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PubMed2000

Effects of nicotinamide and intravenous insulin therapy in newly diagnosed type 1 diabetes.

OBJECTIVE: To investigate the effect of intravenous insulin therapy combined with nicotinamide in the metabolic control and beta-cell function of newly diagnosed type 1 diabetic subjects in comparison with intensive insulin therapy and nicotinamide alone. RESEARCH DESIGN AND METHODS: A total of 34 newly diagnosed type 1 diabetic patients were included. After the correction of initial metabolic disturbances, subjects were randomly assigned to the following three groups within 72 h after admission: 1) intensive insulin therapy + placebo (C) (n = 12); 2) intensive insulin therapy + nicotinamide, 700 mg three times a day (NIC) (n = 11); and 3) 72-h intravenous insulin followed by intensive insulin therapy + nicotinamide, 700 mg three times a day (NIV) (n = 11). The subjects were monitored for 12 months. GAD, tyrosine phosphatase antibodies, and insulin autoantibodies were measured. C-peptide was measured basally and after 2, 4, 6, 8, and 10 min of 1 mg intravenous glucagon. HbA1c, glucagon, and antibody measurements were determined initially and at 1, 3, 6, 9, and 12 months. RESULTS: HbA1c values declined to normal after treatment was initiated in all groups and remained not significantly different during the follow-up period. We did not find differences between experimental (NIC and NIV) and placebo (C) groups in terms of beta-cell function, considering basal or glucagon-stimulated C-peptide (maximal stimulated C-peptide and area under the curve [AUC] of C-peptide) values during the follow-up period. After pooling data from the NIC and NIV groups (both including nicotinamide) and comparing it with data from the C group, the results remained unchanged. At diagnosis, GAD positivity was observed in 10 of 12, 8 of 11, and 10 of 11 subjects (NS) in the C, NIC, and NIV groups, respectively, and IA2 positivity was observed in 3 of 12, 4 of 11, and 4 of 11 subjects (NS) in the C, NIC, and NIV groups, respectively. Antibody titers displayed a similar behavior in all groups during the follow-up period. CONCLUSIONS: Our pilot study failed to demonstrate that the addition of 72-h intravenous insulin and nicotinamide to conventional intensive insulin therapy produces any beneficial effect in newly diagnosed type 1 diabetic subjects in terms of beta-cell function and metabolic control.

Adult↗
PubMed1975

Magnetic enzyme membranes as active elements of electrochemical sensors: specific amino acid enzyme elctrodes.

The basic principle of the described magnetic enzyme electrodes is a kinetic accumulation of CO2 at the active layer electrode interface. The local pCO2 level is linked to three simultaneous phenomena: substrate diffusion in, enzyme reaction CO2 diffusion out. After a transient state there is a stationary state between the quantity of CO2 produced by the enzyme reaction and the CO2 diffusing from the active membrane to the bulk solution. Continuous determination of free amino acids in biological media is useful in biological processing, fermentation, medicine, pharmaceutical industries and biological research. No methods are presently available for any specific continuous measurement of lysine which is of nutritional importance in protein industrial syntheses; of phenylalanine and tyrosine which have to be monitored in several inborn diseases (phenylketonuria being the most important of them); of arginine and histidine which play a still imperfectly understood part in neurochemistry. The use of decarboxylase bearing membranes as sensors in such measurements could offer several novel advantages: (a) a simple device made of a currently manufactured electrode slightly modified by the use of an enzyme membrane; (b) The absence of any enzymic consumption due to the immobilization and the negligible consumption of substrate during the measurements; (c) The sensitivity which can be sharpened by a systematic study of the membrane parameters; (d) the continuous response of the electrode as long as it is in contact with the substrate solution; (e) the further feasibility as a miniature sensor. The magnetic device introduced allows obviously a convenient use of the enzyme electrode, the active part can be removed and replaced without disturbance for the pCO2 electrode itself. The enzyme electrodes are not only useful at the applied point of view but also at the fundamental point of view by allowing a direct measurement of an intra membrane concentration. The influence of simple structures on enzyme kinetics was studied with enzyme electrodes by our group, in the case of memory and oscillations obtained with enzyme systems.

Amino Acids↗
PubMed1993

Effects of neonatal 6-hydroxydopamine injections on glutamate decarboxylase, preproenkephalin and dopamine D2 receptor mRNAs in the adult rat striatum.

The effects of neonatal 6-hydroxydopamine injections on the levels and cellular distribution of glutamate decarboxylase (GAD67), preproenkephalin and dopamine D2 receptor messenger RNAs were studied in the striatum of adult rats. Cerebroventricular injections of 150 micrograms or 100 micrograms of 6-hydroxydopamine to 3-day-old neonate rats resulted in the total disappearance of neurons labeled with a tyrosine hydroxylase probe in sections of the substantia nigra and ventral tegmental area. In the striatum of adults, both doses of 6-hydroxydopamine induced an increase in GAD67 and preproenkephalin mRNA levels compared to controls. A smaller but consistent increase in dopamine D2 receptor mRNA levels was also found on adjacent sections of the striatum only in animals injected with 150 micrograms of 6-hydroxydopamine. Regional analysis of labeling showed that the increased GAD67, preproenkephalin or dopamine D2 receptor mRNA levels occurred in all striatal sectors examined. Emulsion radioautographs confirmed the increased GAD67, preproenkephalin and dopamine D2 receptor mRNA labeling at cellular level. The present study demonstrates that bilateral 6-hydroxydopamine lesions of dopamine neurons in neonate rats are able to induce a long-term and widespread alteration in the expression of genes encoding for GAD67, preproenkephalin and dopamine D2 receptor in the striatum. In view of previous results after 6-hydroxydopamine lesions in adults, it appears that the behavioral differences observed after adult or neonatal 6-hydroxydopamine lesions are accompanied by a similar alteration of GAD67, preproenkephalin and dopamine D2 receptor gene expression in presumed striatal projection neurons.

Animals↗
PubMed1996

Limited loss of tolerance to islet autoantigens in ICA+ first degree relatives of patients with type I diabetes expressing the HLA dqb1*0602 allele.

The DQB1*0602 allele confers dominant protection from Type I diabetes even among islet cell antibody positive (ICA+) first degree relatives of affected individuals. Lack of progression to diabetes in these subjects, despite ICA positivity, could be explained by a loss of tolerance limited to fewer islet autoantigens than in ICA+ relatives progressing to the disease. To test this hypothesis we have determined autoantibodies by radioassay to three islet autoantigens, glutamic acid decarboxylase (GAD), insulin and the novel neuroendocrine antigen ICA512/IA-2 in 84 HLA-typed ICA+ first degree relatives of patients with Type I diabetes. Among the eleven relatives expressing the 0602 allele (0602+) only two were positive for more than one antibody as determined by radioassay. In contrast, 55/73 ICA+ relatives lacking this allele (non-0602) expressed more than one autoantibody (P < 0.01). The prevalence of antibodies to GAD (GAA) was not significantly different in ICA+ relatives with and without the 0602 allele (7/11 in 0602+ versus 60/73 in non-0602). In contrast, anti-insulin antibodies (IAA) were present in only 2/11 0602+ ICA+ relatives versus 47/70 in non-0602 ICA+ relatives (P < 0.01). Similarly, only one individual carrying the 0602 allele was positive for ICA512 autoantibodies versus 33/70 in the non-0602 group (P < 0.01). These data indicate that even among ICA+ relatives the 0602 allele is associated with a limited immune response to islet antigens and amongst 0602+ relatives this response is mostly directed against GAD.

Adolescent↗
PubMed1999

High-titer autoantibodies against glutamic acid decarboxylase plus autoantibodies against insulin and IA-2 predicts insulin requirement in adult diabetic patients.

Antibodies against glutamic acid decarboxylase (GADA) is known to be a good predictive marker for insulin-dependency among adult diabetic patients. However, since not all of the GADA-positive patients will develop insulin requirement, we investigated whether other markers, that is, antibodies against IA-2 (IA-2A), insulin autoantibodies (IAA) and HLA class II type, would affect its predictive value for insulin requirement. Adult diabetic patients in the non-insulin-requiring stage were screened for GADA and registered in the study if positive. At the end of the follow-up period, 15 of the 43 GADA-positive patients required insulin. Among GADA-positive patients, the GADA titers of the insulin-requiring patients were significantly higher (199 U vs. 5.8 U, P<0.001) and high-titer GADA was more frequently detected among insulin-requiring patients (80%vs. 11%, P<0.0001). IAA was more frequently detected in insulin-requiring patients (40%vs. 0%, P<0.001), and IA-2A was detected only among insulin-requiring patients. Combinations of these three antibodies (GADA with either IAA or IA-2A) had 100% positive predictive value. In conclusion, the GADA test is a good screening test for predicting insulin requirement in adult diabetic patients and both the IAA and IA-2A tests are useful second line tests.

Adult↗
PubMed2001

Rapid assays for detection of anti-islet autoantibodies: implications for organ donor screening.

The purpose of the current study was to develop and evaluate rapid assays for autoantibodies to GAD65 (GAA), ICA512bdc/IA-2 (ICA512AA), and insulin (microIAA, mIAA) as a potential tool for identification of cadaveric pancreas donors who were at high risk for developing diabetes. The study included 154 new onset diabetic, prediabetic, and healthy control subjects. Subjects were evaluated for all three autoantibodies in three separate assays: (1) standard (std) assay with a 24-h or 72-h incubation at 4 degrees C (combined GAA/ICA512AA or mIAA, respectively), (2) rapid assay with 1-h room temperature (RT) incubation, and (3) rapid assay with 2-h RT incubation. The serum samples from 777 organ donors were also evaluated for all three autoantibodies and all the positive samples from standard assay evaluated with the 1-h incubation assay. Simple linear regression analyses revealed excellent correlation between the standard assay and the rapid assays for all three autoantibodies, as follows: (1) GAA: std vs. 1 h (R2=0.85) and std vs. 2 h (R2=0.83), (2) ICA512AA: std vs. 1 h (R2=0.85) and std vs. 2 h (R2=0.84), and (3) mIAA: std vs. 1 h (R2=0.70) and std vs. 2 h (R2=0.64). Comparison of assay correlation rates between subject cohorts revealed no significant differences. Compared to their respective standard assays, the 1-h RT GAA assay missed 3.2% and identified an additional 1.3% of samples, the 1-h RT ICA512AA assay had no discordant samples, and the 1-h RT mIAA assay missed 7.1% and identified an additional 5.8% of samples. We analysed a series of 777 stored serum samples from cadaveric donors. Two of 777 (0.25%) were positive for two autoantibodies (both GAA and ICA512AA) and 23 of 777 (3.0%) one autoantibody (11 IAA; 12 GAA). The rapid analysis for all three autoantibodies could be completed in less than 3 h with comparable concordance rates to the more time-consuming standard assays, making these assays an attractive option for organ donor screening to identify potential pancreata for immunopathogenetic research.

Adolescent↗
PubMed1981

Difference in choline acetyltransferase but similarities in catecholamine biosynthetic enzymes in brains of two rat strains differing in their response to stress.

Rats of the Wistar-Kyoto (WKY) strain are more reactive to stress than Brown-Norway (BN) rats as adjudged by their behavioral and plasma catecholamine (CA) responses to stress. Contrary to the strain differences existing in the periphery, brain CA and their biosynthetic enzyme activities were found to be similar in both strains before and after immobilization stress. However, as in the periphery, choline acetyltransferase (CAT) activity was higher in brains of WKY rats. The results suggest that: (1) peripheral and central CA systems may be under different genetic control mechanisms, and (2) strain differences in CAT activity may reflect differences in cholinergic systems both in the brain and periphery, which may be important in the behavioral differences observed.

Animals↗
PubMed1991

Striatal glutamic acid decarboxylase immunoreactivity is increased after dopaminergic deafferentation: densitometric analysis.

Several lines of evidence suggest that dopamine exerts a chronic inhibitory action on GABAergic cells in the striatum, and striatal glutamic acid decarboxylase (GAD) mRNA levels are increased after ipsilateral dopaminergic denervation. In the present study we have used GAD immunocytochemistry to assess whether dopaminergic denervation results in an increase in GAD protein synthesis. In three 6-hydroxydopamine-lesioned animals, there was a perceptible increase in the density of GAD-immunoreactive (ir)staining on the side ipsilateral to the lesion. Computer-assisted densitometric analysis showed a significant increase in GAD-ir staining in the ipsilateral striatum compared to the contralateral (control) side. These data suggest that removal of striatal dopaminergic innervation results in an increase in the amount of immunoreactive GAD, the rate limiting enzyme in the synthesis of GABA.

Afferent Pathways↗
PubMed2005

Cell biology: master regulators of sealing and healing.

The protective layer of the epidermis in Drosophila (cuticle) and mice (stratum corneum) are structurally unrelated. Yet new evidence suggests a conserved transcription factor, Grainyhead, controls both their development and the means by which both structures repair themselves.

Animals↗
PubMed2004

Mapping of catalytically important residues in the rat L-histidine decarboxylase enzyme using bioinformatic and site-directed mutagenesis approaches.

HDC (L-histidine decarboxylase), the enzyme responsible for the catalytic production of histamine from L-histidine, belongs to an evolutionarily conserved family of vitamin B6-dependent enzymes known as the group II decarboxylases. Yet despite the obvious importance of histamine, mammalian HDC enzymes remain poorly characterized at both the biochemical and structural levels. By comparison with the recently described crystal structure of the homologous enzyme L-DOPA decarboxylase, we have been able to identify a number of conserved domains and motifs that are important also for HDC catalysis. This includes residues that were proposed to mediate events within the active site, and HDC proteins carrying mutations in these residues were inactive when expressed in reticulocyte cell lysates reactions. Our studies also suggest that a significant change in quartenary structure occurs during catalysis. This involves a protease sensitive loop, and incubating recombinant HDC with an L-histidine substrate analogue altered enzyme structure so that the loop was no longer exposed for tryptic proteolysis. In total, 27 mutant proteins were used to test the proposed importance of 34 different amino acid residues. This is the most extensive mutagenesis study yet to identify catalytically important residues in a mammalian HDC protein sequence and it provides a number of novel insights into the mechanism of histamine biosynthesis.

Amino Acid Sequence↗
PubMed2005

Role of dopachrome conversion enzyme in the melanization of filarial worms in mosquitoes.

Melanization is an effective defence reaction of mosquito hosts against invading parasites. In mosquitoes, the biosynthesis of melanin is initiated by the hydroxylation of tyrosine to DOPA by phenoloxidase (PO). DOPA is a branch point of the melanization reaction; it may be oxidized to dopaquinone by PO or be decarboxylated to dopamine by dopa decarboxylase. Further oxidation of dopaquinone by PO produces dopachrome. Dopachrome is then converted to 5, 6-dihydroxyindole by dopachrome conversion enzyme (DCE) to produce melanin. The conversion of dopachrome is a rate-limiting step of the melanization reaction, and the presence of PO and DCE significantly accelerates melanization reactions. In this study, a cDNA encoding DCE was cloned from the mosquito Armigeres subalbatus. Real-time PCR analysis revealed increased transcripts from haemocytes in microfilariae (mf)-inoculated mosquitoes. Gene silencing using double-stranded RNA was used to elucidate the role of DCE in the melanization reaction of parasites in Ar. subalbatus. The levels of both DCE transcripts and protein in gene knockdown mosquitoes were dramatically reduced. Compared with controls, the degree of melanization of mf in DCE-knockdown mosquitoes was significantly decreased. These results suggest that DCE is a critical enzyme that is required for effective melanization immune responses.

Amino Acid Sequence↗