Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “TYROSINE DECARBOXYLASE”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 973 records · Page 54Linked to original sources
PubMedDate not supplied

The effect of prolonged vasopressin administration on the level and metabolism of catecholamines in the rat brain and kidneys.

Dopamine (DA) and noradrenaline (NA) levels and activities of the enzymes metabolizing catecholamines were determined in the rat brain and kidneys during prolonged (4 weeks) administration of lysine vasopressin (LVP) and 2 weeks after its withdrawal. DA level was elevated during the whole period of experiment. NA level increased mainly after LVP withdrawal. Dopa-decarboxylase activity was elevated in all the experimental animals. Tyrosine and dopamine-beta-hydroxylase activities increased at the final period of LVP administration and after its withdrawal. Activities of MAO and COMT were markedly increased only after 3 weeks of LVP administration.

Animals↗
PubMed1996

Alpha 2-autoreceptors and alpha 2-heteroreceptors modulating tyrosine and tryptophan hydroxylase activity in the rat brain in vivo: an investigation into the alpha 2-adrenoceptor subtypes.

The subtype determination of auto- and hetero-alpha 2-adrenoceptors modulating the synthesis of noradrenaline (NA) and serotonin (5-HT), respectively, was assessed using the accumulation of 3,4-dihydroxyphenylalanine (dopa) and 5-hydroxytryptophan (5-HTP) after decarboxylase inhibition as a measure of the rate of tyrosine and tryptophan hydroxylation in the rat brain in vivo. In the cerebral cortex and hippocampus, Org 3770 (non-selective alpha 2-adrenoceptor antagonist, 0.5-10 mg/kg, i.p.) increased (43%-58%) and clonidine (non-selective alpha 2-adrenoceptor agonist, 1 mg/kg) decreased (37%-49%) the synthesis of dopa. Also the antagonist ARC 239 (alpha 2B/C selective, 5-40 mg/kg) increased the synthesis of dopa in cortex (39%-46%) and hippocampus (17%-85%). In contrast, the antagonist BRL 44408 (alpha 2D selective, 1-10 mg/kg) did not increase the synthesis of dopa in cortex, and increased it modestly in hippocampus only. The agonist guanoxabenz (alpha 2B/C selective, 0.03-3 mg/kg) decreased the synthesis of dopa in both brain regions (20%-65%), whereas the agonist oxymetazoline (alpha 2D selective, 0.1-3 mg/kg) failed to do so. These results indicated that the alpha 2-autoreceptors that modulate the synthesis of dopa/NA are probably associated with the alpha 2B/C-subtypes. In cortex and hippocampus, clonidine decreased (35%-53%) the synthesis of 5-HTP but Org 3770 failed to induce the opposite effect (except the 2 mg/kg dose in cortex). BRL 44408 markedly increased the synthesis of 5-HTP in cortex (113%-148%) but not in hippocampus. Similarly, also ARC239 increased the formation of 5-HTP in cortex (36%-48%) but not in hippocampus, where it was decreased (30%-55%). Oxymetazoline decreased the synthesis of 5-HTP in hippocampus (28%-30%) but failed to do so in cortex. Guanoxabenz in the low dose range (0.03-0.3 mg/kg) did not decrease the synthesis of 5-HTP in any brain region. These results indicated that the alpha 2-heteroreceptors that modulate the synthesis of 5-HTP/5-HT may well be different from the proposed alpha 2B/C-autoreceptors modulating the synthesis of dopa/NA. These alpha 2-heteroreceptors appear to be associated with the alpha 2D-subtype.

Adrenergic alpha-Agonists↗
PubMed1992

Immunohistochemical studies on the intrinsic pancreatic nerves in the chicken.

A peroxidase anti-peroxidase method or an avidin-biotinylated complex method was used to visualize neural elements immunostained for several neuropeptides in the chicken pancreas. Pancreatic ganglion cells were only immunoreactive with vasoactive intestinal polypeptide (VIP), galanin and substance P (SP) antisera. VIP-immunoreactive (IR) ganglion cells were the most numerous, and most of them also showed the distinct immunoreaction with galanin. VIP- and galanin-IR nerve fibers were observed in the exocrine portion, the adventitia of the artery and the connective tissue of the ductal wall. The number and distribution of the VIP- and galanin-IR nerve fibers around the artery and duct were similar. SP-IR nerve fibers were found mainly close to the blood vessel. SP- and CGRP-IR nerve fibers were detected in the VIP-IR ganglion and extrapancreatic nerve bundle. Tyrosine hydroxylase (TH)- and aromatic L-amino acid decarboxylase (AADC)-IR nerve fibers were observed as nerve bundles in the interlobular space or extrapancreatic nerves. Consequently, VIP and galanin coexist in the intrinsic neural elements. SP is partially located in the intrinsic neural elements, but most of it seems likely to originate from the extrinsic ganglion. It is probable that calcitonin gene related peptide (CGRP)-, TH- and AADC-IR nerve fibers have an extrinsic origin.

Animals↗
PubMed1988

The innervation of the renal cortex in the dog. An ultrastructural study.

Two cytochemical techniques were used at the ultrastructural level to study the distribution of specific axon types to different intrarenal structures in the dog. Using the chromaffin reaction to distinguish catecholaminergic fibres from other axon populations, it was found that the renal cortex of the dog is supplied only by catecholaminergic nerves. Immunostaining for tyrosine hydroxylase (TH) labelled all of the intracortical nerves, and 20% to 25% of these profiles also contained dopa decarboxylase (DDC)-immunoreactivity, indicating they were dopaminergic rather than noradrenergic. Both DDC-positive and DDC-negative axons were seen in close association (approximately 80 nm) with blood vessels and juxtaglomerular cells as well as tubular epithelial cells. The distribution of TH- and DDC-immunoreactive nerves in the renal cortex is compatible with existing functional evidence indicating that both dopaminergic and noradrenergic nerves are involved in the regulation of renal blood flow, tubular reabsorption and renin release.

Animals↗
PubMed1997

Electrophysiological and immunocytochemical characterization of GABA and dopamine neurons in the substantia nigra of the rat.

Neurons in the substantia nigra pars reticulata and pars compacta of the rat were studied using a combination of intracellular electrophysiological recording in in vitro and subsequent immunocytochemical double and triple labelling techniques. The neurons recorded in the pars reticulata were identified as either GABA or dopamine neurons: neurons were considered to be GABA neurons if they were immunopositive for glutamate decarboxylase, whereas those neurons which were immunopositive for tyrosine hydroxylase were considered to be dopaminergic. The GABA neurons had short duration action potentials (0.45+/-0.03 ms halfwidth), no apparent rectifying currents, no low threshold calcium spikes, were spontaneously active (7.4+/-3.7 Hz), and could maintain high firing rates. The dopamine neurons had long duration action potentials (1.49+/-0.10 ms), displayed both anomalous inward and transient outward rectifying currents, and more than half (12/17 neurons) displayed a low threshold calcium spike. Their spontaneous firing rate was lower than that of the GABA neurons (2.3+/-1.0 Hz), and they displayed strong frequency adaptation. Morphological reconstruction of neurobiotin-filled neurons revealed that the pars reticulata GABA neurons had more extensive local dendritic arborization than the dopamine neurons from either the pars reticulata or the pars compacta. All of the neurons recorded from the pars compacta were dopamine neurons; they were found not to be different either electrophysiologically or morphologically from pars reticulata dopamine neurons. The electrophysiology of the GABA neurons suggests that input activity is translated linearly to spike frequency. These GABA neurons probably represent the projection neurons of the pars reticulata, and it is thus likely that this basal ganglia output is frequency coded. The close similarity between the dopamine neurons in the pars compacta, which give rise to the nigrostriatal pathway, and those in the pars reticulata supports the notion that the dopamine neurons in these two regions are part of the same neuronal population.

Animals↗
PubMed1982

The effect of some precursor amino acids and enzyme inhibitors on the mouse striatal concentration of tyramines and homovanillic acid.

The parenteral administration of L-phenylalanine or p-tyrosine increases the mouse striatal concentration of p-tyramine, an effect that is enhanced by monoamine oxidase inhibition and reduced by an L-aromatic aminoacid decarboxylase inhibitor. Striatal m-tyramine was increased following administration of L-phenylalanine or m-tyrosine and enhanced further by monoamine oxidase inhibition. It was also observed that m-tyrosine is a better substrate for decarboxylation than p-tyrosine, and that p-tyrosine decarboxylation was blocked by NSD 1055, while that of m-tyrosine was enhanced. The results obtained indicate that both isomers of tyramine are formed in the mouse striatum by hydroxylation of L-phenylalanine to p- or m-tyrosine followed by decarboxylation by a specific decarboxylase; an alternative pathway could be first the decarboxylation of phenylalanine to beta-phenylethylamine, followed by its hydroxylation to p- or m-tyramine.

Animals↗
PubMed1990

Differential recovery of dopamine synthetic enzymes following MPTP and the consequences of GM1 ganglioside treatment.

After 7 days of treatment with MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), 30 mg/kg i.p., tyrosine hydroxylase (TH) and aromatic L-amino acid decarboxylase (AAAD) activities are decreased by more than 50% in the mouse striatum. Within 30 days, AAAD activity returns while TH activity remains depressed. TH activity can be restored to near normal by chronic treatment with GM1 ganglioside, 30 mg/kg i.p.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2004

Evidence of newly generated neurons in the human olfactory bulb.

The subventricular zone (SVZ) is known to be the major source of neural stem cells in the adult brain. In rodents and nonhuman primates, many neuroblasts generated in the SVZ migrate in chains along the rostral migratory stream (RMS) to populate the olfactory bulb (OB) with new granular and periglomerular interneurons. In order to know if such a phenomenon exists in the adult human brain, we applied single and double immunostaining procedures to olfactory bulbs obtained following brain necropsy in normal adult human subjects. Double immunofluorescence labelling with a confocal microscope served to visualize cells that express markers of proliferation and immature neuronal state as well as markers that are specific to olfactory interneurons. Newborn cells that express cell cycle proteins [Ki-67, proliferating cell nuclear antigen (PCNA)] were detected in the granular and glomerular layers (GLs) of the human olfactory bulb; these cells coexpressed markers of immature neuronal state, such as Doublecortin (DCX), NeuroD and Nestin. Numerous differentiating cells expressed molecular markers of early committed neurons [beta-tubulin class III (TuJ1)] and were also immunoreactive for glutamic acid decarboxylase (GAD), a marker of GABAergic neurons, or tyrosine hydroxylase (TH), a marker of dopaminergic neurons. Other early committed neurons expressed the calcium-binding proteins calretinin (CR) or parvalbumin (PV). These results provide strong evidence for the existence of adult neurogenesis in the human olfactory system. Despite its relatively small size compared to that in rodents and nonhuman primates, the olfactory bulb in humans appears to be populated, throughout life, by new granular and periglomerular neurons that express a wide variety of chemical phenotypes.

Adult↗
PubMed2001

Differential expression of catecholamine synthetic enzymes in the caudal ventral pons.

The analysis of colocalization of multiple catecholamine biosynthetic enzymes within the ventrolateral part of the medulla oblongata of the rat revealed distinct subpopulations of neurons within the C1 region (Phillips et al., J Comp Neurol 2001, 432:20-34). In extending this study to include the caudal pons, it was shown for the first time that the A5 cell group could be distinguished by the presence of immunoreactivity to tyrosine hydroxylase (TH), aromatic l-amino acid decarboxylase (AADC), and dopamine beta hydroxylase (DBH). A novel cell group was also identified. The cells within this new group were immunoreactive to DBH but not TH, AADC, or phenylethanolamine N-methyltransferase (PNMT) and will be referred to as the TH-, DBH+ cell group. The TH-, DBH+ neurons were not immunoreactive for either the dopamine or noradrenaline transporters, suggesting that these neurons do not take up these transmitters. A5 neurons were immunoreactive for the noradrenaline transporter but not the dopamine transporter (as previously shown). Retrograde tracing with cholera toxin B revealed that the TH-, DBH+ neurons do not project to the thoracic spinal cord or to the rostral ventrolateral medulla, but A5 neurons do. A calbindin immunoreactive cell group is located in a region overlapping TH-, DBH+ cell group. However, only a few neurons were immunoreactive for both markers. The physiological role of the TH-, DBH+ cell group remains to be determined.

Animals↗
PubMed1992

Effects of benzo[a]pyrene on steady-state levels of biogenic amines and metabolizing enzymes in mouse brain regions.

Benzo[a]pyrene (BaP) is a product of incomplete fossil fuel combustion, a well-known pollutant, and a carcinogenic agent. In the present study male CD-1 mice received ip injections of 0, 5, 25, and 100 mg/kg body weight BaP twice a week for 3 weeks. Endogenous levels of brain biogenic amines and their selected metabolites, norepinephrine (NE), dopamine (DA), 5-hydroxytryptamine (5-HT), vanillylmandelic acid, dihydroxyphenylacetic acid (DOPAC), homovanillic acid, and 5-hydroxyindoleacetic acid (5-HIAA) were measured using high performance liquid chromatography and electrochemical detection. The brain regions studied were cortex, striatum, hypothalamus, midbrain, medulla oblongata, and cerebellum. BaP treatment increased the steady-state levels of NE, DA, and 5-HT in the hypothalamus and striatum. Increased levels of DA and 5-HT and their major metabolites DOPAC and 5-HIAA were noticed in the same region, an indication of increased metabolism of these amines. The increase in the 5-HT level in the cortex was not dose-related. Levels of NE and DA were significantly higher in the medulla oblongata. There was a concurrent increase in activities of tyrosine hydroxylase and tryptophan hydroxylase in several brain regions. The effect of BaP on Dopa-decarboxylase was not consistent. Monoamine oxidase was occasionally inhibited. Results indicate that exposure to BaP altered the steady-state levels of biogenic amines in various brain regions and these changes were consistent with the activities of metabolizing enzymes.

Animals↗
PubMed1997

Immunohistochemical colocalization of GTP cyclohydrolase I in the nigrostriatal system with tyrosine hydroxylase.

Immunohistochemical colocalization of GTP cyclohydrolase I (GCH) in the mouse nigrostriatal system with tyrosine hydroxylase or aromatic L-amino acid decarboxylase in the somata and terminals of GCH-positive catecholaminergic neurons are proved for the first time by a double-labeling immunofluorescence method with a confocal laser-scanning microscope. GCH-immunoreactive somata in the mouse substantia nigra have synaptic contacts with monoaminergic and non-monoaminergic terminals.

Animals↗
PubMed2002

Behavioral recovery in a primate model of Parkinson's disease by triple transduction of striatal cells with adeno-associated viral vectors expressing dopamine-synthesizing enzymes.

One potential strategy for gene therapy of Parkinson's disease (PD) is the local production of dopamine (DA) in the striatum induced by restoring DA-synthesizing enzymes. In addition to tyrosine hydroxylase (TH) and aromatic-L-amino-acid decarboxylase (AADC), GTP cyclohydrolase I (GCH) is necessary for efficient DA production. Using adeno-associated virus (AAV) vectors, we previously demonstrated that expression of these three enzymes in the striatum resulted in long-term behavioral recovery in rat models of PD. We here extend the preclinical exploration to primate models of PD. Mixtures of three separate AAV vectors expressing TH, AADC, and GCH, respectively, were stereotaxically injected into the unilateral putamen of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated monkeys. Coexpression of the enzymes in the unilateral putamen resulted in remarkable improvement in manual dexterity on the contralateral to the AAV-TH/-AADC/-GCH-injected side. Behavioral recovery persisted during the observation period (four monkeys: 48 days, 65 days, 50 days, and >10 months, each). TH-immunoreactive (TH-IR), AADC-IR, and GCH-IR cells were present in a large region of the putamen. Microdialysis demonstrated that concentrations of DA in the AAV-TH/-AADC/-GCH-injected putamen were increased compared with the control side. Our results show that AAV vectors efficiently introduce DA-synthesizing enzyme genes into the striatum of primates with restoration of motor functions. This triple transduction method may offer a potential therapeutic strategy for PD.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2002

Effects of tyrosine hydroxylase mutants on locomotor activity in Drosophila: a study in functional genomics.

The brain of the adult fruit fly, Drosophila melanogaster, contains tyrosine hydroxylase, the rate-limiting enzyme required for catecholamine biosynthesis, as well as dopa decarboxylase. Catecholamines, principally dopamine, are also present. We have previously shown that pharmacological inhibition of tyrosine hydroxylase with alpha-methyl-p-tyrosine results in a dose-related inhibition of locomotor activity in adult organisms. Similar results were found with reserpine, a well-known inhibitor of catecholamine uptake into storage granules. The drug-induced inhibition could be prevented in each case by the concomitant administration of L-dopa. The single-copy gene coding for tyrosine hydroxylase in Drosophila is pale (ple). Both null and temperature-sensitive loss of function mutant alleles of ple are recessive embryonic lethals. Heterozygous null mutant flies have normal locomotor activity demonstrating that only a single dose of the wild type form of ple is required to support normal function. Both hemizygous and homozygous temperature-sensitive ple mutants (ple(ts1)) also show normal locomotor activity at the permissive temperature for this mutant allele (18 degrees C), which progressively declines as the temperature is increased to its restrictive level (29 degrees C). These abnormal locomotor effects are reversible by L-dopa. Thus the effects on locomotor activity resulting from the pharmacological inhibition of catecholamine synthesis or storage are the same as those resulting from lack of tyrosine hydroxylase expression. These findings indicate that brain catecholamine loss decreases locomotor activity in the fly, as it does in mammals, and demonstrate the ability of functional genomic studies to mimic that of pharmacological inhibition of enzyme function or other similar processes.

Alleles↗
PubMed1991

Genes for human catecholamine-synthesizing enzymes.

Catecholamine neurotransmitters--dopamine, noradrenaline (norepinephrine), adrenaline (epinephrine)--are synthesized in catecholaminergic neurons from tyrosine, via dopa, dopamine and noradrenaline, to adrenaline. Four enzymes are involved in the biosynthesis of adrenaline: (1) tyrosine 3-mono-oxygenase (tyrosine hydroxylase, TH); (2) aromatic L-amino acid decarboxylase (AADC, or DOPA decarboxylase, DDC); (3) dopamine beta-mono-oxygenase (dopamine beta-hydroxylase, DBH); and (4) noradrenaline N-methyltransferase (phenylethanolamine N-methyltransferase, PNMT). We cloned full-length complementary DNAs (cDNAs) and genomic DNAs of human catecholamine-synthesizing enzymes (TH, AADC, DBH, PNMT) and determined the nucleotide sequences and the deduced amino acid sequences. We discovered multiple messenger RNAs (mRNAs) of human TH, human DBH, and human PNMT. Four types (types 1, 2, 3, and 4) of human TH mRNAs are produced by alternative mRNA splicing mechanism from a single gene. We found the multiple forms of TH in two species of monkeys, but only a single mRNA corresponding to human TH type 1 in Sunkus murinus and rat, suggesting that the multiplicity of TH mRNA is primate-specific. Total TH mRNA, especially the most abundant type 2 and type 1 mRNAs in the human brain, were found to be reduced during the process of aging. The multiple forms of human TH may give additional regulation to the human enzyme, probably through altered phosphorylation and activation. We have succeeded in producing transgenic mice carrying multiple copies of the human TH gene in brain and adrenal medulla. The level of human TH mRNA in brain was about 50-fold higher than that of endogenous mouse TH mRNA. In situ hybridization demonstrated an enormous region-specific expression of the transgene in substantia nigra and ventral tegmental area. TH immunoreactivity in these regions, Western blot analysis, and TH activity measurements proved definitely increased TH in transgenic mice, though not comparable to the increment of the mRNA. However, catecholamine levels in transgenics were not significantly different from those in non-transgenics. The results suggest complex regulatory mechanisms for human TH gene expression and for the catecholamine levels in transgenic mice. Kohsaka and Uchida in collaboration with us applied genetically engineered (human TH cDNA-transfected) non-neuronal cells to brain tissue transplantation in parkinsonian rat models. We isolated and sequenced a full-length cDNA encoding human AADC.(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acid Sequence↗
PubMed1986

Phenylethanolamine N-methyltransferase-containing neurons in rat retina: immunohistochemistry, immunochemistry, and molecular biology.

We sought to characterize in detail neurons in rat retina that contain phenylethanolamine N-methyltransferase (PNMT), the epinephrine biosynthetic enzyme. Cell bodies and processes of PNMT-containing neurons in retina were identified by immunohistochemistry. The coexistence of other catecholamine biosynthetic enzymes in the same cells was also investigated. Biochemical, molecular biological and immunochemical methods were applied to determine whether retinal PNMT is similar to the adrenal enzyme, since regulation of PNMT in retina and adrenal appears to be different. The results show that there are two types of PNMT-containing cells: those containing PNMT exclusively and those containing PNMT with two other catecholamine-synthesizing enzymes, tyrosine hydroxylase (TH) and aromatic L-amino acid decarboxylase (AADC), but not dopamine beta-hydroxylase (DBH). PNMT-only cell bodies are localized in the inner nuclear layer (INL) and the ganglion cell layer (GCL). Their processes are observed in outer and inner strata of the inner plexiform layer (IPL). Only a small fraction of PNMT neurons in INL also contain TH and AADC. These cells send their processes to the adjacent stratum of the IPL. Antibodies to bovine adrenal DBH, however, fail to localize DBH in any rat retinal cells. Immunochemical titration shows that PNMT from both retina and adrenal gland has the same immunoreactivity. Furthermore, a PNMT-cDNA probe hybridizes equally with PNMT-mRNA isolated from both the retina and the adrenal gland. These results indicate that PNMT is identical in these tissues.

Adrenal Glands↗
PubMed1999

Ectopic expression of non-catecholaminergic tyrosine hydroxylase in rat hypothalamic magnocellular neurons.

Hypothalamic magnocellular neurons constitute a good model of neurochemical plasticity, because a single neuron can express various combinations of neuropeptides and enzymes under different physiological conditions. Tyrosine hydroxylase has been shown to occur ectopically in various non-catecholaminergic neurons. We investigated the expression of tyrosine hydroxylase and its possible role in the magnocellular neurons of the supraoptic and paraventricular nuclei in salt-loaded and lactating rats, using in situ hybridization and immunohistochemistry, alone or combined, in light and electron microscopy. Our results demonstrated that almost 25% of the magnocellular neurons in the supraoptic nucleus and 15% in the paraventricular nucleus expressed tyrosine hydroxylase in salt-loaded rats, and 10% in the supraoptic nucleus of two-day lactating rats. Double labelling showed that this tyrosine hydroxylase was essentially synthesized in magnocellular neurons expressing vasopressin. The ultrastructural localization of tyrosine hydroxylase was less homogeneous in the cytoplasm of magnocellular neurons than in periventricular neurons. In lactating and salt-loaded rats, magnocellular neurons were devoid of the catecholamine biosynthesis markers aromatic L-amino acid decarboxylase, L-3,4 dihydroxyphenylalanine, dopamine and GTP-cyclohydrolase I. Tyrosine hydroxylase expression did not increase after rats were injected with reserpine. Our results indicate that the phenotype of the magnocellular neurons expressing tyrosine hydroxylase in lactating and salt-loaded rats is non-catecholaminergic, and suggest that this tyrosine hydroxylase might be involved in osmoregulation.

Animals↗
PubMed2001

High levels of antigen-specific islet antibodies predict future beta-cell failure in patients with onset of diabetes in adult age.

It is unclear whether high levels of antigen-specific islet antibodies [GADA (glutamic acid decarboxylase 65 antibodies) and IA2-ab (protein tyrosine phosphatase-like protein antibodies)] predict beta-cell failure in patients with onset of diabetes in adult age. Therefore, GADA and IA2-ab levels at the diagnosis of diabetes were related to fasting plasma C-peptide levels 5 yr later in 148 patients with diabetes onset in adult age (age at onset, 20-77 yr; median, 57 yr). Classical islet cell antibodies (ICA) were also determined. Complete beta-cell failure (undetectable fasting plasma C-peptide) was only present in 4 patients at diagnosis of diabetes, but in 21 patients 5 yr thereafter. At diagnosis, ICA were detected in 20 of 21 (95%) patients with beta-cell failure after 5 yr and in only 7 of 127 (5%) without, whereas GADA and/or IA2-ab (>97.5 percentile of healthy controls) were detected in all 21 (100%) with but also in 23 of 127 (18%) patients without beta-cell failure after 5 yr. Thus, ICA had a higher positive predictive value (74%) than GADA and/or IA2-ab (47%; P < 0.05). With high cutoff values for GADA and IA2-ab, however, GADA and/or IA2-ab were detected in 19 of 21 (90%) patients with beta-cell failure vs. only in 5 of 127 (4%) without, giving a positive predictive value of 79%. Slightly elevated GADA levels in IA2-ab-negative patients were associated with progressive but not complete beta-cell failure within the study period. Hence, high GADA and/or IA2-ab levels predict a future complete beta-cell failure, whereas low GADA levels predict slowly progressive beta-cell insufficiency.

Adult↗