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)

Advanced glycosylation end products (AGE) are implicated in many of the complications of diabetes. In the same way, infectious diseases are frequently associated with this disease. An impaired respiratory burst in macrophages may be a cause of infectious complications in diabetic patients. To establish a possible mechanism of this altered cell function, we have analyzed the effect of AGE-modified proteins on PMA-dependent superoxide anion production (O2.-) from normal rat peritoneal macrophages. We have used AGE-modified bovine serum albumin (AGE-BSA) prepared by incubation with glucose. AGE-BSA partially inhibits the phorbol ester-dependent superoxide production by macrophages in vitro. The specificity of this inhibitory effect is demonstrated by the fact that aminoguanidine, an inhibitor of the formation of AGE products, fully prevents the effect of AGE-BSA in vitro. Macrophages from diabetic rats shown an inhibition on PMA dependent-O2.- production. However, the treatment in vivo with aminoguanidine produced a cancelation of the inhibitory effect observed in the diabetic state. These data suggest that AGE-modified proteins could be implicated in the impairment of macrophage respiratory burst in diabetes.
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PMID:Inhibitory effect of albumin-derived advanced glycosylation products on PMA-induced superoxide anion production by rat macrophages. 919 83

Despite its widespread use, much is wrong with conventional subcutaneous insulin injection. It is more-or-less painful and inconvenient; it delivers insulin slowly with highly inconsistent pharmacokinetics into the peripheral venous system rather than directly to the liver via the portal vein; and, once delivered into the skin, it cannot be "turned off". This review has focused on novel alternative approaches to insulin delivery. The clinically available insulin delivery devices, such as pen injectors and external insulin pumps, are probably underutilized. Pen injectors offer convenience, whereas external pumps offer a basal/bolus approach to insulin delivery unlike that achieved by injections. Of the approaches currently under development, IPPs are closet to general availability. They have been extremely popular in more than 600 patients worldwide, however, an insulin problem has delayed application for their PMA in the United States. Feasibility studies of inhaled insulin, nasal insulin, and oral insulin have produced interesting preliminary findings, with pulmonary delivery for meal coverage with short-acting insulin having perhaps the brightest prospects. Encapsulated islets and biohybrid systems that place live islets into an implanted device are in earlier stages of development. Closing the loop with a continuous glucose sensor will be the only way to achieve truly normal blood glucose homeostasis by directing insulin delivery automatically on demand. Glucose sensors would have many other clinical applications in diabetes management in addition to driving a mechanical delivery system. However, the development of glucose sensing devices has been a formidable technical challenge. Based on an evaluation of current technologic development, glucose oxidase-based, needle-type sensors may become available within the next few years. Clinicians, the research community, and persons with diabetes can join in rejecting the notion that standard regimens of insulin injection do not need to be improved. If there is adequate incentive to continue a broad-based research effort into novel approaches to insulin delivery, the quality of life of persons with diabetes can be improved in the not too distant future.
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PMID:Novel forms of insulin delivery. 931 17

The function of neutrophil can be evaluated by measuring oxidative metabolism using chemiluminescence, tetrazolium dye reduction or the others. Those results are not always satisfactory which would be caused by subtle difference in each preparation of the reagents and the lack of reproducibility. Recently, flow cytometric procedures for semi-quantitating superoxide production in neutrophils have been developed to evaluate their function. This procedure, which requires only small amount of whole blood, can easily and rapidly yield reproducible and reliable data. In this study, we optimized analytical conditions and then determined reference interval to evaluate neutrophil function of patients with various disorders. Optimal concentrations and incubation times of DCFH-DA and PMA were 5 mumol/l for 15 minutes and 25 micrograms/ml for 20 minutes, respectively. Production of superoxide in neutrophil was represented by relative fluorescence intensity(RFI) with assay coefficient of variance(CV) of 4.0-11.1%. Neutrophils had to be examined within 2 hours after venipuncture to obtain reliable data. Reference interval was determined as 170.4 +/- 58.7(mean +/- SD) RFI. Neutrophil function of patients with neutropenia, paroxysmal nocturnal hemoglobinuria(PNH), renal failure, systemic lupus erythematosus(SLE), myeloperoxidase deficiency, myelodysplastic syndrome(MDS), and diabetes mellitus were within the reference interval as evaluated by this method. Only neutrophils of chronic granulomatous disease, which is known to give clearly low superoxide production, showed actually decreased value. These results indicate that this procedure would be clinically useful for diagnosis of patient with impaired neutrophil function.
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PMID:[Determination of neutrophil function by measuring superoxide production with whole blood flow cytometry]. 939 45

Studies were performed to determine the interactive effects of high concentrations of glucose (HG) and epidermal growth factor (EGF) on the release of arachidonic acid (3H-AA) in human glomerular mesangial cells (MC) in culture. Since high glucose has been reported to increase the mass of diacylglycerol (DAG) in MC, the HG-induced release of 3H-AA was compared to that initiated by the phorbol ester, PMA. It was found that when media contained high levels (25 mM) of glucose, the release of 3H-AA was increased significantly by 8.4% (change from control) after 1 h of exposure and was maintained at values not significantly different from this level for the next 2 h. After 3-h exposure, there was no significant difference between 25 and 50 mM glucose, suggesting that the effects of glucose are saturating at 25 mM. After 1-h exposure, 3H-AA release was also increased by PMA; however, the increase was larger and the peak increase was delayed until after 1 h. 3H-AA release was significantly increased by epidermal growth factor (EGF) by 8.5% after 1 h and was maintained at this level after 2 and 3 h of exposure. In the presence of HG, EGF increased 3H-AA release by 24.6% after the 1st hour and by 20.4 and 19.4%, after the 2nd and 3rd hours, respectively. Mannitol (20 mM), added as an osmotic control, increased 3H-AA release by 6.2% and also significantly enhanced the effects of EGF after 3 h. The experimental values (19.0%) for the release of 3H-AA after 3-h exposure to EGF in combination with either high glucose or mannitol were significantly greater than the expected (added) values (12.1%). These results demonstrate that as a result of an elevated solution osmolality, high glucose acts synergistically with EGF to increase the release of 3H-AA in human mesangial cells.
Diabetes Res Clin Pract 1999 Jan
PMID:Potentiating effects of hyper-osmolality and epidermal growth factor on the release of arachidonic acid in human glomerular mesangial cells. 1019 85

By means of systematic abnormal Hb surveys of people living in eight districts (Okayama, Shimane, Kagawa, Hyogo, Osaka, Nara, Aichi, and Yamanashi Prefectures) using isoelectric focusing, the number of abnormal Hbs discovered and identified among 301,190 subjects was 128. The frequency was estimated to be about one per 2,350. Recently, however, abnormal Hb carriers have been found among individuals with high or low levels of Hb A1c or with an abnormal HPLC pattern. These carriers were found when glyco-HPLC was used to determine the HbA1c level for detection and diagnosis of diabetes mellitus in physical check-ups of inhabitants in each prefecture. To date, 1,227 cases of abnormal Hbs have been detected by isoelectric focusing and glyco-HPLC. These Hbs were analyzed by protein chemistry and DNA analytical methods. The most typical Hbs found in Japan have been Hb J-Cape Town (an alpha-chain variant) and Hb Riyadh (a beta-chain variant). Homozygotes for Hb J-Cape Town, Hb Ube-2, Hb Hamadan, Hb G-Szuhu and Hb Takamatsu have been discovered among abnormal Hb carriers. The carriers of Hb M-Hyde Park and Hb Koln, which cause hemolytic anemia due to their molecular instability, have been found in some parts of Japan, but by clinical examination rather than by Hb survey. On the other hand, alpha- and beta-thals have often been detected in blood samples with a high or low HbA2 level or in abnormal Hb such as Hb H, during systematic surveys for abnormal Hb. Peripheral blood examinations of these patients revealed typical data, a low MCV, MCH, and sometimes low Hb levels. The diagnosis was made by DNA analyses of the nucleotide sequencing of the beta-globin gene for beta-thals and of the alpha-globin gene arrangement for alpha-thals. beta-Thals found in Japanese mainly involve a point mutation, such as-31CapA-->G(in ATA box) and beta 90 codon GAG-->TAG(creation of a stop codon). The alpha-thals had genotypes of -alpha 3.7/alpha alpha for alpha-thal-2, -SEA/alpha alpha for alpha-thal-1 and -SEA/-alpha 3.7 for Hb H disease.
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PMID:[Hemoglobinopathy in Japan: detection and analysis]. 1022 86

Type 2 diabetes is characterized by islet amyloid deposits, which are primarily composed of the amyloidogenic human form of islet amyloid polypeptide (IAPP, amylin). The mechanism of islet amyloido-genesis is not known, but other products (e.g., apolipoprotein E and perlecan) contained within islet amyloid may be necessary. Because rodent IAPP does not form islet amyloid, the currently available beta-cell lines are not useful for studying processes involved in amyloid formation. To develop a suitable in vitro cell system for the study of islet amyloid formation, we generated two new beta-cell lines that express the amyloidogenic human IAPP. We did this by crossbreeding human IAPP transgenic mice with RIP-Tag mice that develop islet tumors and then culturing one of these islet tumors from two separate offspring of this cross. The resultant 2350-2C0 and 2511 cell lines produce human as well as mouse IAPP-like immunoreactivity (IAPP-LI) and immunoreactive insulin (IRI). Incubation of both these cell lines with 16.7 mmol/l glucose resulted in a two- to fourfold increase in human IAPP-LI, mouse IAPP-LI, and IRI secretion compared with 1.67 mmol/l glucose and the combination of 16.7 mmol/l glucose and 10 mmol/l arginine, 0.1 mmol/l 3-isobutyl-1-methylxanthine (IBMX), and 5 micromol/l carbachol induced a >50-fold increase in the release of these peptides. The omission of calcium from the above secretagogue cocktail reduced secretion of all three peptides to only two- to sixfold higher than the 16.7 mmol/l glucose condition. Perifusion with 16.7 mmol/l glucose plus 0.1 mmol/l IBMX caused a biphasic secretion of human IAPP-LI and mouse IAPP-LI, as well as IRI, in both cell lines, with the peak of the first phase being five- to sixfold higher than the prestimulated 1.67 mmol/l glucose condition. Immunoelectron microscopic inspection of both 2350-2C0 and 2511 cells after 7 days of culture did not reveal the presence of amyloid fibrils, suggesting the need for other critical components. We conclude that we have established two novel beta-cell lines that produce and secrete human IAPP in a regulated manner. These cell lines will be a useful tool to investigate the secretion of human IAPP as well as the necessity of other components for islet amyloid formation.
Diabetes 1999 Oct
PMID:Two novel immortal pancreatic beta-cell lines expressing and secreting human islet amyloid polypeptide do not spontaneously develop islet amyloid. 1051 60

Sulfonylureas are generally used in the therapeutic treatment of non-insulin-dependent diabetes mellitus. Little is known, however, whether they also affect the lipid metabolism. Using glibenclamide (GB), a typical sulfonylurea, we have investigated its effects on the lipid metabolism in macrophages, J774 and phorbol ester-treated THP-1 cells. In the whole-cell assay system for cholesteryl ester (CE) accumulation that is induced by addition of chemically modified low-density lipoprotein (LDL), such as Ac-LDL and ox-LDL, GB effectively inhibited the CE accumulation of J774 cells in dose-dependent manners. The inhibition was resulted from increase in free cholesterol but not from change in total cholesterol amount. The results suggest that GB acts on acyl-CoA: cholesterol acyltransferase (ACAT) and inhibits its activity. To confirm the possibility, we then tested GB by another assay system using ACAT that was solubilized from the cells and reconstituted into the liposome composed of phosphatidyl choline- cholesterol. GB inhibition was not so much effective as those by CI-976 and NTE-122, known ACAT inhibitors, but the inhibition was complete in the presence of 100 microM GB. Using cell homogenates of PMA-stimulated THP-1 cells, GB also inhibited the ACAT activity to the level of undifferentiated THP-1 cells. These results indicate that GB acts as ACAT inhibitor but the chemical structure is quite different from the conventional ACAT inhibitors, suggesting it can be a seed to generate potential ACAT inhibitors which do not exhibit toxicity in adrenal gland.
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PMID:[Glibenclamide inhibits cholesterol metabolism in macrophage]. 1062 72

Apoptosis, the process of programmed cell death, plays a critical role in many normal and pathological (disease) processes. In normal tissues, apoptosis functions in the homeostatic maintenance of proper tissue and organ size by eliminating aged cells to offset the birth of new cells that arise by mitosis. In disease, apoptosis can affect the pathological process is two disparate ways. There are diseases that have too much apoptosis such as autoimmune diabetes and Alzheimer's, or those that have too little apoptosis, such as cancer. This review will focus on the latter and, more specifically, detail and summarize some important lessons learned about apoptosis and cancer from studying a transgenic mouse model of islet cell carcinoma, RIP-Tag, as outlined below.
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PMID:Tumor cells utilize multiple pathways to down-modulate apoptosis. Lessons from a mouse model of islet cell carcinogenesis. 1066 71

Rat glomerular mesangial cells (GMC) express P2Y(2) purinoceptors and respond to nucleotide stimuli with a transient increase in the cytosolic Ca(2+) concentration and the receptors desensitize upon repeated stimulation with nucleotide. We demonstrate that there is a cross-talk from the signaling of tyrosine kinase to P2Y(2) receptors. For most cells repeated applications of ATP completely abolished the response, as did activation of PKC with 500 nM PMA. In contrast, preincubation with the PKC inhibitor chelerythrine (100 nM) prevented desensitization. Desensitization after application of ATP was reversed by subsequent incubation with PDGF-BB (50 ng/ml) or insulin (660 mU/ml). We conclude that the desensitization is caused by phosphorylation due to PKC and is under the control of growth factors. The findings support the hypothesis that growth hormones potentiate nucleotides as proinflammatory mediators and we hypothesize that they have bearing on the hyperfiltration seen in diabetes.
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PMID:Growth hormones reverse desensitization of P2Y(2) receptors in rat mesangial cells. 1075 69

Type 1 diabetes is a T cell-mediated autoimmune disease where a number of islet beta-cell target autoantigens have been characterized on the basis of reactivity with autoantibodies. Nevertheless, there remains uncertainty of the nature of another group of autoantigens associated with the secretory granule fraction of islet beta-cells that appear to be targeted predominantly by autoreactive T cells. We have previously characterized CD4+, HLA-DR-restricted T cell lines from new onset type 1 diabetic patients that are specific for the secretory granule fraction of rat tumour insulinoma, RIN. The T cell line from the first patient, HS, proliferates in response to crude microsomal membranes prepared from a recently established, pure human islet beta-cell line NES2Y. In addition, the HS line also responds to secretory granule fractions prepared from a murine tumour insulinoma grown in RIP-Tag mice, showing the recognition of species-conserved antigen(s) in beta-cells. Using partially matched antigen-presenting cells, the HS T cells and another line derived from a second patient, MR, were shown to be restricted by disease-associated DRB1*0101 and DRB1*0404 alleles, respectively. Neither the HS or MR T cell lines proliferate in response to a large panel of candidate islet cell antigens, including insulin, proinsulin, glutamic acid decarboxylase, the protein tyrosine phosphatase IA-2/phogrin, imogen-38, ICA69 or hsp60. Our data provide compelling evidence of the presence of a group of antigens associated with the secretory granule fraction of islet beta-cells recognized by the T cell lines, whose definition may contribute to our knowledge of disease induction as well as to diagnosis.
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PMID:Evidence for recognition of novel islet T cell antigens by granule-specific T cell lines from new onset type 1 diabetic patients. 1088 45


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