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)

Twenty six patients with insulin dependent diabetes mellitus underwent a gastric emptying test, a gall bladder contraction test, an orocaecal transit study, and a colon transit test. Eleven patients had signs of cardiovascular autonomic neuropathy, 15 patients were without signs of cardiovascular autonomic neuropathy. Mean gastric clearance of radioopaque markers ingested with a meal averaged 29.5 (2.3) markers per six hours in subjects without cardiovascular autonomic neuropathy compared with 17.8 (2.3) markers per six hours in patients with cardiovascular autonomic neuropathy (p < 0.02). Gall bladder emptying in response to graded CCK8 stimulation was impaired in five of 11 patients with cardiovascular autonomic neuropathy, whereas it was normal in the patients without cardiovascular autonomic neuropathy (p < 0.01). Oral caecal transit times were not significantly different in the two patient groups, whereas colonic transit was slower in the patients with cardiovascular autonomic neuropathy compared with the group without cardiovascular autonomic neuropathy (p < 0.02). There was no correlation between disturbed gastric clearance, impaired gall bladder contraction, and prolonged colonic transit time in the patients with cardiovascular autonomic neuropathy nor was there a correlation between any disturbed motor function and age or duration of diabetes. It is concluded that autonomic neuropathy can affect motor functions throughout the gastro-intestinal tract. Any disturbed motor function in the gut could therefore be one of the numerous expressions of diabetic neuropathy affecting the cardiovascular, the endocrine or the gastrointestinal system.
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PMID:Non-invasive assessment of gastrointestinal motility disorders in diabetic patients with and without cardiovascular signs of autonomic neuropathy. 142 71

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

Two male infants with severe protracted diarrhoea presenting at 4 months (patient 1) and 10 weeks (patient 2) of age are reported. In both patients jejunal biopsy showed subtotal villous atrophy. Both had specific complement-fixing autoantibodies reacting by immunofluorescence with human duodenal, jejunal, and colonic epithelium. Patient 1 also had hypothyroidism and type 1 diabetes mellitus with thyroid and islet cell autoantibodies. His gut antibodies were of IgG class, reached a titre of 1:512, and remained positive throughout his illness. He died at 16 months of age. Patient 2 had gut antibodies of IgM class, which reached a titre of 1:128 and disappeared at the time of spontaneous recovery of the diarrhoea. The findings suggest that an autoimmune process was the basis for the enteropathy in these patients. We recommend that autoantibody tests should be performed in infants with unexplained protracted diarrhoea.
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PMID:Specific autoantibodies to gut epithelium in two infants with severe protracted diarrhoea. 388 68

The relation between islet cell specific antibodies, other autoantibodies and antibodies to cow's milk proteins was studied in IDDM and pre-IDDM by analysing islet cell antibodies (ICA), insulin autoantibodies (IAA), anti-nuclear (ANA), anti-reticulin class IgA [ARA(IgA)], smooth muscle, anti-mitochondria, parietal cell (PCA), adrenal and thyroid antibodies and antibodies to cow's milk formula (CMF), beta-lactoglobulin (BLG) and bovine serum albumin (BSA) in a population based study with more than 650 children with newly diagnosed IDDM and more than 550 initially non-diabetic siblings. After adjustment for age a weak association was seen in the diabetic children between IAA and ANA but none between ICA and autoantibodies directed against the other organ-specific or non-organ-specific antigens. There was no significant difference in cow's milk antibodies between diabetic children with and without ICA or IAA. The siblings with ICA had higher CMF (IgA and IgM) antibody levels and BLG (IgA) antibody levels than the remaining siblings, but no such differences were found when comparing IAA-positive and negative siblings. Siblings positive for ICA had PCA more often than did the ICA-negative siblings, whereas siblings positive for both ICA and PCA had increased levels of antibodies against CMF, BLG and BSA. These findings indicate that the humoral islet cell-associated autoimmunity characteristic of recent-onset childhood IDDM is clearly restricted to the islet cells and not directly related to signs of other organ-specific or non-organ-specific autoimmunity. The observation of increased levels of antibodies to cow's milk proteins in siblings positive for ICA suggests that the immune response to cow's milk proteins may be related to the progressive autoimmune process resulting in beta-cell destruction and ultimately in the clinical manifestation of IDDM. Gastrointestinal autoimmune mechanisms may play a role in the pathogenesis of IDDM, and the association observed between combined ICA and PCA positivity and increased levels of antibodies to cow's milk proteins in the siblings implies that there may be an enhanced transfer of nutritional antigens across the gut barrier in these subjects.
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PMID:Relation between antibodies to islet cell antigens, other autoantigens and cow's milk proteins in diabetic children and unaffected siblings at the clinical manifestation of IDDM. The Childhood Diabetes in Finland Study Group. 887 52

Acarbose represents a new pharmacological approach to achieving the metabolic benefits of a slower carbohydrate absorption in diabetes, by acting as a potent, competitive inhibitor of intestinal alpha-glucosidases. Acarbose molecules attach to the carbohydrate binding sites of alpha-glucosidases, with an affinity constant that is much higher than that of the normal substrate. Because of the reversible nature of the inhibitor-enzyme interaction, the conversion of oligosaccharides to monosaccharides is only delayed rather than completely blocked. Acarbose has the structural features of a tetrasaccharide and does not cross the enterocytes after ingestion. Thus, its pharmacokinetic properties are well suited to the pharmacological action directed exclusively towards the intestinal glucosidases. The most important clinical consequence of the delayed carbohydrate digestion caused by acarbose is the attenuation of postprandial increases in blood glucose levels. Other effects have also been described: a decreased beta-pancreatic response to meals, and influences on gut hormone secretion and plasma lipid levels. Gastrointestinal discomfort is frequently reported as an adverse effect of acarbose administration, but incidence usually decreases with time. The suitability of acarbose for improving glucose homeostasis as an adjunct to dietary control or to administration of sulphonylureas or insulin has been extensively studied in patients both with type 1 (insulin-dependent) and type 2 (non-insulin-dependent) diabetes mellitus. Acarbose can be used as first-line therapy in patients with type 2 diabetes which is poorly controlled by diet alone. Moreover, the lack of bodyweight gain or hypoglycaemic effects reported during acarbose treatment may be advantageous for obese or elderly patients. Finally, the reduction in fluctuations of glucose levels throughout the day may help to control type 1 diabetes in patients with 'brittle diabetes'. Long term prospective studies are still needed to confirm these indications and the usefulness of acarbose in conditions other than diabetes, notably reactive hypoglycaemia and dumping syndrome.
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PMID:Pharmacokinetic-pharmacodynamic relationships of Acarbose. 890 94

So far, a wealth of data originating from in vitro or animal experiments has been collected supporting the concept that the gut hormone, glucagon-like peptide-1 (GLP-1) may serve as a model molecule for the design of a new drug for the treatment of diabetes mellitus. This is supported by observations that GLP-1 has potent insulinotropic action in patients with non-insulin-dependent diabetes mellitus (NIDDM). It enhances beta-cell sensitivity to glucose stimulated insulin secretion. GLP-1 may also have a role in the treatment of impaired glucose tolerance, where the beta-cell is already insensitive to changes in plasma glucose concentrations. It may, as has previously been shown in animal models of 'prediabetes', delay the progressive decline in glucose tolerance to NIDDM. The glucose-dependent action of this peptide is an important feature in the treatment of NIDDM as it will protect against hypoglycaemic reactions, the most serious acute side-effect of antidiabetic therapy. Glucose utilization may be enhanced which would improve metabolic control in both NIDDM and IDDM. A glucagon lowering effect will further enhance metabolic control. This article reviews current experiences of the effects of GLP-1 in human studies. It points out the outcomes and limitations of previous trials and discusses future directions for the investigation of its potential use as a new agent in diabetes treatment.
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PMID:Human studies with glucagon-like-peptide-1: potential of the gut hormone for clinical use. 891 78

Migration of lymphocytes to the pancreas is a prerequisite for insulitis in IDDM. Mucosal vascular addressin (MAdCAM-1), involved in the recirculation of lymphocytes to the gut, has been found in the inflamed islets in NOD mice. In humans, triggers of the gut immune system (e.g., early exposure to cow's milk proteins in infancy, exposure to enteroviral infections) have been associated with IDDM. To study the possible link between the gut immune system and IDDM, we tested the expression of the alpha4beta7-integrin, a homing receptor for MAdCAM-1, on GAD65-reactive lymphocytes. Using immunomagnetic cell sorting, we depleted the lymphocytes with high expression of alpha4beta7-integrin in the peripheral blood mononuclear cell population from IDDM patients and patients with autoimmune polyendocrine disease type 1 (APD-I). The depletion led to a marked decrease (mean 70%) in the cellular response against GAD65 in three of six IDDM patients and in one subject at high risk for IDDM. A decrease of 37% in the GAD response was observed after depletion in the case of one APD-I patient who also had IDDM. Cellular response to tetanus toxoid increased in the majority of patients as well as in three control subjects studied. We demonstrated that a remarkable population of islet cell antigen-reactive lymphocytes express the gut-specific homing receptor, which emphasizes the role of gut immunity in IDDM. The manipulation of the gut immune system is therefore proposed as a tool for modulation of the autoimmunity against pancreatic beta-cells in IDDM.
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PMID:Glutamate decarboxylase-reactive peripheral blood lymphocytes from patients with IDDM express gut-specific homing receptor alpha4beta7-integrin. 907 97

BB rats and nonobese diabetic (NOD) mice spontaneously develop autoimmune insulin dependent diabetes and serve as models for human type I diabetes. During progression of the disease the cytokine pattern elaborated by islet infiltrating immune cells shifts from a Th2 or Th0 toward Th1 type. Only the latter is associated with "destructive" insulitis. We discuss here attempts to modulate disease progression by targeting the gut immune system with bacterial immunostimulants. Oral dosing of diabetes prone BB rats with lipopolysaccharide (LPS) or the Escherichia coli extract OM-89 lead to a Th2-shift of pancreatic mRNA expression. In vitro studies showed that repeated exposure toward LPS or OM-89 lead to downregulation of proinflammatory macrophage responses. In the NOD mouse, repeated oral dosing of OM-89 caused a Th2 shift in the gut cytokine gene expression, probably because of desensitization of macrophages and other antigen presenting cells. Concomitantly, diabetes prevention by oral insulin was improved. In conclusion, oral dosing with bacterial immunostimulants dampens Th1 type immune reactivities of the gut immune system and thereby promotes oral tolerance mechanisms. Downregulation of proinflammatory immune reactivities by repeated exposure to bacterial stimulants requires intact desensitization mechanisms in macrophages or other antigen presenting cells.
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PMID:Intervention in autoimmune diabetes by targeting the gut immune system. 963 57

Treatment of type 1 diabetes mellitus has made tremendous advances within the last decades. With concern to insulin delivery there are two promising new approaches. One is the intrapulmonary insulin delivery which has become feasible by the development of new inhalation devices which provide a sufficient degree of intrapulmonary drug retention. Also oral insulin delivery seems feasible when surface active substances are used to cross the mucosal membrane in the gut. Clinical research has also focussed on coatings for the insulin molecules to solve the problem raised by the proteolytic activity of the digestive system. A very new agent produced by a fungus called Pseudomassaria has been demonstrated to reverse the clinical signs of diabetes mellitus in mice. The compound diffuses through the cell membrane, binds to the inner part of the insulin receptor and activates the insulin typical biological effects. Nowadays a variety of insulin analogs are designed and tested for their clinical use. By shifting the isoelectric point towards to a slightly acidic pH, HOE 901 precipitates at physiologic pH resulting in a constant and peakless insulin delivery. NN 304 is a 14-carbon aliphatic fatty acid acylated analog that binds to serum albumin resulting in a flatter time-action profile than NPH insulin. Also rapid acting insulin analogs are or will be launched in the near future aiming to ensure an improved postprandial glucose regulation. Glucagon-like peptide-1 (GLP-1) improves metabolic control by a variety of effects, e.g. the enhancement of insulin secretion and inhibition of glucagon secretion. Moreover, GLP-1 reduces food and water intake controlled by the brain, and inhibits gastric emptying. A disadvantage of GLP-1 is its very short half-life. Novel derivatives with the beneficial effects of GLP-1 but a better resistance against degradation have been designed. In addition substances have been developed inhibiting GLP-1 degradation or augmenting GLP-1 release from its abundant endogenous pool. Finally, there is a variety of interesting approaches aiming to improve or ease blood glucose self-monitoring. One is the development of subcutaneous catheters for continuous blood glucose control. In another system reverse iontophoresis is used for sampling interstitial fluid which reflects capillary blood glucose levels. Instead of using an electric current, a brandnew system creates micropores in the skin by a laser ablation system. Through these micropores a specific device performs a mild suction to obtain intersitial fluid. Further systems which measure blood glucose by near infrared spectroscopy are still investigated in order to improve their technical function and to reduce their weight. This article intends to give an overview over the new developments in the treatment and management of type-1-diabetes mellitus.
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PMID:New developments in the treatment of type 1 diabetes mellitus. 1052 18

The concept of oral tolerance refers to a form of peripheral tolerance in which mature lymphocytes in the peripheral lymphoid tissues are rendered nonfunctional or hyporesponsive by prior oral administration of an antigen. The primary mechanisms mediating oral tolerance include deletion, anergy of antigen-specific T cells and active cellular suppression, the primary determining factor being the dose of fed antigen. Low doses favor active suppression, whereas high doses favor deletion and anergy. Active cellular suppression is mediated by the induction of regulatory T cells in the gut-associated lymphoid tissue, which migrate to the systemic immune system. One of the primary mechanisms of active cellular suppression is via secretion of suppressive cytokines such as TGF-beta, IL-4, and IL-10 following antigen-specific triggering. TGF-beta is produced both by CD4+ and CD8+ GALT-derived T cells and is an important mediator of the active suppression component of oral tolerance. CD4+ cells that primarily produce TGF-beta appear to be a unique T-cell subset and termed Th3 cells. Oral tolerance was successfully studied in a variety of experimental models for autoimmune diseases, among them experimental autoimmune encephalomyelitis, experimental arthritis, experimental anti-phospholipid syndrome, experimental autoimmune uveoretinitis, experimental insulin dependent diabetes mellitus (IDDM), and experimental autoimmune myasthenia gravis. The results obtained in experimental animal models have led to the conduction of several clinical trials of oral tolerance in patients with multiple sclerosis, rheumatoid arthritis, uveitis, and IDDM. Conflicting results were obtained, and although some improvement has been noted in some of the patients, broad ranging clinical improvement has not yet been observed. A more accurate choice of antigens, as well as more precise dosing and timing of antigen-administration might lead to better results in the future.
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PMID:Immunomodulation of experimental autoimmune diseases via oral tolerance. 1077 Feb 68


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