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

Ketoacidosis is a serious complication of diabetes mellitus, especially type 1, and its secondary consequences account for a large proportion of diabetes-related hospitalizations and mortality in children with type 1 diabetes. Our understanding of the pathophysiology of ketoacidosis has increased considerably, together with methods and means of management. Nevertheless, its incidence has remained constant in most parts of the western world, as has the incidence of cerebral edema, the main cause of death due to ketoacidosis. Therefore, a major goal of clinical teams is to prevent ketoacidosis by early diagnosis of diabetes in new patients, and by appropriate treatment of intercurrent disease in patients with known diabetes, combined with family involvement and psychosocial interventions, as necessary. Although studies of the risk factors for the development of cerebral edema in this setting have yielded discrepant findings, there is a wide consensus regarding ketoacidosis treatment. The accepted protocol consists of slow rehydration with isoosmotic fluids, without bicarbonate solution except in rare cases, with continuous attention to glucose, sodium and potassium levels and the patient's neurological state. The aim of this survey is to present guidelines for the treatment of diabetic ketoacidosis (DKA) in children and to recommend preventive measures.
 ...
PMID:[Diabetic ketoacidosis in children and adolescents]. 1825 47

A recent genome-wide scan of nonsynonymous SNPs and ulterior validation in case-control and family analyses evidenced a susceptibility locus for type 1 diabetes (T1D) on chromosome 2q24.3. We aimed at testing the effect of this locus in other autoimmune diseases with complex genetic background, such as multiple sclerosis (MS). Four SNPs along the locus, rs13422767, rs2111485, rs1990760 and rs2068330, were genotyped using TaqMan MGB chemistry in 311 T1D and 412 MS patients and 535 ethnically matched healthy controls. The previously reported association of this locus was found for the first time in MS (rs2068330, G vs C: P=0.001; OR (95% CI)=0.73 (0.6-0.88)) and a trend for replication was observed in our Spanish diabetic cohort. Therefore, genes included in this locus - IFIH1 interferon induced helicase, GCA grancalcin or the potassium channel KCNH7 - are potential candidates implicated in the pathogenesis of these autoimmune diseases, although strong linkage disequilibrium in the region hampered further localization of the etiologic gene.
 ...
PMID:IFIH1-GCA-KCNH7 locus: influence on multiple sclerosis risk. 1828 33

Diabetes, which is diagnosed before 6 months of age, is patogenetically different than type 1 diabetes. This kind of diabetes also known as a neonatal diabetes is genetically determined with monogenic mode of inheritance. Most of these patients are carriers of heterozygous mutation in the KCNJ11 or ABCC8 gene. These mutations may activate the Kir6.2/SUR1 potassium channel in the beta cells and disturb insulin secretion, which in consequence leads to diabetes. This patological phenomenon is reversible if sulfonylureas are used as a first line therapy. In the current paper a systematic review of clinical aspects of sulfonylurea treatment in neonatal diabetes has been performed. This gives the further evidence that knowlegde of the patogenesis of neonatal diabetes may be easily transferred to bedside and clinical practice.
 ...
PMID:[Permanent neonatal diabetes with known genetic background: oral drugs in treatment of childhood diabetes]. 1857 47

The Kv1.3 potassium channel plays an essential role in effector memory T cells and has been implicated in several important autoimmune diseases including multiple sclerosis, psoriasis and type 1 diabetes. A number of potent small molecule inhibitors of Kv1.3 channel have been reported, some of which were found to be effective in various animal models of autoimmune diseases. We report herein the identification of clofazimine, a known anti-mycobacterial drug, as a novel inhibitor of human Kv1.3. Clofazimine was initially identified as an inhibitor of intracellular T cell receptor-mediated signaling leading to the transcriptional activation of human interleukin-2 gene in T cells from a screen of the Johns Hopkins Drug Library. A systematic mechanistic deconvolution revealed that clofazimine selectively blocked the Kv1.3 channel activity, perturbing the oscillation frequency of the calcium-release activated calcium channel, which in turn led to the inhibition of the calcineurin-NFAT signaling pathway. These effects of clofazimine provide the first line of experimental evidence in support of a causal relationship between Kv1.3 and calcium oscillation in human T cells. Furthermore, clofazimine was found to be effective in blocking human T cell-mediated skin graft rejection in an animal model in vivo. Together, these results suggest that clofazimine is a promising immunomodulatory drug candidate for treating a variety of autoimmune disorders.
 ...
PMID:Clofazimine inhibits human Kv1.3 potassium channel by perturbing calcium oscillation in T lymphocytes. 1910 61

Kv1.3 potassium channels maintain the membrane potential of effector memory (T(EM)) T cells that are important mediators of multiple sclerosis, type 1 diabetes mellitus, and rheumatoid arthritis. The polypeptide ShK-170 (ShK-L5), containing an N-terminal phosphotyrosine extension of the Stichodactyla helianthus ShK toxin, is a potent and selective blocker of these channels. However, a stability study of ShK-170 showed minor pH-related hydrolysis and oxidation byproducts that were exacerbated by increasing temperatures. We therefore engineered a series of analogs to minimize the formation of these byproducts. The analog with the greatest stability, ShK-192, contains a nonhydrolyzable phosphotyrosine surrogate, a methionine isostere, and a C-terminal amide. ShK-192 shows the same overall fold as ShK, and there is no evidence of any interaction between the N-terminal adduct and the rest of the peptide. The docking configuration of ShK-192 in Kv1.3 shows the N-terminal para-phosphonophenylalanine group lying at the junction of two channel monomers to form a salt bridge with Lys(411) of the channel. ShK-192 blocks Kv1.3 with an IC(50) of 140 pM and exhibits greater than 100-fold selectivity over closely related channels. After a single subcutaneous injection of 100 microg/kg, approximately 100 to 200 pM concentrations of active peptide is detectable in the blood of Lewis rats 24, 48, and 72 h after the injection. ShK-192 effectively inhibits the proliferation of T(EM) cells and suppresses delayed type hypersensitivity when administered at 10 or 100 microg/kg by subcutaneous injection once daily. ShK-192 has potential as a therapeutic for autoimmune diseases mediated by T(EM) cells.
 ...
PMID:Engineering a stable and selective peptide blocker of the Kv1.3 channel in T lymphocytes. 1912 5

We discuss the potential use of inhibitors of Kv1.3 potassium channels in T lymphocytes as therapeutics for multiple sclerosis. Current treatment strategies target the immune system in a non-selective manner. The resulting general immunosuppression, toxic side-effects and increased risk of opportunistic infections create the need for more selective therapeutics. Autoreactive effector-memory T (T(EM)) cells, considered to be major mediators of autoimmunity, express large numbers of Kv1.3 channels. Selective blockers of Kv1.3 inhibit calcium signaling, cytokine production and proliferation of T(EM) cells in vitro, and T(EM) cell-motility in vivo. Kv1.3 blockers ameliorate disease in animal models of multiple sclerosis, rheumatoid arthritis, type 1 diabetes mellitus and contact dermatitis without compromising the protective immune response to acute infections. Kv1.3 blockers have a good safety profile in rodents and primates.
 ...
PMID:Kv1.3 potassium channels as a therapeutic target in multiple sclerosis. 1953 97

While insulin remains the mainstay of managing type 1 diabetes, much has changed over the last 15 years. These changes should help in managing patients with type 1 diabetes during the perioperative period. More flexible insulin therapy has three components: (1) basal, (2) prandial and (3) corrective. Many patients, particularly younger patients, are using genetically modified recombinant human insulin analogues. Two of these analogues, aspart and lispro insulin, are rapid-acting with faster onset and offset than subcutaneous regular insulin, allowing both prandial and corrective boluses. Other insulin analogues, particularly glargine and possibly detemir have a flat profile of up to 24 hours, providing improved basal insulin delivery. Basal insulin can also be provided by a continuous subcutaneous infusion of rapid-acting insulin via a computerised pump that also provides boluses on demand. There is little evidence to help choose the best management of patients with type 1 diabetes during surgery. Some authors still recommend glucose-potassium-insulin infusions for all patients with type 1 diabetes. We challenge this approach, given the flexibility of the newer insulin analogues and delivery systems. We suggest that for many procedures, patients' usual regimens can be maintained in the perioperative period, providing less disruption and, possibly, greater safety. Both hyperglycaemia and hypoglycaemia reflect poor management: we suggest a target glucose range of 5 to 10 mmol/l. The importance of frequently measuring blood glucose and appropriate responses cannot be overemphasised.
 ...
PMID:New insulin analogues and perioperative care of patients with type 1 diabetes. 2036 55

Kv1.3 and IKCa1 potassium channels participate in the maintenance of calcium-influx during lymphocyte activation. Kv1.3 channels have a prominent role in specific T cell subsets, presenting a possible target for selective immunomodulation. We investigated the impact of Kv1.3 and IKCa1 channel inhibitors on calcium-influx characteristics in human T cells in type 1 diabetes mellitus. We isolated lymphocytes from 9 healthy and 9 type 1 diabetic individuals and measured the alteration of calcium-influx with flow cytometry in the Th1, Th2, CD4 and CD8 subsets after treatment of samples with specific channel inhibitors. Our results indicate an increased reactivity of type 1 diabetes lymphocytes, which is correlated to their increased sensitivity to Kv1.3 channel inhibition. However, the contribution of Kv1.3 channels to calcium flux is not exclusive for a specific lymphocyte subset as previous reports suggest, but is characteristic for each subset investigated. Therefore, the proposed inhibition of Kv1.3 channels as a novel therapeutic approach for the treatment of type 1 diabetes mellitus may have a major effect on overall lymphocyte function in this disease.
 ...
PMID:Lymphocyte activation in type 1 diabetes mellitus: the increased significance of Kv1.3 potassium channels. 2060 49

Over the last decade our insight into the causes of neonatal diabetes has greatly expanded. Neonatal diabetes was once considered a variant of type 1 diabetes that presented early in life. Recent advances in our understanding of this disorder have established that neonatal diabetes is not an autoimmune disease, but rather is a monogenic form of diabetes resulting from mutations in a number of different genes encoding proteins that play a key role in the normal function of the pancreatic beta-cell. Moreover, a correct genetic diagnosis can affect treatment and clinical outcome. This is especially true for patients with mutations in the genes KCNJ11 or ABCC8 that encode the two protein subunits (Kir6.2 and SUR1, respectively) of the ATP-sensitive potassium channel. These patients can be treated with oral sulfonylurea drugs with better glycemic control and quality of life. Recently, mutations in the insulin gene (INS) itself have been identified as another cause of neonatal diabetes. In this article, we review the role of INS mutations in the pathophysiology of neonatal diabetes.
 ...
PMID:Clinical and molecular genetics of neonatal diabetes due to mutations in the insulin gene. 2093 45

The purpose of this article is to describe diabetes diagnosed during the first 6 months of life. Neonatal diabetes, also known as congenital diabetes, presents a unique set of challenges for the pediatric healthcare provider. Neonatal diabetes is not type 1 diabetes. While the etiology of type 1 diabetes is multifactorial and includes genetic and environmental factors, neonatal diabetes is strictly a genetic condition. Management of children with neonatal diabetes, treatment of the disease, psychosocial considerations for the family, and nursing care required for this population are all included in this article. Unique issues related to the diagnosis of a genetic mutation resulting in a defect in the potassium channel are also discussed.
 ...
PMID:Neonatal diabetes: current trends in diagnosis and management. 2096 76


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>