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)

It has been proposed that the cytokine interleukin-1 beta (IL-1 beta), secreted by islet-infiltrating macrophages, may be involved in the pathogenesis of insulin-dependent diabetes mellitus by participation in beta-cell destruction. Addition of IL-1 beta to isolated pancreatic islets in vitro results in cytotoxic effects on beta-cell function, but there is little information on the intracellular events that convey the actions of the cytokine. In the present study, fetal rat pancreatic islets containing a high fraction of beta-cells were exposed in culture to IL-1 beta. It was found that IL-1 beta markedly decreased beta-cell DNA synthesis, insulin secretion and cyclic AMP content. In order to explore whether the decrease in cAMP resulted from IL-1 beta interaction with GTP-binding proteins coupled to adenylyl cyclase, islets were treated for 24 h with pertussis toxin prior to addition of cytokine. While this treatment restored the decrease in cAMP, the reduced DNA synthesis and insulin secretion persisted. Pertussis toxin treatment without the addition of IL-1 beta resulted in increases in cAMP, DNA synthesis and insulin secretion. Addition of the stimulatory cAMP analog Sp-cAMPS also increase DNA synthesis and insulin secretion, but failed to affect the decrease in these functions evoked by IL-1 beta. The protease inhibitor N alpha-p-tosyl-L-lysine chloromethyl ketone, recently shown to protect completely against IL-1 beta-induced suppression of insulin production and secretion, was found to markedly reduce DNA synthesis without affecting insulin secretion. When the protease inhibitor was combined with IL-1 beta, the suppressed secretion was counteracted while DNA synthesis inhibition was not. It is concluded that cAMP stimulates DNA synthesis and insulin secretion in beta-cells, but that the inhibitory effect of IL-1 beta on these functions cannot be ascribed to the decrease in cAMP evoked by the cytokine. However, the repressive effect of the cytokine on insulin secretion, but not DNA synthesis, may be prevented by protease inhibition.
 ...
PMID:Inhibition of fetal rat pancreatic beta-cell replication by interleukin-1 beta in vitro is not mediated through pertussis toxin-sensitive G-proteins, a decrease in cyclic AMP, or protease activation. 165 27

In order to assess the mode of the extrapancreatic action of the sulfonylureas, we evaluated the contribution of a proteolytic mechanism for sulfonylurea action by analyzing the effects of a protease inhibitor on insulin- or tolbutamide-stimulated liver fructose-2,6-bisphosphate (F-2,6-P2) formation using isolated rat hepatocytes. The F-2,6-P2 level in hepatocytes was significantly increased by the addition of insulin or tolbutamide. The stimulatory effect of insulin on the F-2,6-P2 formation was most significant when its level was reduced by the addition of 2 microM of forskolin. Insulin action on F-2,6-P2 formation was inhibited by the addition of a protease inhibitor, p-tosyl-L-arginine methyl ester hydrochloride (TAME). Tolbutamide (2 mM) significantly increased hepatocyte F-2,6-P2 level (P less than 0.01 vs the control level). In the presence of TAME, the stimulatory effect of tolbutamide was also suppressed. The present data suggest that a proteolytic mechanism is important in both insulin and tolbutamide action on the F-2,6-P2 formation, and it may be hypothesized that, like insulin, the chemical mediator of tolbutamide action is formed proteolytically.
Diabetes Res Clin Pract 1991 Apr
PMID:Possible mechanism of proteolysis for the extrapancreatic action of tolbutamide. 185 39

Sera containing islet cell surface antibody were obtained from seven children with insulin-dependent diabetes mellitus soon after the onset of disease. After incubation of 51Cr-labelled rat islet cells with islet cell surface antibody, human AB-type serum with or without nafamostat mesylate was added before further incubation. Radioactivity in the supernatant was measured to determine complement-dependent antibody-mediated cytotoxicity. Cytotoxicity in untreated sera [mean (+/- SD) 19.4 +/- 4.0%] was significantly (P less than 0.001) inhibited by ethyleneglycoltetraacetic acid (EGTA) (7.1 +/- 4.9%), ethylenediaminetetraacetic acid (EDTA) (2.5 +/- 0.9%) and nafamostat mesylate (2.8 +/- 1.8%). Cytotoxicity of nafamostat mesylate-treated serum was significantly (P less than 0.05) lower than that of EGTA-treated serum but not significantly different from that of EDTA-treated serum. There was no difference in cytotoxicity between nafamostat mesylate-treated and untreated, inactivated human serum. The results indicate that the protease inhibitor nafamostat mesylate completely inhibited the complement activation of the immune complex associated with islet cell surface antibody by the classical and alternative pathways.
 ...
PMID:Does protease inhibitor inhibit complement activation caused by the immune complex associated with islet cell surface antibody? 193 12

To elucidate the putative role of proteases in the action of interleukin 1 beta (IL-1 beta) on pancreatic beta-cells, we studied the effects on islet function of different protease inhibitors when added together with recombinant IL-1 beta to isolated rat pancreatic islets. It was found that the trypsin inhibitor N alpha-p-tosyl-L-lysine chloromethyl ketone (TLCK) counteracted the acute stimulatory effects of IL-1 beta on islet glucose oxidation, insulin release, and biosynthesis. TLCK also partially or completely counteracted the long-term inhibitory effects of IL-1 beta on islet glucose oxidation, insulin biosynthesis, content, and release. This protease inhibitor also counteracted IL-1 beta-induced beta-cell cytotoxicity as assessed by DNA content measurements. Of the other group-specific protease inhibitors investigated, only N-tosyl-L-phenylalanine chloromethyl ketone, N alpha-p-tosyl-L-arginine methyl ester, and chloromercuriphenylsulfonic acid were found to partially protect against IL-1 beta action. We concluded that protease activation, putatively a serine protease, may be an early and perhaps primary event in the action of IL-1 beta on beta-cells.
Diabetes 1991 Feb
PMID:Influence of protease on inhibitory and stimulatory effects of interleukin 1 beta on beta-cell function. 199 76

The case of a young Type 1 diabetic patient with subcutaneous insulin resistance, causing recurrent ketoacidosis, is reported. Intramuscular and intravenous insulin administration remained effective. After failure of CSII, continuous intramuscular insulin infusion was used during 10 months followed by a combination of insulin and a protease inhibitor aprotinin, with good results. After 18 months' aprotinin therapy, subcutaneous insulin resistance disappeared. The subcutaneous insulin resistance syndrome and the role of aprotinin are discussed.
Diabetes Res 1986 Sep
PMID:Subcutaneous insulin resistance syndrome. Effects of long-term aprotinin therapy. 243 Jul 51

Processing of circulating polypeptide hormones by vascular endothelial cells may be critical to hormone transport from the vascular lumen to tissue sites of action. The comparative processing of insulin-like growth factor II (IGF II) and insulin by cultured bovine aortic endothelial cells was examined. These cells possess high-affinity receptors for IGF II and insulin, as shown by competitive-binding studies. At 37 degrees C, internalization determined by both resistance to an acid wash and electron microscopy was rapid with 50-70% of bound IGF II and insulin internalized at 60 min. Subsequently, between 70 and 75% of the internalized hormones were released from the cells within 60 min. Although most of both hormones were released intact, degradation of IGF II was greater than that of insulin by two- to threefold, as assessed by G-50 chromatography and trichloroacetic acid precipitability. Leupeptin, a specific lysosomal protease inhibitor, increased cell-associated 125I-labeled IGF II by 53.0 +/- 6.0% and decreased degradation by 55%; however, it was without effect on 125I-labeled insulin. Chloroquine and monensin, which act at the lysosomes and at other sites, increased both cell-associated IGF II and insulin and decreased the degradation of both hormones. The increases in cell-associated 125I-IGF II produced by chloroquine (42.0 +/- 7.4%) and monensin (78.3 +/- 8.5%) were quantitatively similar to the decreases in IGF II degradation caused by the agents; however, the increase in cell-associated insulin was approximately threefold greater than could be accounted for simply by decreased insulin degradation.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1986 Oct
PMID:Comparative studies on insulin-like growth factor II and insulin processing by vascular endothelial cells. 294 81

We investigated possible alterations in serum alpha 1-protease inhibitor (alpha 1-PI) concentration and activity from insulin-dependent diabetic subjects (IDDs) and in vitro in serum samples containing high glucose concentrations. The in vivo measurements were compared to others taken from normal reference subjects and the in vitro measurements were performed in serum samples containing 0, 10, 20, and 40 mmol/l of glucose. The diabetics had a significantly lower mean alpha 1-PI concentration in their serum than did the reference subjects (1.74 +/- 0.1 g/l vs. 2.1 +/- 0.1 g/l, P less than 0.05), as well as a lower total alpha 1-PI inhibitory activity (201 +/- 0.7 vs. 246.9 +/- 13.5 U/l, P less than 0.02). Addition of glucose to the serum samples in the in vitro study significantly reduced the mean alpha 1-PI concentrations (P less than 0.01 in the case of 10 mmol/l glucose, and P less than 0.001 in the cases of 20 and 40 mmol/l). Added glucose also significantly reduced the mean serum alpha 1-PI activity as determined by the percentage of elastase inhibition in 1, 2, and 3 microliters of reference serum (P less than 0.02 in the case of 10 mmol/l glucose, P less than 0.01 in 20 mmol/l, and P less than 0.001 in 40 mmol/l). Hyperglycaemia thus impaired serum alpha 1-PI concentration and activity both in vivo and in vitro. While the underlying mechanisms and clinical implications of these observations are unknown, the abnormally low alpha 1-PI activity in diabetics may worsen the severity and contribute to the chronicity of their infections.
Diabetes Res Clin Pract 1988 Oct 14
PMID:Serum alpha 1-protease inhibitor in diabetes mellitus: reduced concentration and impaired activity. 326 37

Patients with diabetes that is insensitive to subcutaneous insulin but sensitive to intravenous insulin have recently been described. We have studied this phenomenon is five female diabetics (14 to 31 years of age) who required excessive amounts of insulin (2.5 to 30.0 units per kilogram of body weight per day) to avoid recurrent ketoacidosis. Known causes of insulin resistance were excluded. All patients had normal responses to conventional doses of intravenous insulin (0.35 to 0.9 unit per kilogram per day). Four patients required continuous intravenous infusion of insulin for one to six months. When a mixture of aprotinin (a protease inhibitor) and regular porcine insulin was given subcutaneously, conventional doses (0.7 to 1.4 units per kilogram per day) produced euglycemia; plasma levels of free insulin rose, and ketonuria disappeared. Four patients had episodes of spontaneous, severe hypoglycemia before and during aprotinin therapy, necessitating continuous infusion of glucose for two to 14 days. Although no insulin was administered, hyperinsulinemia (50 to 2000 muU of free insulin per milliliter [359 to 14,350 pmol per liter]) was present. These findings suggest excessive degradation or sequestration of insulin at the site of injection.
 ...
PMID:Diabetes responsive to intravenous but not subcutaneous insulin: effectiveness of aprotinin. 701 7

Insulin resistance is a common clinical feature of obesity and non-insulin-dependent diabetes mellitus, and is characterized by elevated serum levels of glucose, insulin, and lipids. The mechanism by which insulin resistance is acquired is unknown. We have previously demonstrated that upon chronic treatment of fibroblasts with insulin, conditions that mimic the hyperinsulinemia associated with insulin resistance, the membrane-associated insulin receptor beta subunit is proteolytically cleaved, resulting in the generation of a cytosolic fragment of the beta subunit, beta', and that the generation of beta' is inhibited by the thiol protease inhibitor E64 (Knutson, V. P. (1991) J. Biol. Chem. 266, 15656-15662). In this report, we demonstrate that in 3T3-L1 adipocytes: 1) cytosolic beta' is generated by chronic insulin administration to the cells, and that E64 inhibits the production of beta'; 2) chronic administration of insulin to the adipocytes leads to an insulin-resistant state, as measured by lipogenesis and glycogen synthesis, and E64 totally prevents the generation of this insulin-induced cellular insulin resistance; 3) E64 has no effect on the insulin-induced down-regulation of insulin receptor substrate-1, and therefore insulin resistance is not mediated by the down-regulation of insulin receptor substrate-1; 4) under in vitro conditions, partially purified beta' stoichiometrically inhibits the insulin-induced autophosphorylation of the insulin receptor beta subunit; and 5) administration of E64 to obese Zucker fatty rats improves the insulin resistance of the rats compared to saline-treated animals. These data indicate that beta' is a mediator of insulin resistance, and the mechanism of action of beta' is the inhibition of the insulin-induced autophosphorylation of the beta subunit of the insulin receptor.
 ...
PMID:Insulin resistance is mediated by a proteolytic fragment of the insulin receptor. 755 25

During the past few years, interest in xenotransplantation of porcine islets of Langerhans for the future therapy of type I diabetes has increased markedly. Therefore, we established a semiautomated digestion method for isolating islets from the porcine pancreas. However, although the isolation technique was standardized and collagenase of controlled quality was used, we were unable to attain high islet yields with a satisfactory degree of reproducibility. One hypothesis was that varying degrees of interference by donor pancreatic enzymes were responsible for this failure. The aim of this study was to examine the kinetics of four types of enzymatic activity during the isolation procedure, as well as their effects on islet yield: collagenase, trypsin, neutral protease, and clostripain. Our results indicate that while exogenous collagenase activity decreases slightly during the isolation procedure, the activity of the pancreas enzymes neutral protease and trypsin increases. In some cases, trypsin activity increases very strongly. A strong increase in trypsin activity correlates with poor islet yield, whereas low trypsin activity always correlates with high islet yield. Addition of the protease inhibitor Pefabloc to the isolation medium results in low trypsin activity and reproducible high islet yields.
 ...
PMID:Isolation of porcine pancreatic islets: low trypsin activity during the isolation procedure guarantees reproducible high islet yields. 786 80


1 2 3 4 5 6 7 8 9 10 Next >>