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

Type 2 diabetes develops spontaneously in obese aging rhesus monkeys (Macaca mulatta). This study investigates the association between polymorphonuclear leukocytes and development of retinopathy. Blood pressure and plasma glucose levels were determined in 15 diabetic and 6 nondiabetic monkeys. The plasma levels of total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides were determined just before the start of the animal's final decline and elective necropsy. Retinas were incubated for ADPase (labels viable retinal blood vessels) and nonspecific esterase (labels neutrophils) activities. Polymorphonuclear leukocytes were counted per millimeter squared of retina. After the retina was flat-embedded in glycol methacrylate, tissue sections were taken through areas of interest and observed microscopically. Elevated numbers of intravascular polymorphonuclear leukocytes were present adjacent to areas with retinal capillary nonperfusion. There were significantly more polymorphonuclear leukocytes per millimeter squared in diabetic retinas (6.91 +/- 5.01) compared with normal retinas (1.45 +/- 1.62, P = 0.018). Severity of hypertension in diabetes was also significantly associated with greater numbers of polymorphonuclear leukocytes (P = 0.02). There was a significant positive exponential correlation between the number of polymorphonuclear leukocytes per millimeter squared and the level of total cholesterol (R = 0.907), LDL cholesterol (R = 0.875), the total cholesterol-to-HDL cholesterol ratio (R = 0.86), and total triglycerides (R = 0.888). This study demonstrates that severity of diabetes and the development of retinopathy are associated with increased numbers of polymorphonuclear leukocytes in the retina of diabetic monkeys. Hypertension, high plasma levels of LDL cholesterol and triglycerides, and low plasma levels of HDL cholesterol also are associated with increased polymorphonuclear leukocytes in retina.
Diabetes 2005 May
PMID:Neutrophils are associated with capillary closure in spontaneously diabetic monkey retinas. 1585 43

Carnosine, an endogenous histidine-containing dipeptide, protects protein from oxidation and glycation, which may contribute to a potential treatment for some conformational diseases including cataract. Glycation, the non-enzymic reaction of sugars with proteins, promotes cross-linking and further aggregation. Prolonged use of glucocorticoids is a risk factor for cataract, as is diabetes. Esterase activity in the lens is decreased in senile cataract and diabetes. Previously, we reported that glycation and a steroid inactivate esterase. Here we tested the inactivation of esterase with fructose, fructose 6-phosphate (F6P) and ribose as model glycation reactions and prednisolone-21-hemisuccinate (P-21-H) as a model steroid and investigated the ability of carnosine to protect esterase against inactivation. The activity of esterase was measured by a spectrophotometric assay using p-nitrophenyl acetate as the substrate. The modified esterase was examined electrophoretically. The esterase was progressively inactivated by F6P, fructose, ribose and P-21-H. P-21-H was more effective than the sugars. Carnosine significantly inhibited the inactivation of esterase induced by all four compounds. Carnosine decreased the extent of the cross-linking. These results provide further evidence for carnosine's role as an anti-glycation compound. It is also proposed that carnosine may be an anti-steroid agent.
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PMID:Carnosine protects against the inactivation of esterase induced by glycation and a steroid. 1595 55

Human serum paraoxonase (PON1) has been implicated to play an important role in cardiovascular disease and diabetes. Studies in the literature indicate that PON1 has two different enzyme activities, i.e., esterase and hydroperoxide reducing activities. The objective of this study was to establish the importance of these two activities and to distinguish between them. As the addition of copper immediately inactivated the enzyme, we used auto-oxidation as the model system. Auto-oxidation of HDL resulted in more than 80% reduction of the esterolytic activity, which was protected by antioxidants, Vitamin E (50%) and PDTC (95%) and completely by 1 M glucose. In contrast, the hydroperoxide reducing activity, using unesterified hydroperoxides remained unaffected with time. We also used pNPHPODE (novel substrate) to establish that hydrolysis might be a prerequisite for the enzyme to act on the esterified hydroperoxide. The results indicated that the hydrolysis of the substrate was inhibited under oxidizing conditions with no reduction of the hydroperoxide. Overall, our findings suggest that protecting the esterolytic activity of PON1 by antioxidants might be important in preserving its action on phospholipid peroxides and a concerted reaction involving the esterolytic and hydroperoxide reducing activities might be suggested for the action of PON1.
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PMID:Oxidative inactivation of paraoxonase--implications in diabetes mellitus and atherosclerosis. 1611 60

Heme proteins--hemoglobin and myoglobin possess esterase activities. Studies with purified hemoglobin from normal individuals and diabetic patients revealed that the esterase activity as measured from hydrolysis of p-nitrophenyl acetate (p-NPA) was higher in diabetic condition and increased progressively with extent of the disease. HbA(1c), the major glycated hemoglobin, which increases proportionately with blood glucose level in diabetes mellitus, exhibited more esterase activity than the non-glycated hemoglobin fraction, HbA(0), as demonstrated spectrophotometrically as well as by activity staining. Glycation influenced esterase activity of hemoglobin by increasing the affinity for the substrate and the rate of the reaction. Both HbA(0) and HbA(1c)-mediated catalysis of p-NPA hydrolysis was pH-dependent. Esterase activity of in vitro-glycated myoglobin (GMb) was also higher than that of its non-glycated analog (Mb). The amplified esterase activities of hemoglobin and myoglobin might be associated with glycation-induced structural modifications of the proteins.
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PMID:Effect of non-enzymatic glycation on esterase activities of hemoglobin and myoglobin. 1754 9

Excessive glucose production by the liver coupled with decreased glucose uptake and metabolism by muscle, fat, and liver results in chronically elevated blood glucose levels in patients with type 2 diabetes. Efforts to treat diabetes by reducing glucose production have largely focused on the gluconeogenesis pathway and rate-limiting enzymes within this pathway such as fructose-1,6-bisphosphatase (FBPase). The first potent FBPase inhibitors were identified using a structure-guided drug design strategy (Erion, M. D.; et al. J. Am. Chem. Soc. 2007, 129, 15480-15490) but proved difficult to deliver orally. Herein, we report the synthesis and characterization of a series of orally bioavailable FBPase inhibitors identified following the combined discoveries of a low molecular weight inhibitor series with increased potency and a phosphonate prodrug class suitable for their oral delivery. The lead inhibitor, 10A, was designed with the aid of X-ray crystallography and molecular modeling to bind to the allosteric AMP binding site of FBPase. High potency (IC50 = 16 nM) and FBPase specificity were achieved by linking a 2-aminothiazole with a phosphonic acid. Free-energy perturbation calculations provided insight into the factors that contributed to the high binding affinity. 10A and standard phosphonate prodrugs of 10A exhibited poor oral bioavailability (0.2-11%). Improved oral bioavailability (22-47%) was achieved using phosphonate diamides that convert to the corresponding phosphonic acid by sequential action of an esterase and a phosphoramidase. Oral administration of the lead prodrug, MB06322 (30, CS-917), to Zucker Diabetic Fatty rats led to dose-dependent inhibition of gluconeogenesis and endogenous glucose production and consequently to significant blood glucose reduction.
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PMID:Discovery of potent and specific fructose-1,6-bisphosphatase inhibitors and a series of orally-bioavailable phosphoramidase-sensitive prodrugs for the treatment of type 2 diabetes. 1804 34

Increased fructose concentration in diabetes mellitus causes fructation of several proteins. Here we have studied fructose-induced modifications of hemoglobin. We have demonstrated structural changes in fructose-modified hemoglobin (Fr-Hb) by enhanced fluorescence emission with excitation at 285 nm, more surface accessible tryptophan residues by using acrylamide, changes in secondary and tertiary structures by CD spectroscopy, and increased thermolability by using differential scanning calorimetry in comparison with those of normal hemoglobin, HbA(0). Release of iron from hemoglobin is directly related with the extent of fructation. H2O2-induced iron release from Fr-Hb is significantly higher than that from HbA(0). In the presence of H2O2, Fr-Hb degrades arachidonic acid, deoxyribose and plasmid DNA more efficiently than HbA(0), and these processes are significantly inhibited by desferrioxamine or mannitol. Thus increased iron release from Fr-Hb may cause enhanced formation of free radicals and oxidative stress in diabetes. Compared to HbA(0), Fr-Hb exhibits increased carbonyl formation, an index of oxidative modification. Functional modification in Fr-Hb has also been demonstrated by its decreased peroxidase activity and increased esterase activity in comparison with respective HbA(0) activities. Molecular modeling study reveals Lys 7alpha, Lys 127alpha and Lys 66beta to be the probable potential targets for fructation in HbA(0).
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PMID:Fructose-induced structural and functional modifications of hemoglobin: implication for oxidative stress in diabetes mellitus. 1833 26

Uncomplicated urinary tract infections (uUTIs) are common in adult women across the entire age spectrum, with mean annual incidences of approximately 15% and 10% in those aged 15-39 and 40-79 years, respectively. By definition, UTIs in males or pregnant females and those associated with risk factors known to increase the risk of infection or treatment failure (e.g. acquisition in a hospital setting, presence of an indwelling urinary catheter, urinary tract instrumentation/interventions, diabetes mellitus or immunosuppression) are not considered herein. The majority of uUTIs are caused by Escherichia coli (70-95%), with Proteus mirabilis, Klebsiella spp. and Staphylococcus saprophyticus accounting for 1-2%, 1-2% and 5-10% of infections, respectively. If clinical signs and symptoms consistent with uUTI are present (e.g. dysuria, frequency, back pain or costovertebral angle tenderness) and there is no vaginal discharge or irritation present, the likelihood of uUTI is >90-95%. Laboratory testing (i.e. urinary nitrites, leukocyte esterase, culture) is not necessary in this circumstance and empirical treatment can be initiated. The ever-increasing incidence of antimicrobial resistance of the common uropathogens in uUTI has been and is a continuing focus of intensive study. Resistance to cotrimoxazole (trimethoprim/sulfamethoxazole) has made the empirical use of this drug problematic in many geographical areas. If local uropathogen resistance rates to cotrimoxazole exceed 10-25%, empirical cotrimoxazole therapy should not be utilized (fluoroquinolones become the new first-line agents). In a few countries, uropathogen resistance rates to the fluoroquinolones now exceed 10-25%, rendering empirical use of fluoroquinolones problematic. With the exception of fosfomycin (a second-line therapy), single-dose therapy is not recommended because of suboptimal cure rates and high relapse rates. Cotrimoxazole and the fluoroquinolones can be administered in 3-day regimens. Nitrofurantoin, a second-line therapy, should be given for 7 days. beta-Lactams are not recommended because of suboptimal clinical and bacteriological results compared with those of non-beta-lactams. If a beta-lactam is chosen, it should be given for 7 days. Management of uUTIs can frequently be triaged to non-physician healthcare personnel without adverse clinical consequences, resulting in substantial cost savings. It can be anticipated that the optimal approach to the management of uUTIs will change substantially in the future as a consequence of antimicrobial resistance.
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PMID:Contemporary management of uncomplicated urinary tract infections. 1854 31

Acetylcholine (ACh), the first neurotransmitter to be identified, regulate the activities of central and peripheral functions through interactions with muscarinic receptors. Changes in muscarinic acetylcholine receptor (mAChR) have been implicated in the pathophysiology of many major diseases of the central nervous system (CNS). Previous reports from our laboratory on streptozotocin (STZ) induced diabetic rats showed down regulation of muscarinic M1 receptors in the brainstem, hypothalamus, cerebral cortex and pancreatic islets. In this study, we have investigated the changes of acetylcholine esterase (AChE) enzyme activity, total muscarinic and muscarinic M1 receptor binding and gene expression in the corpus striatum of STZ--diabetic rats and the insulin treated diabetic rats. The striatum, a neuronal nucleus intimately involved in motor behaviour, is one of the brain regions with the highest acetylcholine content. ACh has complex and clinically important actions in the striatum that are mediated predominantly by muscarinic receptors. We observed that insulin treatment brought back the decreased maximal velocity (Vmax) of acetylcholine esterase in the corpus striatum during diabetes to near control state. In diabetic rats there was a decrease in maximal number (Bmax) and affinity (Kd) of total muscarinic receptors whereas muscarinic M1 receptors were increased with decrease in affinity in diabetic rats. We observed that, in all cases, the binding parameters were reversed to near control by the treatment of diabetic rats with insulin. Real-time PCR experiment confirmed the increase in muscarinic M1 receptor gene expression and a similar reversal with insulin treatment. These results suggest the diabetes-induced changes of the cholinergic activity in the corpus striatum and the regulatory role of insulin on binding parameters and gene expression of total and muscarinic M1 receptors.
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PMID:Enhanced muscarinic M1 receptor gene expression in the corpus striatum of streptozotocin-induced diabetic rats. 1934

In the present study, we have investigated acetylcholine esterase (AChE) activity and muscarinic M(1), M(3) receptors kinetics in the brainstem of both young and old streptozotocin induced and insulin treated diabetic rats (D + I). Also, the functional role of acetylcholine and muscarinic receptors in insulin secretion from the pancreatic islets was studied in vitro. 90 week old control rats showed decreased V(max) (P < 0.001) for AChE compared to 7 week old control rats. V(max) was decreased (P < 0.001) in 7 week diabetic groups whereas 90 week old diabetic groups showed increased (P < 0.001) V(max) when compared to their respective controls. Binding studies using [(3)H]QNB and [(3)H]DAMP of 90 week old control showed significant increase in the B(max) (P < 0.001) and K(d) (P < 0.01) of muscarinic M(1) receptors whereas M(3) receptor number was decreased significantly (P < 0.001) with no change in affinity when compared to 7 week old control respectively. M(1) receptor number was decreased significantly (P < 0.001) whereas M(3) receptor number was increased significantly (P < 0.001) in both 7 week and 90 week old diabetic rat groups compared to their respective controls. The competition curve for [(3)H]QNB fitted for two sited model in 7 week old groups whereas fitted for one sited model in 90 week old groups. [(3)H]DAMP was fitted for two sited model in both 7 week and 90 week old groups. Insulin treatment significantly reversed (P < 0.001) the binding parameters to near control level. In vitro studies showed that acetylcholine through muscarinic M(1) and M(3) receptors stimulated insulin secretion from the pancreatic islets. Thus our studies suggest that both brainstem and pancreatic muscarinic M(1), M(3) receptors differentially regulate the cholinergic activity and insulin secretion which will have clinical significance in the management of diabetes and insulin treatment as a function of age.
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PMID:Muscarinic M(1), M(3) receptors function in the brainstem of streptozotocin induced diabetic rats: their role in insulin secretion from the pancreatic islets as a function of age. 1934 82

Cinnamic acids (i.e., ferulic and caffeic acids) that are esterified to the vegetable cell walls should be enzymatically released to be absorbed in a mammal's intestines. A low dosage of ferulic acid in rodent diets stimulates insulin production and alleviates symptoms caused by diabetes (M. Sri Balasubashini, R. Rukkumani, and V. P. Menon, Acta Diabetol. 40:118-122, 2003). Several lactic acid bacteria are able to display ferulic acid esterase (FAE) activity, suggesting that their probiotic activity could be, in part, mediated by the slow release of ferulic acid. In the present work, we describe the isolation of one strain identified as being Lactobacillus johnsonii that displayed strong FAE activity in stool samples from diabetes-resistant biobreeding rats. These animals are genetically susceptible to becoming diabetic but do not develop the disease. By using genomic analysis coupled to protein purification and catalytic screening, we were able to purify two proteins with FAE activity. The enzymes displayed 42% sequence identity and a broad range of substrate preferences. High affinities and catalytic efficiencies toward aromatic compounds such as ethyl ferulate (K(m) = 20 to 60 microM) and chlorogenic acid (K(m) = 10 to 50 microM) were observed. The strain isolated herein as well as the enzymes studied could be potentially useful for the formulation of probiotics to ameliorate diabetes symptoms.
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PMID:Biochemical properties of two cinnamoyl esterases purified from a Lactobacillus johnsonii strain isolated from stool samples of diabetes-resistant rats. 1950 37


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