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)

GAD is an autoantigen in IDDM. Molecular cloning and specific antibodies allowed us to demonstrate that only the lower M(r) GAD64 isoform is expressed in human islets, in contrast to human brain, rat islets, and rat brain, all of which express both GAD64 and GAD67. Expression of the human islet GAD64 isoform in COS-7 and BHK cells resulted in an enzymatically active rGAD64, which is immunoreactive with diabetic sera comparable with that of the islet 64,000-M(r) autoantigen. Immunoprecipitation analyses showed that 21/28 (75%) IDDM sera had rGA D64 antibodies compared with only 1/59 (1.7%) of the healthy control sera. In immunoblot analyses, an SMS serum--but only 1/10 randomly selected IDDM sera--recognized the blotted rGAD64 without relation to immunoprecipitation titers. In conclusion, only the GA D64 isoform is expressed in human islets, in contrast to rat islets, which also express the GAD67 isoform. The immunological properties of human rGAD64 are comparable with the native 64,000-M(r) islet autoantigen, allowing further studies of the immunopathogenesis of IDDM.
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PMID:Recombinant glutamic acid decarboxylase (representing the single isoform expressed in human islets) detects IDDM-associated 64,000-M(r) autoantibodies. 139 11

We studied the effects of a premeal sc injection of an analog of somatostatin (SMS 201-995, Sandoz) on the postprandial glycemic excursions, insulin requirement and hormone profiles (GH, glucagon and C-peptide) in 8 IDDM patients (diabetes duration 14.0 +/- 6.5 yr, daily insulin requirement 36 +/- 6.4 U) maintained normoglycemic by connecting them to a closed-loop insulin infusion system (Betalike, Genoa). The morning of the test the patients were connected to the Betalike and their glucose levels stabilized for at least 4 h. At 13:00 h the study was begun with a sc injection of 50 micrograms of SMS 201-995 or placebo (randomly) and a standardized mixed meal (800 Kcal) was given. Blood samples were obtained 0, 15, 30, 60, 120 and 180 min after the injection. Each patient was tested both with SMS 201-995 and placebo. Postmeal glycemic peaks were decreased after SMS 201-995 (119.6 +/- 5.4 mg/dl vs 149.1 +/- 4.2; p less than 0.05) as well as insulin requirements (3.2 +/- 0.8 U vs 13.3 +/- 1.9; p less than 0.01) for the 180 min postprandial period. Similarly, glucagon level was reduced 30 min postprandially (24 +/- 6 pg/ml vs 59 +/- 24; p less than 0.05) and so GH level only 180 min after lunch (p less than 0.05). The premeal injection of SMS decreases postprandial glycemic excursions and the corresponding insulin requirement. The action of SMS 201-995 may be mainly mediated by the suppression of postprandial glucagon peak.
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PMID:Effects of a somatostatin derivative (SMS 201-995) on postprandial hyperglycemia in insulin-dependent diabetics studied by means of a closed-loop device. 267 Nov 12

The effect of a new octapeptide analogue of somatostatin (SMS 201-995) on blood glucose and gut hormone levels was studied in 10 C-peptide-negative, insulin-dependent diabetic (IDDM) subjects. On separate days, either 50 or 100 micrograms SMS or placebo was s.c. injected simultaneously with an identical insulin dose 30 min before a mixed meal. Postprandial blood glucose decreased after 100 micrograms SMS s.c. within 30 min from 8.9 +/- 0.7 to 7.8 +/- 0.6 mmol/L (P less than 0.001) and remained at similar levels during 180 min. In contrast, postprandial blood glucose concentration increased after placebo from 9.9 +/- 0.8 to 13.8 +/- 0.9 mmol/L (SMS versus placebo P less than 0.001). Plasma glucagon decreased rapidly after SMS to the limit of detection (P less than 0.001) and remained lowered during 180 min; in contrast, glucagon levels increased after the meal during the placebo study (SMS versus placebo P less than 0.001). Plasma growth hormone concentrations were significantly lower after SMS than after placebo (P less than 0.05). SMS abolished completely the postprandial increase in plasma gastrin and pancreatic polypeptide (PP) concentrations. Plasma free fatty acid (FFA) and triglyceride concentrations decreased after SMS, reaching significantly lower levels than after placebo (P less than 0.05 and P less than 0.01), respectively). Plasma SMS concentration increased rapidly after s.c. administration of SMS; its appearance preceded that of plasma free insulin after s.c. insulin injection. Fifty micrograms SMS was similarly effective as 100 micrograms in decreasing blood glucose, triglycerides, glucagon, and gut hormone concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Reduced postprandial hyperglycemia after subcutaneous injection of a somatostatin-analogue (SMS 201-995) in insulin-dependent diabetes mellitus. 286 93

We have recently obtained encouraging short-term results after a single subcutaneous injection of the long-acting somatostatin analogue SMS 201-995 in acromegalic patients. Increased growth hormone (GH) levels may be involved in the pathogenesis of proliferative retinopathy in type I diabetes mellitus. In this study we thus investigated the effect of 3 X 50 micrograms SMS 201-995 daily on the metabolic control and hormone secretion of eight type I diabetics over a 3-day period. GH levels decreased by 32% (p less than 0.05) and somatomedin C levels by 31% (p less than 0.01) on the 3rd day of treatment compared with a control day. The insulin requirements during conventional subcutaneous insulin therapy were reduced by 28% (p less than 0.01) in seven patients without deterioration of metabolic control (mean blood glucose levels, 153.8) versus 154.7 mg/dl). Triiodothyronine, thyroxine, glucagon, prolactin, luteinizing hormone and follicle-stimulating hormone showed no significant changes. We conclude that SMS 201-995 could be an excellent tool for further clinical investigation and therapy of diabetic vascular complications.
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PMID:Somatostatin analogue SMS 201-995 in type I diabetes mellitus. Initial experience after repeated administration. 287 2

Comparisons of soluble and bound GAD activities in brain, pancreas, and kidneys were performed. In all three organs GAD was present in three forms: soluble GAD; GAD, the solubility of which was achievable by means of CHAPS detergent; and GAD, refractory towards the detergent affect. The activity of these three GAD fractions, each belonging to a different cellular compartment, proportionally differed. The ratio of free, bound, and irreversibly bound activity expressed in percentage was 63:21:15 in the brain, and 14:40:36 in the pancreas. In coincidence with the occurrence of autoantibodies to GAD from the brain under the condition of SMS, and that from the pancreatic beta-cells under the condition of IDDM, it is supposed that the conditions favourable for the origin of the immune response are rendered by GAD bound in membranes. In kidneys the proportions of free (15%) and bound GAD (29%) are complicated by until now unassessed factors, since their isolation from the free, eventually bound GAD causes an activity waste of 50% which supervenes following the homogenate separation by the use of centrifuge. Effect of ATP and chlorides displays both, different and common properties of GAD from the mentioned three organs. ATP inhibited the brain GAD and the renal supernatant GAD, whereas it activated GAD from the homogenate and sediment of the kidneys and the pancreatic GAD. Chlorides inhibited the brain and pancreatic GAD and activated the renal GAD. (Fig. 8, Tab. 1, Ref. 16.).
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PMID:[Glutamic acid decarboxylase in the brain, pancreas and kidneys. Comparison of its properties]. 800 91

The study of SMS, a rare disease, has resulted in a better understanding of a more common disorder, IDDM, and has allowed investigators to gain insights into the molecular mechanisms of autoimmunity. Many unanswered questions remain, such as the specific site of disease activity in SMS, both at the bedside (cortex, brain stem, or spinal cord) and at the bench (neuronal cytoplasma or synapse). The association of SMS with neoplastic disease and the development of autonomicdysfunction are not understood. The next decade may provide answers to these puzzling issues.
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PMID:Stiff-man syndrome: from the bedside to the bench. 1040 57

The generation of an autoimmune response against islet beta-cells is central to the pathogenesis of type 1 diabetes mellitus, and this response is driven by the stimulation of autoreactive lymphocytes by components of the beta-cells themselves. Reactive oxygen species (ROS) have been implicated in the beta-cell destruction which leads to type 1 diabetes and may modify beta-cell components so as to enhance their immunogenicity. We investigated the effects of oxidation reactions catalysed by copper or iron on the major beta-cell autoantigen glutamic acid decarboxylase (GAD). Lysates of purified rat islets were exposed to copper or iron sulphate with or without hydrogen peroxide or ascorbic acid. Immunostaining showed that these treatments generated high molecular weight covalently linked aggregates containing GAD. These are not formed by intermolecular disulphide bonds between cysteine residues since they cannot be resolved into monomeric form when electrophoresed under extreme reducing conditions. There was no modification of insulin or pro-insulin by ROS. The same oxidative changes to GAD could be induced in viable islet cells treated with copper sulphate and hydrogen peroxide, and thus the modifications are not an artefact of the catalysed oxidation of cell-free lysates. Sera from patients with type 1 diabetes and stiffman syndrome containing GAD antibodies reacted predominantly with the highest molecular weight modified protein band of GAD: normal human sera did not precipitate GAD. Thus, oxidatively modified aggregates of GAD react with serum antibodies of type 1 diabetes patients and some SMS patients: this is consistent with oxidative modifications of autoantigens being relevant to the pathogenesis of type 1 diabetes.
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PMID:Islet glutamic acid decarboxylase modified by reactive oxygen species is recognized by antibodies from patients with type 1 diabetes mellitus. 1170 67