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Gut Peptide Signals in the Control of Food Intake

Defective Gene Causes Most Common Monogenic Form of Obesity

Obesity has increasingly become a major health problem of pandemic proportions. The U.S. CDC reported on June 14 that one in three children born in year 2000 will eventually develop diabetes, mostly type 2 which results largely from obesity and certain life styles. Genetic abnormalities associated with childhood obesity have been reported but remain short of a definitive correlation.

I.S. Farooqi and colleagues from Addenbrooke’s Hospital, Cambridge, UK and R. Branson and colleagues from Klinik Hirslanden, Zurich, Switzerland both reported recently in New England Journal of Medicine (348:1085-1095, 348:1096-1103, March 20, 2003) that a deficiency in melanocortin 4 receptor (MC4R) is ... Read more

Statins Lower Heart Disease Complications Among Diabetic Patients

A recent large clinical trial study concluded that cholesterol lowering statin drugs should be taken by diabetic patients to prevent heart disease complications regardless of their initial cholesterol levels (International Statin Study Group, Lancet 361:2005-2016, June 14, 2003). 5,963 UK adults with diabetes and 14,573 with occlusive arterial disease but no diagnosed diabetes were randomized into the treatment group who received Merck’s Zocor (simvastatin) 40 mg daily and the control group who received the placebo, for 5 years. In the three subgroups of patients evaluated: the diabetic patients with occlusive artery disease, diabetic patients who do not have occlusive artery ... Read more

Islet-derived progenitor cell transplantation helps diabetes patients

A team led by Dr. Edmond A. Ryan of the University of Alberta, Admonton, Alberta, Canada reported in Diabetes this month (51:2148-2157, Jul. 2002) the results of a small clinical trial of treatment of autoimmune type 1 diabetes by islet cell transplantation.

Seventeen patients who received the transplantation were followed up for an average of 20 months. Of the 15 patients who have been followed for at least one year, 9 (60%) no longer need to take insulin. Of the 6 patients who have been followed for at least 2 years, 4 (67%) are off insulin. The transplantations are of an ... Read more

Bimodal Plasma Metabolomics Strategy Identifies Novel Inflammatory Metabolites in Inflammatory Bowel Diseases

Abstract: Introduction: Crohn's disease (CD) and ulcerative colitis (UC) are inflammatory bowel diseases (IBD) characterized by variable phenotypes. Metabolites are signatures of biochemical activity that can reveal unknown pathogenic pathways. We employed untargeted mass spectrometry (MS) based metabolomics to identify novel inflammatory mechanisms in IBD and a targeted assay to quantify metabolites of the auto-immunomodulating kynurenine pathway (KP) in IBDs and health. Materials and Methods: Metabolome analysis of CD, UC, and control plasmas was performed on a Liquid Chromatography (LC)-MS/MS system. KP metabolites quinolinic acid (QA) and picolinic acid (PA) were quantified by gas chromatography/MS. Results: Nineteen UC, 25 CD, and 9 control plasmas were analyzed: 34 metabolites exhibited abundance profiles associated with CD by global metabolome analysis (P≤0.05, false discovery rate q≤0.01). Notably, inflammatory-implicated metabolites angiotensin IV (P=0.049, q<0.001), diphthamide (P=0.018, q<0.001), and GM3 gangliosides (P<0.001, q<0.001) were increased in CD. By targeted kynurenine metabolites assay, QA (73.53 ng/mL ± 23.40 SD) and combined kynurenine metabolites (CKM) were increased in CD (120.19 ± 39.71) compared to controls (QA  50.14 ± 15.04; P<0.01; CKM 92.73 ± 26.30; P<0.01). CD QA positively correlated with CDAI (r=0.85; P<0.01), CRP (r=0.46; P=0.01), and ESR (r=0.42; P=0.03), while CKMs correlated with CDAI (r=0.615; P<0.01) and CRP (r=0.615; P=0.02). Conclusions: Associations of angiotensin IV, diphthamide, and GM3 gangliosides with CD implicate novel pathways in activating a Th1/Th17 inflammatory profile. Increased QA concentrations in CD may indicate a defective auto-immunomodulation mechanism. ... Read more

Advances in the Pharmacotherapy of Patients with Acromegaly

Abstract: Acromegaly is a disease characterized by growth hormone (GH) excess originating, in approximately 95% of cases, from a somatotroph pituitary adenoma. Symptomatology and clinical features are due to GH and insulin-like growth factor 1 excess; unfortunately, for most patients diagnosis is delayed by several years. Acromegaly patients' morbidity and mortality are higher than those of the normal population. However, with adequate biochemical control mortality rates can be restored to normal. Tumor size and location, symptoms, comorbidities, and lastly, but not least, patient preference, are all important aspects in treatment decision making, and treatment approach should be individualized. Current therapy includes medical, surgical, and radiation. This review focuses on recent significant developments in medical therapy. There are three major therapeutic drug classes: somatostatin receptor ligands (SRLs), which represent the mainstay of medical therapy, GH receptor blockers, and dopamine agonists. Multi-ligand receptor SRLs such as pasireotide, should increase therapeutic choices for acromegaly patients currently uncontrolled on available SRLs. Furthermore, significant research has been focused in the development of novel delivery modalities (e.g., oral and long acting subcutaneous administration). ... Read more

Novel Therapeutic Approaches for Celiac Disease

Abstract: Celiac disease (CD), which mainly affects the small intestine, is the only systemic autoimmune disorder with an identified environmental trigger which is dietary gluten. Lifelong adherence to a strict gluten free diet (GFD) is currently the only accepted treatment. CD is increasingly diagnosed and the GFD is known to be associated with a large treatment burden. Furthermore, a substantial number of CD patients show an incomplete clinical response to the GFD. These factors have led to demands for the development and testing of novel, non-dietary, therapeutic agents that are both safe and effective. CD pathogenesis is well elucidated which has greatly aided targeted drug development. Compounds currently being tested in phase II clinical trials include glutenase enzymes (to detoxify gluten) and a tight junction modulator (to reduce access of gluten peptides to lamina propria antigen presenting cells). Other promising approaches include inhibition of the transglutaminase 2 enzyme, blocking antigen presentation by HLA-DQ2 or HLA-DQ8, induction of tolerance, and modulation of the inflammatory response. It is hoped that non-dietary therapy for CD will become available in the coming years and can both reduce the burden of treatment of CD and help patients whose symptoms do not respond completely to the GFD. ... Read more

Advances in Understanding the Pathogenesis of Barrett's Esophagus

Abstract: Barrett's esophagus (BE) is an intestinal-like columnar metaplasia that replaces the normal stratified squamous epithelium in the distal esophagus. Clinically, BE is an important entity as it is the only established precursor to esophageal adenocarcinoma (EAC), a disease with an extremely poor prognosis and an incidence that is rising faster than any other solid cancer worldwide. Therefore, because of the increasing burden of EAC, there has been much research aimed at understanding the development of BE, in order to develop new ways to combat this disease. BE arises as a consequence of chronic reflux. Whilst the central role of reflux in driving the development of BE has been well established, the cellular and molecular mechanisms that accompany this process remain to be fully elucidated. Understanding the drivers at a fundamental level is crucial for the rational design of novel therapeutic strategies aimed at preventing the progression of, or even reversing, BE. In this article we review some of the recent advances that have contributed to our understanding of BE pathogenesis, including new findings on the possible cellular origins of the metaplastic epithelium, and the morphogens and transcription factors that putatively drive the conversion of the squamous epithelium to an intestinal-like columnar epithelium. ... Read more

Antidiabetic Drugs and Their Potential Role in Treating Mild Cognitive Impairment and Alzheimer's Disease

Abstract: The incidence of both diabetes mellitus (DM) and dementia increases with aging and the incidence of dementia are higher in people with diabetes. Epidemiological and pathological data suggest that DM contributes to mild cognitive impairment (MCI) and dementia. DM seems to be an independent risk factor for MCI and Alzheimer's disease (AD) and is associated with more rapid cognitive decline. Recent evidence points out that insulin affects central nervous system functions, and can modulate cognitive functions. Impaired insulin signaling and insulin resistance in brain have been found to play an important role in the pathogenesis of AD. Human studies have shown that some oral antidiabetic medications can improve cognition in patients with MCI and AD. Intranasal insulin has also been shown to improve memory and cognitive abilities in MCI and AD patients. While it remains unclear whether management of diabetes will reduce the incidence of MCI and AD, emerging evidence suggests that diabetes therapies may improve cognitive function. ... Read more

Disorders of Sex Development: Clinically Relevant Genes Involved in Gonadal Differentiation

Abstract: After the characterization of the sex-determining region of Y (SRY) in 1990, there have been an increasing number of genes recognized to play a role in sex development. The most common disorders of sex development (DSD) result from disruption of androgen levels and activity that affect later embryonal development, such as congenital adrenal hyperplasia and androgen insensitivity syndrome. However, genetic diagnosis of mutations affecting early gonadal development is becoming increasingly accessible to clinicians. More powerful genetic techniques are allowing for interrogation of the entire genome for causative changes and it is important to be able to critically assess the flood of genetic data for meaningful information. Recent discoveries have clarified the role of a variety of transcription factors in DSD such as SOX9, SF1, and WT1. Additionally, disruptions of signaling molecules such as hedgehog, WNT, cyclin-dependent kinase, and Ras/MAP kinase are now known to cause DSD. The dosage-dependence of genes involved in gonadal development is a recurrent theme, and genetic changes in promoter and repressor regions are being revealed by chromosomal microarray analysis and other techniques. In some cases, there are multiple different phenotypes caused by deletion, duplication, homozygous, heterozygous, and regulatory-region changes in the same gene. We aim to provide a concise and clinically-applicable overview of recent developments in the understanding of DSD caused by genetic changes affecting gonadal development. ... Read more

Nongenomic Regulation by Thyroid Hormone of Plasma Membrane Ion and Small Molecule Pumps

Abstract: The sodium/proton (Na/H) exchanger, Na,K-ATPase, and Ca2+-ATPase are membrane ion pumps whose basal activities may be regulated by local nongenomic actions of thyroid hormone and hormone analogues via a hormone receptor on plasma membrane integrin αvβ3. System A amino acid transport and the activity of P-glycoprotein (P-gp; ABCB1), a multidrug efflux pump, are also modulated by thyroid hormone and αvβ3. Where signal transduction has been studied, the presence of the hormone at the receptor is transduced by mitogen-activated protein kinase (MAPK) isoforms (ERK1/2; p38) or phosphatidylinositol 3-kinase into local actions. The existence of the cell surface receptor offers opportunities to pharmacologically modify actions of these important transport functions with nanoparticulate formulations of T4 and T3 that do not enter the cell. Such formulations may reverse complex intracellular accumulations of H+, Na+, and Ca2+ that occur in clinical settings such as ischemia. In addition, nanoparticulate tetraiodothyroacetic acid (tetrac), a thyroid hormone analogue that inhibits binding of T4 and T3 to integrin αvβ3 as well as certain other functions of the integrin, may reverse P-gp-dependent resistance to anti-cancer drugs in tumor cells. ... Read more

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