Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Vitamin D from ultraviolet-B (UVB) irradiance, food, and supplements is receiving increased attention lately for its role in maintaining optimal health. Although the calcemic effects of vitamin D have been known for about a century, the non-calcemic effects have been studied intently only during the past two-three decades. The strongest links to the beneficial roles of UVB and vitamin D to date are for bone and muscle conditions and diseases. There is also a preponderance of evidence from a variety of studies that vitamin D reduces the risk of colon cancer, with 1000 IU/day of vitamin D or serum 25-hydroxyvitamin D levels >33 ng/mL (82 nmol/L) associated with a 50% lower incidence of colorectal cancer. There is also reasonable evidence that vitamin D reduces the risk of breast, lung, ovarian, and prostate cancer and non-Hodgkin's lymphoma. There is weaker, primarily ecologic, evidence for the role of vitamin D in reducing the risk of an additional dozen types of cancer. There is reasonably strong ecologic and case-control evidence that vitamin D reduces the risk of autoimmune diseases including such as multiple sclerosis and type 1 diabetes mellitus, and weaker evidence for rheumatoid arthritis, osteoarthritis, type 2 diabetes mellitus, hypertension and stroke. It is noted that mechanisms whereby vitamin D exerts its effect are generally well understood for the various conditions and diseases discussed here.
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PMID:Epidemiology of disease risks in relation to vitamin D insufficiency. 1654 42

Insulin resistance (reduced ability of insulin to stimulate glucose utilization) is common in North American and Europe, where as many as one third of all older adults suffer from prodromal or clinical type 2 diabetes mellitus. It has long been known that insulin-resistant conditions adversely affect general health status. A growing body of findings suggests that insulin contributes to normal brain functioning and that peripheral insulin abnormalities increase the risk for memory loss and neurodegenerative disorders such as Alzheimer's disease. Potential mechanisms for these effects include insulin's role in cerebral glucose metabolism, peptide regulation, modulation of neurotransmitter levels, and modulation of many aspects of the inflammatory network. An intriguing question is whether insulin abnormalities also influence the pathophysiology of multiple sclerosis (MS), an autoimmune disorder characterized by elevated inflammatory biomarkers, central nervous system white matter lesions, axonal degeneration, and cognitive impairment. MS increases the risk for type 1 diabetes mellitus. Furthermore, the lack of association between MS and type 2 diabetes may suggest that insulin resistance affects patients with MS and the general population at the same alarming rate. Therefore, insulin resistance may exacerbate phenomena that are common to MS and insulin-resistant conditions, such as cognitive impairments and elevated inflammatory responses. Interestingly, the thiazolidinediones, which are used to treat patients with type 2 diabetes, have been proposed as potential therapeutic agents for both Alzheimer's disease and MS. The agents improve insulin sensitivity, reduce hyperinsulinemia, and exert anti-inflammatory actions. Ongoing studies will determine whether thiazolidinediones improve cognitive functioning for patients with type 2 diabetes or Alzheimer's disease. Future studies are needed to examine the effects of thiazolidinediones on patients with MS.
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PMID:Insulin resistance, inflammation, and cognition in Alzheimer's Disease: lessons for multiple sclerosis. 1663 Dec 7

Restless legs syndrome (RLS) is a sensorimotor disorder characterised by a complaint of an almost irresistible urge to move the legs. RLS is diagnosed clinically by means of the four essential criteria of the International Restless Legs Syndrome Study Group. In doubtful cases, neurophysiological examinations, such as polysomnography and/or a suggested immobilisation test, can be performed to confirm a clinical suspicion of RLS. Several other conditions may present sensorimotor complaints with features similar to RLS; a careful sleep history is required to avoid a misdiagnosis. Three different scales have been validated to assess the severity of RLS. In the general population, RLS prevalence ranges from 0.1% to 11.5%, with a high number of patients affected by a primary form of the sleep disturbance (70%-80%). However, several clinical conditions have been associated with RLS, such as iron deficiency, uraemia, pregnancy and polyneuropathy. Furthermore, recent studies show that RLS may be associated also to type 2 diabetes mellitus and to multiple sclerosis. RLS has a negative impact on sleep, cognitive functions, quality of life and mental status. Higher awareness of RLS among physicians is required; it remains an underdiagnosed clinical condition.
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PMID:Restless legs syndrome: diagnosis, epidemiology, classification and consequences. 1723 30

Chemokines are small molecular weight water-soluble proteins playing a key role in immunomodulation and host-defense mechanisms. CCR2 receptor is targeted for diseases like arthritis, multiple sclerosis, vascular disease, obesity, and type 2 diabetes. Reported, herein are the QSAR studies performed on a diverse set of enantiopure analogues reported as CCR2 antagonists by hologram analysis. The best model highlights the importance of chirality feature in comparison with the other models developed without the chirality. The validated model showed high internal and external predictive power. The robustness of the model was achieved with good statistical r(2) of 0.945 and cross-validated r(cv)(2) of 0.837. The challenging test predictivity of the model was confirmed with r(pred)(2) of 0.807. The fragment fingerprints help in understanding essential pharmacophoric features for CCR2 antagonism and provide basis for SAR of the molecules. The 2D contribution maps with fragment information will be useful for the design of novel CCR2 antagonists having improved efficacy.
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PMID:QSAR studies on CCR2 antagonists with chiral sensitive hologram descriptors. 1825 26

Dipeptidyl peptidase IV (DPP IV) is a widely distributed physiological enzyme that can be found solubilized in blood, or membrane-anchored in tissues. DPP IV and related dipeptidase enzymes cleave a wide range of physiological peptides and have been associated with several disease processes including Crohn's disease, chronic liver disease, osteoporosis, multiple sclerosis, eating disorders, rheumatoid arthritis, cancer, and of direct relevance to this review, type 2 diabetes. Here, we place particular emphasis on two peptide substrates of DPP IV with insulin-releasing and antidiabetic actions namely, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). The rationale for inhibiting DPP IV activity in type 2 diabetes is that it decreases peptide cleavage and thereby enhances endogenous incretin hormone activity. A multitude of novel DPP IV inhibitor compounds have now been developed and tested. Here we examine the information available on DPP IV and related enzymes, review recent preclinical and clinical data for DPP IV inhibitors, and assess their clinical significance.
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PMID:Dipeptidyl peptidase IV (DPP IV) and related molecules in type 2 diabetes. 1850 62

Recent large-scale genome-wide association (GWA) studies of SNP variations captured many thousands individual genetic profiles of H. sapiens and facilitated identification of significant genetic traits which are highly likely to influence the pathogenesis of several major human diseases. Here we apply the integrative genomics principles to interrogate relationships between structural features and gene expression patterns of disease-linked SNPs, microRNAs and mRNAs of protein-coding genes in association to phenotypes of 15 major human disorders, namely bipolar disease (BD); rheumatoid arthritis (RA); coronary artery disease (CAD); Crohn's disease (CD); type 1 diabetes (T1D); type 2 diabetes (T2D); hypertension (HT); ankylosing spondylitis (AS); Graves' disease (autoimmune thyroid disease; AITD); multiple sclerosis (MS); breast cancer (BC); prostate cancer (PC); systemic lupus erythematosus (SLE); vitiligo-associated multiple autoimmune disease (VIT); and ulcerative colitis (UC). We selected for sequence homology profiling a set of approximately 250 SNPs which were unequivocally associated with common human disorders based on multiple independent studies of 220,124 individual samples comprising 85,077 disease cases and 129,506 controls. Our analysis reveals a systematic primary sequence homology/complementarity-driven pattern of associations between disease-linked SNPs, microRNAs and protein-coding mRNAs defined here as a human disease phenocode. We utilize this approach to draw SNP-guided microRNA maps of major human diseases and define a consensus disease phenocode for fifteen major human disorders. A consensus disease phenocode comprises 72 SNPs and 18 microRNAs with an apparent propensity to target mRNA sequences derived from a single protein-coding gene, KPNA1. Each of microRNAs in this elite set appears linked to at least three common human diseases and has potential protein-coding mRNA targets among the principal components of the nuclear import pathway. We confirmed the validity of our findings by analyzing independent sets of most significant disease-linked SNPs and demonstrating statistically significant KPNA1-gene expression phenotypes associated with human genotypes of CD, BD, T2D and RA populations. Our analysis supports the idea that variations in DNA sequences associated with multiple human diseases may affect phenotypes in trans via non-protein-coding RNA intermediaries interfering with functions of microRNAs and defines the nuclear import pathway as a potential major target in 15 common human disorders.
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PMID:An SNP-guided microRNA map of fifteen common human disorders identifies a consensus disease phenocode aiming at principal components of the nuclear import pathway. 1871 69

Chemokine receptors have evolved as attractive targets for disease conditions which arise due to immunomodulation involving host-defense mechanisms. CCR2, a chemokine receptor, is targeted for diseases like arthritis, multiple sclerosis, vascular disease, obesity, and type 2 diabetes. This study provides a new strategy of a ligand based technique which exploits fingerprint led fragment features in conjunction with structure-guided design for identifying new scaffolds for CCR2. A fragment based mining (FBM) technique was employed on a chemical database to identify novel scaffold hops. The hits were subjected to 3-point pharmacophore fingerprint procedures with Tanimoto similarity metric to compare pharmacophoric fingerprints. The final 66 hits generated by these exercises were predicted by the validated HQSAR model, and the top predicted were suggested as probable scaffolds for CCR2 antagonism. The identified scaffolds were validated through molecular docking studies. The ligands were docked by providing receptor flexibility in the extra cellular domain (1 and 3), N terminal domain, and in the transmembrane (TM1 & TM7) helix region with IFD approach. Some of the scaffolds showed H-bonding potential which was not explored by the data set molecules. All identified scaffolds highlighted a key hydrogen bonding interaction with Thr292 as supported by mutational studies. The observed pi stacking interaction with Tyr188 in data set molecules was also produced by the new scaffolds. Taking the advantage of receptor flexibility the scaffolds explored the hydrophobic binding cleft between helix 1 and 7 occupied by residues Leu44, Leu45, Leu48 and Ile300, Ile303, Ile304, respectively. Two of the identified molecules have promising outcomes and can be considered as novel scaffolds for CCR2 binding.
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PMID:Fingerprint directed scaffold hopping for identification of CCR2 antagonists. 1876 38

The Insulin-like growth factor-1 (IGF-1) system is dynamic and complex, involving many binding proteins, binding-protein-related proteases, and receptors. It has emerged in time as a powerful defence to life processes of many cytotypes, tissues and systems. Mainly in body metabolism, diabetes and cardiovascular system, but also in brain and kidney, IGF-1 plays a key role in maintaining homeostasis, increasing progenitor cell potential, and improving physiologic performance both in rest and stress conditions. Its vasculoprotective and insulin sensitizing ability exerts a protective role on flow-metabolism coupling and organs function. Therapeutical human use of recombinant human IGF-1 (rhIGF-1) has been widely applied only in Laron syndrome, while being verified in many randomized controlled trials to improve glycemic control in type 1 and type 2 diabetes, and proposed in neurological disease such as amyotrophic lateral sclerosis, multiple sclerosis and Alzheimer disease. Sparse evidence exists moreover about rhIGF-1 use in insulin resistance, burns, catabolic and post-surgery states, acute and chronic renal failure, amyotrophic lateral and multiple sclerosis, brain injury, and immunoincompetence. Along with these data, results are available on cardiovascular benefit of administration of other growth factors, such as erythropoietin and vascular endothelial growth factor, or on cardiovascular side effects of growth factor antagonists such as trastuzumab in cancer therapy. We intended therefore to summarize in this review available human and animals evidence about rhIGF-1 effects on different systems with insights on rhIGF-1 cardiovascular effects. In view of its ability to improve flow-metabolism coupling, IGF-1 could indeed represent a new cardiovascular disease treatment option for many cardiac disorders such as ischemic heart disease and heart failure.
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PMID:Recombinant human insulin-like growth factor-1: a new cardiovascular disease treatment option? 1885 38

Dipeptidyl peptidase (DPP)-4 is a member of the S9b serine protease family, which also includes DPP8 and DPP9. DPP4 cleaves a number of regulatory factors, including chemokines and growth factors. DPP4 inhibitors have recently emerged as an effective treatment option for type 2 diabetes. Early in vitro studies demonstrated that DPP4 inhibitors inhibit T-cell proliferation and cytokine production, leading to their investigation in numerous pre-clinical models of inflammatory diseases, including arthritis, multiple sclerosis and inflammatory bowel disease. Recent data suggest that the early DPP4-specific inhibitors might also bind DPP8 and DPP9, thus exerting their effects through non-specific binding. This review highlights recent insights into the applicability of DPP inhibitors as novel pharmacological agents for inflammatory disease.
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PMID:Dipeptidyl peptidase inhibitors, an emerging drug class for inflammatory disease? 1983 68

Large-scale DNA databanks linked to electronic medical record (EMR) systems have been proposed as an approach for rapidly generating large, diverse cohorts for discovery and replication of genotype-phenotype associations. However, the extent to which such resources are capable of delivering on this promise is unknown. We studied whether an EMR-linked DNA biorepository can be used to detect known genotype-phenotype associations for five diseases. Twenty-one SNPs previously implicated as common variants predisposing to atrial fibrillation, Crohn disease, multiple sclerosis, rheumatoid arthritis, or type 2 diabetes were successfully genotyped in 9483 samples accrued over 4 mo into BioVU, the Vanderbilt University Medical Center DNA biobank. Previously reported odds ratios (OR(PR)) ranged from 1.14 to 2.36. For each phenotype, natural language processing techniques and billing-code queries were used to identify cases (n = 70-698) and controls (n = 808-3818) from deidentified health records. Each of the 21 tests of association yielded point estimates in the expected direction. Previous genotype-phenotype associations were replicated (p < 0.05) in 8/14 cases when the OR(PR) was > 1.25, and in 0/7 with lower OR(PR). Statistically significant associations were detected in all analyses that were adequately powered. In each of the five diseases studied, at least one previously reported association was replicated. These data demonstrate that phenotypes representing clinical diagnoses can be extracted from EMR systems, and they support the use of DNA resources coupled to EMR systems as tools for rapid generation of large data sets required for replication of associations found in research cohorts and for discovery in genome science.
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PMID:Robust replication of genotype-phenotype associations across multiple diseases in an electronic medical record. 2036 71


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