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Gut Peptide Signals in the Control of Food Intake

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

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

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

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

Hormonal Interactions Between Gut and Brain

Abstract: No truly effective drugs exist to treat obesity, which is reaching pandemic proportions. The search for new treatments has led to an interest into the homeostatic system of central appetite regulation. Key components of this system include the hypothalamus and brainstem, the gut, and adipose tissue. It is now recognized that food intake leads to the release of various gut hormones. There are several anorectic (appetite suppressing) gut hormones released, including cholecystokinin, glucagon like peptide-1, oxyntomodulin, peptide tyrosine tyrosine, and pancreatic polypeptide. To date, only one example is known of an orexigenic (appetite stimulating) hormone, ghrelin. These hormones circulate in the blood and signal via vagal nerve afferents to communicate with the hypothalamus and brainstem. This information is integrated and processed in key hypothalamic nuclei. The arcuate nucleus appears to be a central controller of the appetite circuit, integrating both peripheral and central signals. This information is translated into downstream signals affecting body metabolism and food intake. Increased understanding and successful manipulation of this system should enable the design of a successful and much needed anti-obesity treatment. ... Read more

The Interplay of Autoimmunity and Insulin Resistance in Type 1 Diabetes

Abstract: Type 1 diabetes (T1D) is a common chronic disease characterized by selective autoimmune destruction of the pancreatic islet beta cells and subsequent dependence on exogenous insulin. Certain alleles including the high-risk HLA genotype, HLA-DR3-DQ2/DR4-DQ8, place individuals at increased risk of developing T1D. Autoantibodies to beta cell antigens are used in the diagnosis of T1D, and studies have shown that they can be used to predict risk of developing T1D in first degree relatives of probands. The annual global incidence of T1D is increasing by 3-5% per year. Many environmental factors have been implicated in the rising incidence of T1D. Proponents of the accelerator hypothesis argue that T1D and type 2 diabetes (T2D) are the same disorder of insulin resistance, although with different genetic backgrounds. While insulin resistance is a recognized hallmark of T2D, it also appears to play a significant role in the pathogenesis of T1D and its vascular complications. In this article, we will review: 1) immunogenetics of T1D, 2) risk factors for the development of islet autoimmunity and T1D, 3) mechanisms of insulin resistance in T1D, and 4) links between insulin resistance and complications in T1D. Further studies are needed to define environmental factors causing T1D as well as the role of insulin resistance in the pathogenesis of T1D and its complications. ... Read more

Identification and Functions of the Plasma Membrane Receptor for Thyroid Hormone Analogues

Abstract: Integrin αvβ3 is a heterodimeric structural protein of the plasma membrane that bears a cell surface receptor for thyroid hormone. The functions of this receptor are distinct from those of the classical nuclear receptor (TR) for thyroid hormone. The integrin is expressed primarily by cancer cells, dividing endothelial and vascular smooth muscle cells, and osteoclasts. The hormone receptor on αvβ3 enables L-thyroxine (T4) and 3, 5, 3'-triiodo-L-thyronine (T3) to stimulate cancer cell proliferation and angiogenesis and to regulate the activity of certain membrane ion pumps. Bound to the receptor, the hormone ligand also stimulates protein trafficking within the cell. A deaminated derivative of T4, tetraiodothyroacetic acid (tetrac), blocks binding and actions of T4 and T3 at the receptor on αvβ3; tetrac also has anti-proliferative actions at the integrin thyroid hormone receptor beyond the effects of antagonizing actions of agonist thyroid hormone analogues at the receptor. The structure-activity relationships of hormone analogues at the receptor have been computer-modeled and indicate that the receptor includes a site that binds T3 and a site that binds both T4 and T3. Mathematical modeling of the kinetics of hormone-binding also suggests the existence of two sites. Cell proliferation is modulated from the T4/T3 site. Tetrac has been re-formulated as a nanoparticle (nanotetrac) that acts exclusively at the αvβ3 receptor and does not enter cells. Nanotetrac disrupts expression of genes in multiple cancer cell survival pathways. The tetrac formulations block human cancer cell proliferation in vitro and in tumor xenografts. Nanotetrac and tetrac inhibit the pro-angiogenic actions in vitro of vascular endothelial growth factor, basic fibroblast factor, and other growth factors. Thus, the receptor described on integrin αvβ3 for T4 and T3, the function of which is materially affected by tetrac and nanotetrac, provides insight into tumor cell biology and vascular biology. ... Read more

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