Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In some tissues containing aldose reductase, increased flux through the polyol pathway has been implicated as being causative in diabetic complications (e.g., cataracts, peripheral neuropathy). We have found CP-45,634 (d-6-fluoro-spiro[chroman-4,4'-imidazolidine]-2',5'-dione) to be a highly potent, structurally novel, uncompetitive inhibitor of calf lens aldose reductase (IC50 approximately 5 X 10(-7)M). In a system in which sorbitol accumulation in isolated rat sciatic nerves was monitored in the presence of high (50 mM) glucose concentrations, CP-45,634 produced inhibition of polyol accumulation at levels as low as 1 X 10(-6)M. To determine if in vitro activity would translate to in vivo models, sorbitol accumulation in rat sciatic nerves was measured 27 hr after induction of diabetes with streptozotocin. Orally administered CP-45,634 was effective at dose levels as low as 0.25 mg/kg, t.i.d., and at 0.75 mg/kg produced an 85% inhibition of sorbitol accumulation. Two weeks after induction of diabetes by streptozotocin, sorbitol levels in rat lens and the sciatic nerve rose to 21,203 nmole/gm and 1,161 nmole/gm, respectively. Subsequent oral administration of CP-45,634 (2.5 mg/kg, b.i.d.) for 1 wk reduced these levels by 92% in nerves and 90% in lenses. In galactosemic rats, CP-45,634 inhibited the rise in lens galactitol and effectively delayed cataract formation at oral doses as low as 5 mg/kg/day. These high levels of in vivo activity suggest that CP-45,634 has potential for assessing the role of the polyol pathway in diabetic complications.
 ...
PMID:CP-45,634: a novel aldose reductase inhibitor that inhibits polyol pathway activity in diabetic and galactosemic rats. 12 97

Testosterone affects glycogen levels in perineal and skeletal muscles by two distinct mechanisms. Both of them show similar sensitivity to androgens (0.1 mg/rat/day of testosterone being effective) and to antiandrogen administration. However, they differ because of the pattern of glycogen increase (early after the androgen injection in the perineal muscles; slowly and with a linear function of time in the skeletal muscles), and because of the different sensitivities to adrenolectomy, diabetes and hypophysectomy. Also, the biochemical changes induced by testosterone in muscles differ. The rate of sugar uptake and phosphorylation is increased in the perineal muscle only; the rate of glucose incorporation into glycogen is increased in the perineal but depressed in the skeletal muscles. Therefore, in the former case glycogen accumulation depends mainly on increased synthesis; in the latter, it is probably the result of a glycogen sparing effect.
 ...
PMID:Different mechanisms in testosterone action on glycogen metabolism in rat perineal and skeletal muscles. 12 15

Diabetes was induced in Lewis rats with streptozotocin. Six to eight months later glomeruli showed mesangial thickening: IgG, IgM and C3 were seen in large quantities in the mesangium by immunofluorescent microscopy. Ten animals then had successful pancreatic transplantation resulting in normal glucose and insulin levels within one to three weeks. Biopsies obtained within the first two weeks following transplantation demonstrated a significant reduction in mesangial thickening and in mesangial staining for IgG, IgM and C3. Three to four weeks after transplantation C3 staining was no longer detected. A gradual reduction in mesangial IgG and IgM localization continued so that by nine weeks following islet transplantation only minimal staining for immunoglobulins was present. Although mesangial thickening was reduced, this abnormality could still be detected in most animals six to nine weeks after transplantation. Three rats showed improvement in glomerular morphology within two weeks despite persistent hyperglycemia. These rats had normal insulin levels at this time. Islet transplantation in inbred diabetic rats effectively returns glucose and insulin levels to normal and results in rapid regression of the light microscopic and immunopathologic glomerular lesions. These studies support the concept of reversible mesangial dysfunction in diabetic rats.
Diabetes 1975 Mar
PMID:Studies of the rate of regression of the glomerular lesions in diabetic rats treated with pancreatic islet transplantation. 12 9

The hyperglucagonemia that occurs in vivo in animals made diabetic with alloxan or streptozotocin is not suppressed by high glucose but is suppressed by exogenous insulin. These observations together with other studies suggested that insulin-dependent glucose transport and metabolism by the alpha-cells serves as the primary mechanism controlling glucagon secretion. This hypothesis was tested in the present investigation. The possible interactions between glucose, insulin, and a mixture of 20 amino acids at physiological proportions were examined in the isolated-perfusin diabetic rats. Release of insulin and glucagon were used as indicators of theta-cell and alpha-cell function. According to rigid criteria the diabetic animals entering the study were severely diabetic. It was found that in vitro: (a) basal glucagon release (measured in the absence of an alpha-cell stimulus or inhibitor) was extremely low, even lower (i.e. 10%) than the basal rates seen in controls; (b) the alpha-cells of alloxanized- and streptozotocin-treated rats responded with a biphasic glucagon release to stimulation by an amino acid mixture; (c) this alpha-cell response was reduced after both streptozotocin and alloxan; (d) glucose at 5 mM was a potent inhibitor of amino acid-induced glucagon secretion in both types of experimental diabetes; (e) in alloxan diabetes alpha-cell stimulation by amino acids can be curbed by exogenous insulin, whereas glucagon secretion by the perfused pancreas of streptoxotocin diabetic rats appeared to be resistant to insulin action. The data indicate that the modulation of glucagon secretion by glucose in vitro is indipendent of insulin and that other unknown factors extrinsic to the pancreatic islets are responsible for the hyperglucagonemia observed in vivo.
 ...
PMID:Insulin and glucose as modulators of the amino acid-induced glucagon release in the isolated pancreas of alloxan and streptozotocin diabetic rats. 12 28

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.
 ...
PMID:Effects of insulin and dietary myoinositol on impaired peripheral motor nerve conduction velocity in acute streptozotocin diabetes. 12 20

The effect of streptozotocin-induced diabetes mellitus on both the host and the parasite was studied in mice infected with Schistosoma mansoni. Neither the drug nor the marked rise in concentration of blood glucose had any effect on penetration of the skin by the cercariae, their subsequent maturation into adult worms, or their output of eggs. During the acute stages of the infection (at eight weeks), the diabetic animals showed marked suppression of the host granulomatous reaction to schistosome eggs trapped in the liver, accompanied by an alleviation of hepatosplenic disease. During the chronic stages of infection (at 16 weeks), there was a pronounced megalocytosis of the hepatocytes only in the infected animals with streptozotocin-induced diabetes; these animals also had an exacerbation of hepatosplenic disease.
 ...
PMID:Streptozotocin-induced diabetes mellitus and the host-parasite relation in murine schistosomiasis mansoni. 12 23

The intravenous application of 60 mg streptozotocin/kg body weight to a Hanford miniature pig 8 days after a first dose of 30 mg/kg led to a diabetes with loss of insulin response to glucose, hyperglycaemia, glucosuria and a considerable increase of triglycerides and cholesterol. The application of 40 mg streptozotocin/kg to a second pig had no effect.
 ...
PMID:[Streptozotocin diabetes in a miniature pig (author's transl)]. 12 57

Pancreatic tissue fragments from neonatal inbred Lewis rats were distributed throughout the peritoneal cavities of isologous diabetic recipients receiving prednisolone on a schedule similar to that used in clinical transplantation beginning 9-44 days before transplantation. Plasma glucose levels in six of seven diabetic rats receiving prednislone returned to normal levels 3 weeks after transplantation. Plasma insulin levels in the animals with successful transplants reached, at 1 week after transplantation, levels measured in normal control rats, but never attained the high insulin levels observed in the normal control animals receiving steroids. As with glucose the insulin levels remained in the normal range, and the animals steadily gained weight. During i.v. glucose tolerance tests (IVGTTs) in the rats with successful transplants at 4, 11-14, and 26-29 weeks after transplantation, the glucose levels were similar to those observed during IVGTTs in the control animals before and during corticosteroid therapy. In contrast, insulin levels during the IVGTTs were lower in the rats with successful transplants than in the control rats with or without steroids; however, insulin release during the IVGTTs was rapid in all animals, both with successful transplants and controls. These observations demonstrate that islet tissue implanted in the peritoneal cavities of diabetic rats receiving immunosuppressive chronic corticosteroid therapy can respond with a rapid and sufficient release of insulin to reverse diabetes as documented by normal glucose levels under stimulated and nonstimulated conditions.
 ...
PMID:Islet transplantation in diabetic rats receiving corticosteroids. 12 86

To evaluate the role of the glucose residue of the diabetogenic substance streptozotocin, the effect of its aglucone derivate N-nitrosomethylurea was tested in Chinese hamsters. At a dose of 50 mg/kg body weight of N-nitrosomethylurea a triphasic blood glucose curve was recorded with an initial hyperglycaemic peak after 3 hours followed by a decrease at 6 hours. After 24 hours and during the following days the values were moderately elevated. There was a high mortality in the diabetic animals, about 80 per cent of them dying within one week. The approximate L.D. 50 of N-nitrosomethylurea injected intraperitoneally in non-fasting adult animals was about 125 mg/kg body weight at an observation time of 48 hours. On light microscopy, degenerative changes with nuclear pyknosis were seen after 3 hours in the pancreatic islet cells, followed by cellular disintegration. Both beta-, alpha2- and alpha1-cells were obviously affected. Pretreatment with 500 mg nicotinamide/kg body weight given intraperitoneally 10 minutes before the injection of N-nitrosomethylurea inhibited and hyperglycaemia and seemed to prevent the injurious effects of N-nitrosomethylurea on the islet cells. The results show that the glucose residue of the streptozotocin molecule is not necessary for the induction of diabetes in Chinese hamsters, but it seems to increase the selectivity of the toxic effects for the islet cells. This is a clear advantage in studies of experimental diabetes, especially when longer observation periods are desired.
 ...
PMID:Diabetogenic effects of n-nitrosomethylurea in the chinese hamster. 12 26

A series of in vivo and in vitro investigations was performed to examine the localisation of sorbitol pathway activity in the rat renal cortex and to investigate the possible relation that the acculumation of sorbitol pathway intermediates in renal cortical tissue may have to the pathogenesis of renal complications in diabetes mellitus. Neither of the sorbitol pathway intermediates, sorbitol or fructose, were detected either in intact glomeruli which had been isolated from rats rendered chronically diabetic with streptozotocin, or in metabolically active glomeruli which had been incubated in vitro in high glucose media. Such data agreed with previously published observations that the enzyme aldose reductase is not present in renal glomeruli, and suggested that changes in sorbitol pathway activity cannot be directly related to the pathogenesis of diabetic glomerulosclerosis. Sorbitol was detected in low concentrations (3.1 mu-mol/g protein) in cortical tubules which had been isolated from the renal cortex of rats rendered chronically diabetic with streptozotocin. This concentration of sorbitol was higher than that in the intact renal cortex of the diabetic animal (0.3 mu-mol/g protein) or in the cortical tubules of non-diabetic animals (0.5 mu-mol/g protein). It is apparent that the renal cortical tubule is a major site of sorbitol pathway activity in the renal cortex. However, there is presently no obvious causal relationship between the accumulation of such relatively low concentrations of sorbitol in the renal cortical tubule and the pathogenesis of glomerulosclerosis or cortical tubular lesions in diabetes.
 ...
PMID:The localisation of sorbitol pathway activity in the rat renal cortex and its relationship to the pathogenesis of the renal complications of diabetes mellitus. 12 79


<< Previous 1 2 3 4 5 6 7 8 9 10