellular content, but myo-inositol incorporation into phospholipids was not increased. The data indicate that myo-inositol exists as separate pools in neuroblastoma cells, and one or more of these pools may contribute to phospholipid synthesis. Exposing neuroblastoma cells to an increased concentration of glucose caused a decrease in myo-inositol uptake by two separate mechanisms. Acute exposure of the cells to 30 mM glucose caused a myo-inositol concentration-dependent decrease in Na(+)-dependent myo-inositol uptake. We propose that the acute inhibition of myo-inositol uptake by glucose is likely due to a competitive type of inhibition. Chronic exposure of cells to media containing 30 mM glucose or 30 mM galactose also caused decreases in myo-inositol uptake and incorporation into inositol phospholipids and intracellular myo-inositol content. This decrease in myo-inositol metabolism persisted at a higher concentration of external myo-inositol than the acute inhibition. Supplementing media containing 30 mM glucose or 30 mM galactose with 250 microM myo-inositol restored myo-inositol metabolism and content. The inhibition of myo-inositol uptake by cells chronically exposed to increased concentrations of glucose or galactose was due to a noncompetitive type of inhibition that was blocked by the addition of sorbinil. Chronic exposure of neuroblastoma cells to media containing 30 mM glucose or 30 mM galactose caused a decrease in Na(+)-K(+)-ATPase transport activity and resting membrane potential.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1991 Feb
PMID:Restoration of Na(+)-K+ pump activity and resting membrane potential by myo-inositol supplementation in neuroblastoma cells chronically exposed to glucose or galactose. 184 27

Previous studies indicate that experimental diabetic autonomic neuropathy can be largely prevented by initiating therapy at the onset of diabetes. More clinically relevant, however, is the ability of therapy to reverse established neuropathy produced by long-standing diabetes. We have examined the effect of selected therapies on established neuroaxonal dystrophy (NAD) in ileal mesenteric nerves, a rat model of diabetic autonomic neuropathy. Groups of 3-mo-old rats were made diabetic with streptozocin (STZ-D) and allowed to survive untreated for 5 mo, at which time they were begun on sorbinil, dietary myo-inositol, and daily insulin therapies or left untreated for an additional 2 or 4 mo. Ultrastructural evidence of NAD was demonstrated in ileal mesenteric nerves of rats with untreated 5-mo STZ-D and increased with the duration of diabetes. No lesions were demonstrated in control rats of any age. myo-Inositol or sorbinil administration failed to alter the severity of diabetes as measured by its metabolic indices. Institution of sorbinil or insulin treatment at 5 mo of diabetes prevented the increase in, but did not normalize, NAD at 7 or 9 mo. Dietary myo-inositol failed to significantly reverse established NAD or prevent its initial development. Morphometric examination of ileal mesenteric nerves demonstrated a decrease in the number of axons comprising each diabetic Schwann cell unit, suggestive of chronic cycles of axonal degeneration and regeneration. This parameter, clearly abnormal by 5 mo of diabetes, was not normalized by 2 or 4 mo of insulin, sorbinil, or myo-inositol treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1991 May
PMID:Effects of sorbinil, dietary myo-inositol supplementation, and insulin on resolution of neuroaxonal dystrophy in mesenteric nerves of streptozocin-induced diabetic rats. 190 27

The "myo-inositol depletion hypothesis" remains a leading but still controversial contender among proposed pathogenetic mechanisms for the chronic complications of diabetes. The multifaceted interrelationships among altered tissue myo-inositol content and metabolism and tissue function have been difficult to elucidate in diabetic animal models due in part to the complex, heterogeneous nature of tissues prone to diabetic complications. The retinal pigment epithelium consists of a homogenous cell monolayer that exhibits related alterations in myo-inositol metabolism and function in diabetic animals. Nontransformed human retinal pigment epithelial (hRPE) cells, which retain their general phenotypic and morphological characteristics during monolayer culture in vitro, were examined for parallel alterations in myoinositol metabolism and cell function when grown under carefully controlled conditions in medium containing hyperglycemic concentrations of glucose. Exposure of hRPE cells to 20-40 mM glucose produced time- and dose-dependent increases in sorbitol content and decreases in myo-inositol content that were partially blocked by the aldose reductase inhibitor sorbinil. myo-Inositol was taken up by two Na-dependent transport systems, at least one of which was competitively inhibited by glucose. Exposure to 20 mM glucose impaired the ability of hRPE cells to take up human retinal rod outer segments, an important physiological function of these cells. The impairment of rod outer segment uptake by high glucose levels was prevented by an aldose reductase inhibitor or elevated medium myo-inositol that corrected the fall in myo-inositol content. Thus, hRPE cells provide a new in vitro model in which to examine the biochemical-functional interrelationships of the myo-inositol depletion hypothesis.
Diabetes 1991 Oct
PMID:Sorbitol, myo-inositol, and rod outer segment phagocytosis in cultured hRPE cells exposed to glucose. In vitro model of myo-inositol depletion hypothesis of diabetic complications. 193 95

Although activation of polyol pathway has been proposed as one of the etiologic factors of diabetic complications, precise mechanism of the effect of polyol accumulation is still unclear. In order to test the hypothesis that there is an association of polyol pathway with myo-inositol metabolism, we measured myo-inositol content in cultured rat glomerular mesangial cells. By exposing the cells to high concentrations of glucose, intracellular myo-inositol content was reduced from 12.39 +/- 0.64 nmol/mg protein at 0 mmol/L glucose to 6.54 +/- 0.38 nmol/mg protein at 27.5 mmol/L glucose and 4.88 +/- 0.43 nmol/mg protein at 55 mmol/L glucose. This decrease of myo-inositol content was partially prevented by co-incubation with aldose reductase inhibitor, sorbinil. To examine further the mechanism of myo-inositol depletion, myo-inositol uptake by mesangial cells was studied. Major myo-inositol uptake process was sodium-dependent, saturable, and ouabain sensitive with Vmax of 171 pmol/mg protein/20 min and Km of 33 mumol/L. Sodium-dependent myo-inositol uptake was significantly inhibited by glucose in a dose-dependent manner only when glucose was present during uptake experiment, and kinetic analysis revealed the inhibition was competitive. Aldose reductase inhibition failed to prevent inhibitory effect of glucose on myo-inositol uptake. These data suggest that myo-inositol content of glomerular mesangial cells, which is reduced by high concentrations of glucose, is maintained by two processes: a glucose-sensitive but sorbitol-insensitive process, sodium-dependent myo-inositol uptake; and a sorbitol (aldose reductase) sensitive process, myo-Inositol depletion under high glucose condition may induce dysfunction of mesangial cells seen in diabetes.
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PMID:Glucose inhibits myo-inositol uptake and reduces myo-inositol content in cultured rat glomerular mesangial cells. 210 41

This review considers the definition of clinical diabetic neuropathy and the theoretical basis for the use of aldose reductase inhibitors in the treatment of distal sensorimotor neuropathy, the most common clinical problem. Myoinositol depletion is related to hyperglycaemia-induced polyol activity, changes which are associated with early functional deficits in acute experimental diabetes. These changes are reversible by the administration of aldose reductase inhibitors, and this provides the rationale for the treatment of human diabetic neuropathy with these agents. Many early trials of these drugs have produced some evidence of clinical benefit in patients with diabetic neuropathy, but interpretation of data is difficult as patient selection and neuropathy definition are not yet standardised. In addition, it is possible that once the neuropathic process is initiated, there is a point where it becomes irreversible, and treatment with aldose reductase inhibitors may therefore be of more relevance in early neuropathy. Long term double-blind multicentre trials are in progress, and preliminary data from some of these are reasonably encouraging. In conclusion, the results from clinical trials of the aldose reductase inhibitors in this difficult area are sufficiently encouraging to lead us to be optimistic about their future development, and continuing work should clarify their potential role with respect to the prophylaxis and treatment of diabetic neuropathy.
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PMID:Aldose reductase inhibitors in the treatment of diabetic neuropathy. A review of the rationale and clinical evidence. 210 78


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