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

Liver protein kinase was determined in the absence and presence of cAMP4. Experimental alloxan diabetes resulted in a decrease in total protein kinase (+cAMP) and an increase in the activity ratio (-cAMP) divided by (+cAMP) in liver. Insulin treatment of diabetic rats reversed the observed changes in protein kinase in liver. Glucagon administered in vivo to normal rats caused an increase in the activity ratio and a decrease in total protein kinase activity in liver. The changes are similar to those in diabetes. A decrease in the ratio of insulin to glucagon in diabetes may account for the changes in protein kinase observed.
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PMID:Effect of experimental diabetes and glucagon on cAMP-dependent protein kinase in rat liver. 19 20

The effects of streptozotocin-induced diabetes and of insulin supplementation to diabetic rats on glycogen-metabolizing enzymes in liver were determined. The results were compared with those from control animals. The activities of glycogenolytic enzymes, i.e. phosphorylase (both a and b), phosphorylase kinase and protein kinase (in the presence or in the absence of cyclic AMP), were significantly decreased in the diabetic animals. The enzyme activities were restored to control values by insulin therapy. Glycogen synthase (I-form) activity, similarly decreased in the diabetic animals, was also restored to control values after the administration of insulin. The increase in glycogen synthase(I-form) activity after insulin treatment was associated with a concomitant increase in phosphoprotein phosphatase activity. The increase in phosphatase activity was due to (i) a change in the activity of the enzyme itself and (ii) a decrease in a heat stable protein inhibitor of the phosphatase activity.
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PMID:The effect of streptozotocin-induced diabetes and of insulin supplementation on glycogen metabolism in rat liver. 20 91

The loss of glucose regulation of glycogen synthase in perfused livers from diabetic rats was associated with a substantial reduction in synthase phosphatase activity. Treatment of diabetic rats with insulin alone resulted in total restoration of the glucose effect and synthase phosphatase activity, while simultaneous treatment with cycloheximide severely reduced the hormonal effect. Although treatment of normal rats with cycloheximide had no effect on glucose activation of synthase, it did result in severe depletion of liver glycogen, increased liver glycogen phosphorylase activity, and elevation of liver adenosine 3',5'-monophosphate (cyclic AMP), but without elevation of liver protein kinase activity. Simultaneous treatment of alloxan-diabetic rats with insulin and cycloheximide resulted in reduction of total liver glycogen, increased phosphorylase activity, a reduction in the ability of insulin to lower hepatic cyclic AMP, and a further reduction of protein kinase activity. In summary, the effect of insulin treatment of diabetic rats to restore glucose regulation of hepatic glycogen synthase probably involves synthesis of new protein, and the data remain consistent with the hypothesis that the defect may be due to a diabetes-related deficiency in a specific synthase phosphatase and/or alteration of the synthase molecule itself.
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PMID:Glucose activation of liver glycogen synthase. Insulin-mediated restoration of glucose effect in diabetic rats is blocked by protein synthesis inhibitor. 21 47

1. Regulation of gluconeogenic substrate supply and modulation of the gluconeogenic pathway in the liver are both important in the control of gluconeogenesis by glucocorticoids. 2. Adrenal deficiency decreases the release of gluconeogenic and other amino acids from skeletal muscle during starvation. The effect is reversed by glucocorticoid replacement. The changes in amino acid release are accompanied by similar alterations in tissue amino acid levels and are not explained by alterations in net protein breakdown. Glucocorticoids do not alter protein catabolism and cause a small inhibition of protein synthesis. The biochemical alterations underlying the changes in amino acid metabolism induced by these steroids remain to be elucidated. Glucocorticoids may also regulate the supply of gluconeogenic substrates through permissive effects on the lipolytic action of catecholamines and other hormones in adipose tissue and on the glycogenolytic action of catecholamines on skeletal muscle. 3. Glucocorticoids are required for the increases in gluconeogenesis in starvation and diabetes. Part of their action is exerted directly on the liver and appears to involve modulation of P-enlopyruvate carboxykinase levels. Glucocorticoids increase the synthesis of this enzyme apparently through effects at the level of transcription. 4. Glucocorticoids exert permissive effects on the stimulation of gluconeogenesis in the liver by glucagon and epinephrine. The steroids are not required for cAMP generation or protein kinase activation by these hormones, but appear to act by maintaining the responsiveness of certain enzymes to the effects of the cAMP and alpha-adrenergic systems. It is proposed that this involves the maintenance of a normal intracellular ionic environment.
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PMID:Regulation of gluconeogenesis by glucocorticoids. 38 91

PGE1 has been found to improve the symptoms of diabetic neuropathy. We considered that a PGI2 derivative may also have a similar action and therefore studied its effect in diabetic rats. Iloprost was administered intraperitoneally to streptozotocin-induced diabetic rats at a dose of 10 micrograms/kg/day for a month. The changes in nerve conduction velocity (NCV) were measured in the tail. One day after the last dose of iloprost, both sciatic nerves were removed from each rat, homogenized, and extracted with 6% TCA. The sorbitol and myo-inositol concentrations were determined by a combination of HPLC and an enzymatic method. Cyclic AMP (cAMP) levels were determined by RIA, and Na+, K+ ATPase activity was assessed by the enzyme cycling method of Greene and Lattimer. Iloprost was found to improve the NCV in the diabetic rats. The sorbitol content was not affected by iloprost, but the myo-inositol content was higher in the iloprost group than in the untreated group, although the difference was not statistically significant. The Na+, K+ ATPase activity and cAMP content were significantly higher in the iloprost group than in the untreated group. These findings suggest the possibility that the cAMP-dependent protein kinase (A-kinase) system has an important influence on improvement in Na+, K+ ATPase activity.
Diabetes Res Clin Pract 1992 Nov
PMID:Effect of a prostaglandin I2 derivative (iloprost) on peripheral neuropathy of diabetic rats. 128 52

The growth of new blood vessels plays an important role in the pathogenesis of several diseases including cancer, diabetes, and arthritis. Beta-cyclodextrin tetradecasulfate, when administered with an appropriate steroid inhibits angiogenesis, and can stimulate angiogenesis when given alone. The regulation of angiogenesis is not well understood, and the mechanism of action of beta-cyclodextrin tetradecasulfate is similarly not well defined. Ecto-protein kinase activity that utilizes extracellular ATP has recently been reported on several types of cells. Human neutrophils appear to possess two distinct ecto-protein kinase activities; one that phosphorylates exogenous substrates including vitronectin and basic fibroblast growth factor, and one that phosphorylates endogenous cell-surface proteins. This report shows that beta-cyclodextrin tetradecasulfate inhibits the phosphorylation of the exogenous substrates casein, vitronectin (the major ecto-protein kinase substrate in serum), and basic fibroblast growth factor by human neutrophil ecto-protein kinase activity. In contrast, beta-cyclodextrin tetradecasulfate had no effect on the phosphorylation of endogenous cell-surface proteins by the neutrophil ecto-protein kinase activity. Ecto-protein kinase activity that was inhibited by beta-cyclodextrin tetradecasulfate was also detected on porcine aortic and human umbilical vein endothelial cells. The effects of beta-cyclodextrin tetradecasulfate on ecto-protein kinase activities may play a role in its effects on angiogenesis.
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PMID:The angiogenesis inhibitor beta-cyclodextrin tetradecasulfate inhibits ecto-protein kinase activity. 128 48

Patients with non-insulin-dependent diabetes mellitus (NIDDM) had an impaired capability to activate exogenous ATP.Mg-dependent protein phosphatase in lymphocytes compared with nondiabetic subjects. More importantly, the impaired protein phosphatase activation in the lymphocytes of patients with NIDDM could be consistently and completely restored to normal by exogenous pure protein kinase FA (the activating factor of ATP.Mg-dependent protein phosphatase), indicating that the molecular mechanism for the impaired protein phosphatase activation in patients with NIDDM is due to a functional loss of kinase FA. By contrast, both NIDDM patients and nondiabetic subjects had similar levels of total cell proteins and spontaneously active protein phosphatase activity in their lymphocytes, indicating that the dysfunction of kinase FA in patients with NIDDM is very specific. Statistical analysis further revealed that the lymphocytes isolated from 21 nondiabetic subjects contained high levels of FA activity (148 +/- 22 mU/mg cell protein), whereas, the lymphocytes of 21 patients with NIDDM contained low levels of FA activity (50 +/- 22 mU/mg), indicating statistically significant differences in FA activity between diabetic patients and nondiabetic subjects. This is the first report providing initial evidence that patients with NIDDM may statistically have a common impairment in the protein phosphatase activation in their lymphocytes and that the molecular mechanism for this defect is due to a biochemical dysfunction of protein kinase FA, a biological mediator for both insulin and epidermal growth factor.
Diabetes 1992 Jan
PMID:Dysfunction of insulin mediator protein kinase FA in lymphocytes of patients with NIDDM. 130 56

The activity of a bifunctional enzyme, liver 6-phosphofructo-2-kinase (PFK-2)/fructose-2,6-bisphosphatase (F-2,6-Pase), which regulates the level of liver fructose-2,6-bisphosphate (F-2,6-P2), the most potent activator of PFK, is modulated by its phosphorylation rate mainly catalyzed by cAMP-dependent protein kinase A (PKA). To elucidate the action mechanism of sulfonylurea on liver F-2,6-P2 production, effects of tolbutamide on PKA-dependent phosphorylation of purified liver PFK-2/F-2,6-Phase protein and on kinase and phosphatase activities of the purified enzyme were examined in vitro. The purified enzyme was phosphorylated in the presence of the catalytic subunit of PKA, and tolbutamide inhibited the enzyme phosphorylation catalyzed by PKA in a dose-dependent manner. By adding the same dosages of tolbutamide used in the phosphorylation experiment, reduced activity of PFK-2 and increased activity of F-2,6-Pase in the presence of PKA were restored to the levels observed in the absence of PKA. On the other hand, carboxytolbutamide, an inactive metabolite of tolbutamide, had little effect on enzyme phosphorylation and activity. Our results indicate that tolbutamide inhibits a phosphorylation of the liver PFK-2/F-2,6-Pase catalyzed by PKA along with an activation of PFK-2 and an inactivation of F-2,6-Pase, leading to liver F-2,6-P2 production.
Diabetes 1992 Mar
PMID:Tolbutamide inhibits cAMP-dependent phosphorylation of liver 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase. 131 65

In human diabetes, inherent impaired insulin secretion can be exacerbated by desensitization of the beta cell by chronic hyperglycemia. Interest in this phenomenon has generated extensive studies in genetic or experimentally induced diabetes in animals and in fully in vitro systems, with often conflicting results. In general, although chronic glucose causes decreased beta-cell response to this carbohydrate, basal response and response to alternate stimulating agents are enhanced. Glucose-stimulated insulin synthesis can be increased or decreased depending on the system studied. Using a two-compartment beta-cell model of phasic insulin secretion, a unifying hypothesis is described which can explain some of the apparent conflicting data. This hypothesis suggests that glucose-desensitization is caused by an impairment in stimulation of a hypothetical potentiator singularly responsible for: 1) some of the characteristic phases of insulin secretion; 2) basal release; 3) potentiation of non-glucose stimulators; and 4) apparent "recovery" from desensitization. Review of some of the pathways that regulate insulin secretion suggest that phosphoinositol metabolism and protein kinase-C production are regulated similarly to the theoretical potentiator and their impairment is a major contributor to glucose desensitization in the beta cell.
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PMID:Desensitization of the insulin-secreting beta cell. 131 59

Transgenic mice with elevated levels of beta-cell calmodulin develop severe diabetes even though pancreatic beta-cells contain reserve levels of insulin. Electron microscopic examination of transgenic pancreas confirmed the presence of abundant insulin secretory granules and failed to reveal obvious morphological abnormalities. These observations suggested that excess calmodulin may specifically impair the secretory process. To directly assess the effect of excess calmodulin on beta-cell function we have isolated pancreatic islets from transgenic animals. Transgenic islets from 6- to 8-day-old mice used 40% less glucose than normal islets and contained 58% of the normal insulin content, 90% of the normal glucagon content, and 5-fold higher levels of calmodulin than islets from control mice of the same age. Parallel perifusions of normal and transgenic islets confirmed that excess calmodulin inhibited glucose-stimulated insulin secretion; first phase secretion was reduced by 60%, and second phase secretion was essentially absent. Static assays were performed to assess the response to other secretagogues. All fuel secretagogues tested were ineffective in stimulating insulin secretion from transgenic islets. Secretion in response to depolarizing levels of potassium was also severely impaired. The phosphodiesterase inhibitor 3-isobutyl-1-methyl-xanthine increased transgenic secretion, but not to the level obtained in normal islets. Of the compounds examined, only phorbol 12-myristate 13-acetate and carbachol, two substances thought to act in beta-cells by stimulation of protein kinase-C, produced equivalent secretion in normal and transgenic islets. Phorbol 12-myristate 13-acetate also appeared to restore second phase secretion in transgenic islets. These results indicate that the initial period of calmodulin-induced diabetes is due to a secretory defect. This defect appears to be distal to membrane depolarization and is selective for the second phase of insulin secretion.
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PMID:Elevated beta-cell calmodulin produces a unique insulin secretory defect in transgenic mice. 137 47


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