The O-GlcNAc modification: three-dimensional structure, enzymology and the development of selective inhibitors to probe disease

2010 ◽  
Vol 38 (5) ◽  
pp. 1179-1188 ◽  
Author(s):  
Gideon J. Davies ◽  
Carlos Martinez-Fleites
Keyword(s):  
Type 2 Diabetes ◽  
Three Dimensional ◽  
Causal Link ◽  
Dimensional Structure ◽  
Mechanistic Studies ◽  
Small Molecule Probes ◽  
Intracellular Dynamic ◽  
Medical Interest ◽  
Synthesis And Degradation

Carbohydrates, their structures and the enzymes responsible for their synthesis and degradation, offer numerous possibilities for the design and application of probes with which to study and treat disease. The intracellular dynamic O-GlcNAc (O-linked β-N-acetylglucosamine) modification is one such glycosylation with considerable medical interest, reflecting its implication in diseases such as Type 2 diabetes and neurodegeneration. In the present paper, we review recent structural and mechanistic studies into the enzymes responsible for this modification, highlighting how mechanism-inspired small-molecule probes may be applied to study potential disease processes. Such studies have questioned a causal link between O-GlcNAc and Type 2 diabetes, but do offer potential for the study, and perhaps the treatment, of tauopathies.

Abstract 209: Dimethylarginine Dimethylaminohydrolase 1 and Insulin Resistance

2014 ◽  
Vol 34 (suppl_1) ◽  
Author(s):  
Sophie E Piper ◽  
James M Leiper
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Skeletal Muscle ◽  
Plasma Glucose ◽  
Knockout Mice ◽  
Physiological Role ◽  
Causal Link ◽  
Chow Diet ◽  
Dimethylarginine Dimethylaminohydrolase

Type 2 diabetes is a prevalent metabolic condition and is the result of an impaired response to insulin. Insulin resistance and type 2 diabetes are clearly associated with obesity and the secondary cardiovascular complications of this condition are serious and life threatening. Asymemetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthases and increased levels are seen in multiple pathologies. Increased plasma levels of ADMA have been associated with patients with type 2 diabetes, insulin resistance and obesity, although a causal link between ADMA and diabetes has not been established. Dimethylarginine dimethylaminohydrolase (DDAH) is the enzyme that catalyses the metabolism of ADMA. There are two isoforms of the enzyme which are both involved in the control of ADMA and NO. The interplay of insulin with NO release is well established but the initial causes for the onset of insulin resistance are not well defined. Elevated levels of ADMA are linked to insulin resistance and transgenic mice that over-express ddah1 show increased insulin sensitivity. Of note is that metformin, an insulin sensitising drug that is widely used in the treatment of insulin resistance, reduces plasma glucose and ADMA concentrations. In order to elucidate the physiological role of DDAH1 in glucose homeostasis we investigated the glucose handling in a ddah1 global knockout model. Intra-peritoneal glucose tolerance tests in ddah1 global knockout mice demonstrate insulin resistance. Baseline plasma glucose levels were 25% higher in ddah1 knockouts and peak levels were 53% higher in ddah1 knockouts. The kinetics of plasma glucose accumulation and clearance in ddah1 knockout mice suggests dysfunction in both the liver and skeletal muscle. On a normal chow diet, hepatocyte specific ddah1 knockout mice and skeletal muscle specific ddah1 knockout mice show no insulin resistance. On a high fat diet however the hepatocyte specific ddah1 knockout mice show significant insulin resistance and lower metabolic rate than their fat fed wild-type counterparts. These studies demonstrate for the first time a causal link between ADMA accumulation and insulin resistance. Furthermore these data establish DDAH1 activity is a significant regulator of insulin resistance.

scholarly journals Gastrointestinal Mechanisms Underlying the Cardiovascular Effect of Metformin

2020 ◽  
Vol 13 (11) ◽  
pp. 410
Author(s):  
Malcolm J. Borg ◽  
Christopher K. Rayner ◽  
Karen L. Jones ◽  
Michael Horowitz ◽  
Cong Xie ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Cardiovascular Risk ◽  
Cardiovascular Effect ◽  
Elevated Blood ◽  
Direct Effects ◽  
Mechanistic Studies ◽  
Glucose Lowering ◽  
Glucose Levels ◽  
Blood Glucose Levels

Metformin, the most widely prescribed drug therapy for type 2 diabetes, has pleiotropic benefits, in addition to its capacity to lower elevated blood glucose levels, including mitigation of cardiovascular risk. The mechanisms underlying the latter remain unclear. Mechanistic studies have, hitherto, focused on the direct effects of metformin on the heart and vasculature. It is now appreciated that effects in the gastrointestinal tract are important to glucose-lowering by metformin. Gastrointestinal actions of metformin also have major implications for cardiovascular function. This review summarizes the gastrointestinal mechanisms underlying the action of metformin and their potential relevance to cardiovascular benefits.

Effect of cilostazol on carotid plaque volume measured by three‐dimensional ultrasonography in patients with type 2 diabetes: The FANCY study

2020 ◽  
Vol 22 (12) ◽  
pp. 2257-2266
Author(s):  
Dong‐Hwa Lee ◽  
Eun Ju Chun ◽  
Ji Hye Moon ◽  
Han Mi Yun ◽  
Soo Lim
Keyword(s):  
Type 2 Diabetes ◽  
Carotid Plaque ◽  
Three Dimensional ◽  
Plaque Volume

scholarly journals Molecular Cloning, Modeling, and Characterization of Type 2 Metallothionein from Plantago ovata Forsk

Sequencing ◽  
2013 ◽  
Vol 2013 ◽  
pp. 1-10 ◽  
Author(s):  
Amitava Moulick ◽  
Debashis Mukhopadhyay ◽  
Shonima Talapatra ◽  
Nirmalya Ghoshal ◽  
Sarmistha Sen Raychaudhuri
Keyword(s):  
Molecular Cloning ◽  
Structure Prediction ◽  
3D Structure ◽  
Three Dimensional ◽  
Transcript Level ◽  
Copper Stress ◽  
Dimensional Structure ◽  
Functional Study ◽  
Plantago Ovata

Plantago ovata Forsk is a medicinally important plant. Metallothioneins are cysteine rich proteins involved in the detoxification of heavy metals. Molecular cloning and modeling of MT from P. ovata is not reported yet. The present investigation will describe the isolation, structure prediction, characterization, and expression under copper stress of type 2 metallothionein (MT2) from this species. The gene of the protein comprises three exons and two introns. The deduced protein sequence contains 81 amino acids with a calculated molecular weight of about 8.1 kDa and a theoretical pI value of 4.77. The transcript level of this protein was increased in response to copper stress. Homology modeling was used to construct a three-dimensional structure of P. ovata MT2. The 3D structure model of P. ovata MT2 will provide a significant clue for further structural and functional study of this protein.

scholarly journals Prenatal Malnutrition-Induced Epigenetic Dysregulation as a Risk Factor for Type 2 Diabetes

2019 ◽  
Vol 2019 ◽  
pp. 1-11 ◽  
Author(s):  
Alexander Vaiserman ◽  
Oleh Lushchak
Keyword(s):  
Type 2 Diabetes ◽  
Critical Role ◽  
Regulation Of Gene Expression ◽  
Epidemiological Data ◽  
Later Life ◽  
Causal Link ◽  
Related Factors ◽  
Insulin Metabolism ◽  
Prenatal Malnutrition

Type 2 diabetes (T2D) is commonly regarded as a disease originating from lifestyle-related factors and typically occurring after the age of 40. There is, however, consistent experimental and epidemiological data evidencing that the risk for developing T2D may largely depend on conditions early in life. In particular, intrauterine growth restriction (IUGR) induced by poor or unbalanced nutrient intake can impair fetal growth and also cause fetal adipose tissue and pancreatic β-cell dysfunction. On account of these processes, persisting adaptive changes can occur in the glucose-insulin metabolism. These changes can include reduced ability for insulin secretion and insulin resistance, and they may result in an improved capacity to store fat, thereby predisposing to the development of T2D and obesity in adulthood. Accumulating research findings indicate that epigenetic regulation of gene expression plays a critical role in linking prenatal malnutrition to the risk of later-life metabolic disorders including T2D. In animal models of IUGR, changes in both DNA methylation and expression levels of key metabolic genes were repeatedly found which persisted until adulthood. The causal link between epigenetic disturbances during development and the risk for T2D was also confirmed in several human studies. In this review, the conceptual models and empirical data are summarized and discussed regarding the contribution of epigenetic mechanisms in developmental nutritional programming of T2D.

scholarly journals Three-dimensional structure of a mouse-adapted type 2/type 1 poliovirus chimera.

1991 ◽  
Vol 10 (9) ◽  
pp. 2331-2341 ◽  
Author(s):  
T.O. Yeates ◽  
D.H. Jacobson ◽  
A. Martin ◽  
C. Wychowski ◽  
M. Girard ◽  
...  
Keyword(s):  
Three Dimensional ◽  
Dimensional Structure ◽  
Three Dimensional Structure
Sign in / Sign up

Export Citation Format

Share Document