Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011854 (type 1 diabetes)
 20,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We measured net uptake and release of amino acids in the brain of 7 nondiabetic and six diabetic subjects. Duration of insulin-dependent diabetes (IDDM) was 19.4 +/- 2.1 years. Arteriojugular vein measurements were performed before and after 120 minutes of insulin infusion and ensuing Biostator-regulated normoglycemia. Cerebral blood flow was measured during normoglycemia by 11-CH3-F and positron emission tomography. During hyperglycemia in the IDDM subjects, arterial concentrations of valine and leucine were higher, and those of glutamic acid and arginine lower, than in nondiabetic subjects. Insulin infusion lowered levels of most amino acids in both groups. Insulin treatment did not significantly affect the uptake or release of amino acids. Significant net uptake of branched-chain amino acids was noted in both groups, as well as uptake of lysine and phenylalanine in the IDDM subjects. The sum of measured differences was not different from zero in either group. Nitrogen balance depended on impressive release of glutamine from the brain (-963 +/- 147 and -960 +/- 303 nmol/100 g/min), which amounted to 73% and 69% of net release in nondiabetic and IDDM subjects, respectively. We conclude that balance between uptake and release of amino acids is similar in nondiabetic and in long-term IDDM subjects.
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PMID:Brain uptake and release of amino acids in nondiabetic and insulin-dependent diabetic subjects: important role of glutamine release for nitrogen balance. 153 41

Cell-mediated autoimmune attack directed against islet proteins of approximately 38 kD in size has been associated with type 1 diabetes. A novel murine cDNA encoding an antigen of this size was cloned using a screening procedure based on the proliferative response of a human diabetic T cell clone (1C6) to a recombinant antigen epitope library. Membrane preparations from COS 7 cells transfected with the full-length 1,267-bp cDNA elicited a proliferative response from the reporter T cells comparable to that of the defined peptide epitope and native insulinoma antigen. In vitro translation and transfection experiments suggested that the protein is initially synthesized as a 44-kD protein and then processed to the native 38-kD form through the proteolytic removal of a 54-aa NH2-terminal mitochondrial targeting sequence. Differential centrifugation, Percoll density gradient centrifugation, and immunofluorescence studies confirmed localization of the antigen to mitochondria. Northern blot, Western blot, and 1C6 T cell proliferation assays showed that, although imogen 38 was more highly expressed in beta cell than alpha cell lines, it was also present in other tissues. It is concluded that imogen 38 may be a target for bystander autoimmune attack in diabetes rather than a primary autoantigen.
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PMID:Imogen 38: a novel 38-kD islet mitochondrial autoantigen recognized by T cells from a newly diagnosed type 1 diabetic patient. 856 80

N-Myristoyltransferase (NMT) catalyses the transfer of myristate from myristoyl-CoA to the NH2-terminal glycine residue of several proteins and are important in signal transduction. STZ-induced diabetes (an animal model for insulin-dependent diabetes mellitus, IDDM) resulted in a 2-fold increase in rat liver NMT activity as compared with control animals. In obese Zucker (fa/fa) rats (an animal model for non-insulin dependent diabetes mellitus, NIDDM) there was a approximately 4.7-fold lower liver particulate NMT activity as compared with the control lean rat livers. Administration of sodium orthovanadate to the diabetic rats normalised liver NMT activity. These results would indicate that the rat liver particulate N-myristoyltransferase activity appears to be inversely proportional to the level of plasma insulin, implicating insulin in the control of N-myristoylation.
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PMID:In vivo modulation of N-myristoyltransferase activity by orthovanadate. 892 31

Thirty-three IDDM sera that immunoprecipitated full-length IA-2 were tested for reactivity with different fragments of the IA-2 molecule. The fragments were prepared by PCR amplification of IA-2 cDNA and by expression in a rabbit reticulocyte transcription/translation system. Whereas all 33 sera reacted with the intracellular domain (amino acid 604 to 979), none of the sera reacted with the extracellular domain of IA-2 (amino acid 31 to 577). Analysis of the reactivity of IDDM sera with the different regions of the intracellular domain showed that 94% (31 of the 33) reacted with the COOH-terminus (amino acid 771 to 979), 40% reacted with the NH2-terminus (amino acid 604 to 776), and 40% reacted with the middle portion (amino acid 692 to 875). Of the 31 sera that reacted with the COOH-terminus, 14 of these reacted only with the COOH-terminus and with no other region. Of the 13 sera that reacted with the NH2-terminus, only one reacted exclusively with the NH2-terminus. Treatments of the different domains of IA-2 with trypsin showed that only the COOH-terminus was resistant to trypsin, arguing that it is from this region of the IA-2 molecule that the 40-kDa tryptic fragment from insulinoma cells is derived. From these experiments, it is concluded that the major antigenic determinant of IA-2 is located at the COOH-terminus and that minor antigenic determinants are located at the NH2-terminus and middle portion of the intracellular domain.
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PMID:Autoantibodies to IA-2 in IDDM: location of major antigenic determinants. 897 Oct 79

Insulin-dependent (type I) diabetic patients are known to have an exaggerated growth hormone (GH) response to GH-releasing hormone (GHRH), which is hypothesized to be due to a decrease in somatostatin tone. The aim of the study was to ascertain the influence of the presence and activity of the autoimmune process involving a key enzyme (glutamic acid decarboxylase [GAD]) in the synthetic pathway of a neurotransmitter regulating somatostatin secretion, ie, gamma-aminobutyric acid (GABA), on the GH response to GHRH alone or combined with an acetylcholinesterase inhibitor, pyridostigmine (PD), in patients with type I diabetes mellitus. Twenty non-obese type I diabetic patients and 17 normal subjects underwent an intravenous (IV) injection of 100 micrograms GHRH(1-29)NH2. Twelve of 20 diabetic subjects and all of the control subjects also underwent a second experimental procedure, administration of 120 mg oral PD 60 minutes before IV injection of 100 micrograms GHRH. Diabetic subjects with serum GAD antibody (GADA) levels more than 3 U (n = 10) showed significantly higher serum GH levels after GHRH injection as compared both with diabetic patients with GADA less than 3 U (n = 10) and with normal controls, whether expressed as absolute or peak values. GH peaks after GHRH were significantly (rs = .46, P < .05) correlated with the level of GADA in the whole population of type I diabetic subjects studied. PD significantly enhanced the GH response to GHRH, in terms of both absolute and peak values, in patients without GADA (n = 6) and in normal subjects. On the contrary, PD failed to enhance the GH response to GHRH in diabetic patients with GADA (n = 6). Our findings suggest that autoimmunity may play a key role in determining the exaggerated GH response to GHRH in type I diabetes mellitus. The mechanism underlying this effect is hypothesized to be the production of antibodies to GAD, a key enzyme in the synthesis of GABA, and in turn a reduced GABAergic stimulatory tone on somatostatin production at the hypothalamic level.
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PMID:Glutamate decarboxylase autoimmunity and growth hormone secretion in type I diabetes mellitus. 910 40

Proglucagon contains the sequence of two glucagon-like peptides, GLP-1 and GLP-2, secreted from enteroendocrine cells of the small and large intestine. GLP-1 lowers blood glucose in both NIDDM and IDDM patients and may be therapeutically useful for treatment of patients with diabetes. GLP-1 regulates blood glucose via stimulation of glucose-dependent insulin secretion, inhibition of gastric emptying, and inhibition of glucagon secretion. GLP-1 may also regulate glycogen synthesis in adipose tissue and muscle; however, the mechanism for these peripheral effects remains unclear. GLP-1 is produced in the brain, and intracerebroventricular GLP-1 in rodents is a potent inhibitor of food and water intake. The short duration of action of GLP-1 may be accounted for in part by the enzyme dipeptidyl peptidase 4 (DPP-IV), which cleaves GLP-1 at the NH2-terminus; hence GLP-1 analogs or the lizard peptide exendin-4 that are resistant to DPP-IV cleavage may be more potent GLP-1 molecules in vivo. GLP-2 has recently been shown to display intestinal growth factor activity in rodents, raising the possibility that GLP-2 may be therapeutically useful for enhancement of mucosal regeneration in patients with intestinal disease. This review discusses recent advances in our understanding of the biological activity of the glucagon-like peptides.
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PMID:Glucagon-like peptides. 951 8

Aberrant neurofilament phosphorylation occurs in many neurodegenerative diseases, and in this study, two animal models of type 1 diabetes--the spontaneously diabetic BB rat and the streptozocin-induced diabetic rat--have been used to determine whether such a phenomenon is involved in the etiology of the symmetrical sensory polyneuropathy commonly associated with diabetes. There was a two- to threefold (P < 0.05) elevation of neurofilament phosphorylation in lumbar dorsal root ganglia (DRG) of diabetic rats that was localized to perikarya of medium to large neurons using immunocytochemistry. Additionally, diabetes enhanced neurofilament M phosphorylation by 2.5-fold (P < 0.001) in sural nerve of BB rats. Neurofilaments are substrates of the mitogen-activated protein kinase (MAPK) family, which includes c-jun NH2-terminal kinase (JNK) or stress-activated protein kinase (SAPK1) and extracellular signal-regulated kinases (ERKs) 1 and 2. Diabetes induced a significant three- to fourfold (P < 0.05) increase in phosphorylation of a 54-kDa isoform of JNK in DRG and sural nerve, and this correlated with elevated c-Jun and neurofilament phosphorylation. In diabetes, ERK phosphorylation was also increased in the DRG, but not in sural nerve. Immunocytochemistry showed that JNK was present in sensory neuron perikarya and axons. Motoneuron perikarya and peroneal nerve of diabetic rats showed no evidence of increased neurofilament phosphorylation and failed to exhibit phosphorylation of JNK. It is hypothesized that in sensory neurons of diabetic rats, aberrant phosphorylation of neurofilament may contribute to the distal sensory axonopathy observed in diabetes.
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PMID:Aberrant neurofilament phosphorylation in sensory neurons of rats with diabetic neuropathy. 1010 7

GAD is a major target of autoimmunity in preclinical type 1 diabetes. Here we examine the maturation of the humoral response to GAD epitopes sequentially from birth to diabetes onset or current follow-up in 29 GAD antibody (GADA)+ offspring of parents with diabetes from the BABYDIAB Study. Antibodies were measured against GAD65, GAD67, and GAD65/67 chimeras by radiobinding assay. In 28 of 29 offspring, the first GADAs contained reactivity against epitopes within GAD65 residues 96-444, suggesting that the middle GAD65 region is a primary target of GAD humoral autoimmunity. In 7 of these 28 offspring, initial antibody reactivity was against all epitope regions tested (middle GAD65, COOH-terminal GAD65 residues 445-585, NH2-terminal GAD65 residues 1-95, and GAD67); in 16 offspring, reactivity was to middle and COOH-terminal GAD65 epitopes, and in 5 offspring, reactivity was only to the middle GAD65 epitopes. The single offspring without middle GAD65 reactivity had antibodies to the NH2-terminal epitopes in the absence of all other islet autoimmunity. Subsequent GADA epitope spreading was frequent and seen in 10 of 15 offspring with informative follow-up samples. Spreading was mostly (eight cases) to NH2-terminal GAD65 epitopes. In two offspring, spreading to new epitopes was found when antibody titers to GAD65 and early epitopes were declining, suggesting determinant-specific regulation of the humoral response. None of the GADA reactivities nor any changes in reactivity over time were specifically associated with diabetes onset. The findings suggest that the humoral autoimmune response to GAD found in childhood is dynamic, is initially against epitopes within the middle portion of GAD65, and spreads to epitopes in other regions of GAD65 and GAD67.
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PMID:Maturation of the humoral autoimmune response to epitopes of GAD in preclinical childhood type 1 diabetes. 1086 36

Indirect biochemical techniques have solely been used to ascertain whether type 1 diabetes mellitus patients are more susceptible to resting and exercise-induced oxidative stress. To date there is no direct evidence to support the contention that type 1 diabetic patients have increased levels of free radical species. Thus, the aim of this study was to use electron spin resonance (ESR) spectroscopy in conjunction with alpha-phenyl-tert-butylnitrone (PBN) spin trapping to measure pre- and postexercise free radical concentration in the venous blood of young male patients with type 1 diabetes mellitus (HbA(1c) = 8.2 +/- 1%, n = 12) and healthy matched controls (HbA(1c) = 5.5 +/- 0.2%, n = 13). Supporting measures of lipid peroxidation (malondialdehyde and lipid hydroperoxides), ambient blood glucose and selected antioxidants were also measured. The diabetic patients presented with a comparatively greater concentration of free radicals as measured by ESR and lipid hydroperoxides (LH) compared to the healthy group (p <.05, pooled rest and exercise data), although there was no difference in malondialdehyde (MDA) concentration. alpha-Tocopherol was comparatively lower in the healthy group (p <.05, pooled rest and exercise data vs. diabetic group) due to a selective decrease during physical exercise (p <.05 vs. rest). The hyperfine coupling constants recorded from the ESR spectra (a(Nitrogen) = 1.37 mT and abeta(Hydrogen) = 0.17 mT) are suggestive of either oxygen or carbon-centered species and are consistent with literature values. We suggest that the greater concentration of oxidants seen in the diabetic group may be due to increased glucose autoxidation as a function of this pathology and/or a lower exercise-induced oxidation rate of the major lipid soluble antioxidant alpha-tocopherol. We suggest that the ESR-detected radicals are secondary species derived from decomposition of LH because these are the major initial reaction products of free radical attack on cell membranes.
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PMID:Exercise, free radicals, and lipid peroxidation in type 1 diabetes mellitus. 1244 12

Vascular adhesion protein-1 (VAP-1) is one of the molecules on the endothelial cell membrane, which may guide inflammatory cells into atherosclerotic lesions. This dual function molecule may also contribute to the pathogenesis of atherosclerosis and other vasculopathies via its enzymatic activity that oxidizes primary amines to produce their corresponding aldehydes, hydrogen peroxide, and ammonium. Because VAP-1 also exists in a soluble form, we analyzed its potential usefulness as a biomarker to monitor and predict the extent of ongoing atherosclerotic processes. Soluble VAP-1 (sVAP-1) levels were determined from the sera of 136 Finnish men with established coronary heart disease and in 275 controls using sandwich enzyme immunoassays and correlated to multiple risk factors for coronary events. Intriguingly, sVAP-1 showed a statistically significant correlation with diabetes in both cohorts. We then collected patients with type 1 diabetes and observed that sVAP-1 levels were highly elevated when the patients were metabolically compromised. On normalization of their blood glucose and ketone body levels by exogenous insulin, their sVAP-1 concentration rapidly decreased to control levels. Intravenous glucose tolerance and hyperinsulinemic clamp tests further showed that elevation of blood glucose per se did not increase sVAP-1 levels, but rather, sVAP-1 was inversely correlated with circulating insulin concentrations. In conclusion insulin appears to regulate shedding or clearance of VAP-1, and an increase in sVAP-1 because of absolute or relative insulin deficiency may be directly involved in the pathogenesis of diabetic angiopathy.
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PMID:Insulin-regulated increase of soluble vascular adhesion protein-1 in diabetes. 1246 39


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