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

Obesity-resistance in AHSG-knockout mice indicate an important role of alpha2-Heremans-Schmid glycoprotein/fetuin-A (AHSG) in the development of obesity. We studied whether genetic variation within AHSG affects whole-body adiposity and regional fat distribution in humans. We genotyped 321 subjects at increased risk for type 2 diabetes for five single nucleotide polymorphisms (SNP) rs2248690, rs4831, rs2070635, rs4917, and rs1071592. Body fat distribution and ectopic hepatic and intramyocellular lipids were assessed by magnetic resonance techniques. AHSG levels were determined by immunoturbidimetry. The five chosen SNPs covered 100% of common genetic variation (minor allele frequency >/=0.05) within AHSG (r (2)>/=0.8). All SNPs were significantly associated with AHSG levels (p<0.0001), except for rs4831 (p=0.9) after adjustment for gender, age, and body mass index (BMI). AHSG levels were associated with liver fat content (p=0.0160) and BMI (p=0.0247) after adjustment for gender and age. While rs2248690 was nominally associated with BMI in the dominant model (p=0.0432), none of the SNPs was associated with regional fat distribution. Common genetic variation within AHSG does not appear to influence regional body fat distribution, but may affect whole-body adiposity in humans.
 ...
PMID:AHSG gene variation is not associated with regional body fat distribution--a magnetic resonance study. 1935 88

Plasma phospholipid transfer protein (PLTP) is a lipid transfer glycoprotein that binds to and transfers a number of amphipathic compounds. In earlier studies, the attention of the scientific community focused on the positive role of PLTP in high-density lipoprotein (HDL) metabolism. However, this potentially anti-atherogenic role of PLTP has been challenged recently by another picture: PLTP arose as a pro-atherogenic factor through its ability to increase the production of apolipoprotein B-containing lipoproteins, to decrease their antioxidative protection and to trigger inflammation. In humans, PLTP has mostly been studied in patients with cardiometabolic disorders. Both PLTP and related cholesteryl ester transfer protein (CETP) are secreted proteins, and adipose tissue is an important contributor to the systemic pools of these two proteins. Coincidently, high levels of PLTP and CETP have been found in the plasma of obese patients. PLTP activity and mass have been reported to be abnormally elevated in type 2 diabetes mellitus (T2DM) and insulin-resistant states, and this elevation is frequently associated with hypertriglyceridemia and obesity. This review article presents the state of knowledge on the implication of PLTP in lipoprotein metabolism, on its atherogenic potential, and the complexity of its implication in obesity, insulin resistance and T2DM.
 ...
PMID:Plasma phospholipid transfer protein (PLTP): review of an emerging cardiometabolic risk factor. 1941 3

Diabetic nephropathy (DN) has an important impact on morbidity/mortality in diabetic patients. Genetic factors are probably involved in the development of this microvascular complication. Haptoglobin (Hp) is a genetically polymorphic glycoprotein that forms stable complexes with plasma-free hemoglobin (Hb) providing protection against heme-induced oxidative stress and kidney damage. The aim of the present study was to investigate the existence of association between the Hp genotypes and the presence of DN in Brazilian diabetic patients. The Hp genotypes of 265 patients, 95 type 1 diabetes mellitus (DM1) sufferers with at least 10 years of disease and 170 type 2 diabetes mellitus (DM2) sufferers with at least 5 years of disease were determined by allele-specific PCR; both groups included patients with and without DN. Hp allele and genotype frequencies were compared among the patient groups and between the patient groups and a control group of 142 healthy individuals. No association between Hp genotypes and DN could be demonstrated. Additionally, urinary albumin excretion values and the presence or absence of systemic arterial hypertension (SAH) were compared among the patient groups. Again, no significant correlations were found. The Hp polymorphism could not be associated with DN in the population studied here.
 ...
PMID:Haptoglobin polymorphism and diabetic nephropathy in Brazilian diabetic patients. 1945 68

Recent research and clinical data have begun to demonstrate the huge potential therapeutic importance of ligands that modulate the activity of the secretin-like, Class II, G protein-coupled receptors (GPCRs). Ligands that can modulate the activity of these Class II GPCRs may have important clinical roles in the treatment of a wide variety of conditions such as osteoporosis, diabetes, amyotrophic lateral sclerosis and autism spectrum disorders. While these receptors present important new therapeutic targets, the large glycoprotein nature of their cognate ligands poses many problems with respect to therapeutic peptidergic drug design. These native peptides often exhibit poor bioavailability, metabolic instability, poor receptor selectivity and resultant low potencies in vivo. Recently, increased attention has been paid to the structural modification of these peptides to enhance their therapeutic efficacy. Successful modification strategies have included d-amino acid substitutions, selective truncation, and fatty acid acylation of the peptide. Through these and other processes, these novel peptide ligand analogs can demonstrate enhanced receptor subtype selectivity, directed signal transduction pathway activation, resistance to proteolytic degradation, and improved systemic bioavailability. In the future, it is likely, through additional modification strategies such as addition of circulation-stabilizing transferrin moieties, that the therapeutic pharmacopeia of drugs targeted towards Class II secretin-like receptors may rival that of the Class I rhodopsin-like receptors that currently provide the majority of clinically used GPCR-based therapeutics. Currently, Class II-based drugs include synthesized analogs of vasoactive intestinal peptide for type 2 diabetes or parathyroid hormone for osteoporosis.
 ...
PMID:Chemical modification of class II G protein-coupled receptor ligands: frontiers in the development of peptide analogs as neuroendocrine pharmacological therapies. 1968 75

Dipeptidyl peptidase-4 (DPP4) or adenosine deaminase complexing protein 2 (ADCP 2) or T-cell activation antigen CD26 (EC 3.4.14.5.) is a serine exopeptidase belonging to the S9B protein family that cleaves X-proline dipeptides from the N-terminus of polypeptides, such as chemokines, neuropeptides, and peptide hormones. The enzyme is a type II transmembrane glycoprotein, expressed on the surface of many cell types, whose physiological functions are largely unknown. Protein dimerisation should be required for catalytic activity and glycosylation of the enzyme could impact on its physiological functions. The dimeric glycoprotein ADCP has been found linked to adenosine deaminase (ADA) whose relationship with lymphocyte maturation-differentiation is well-established. Since implicated in the regulation of the biological activity of hormones and chemokines, such as glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide, DPP4 inhibition offers a new potential therapeutic approach for type 2 diabetes mellitus, as monotherapy and adjunct therapy to other oral agents. The clinical use of presently available orally active inhibitors of DPP4, however, has been associated with side effects that have been in part attributed to the inhibition of related serine proteases, such as DPP8 and DPP9. Indeed, it is noteworthy that CD26 has a key role in immune regulation as a T cell activation molecule and in immune-mediated disorder. All-cause infections were increased after sitagliptin treatment. It is noteworthy that the effects of DPP4 inhibition on the immune system have not been extensively investigated. So far, only routine laboratory safety variables have been measured in published randomised controlled trials. The review summarises present knowledge in the field and suggests some potential directions of future research.
 ...
PMID:Dipeptidyl peptidase-4 (CD26): knowing the function before inhibiting the enzyme. 1968 75

Several inflammatory cytokines are involved in vascular inflammation resulting in endothelial dysfunction which is the earliest event in the atherosclerotic process leading to manifest cardiovascular disease. YKL-40 is an inflammatory glycoprotein involved in endothelial dysfunction by promoting chemotaxis, cell attachment and migration, reorganization and tissue remodelling as a response to endothelial damage. YKL-40 protein expression is seen in macrophages and smooth muscle cells in atherosclerotic plaques with the highest expression seen in macrophages in the early lesion of atherosclerosis. Several studies demonstrate, that elevated serum YKL-levels are independently associated with the presence and extent of coronary artery disease and even higher YKL-40 levels are documented in patients with myocardial infarction. Moreover, elevated serum YKL-40 levels have also been found to be associated with all-cause as well as cardiovascular mortality. Finally, YKL-40 levels are elevated both in patients with type 1 and type 2 diabetes, known to be at high risk for the development of cardiovascular diseases, when compared to non-diabetic persons. A positive association between elevated circulating YKL-40 levels and increasing levels of albuminuria have been described in patients with type 1 diabetes indicating a role of YKL-40 in the progressing vascular damage resulting in microvascular disease. This review describes the present knowledge about YKL-40 and discusses its relation to endothelial dysfunction, atherosclerosis, cardiovascular disease and diabetes and look ahead on future perspectives of YKL-40 research.
 ...
PMID:YKL-40--an emerging biomarker in cardiovascular disease and diabetes. 1993 Jun 30

Fetuin-A is a multifunctional circulating glycoprotein. Among its roles, inhibition of ectopic calcification is a prominent feature. Low fetuin-A levels in dialysis patients are associated with cardiovascular mortality, possibly via accelerating vascular calcification. However, except for dialyzed conditions, a correlation between fetuin-A levels and vascular calcification remains controversial. Furthermore, any inhibitory effect of fetuin-A on atherosclerotic calcified plaques (CPs) remains unclear compared with its effect on medial artery calcification that is often found in dialyzed patients. Therefore, we examined the association between fetuin-A levels and atherosclerotic CPs. For this study, 416 consecutive patients with type 2 diabetes mellitus and without renal dysfunction were examined. We measured serum fetuin-A levels and investigated for the presence of CP in the common carotid and femoral arteries using ultrasonography. Fetuin-A levels were significantly lower in patients with CP than those without CP (262.6 +/- 56.7 and 281.5 +/- 64.6 microg/mL, respectively; P = .001). Multivariate logistic regression analysis showed that fetuin-A levels were inversely associated with the presence of CP (odds ratio = 0.753; 95% confidence interval, 0.608-0.933; P = .010). These results suggest that fetuin-A may inhibit the calcification of atherosclerotic plaques independently of the dialyzed condition.
 ...
PMID:Fetuin-A and atherosclerotic calcified plaque in patients with type 2 diabetes mellitus. 2001 22

Zinc-alpha(2)-glycoprotein (ZAG) is an adipokine associated with fat loss in cancer cachexia. The purpose of this study was to evaluate the ability of recombinant human ZAG to attenuate type 2 diabetes in the ob/ob mouse model. ZAG (50 microg daily, iv) induced a progressive loss of body weight (3.5 g in 5 d), without an effect on food or water intake but with a 0.4 C rise in body temperature, suggesting an increased energy expenditure. Despite an increased plasma glycerol, indicative of increased lipolysis, levels of glucose, triglycerides, and nonesterified fatty acids were decreased by 17, 25, and 62%, respectively, due to an increased use of both glucose and lipids by muscle and brown adipose tissue. The weight of the latter increased 2-fold, and there was increased expression of uncoupling proteins-1 and -3. Plasma insulin levels were reduced by 36%, whereas pancreatic insulin was increased 4-fold, and there was a 53% decrease in the total area under the glucose curve in the glucose tolerance test and reduced insulin requirement. There was an increase in skeletal muscle mass due to an increase in protein synthesis and a decrease in protein degradation. These results suggest that ZAG may potentially be effective in the treatment of type 2 diabetes.
 ...
PMID:Antidiabetic properties of zinc-alpha2-glycoprotein in ob/ob mice. 2003 55

The prevalence of obesity has dramatically increased in recent years and now includes a significant proportion of the world's children, adolescents and adults. Obesity is linked to a number of co-morbidities, the most prominent being type 2 diabetes mellitus. While many agents are available to treat these conditions, the current knowledge regarding their disposition in the obese remains limited. Over the years, both direct and indirect methodologies have been utilized to assess body composition. Commonly used direct measures include underwater weighing, skinfold measurement, bioelectrical impedance analysis and dual-energy x-ray absorptiometry. Unfortunately, these methods are not readily available to the majority of clinicians. As a result, a number of indirect measures to assess body composition have been developed. Indirect measures rely on patient attributes such as height, bodyweight and sex. These size metrics are often utilized clinically and include body mass index (BMI), body surface area (BSA), ideal bodyweight (IBW), percent IBW, adjusted bodyweight, lean bodyweight (LBW) and predicted normal weight (PNWT). An understanding of how the volume of distribution (V(d)) of a drug changes in the obese is critical, as this parameter determines loading-dose selection. The V(d) of a drug is dependent upon its physiochemical properties, the degree of plasma protein binding and tissue blood flow. Obesity does not appear to have an impact on drug binding to albumin; however, data regarding alpha(1)-acid glycoprotein binding have been contradictory. A reduction in tissue blood flow and alterations in cardiac structure and function have been noted in obese individuals. At the present time, a universal size descriptor to describe the V(d) of all drugs in obese and lean individuals does not exist. Drug clearance (CL) is the primary determinant to consider when designing a maintenance dose regimen. CL is largely controlled by hepatic and renal physiology. In the obese, increases in cytochrome P450 2E1 activity and phase II conjugation activity have been observed. The effects of obesity on renal tubular secretion, tubular reabsorption, and glomerular filtration have not been fully elucidated. As with the V(d), a single, well validated size metric to characterize drug CL in the obese does not currently exist. Therefore, clinicians should apply a weight-normalized maintenance dose, using a size descriptor that corrects for differences in absolute CL between obese and non-obese individuals. The elimination half-life (t((1/2))) of a drug depends on both the V(d) and CL. Since the V(d) and CL are biologically independent entities, changes in the t((1/2)) of a drug in obese individuals can reflect changes in the V(d), the CL, or both. This review also examines recent publications that investigated the disposition of several classes of drugs in the obese--antibacterials, anticoagulants, antidiabetics, anticancer agents and neuromuscular blockers. In conclusion, pharmacokinetic data in obese patients do not exist for the majority of drugs. In situations where such information is available, clinicians should design treatment regimens that account for any significant differences in the CL and V(d) in the obese.
 ...
PMID:Effect of obesity on the pharmacokinetics of drugs in humans. 2006 34

Obesity and hyperlipidemia are associated with impaired insulin sensitivity in human type 2 diabetes mellitus, possibly due to activation of a mild inflammatory response. Because obesity-induced insulin resistance predisposes cats to diabetes and because hyperlipidemia is a frequent concurrent finding, excess lipids may also impair insulin sensitivity in cats. Healthy cats (n=6) were infused with lipids (Lipovenoes 10%) for 10 days to clamp blood triglycerides at the approximate concentration of untreated feline diabetes (3-7 mmol/l). Controls received saline (n=5). On day 10, plasma adiponectin and proinflammatory markers were measured. Whole-body insulin sensitivity was calculated following an intravenous glucose tolerance test. Tissue mRNAs of glucose metabolism-related genes were quantified in subcutaneous and visceral fat, liver, and skeletal muscles. Accumulation of lipids was assessed in liver. At the termination of infusion, whole-body insulin sensitivity did not differ between groups. Compared to saline, cats infused with lipids had 50% higher plasma adiponectin and 2-3 times higher alpha(1)-acid glycoprotein and monocyte chemoattractant protein-1. Unexpectedly, lipid-infused cats had increased glucose transporter-4 (GLUT4) mRNA in the visceral fat, and increased peroxisome proliferative activated receptor-gamma2 (PPARgamma2) in subcutaneous fat; adiponectin expression was not affected in any tissue. Lipid-infused cats developed hepatic steatosis. Although hyperlipidemia induced systemic inflammation, whole-body insulin sensitivity was not impaired after 10 day infusion. Increased circulating adiponectin may have contributed to prevent insulin resistance, possibly by increasing GLUT4 and PPARgamma2 transcripts in fat depots.
 ...
PMID:10-day hyperlipidemic clamp in cats: effects on insulin sensitivity, inflammation, and glucose metabolism-related genes. 2016 4


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