Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The glucagon-like peptide 1 receptor (GLP-1R) mediates important effects on beta-cell function and glucose homeostasis and is one of the most promising therapeutic targets for type 2, and possibly type 1, diabetes. Yet, little is known regarding the molecular and cellular mechanisms that regulate its function. Therefore, we examined the cellular trafficking of the GLP-1R and the relation between receptor localization and signaling activity. In resting human embryonic kidney 293 and insulinoma MIN6 cells, a fully functional green fluorescent protein-tagged GLP-1R was localized both at the cell membrane and in highly mobile intracellular compartments. Real-time confocal fluorescence microscopy allowed direct visualization of constitutive cycling of the receptor. Overexpression of K44A-dynamin increased the number of functional receptors at the cell membrane. Immunoprecipitation, sucrose sedimentation, and microscopy observations demonstrated that the GLP-1R localizes in lipid rafts and interacts with caveolin-1. This interaction is necessary for membrane localization of the GLP-1R, because overexpression of a dominant-negative form of caveolin-1 (P132L-cav1) or specific mutations within the putative GLP-1R's caveolin-1 binding domain completely inhibited GLP-1 binding and activity. Upon agonist stimulation, the GLP-1R underwent rapid and extensive endocytosis independently from arrestins but in association with caveolin-1. Finally, GLP-1R-stimulated activation of ERK1/2, which involves transactivation of epidermal growth factor receptors, required lipid raft integrity. In summary, the interaction of the GLP-1R with caveolin-1 regulates subcellular localization, trafficking, and signaling activity. This study provides further evidence of the key role of accessory proteins in specifying the cellular behavior of G protein-coupled receptors.
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PMID:Caveolin-1 regulates cellular trafficking and function of the glucagon-like Peptide 1 receptor. 1693 72

Coronary artery disease (CAD) is the leading cause of death worldwide and is commonly caused by a constellation of risk factors called the metabolic syndrome. We characterized a family with autosomal dominant early CAD, features of the metabolic syndrome (hyperlipidemia, hypertension, and diabetes), and osteoporosis. These traits showed genetic linkage to a short segment of chromosome 12p, in which we identified a missense mutation in LRP6, which encodes a co-receptor in the Wnt signaling pathway. The mutation, which substitutes cysteine for arginine at a highly conserved residue of an epidermal growth factor-like domain, impairs Wnt signaling in vitro. These results link a single gene defect in Wnt signaling to CAD and multiple cardiovascular risk factors.
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PMID:LRP6 mutation in a family with early coronary disease and metabolic risk factors. 1733 14

The regenerative capacity of the liver is an important factor following liver surgery. The dramatic change in portal venous flow, due to either portal vein embolization or partial hepatectomy, induces a rapid change in liver volume. In response to these stresses, hepatocytes are primed, through the release of inflammatory cytokines, to increase the expression of immediate early genes and increase the activation of transcriptional factors. The primed hepatocytes then respond to growth factors, including hepatocyte growth factor, epidermal growth factor, and transforming growth factor-alpha. Several pathologic conditions have been shown to inhibit hepatic regeneration. These include diabetes mellitus, malnutrition, aging, infection, chronic ethanol consumption, and biliary obstruction. Impaired hepatic regeneration in the setting of biliary obstruction is an especially serious problem because it can be a major determinant in not considering surgical treatment. The mechanism responsible for impaired hepatic regeneration in patients with biliary obstruction includes decreased portal venous flow, attenuated production of liver proliferation-associated factors, an increased rate of apoptosis, and lack of enterohepatic circulation. Restoring these factors may lead to an improvement in regeneration in a cholestatic liver following portal vein embolization or partial hepatectomy. This review article summarizes the current understanding of the mechanism of hepatic regeneration, with particular emphasis on that in the cholestatic liver.
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PMID:Mechanism of impaired hepatic regeneration in cholestatic liver. 1738 7

Diabetes impairs multiple aspects of the wound-healing response. Delayed wound healing continues to be a significant healthcare problem for which effective therapies are lacking. We have hypothesized that local delivery of mesenchymal stromal cells (MSC) at a wound might correct many of the wound-healing impairments seen in diabetic lesions. We treated excisional wounds of genetically diabetic (Db-/Db-) mice and heterozygous controls with either MSC, CD45(+) cells, or vehicle. At 7 days, treatment with MSC resulted in a decrease in the epithelial gap from 3.2 +/- 0.5 mm in vehicle-treated wounds to 1.3 +/- 0.4 mm in MSC-treated wounds and an increase in granulation tissue from 0.8 +/- 0.3 mm(2) to 2.4 +/- 0.6 mm(2), respectively (mean +/- SD, P < 0.04). MSC-treated wounds also displayed a higher density of CD31(+) vessels and exhibited increases in the production of mRNA for epidermal growth factor, transforming growth factor beta 1, vascular endothelial growth factor, and stromal-derived growth factor 1-alpha. MSC also demonstrated greater contractile ability than fibroblast controls in a collagen gel contraction assay. The effects of locally applied MSC are thus sufficient to improve healing in diabetic mice. Possible mechanisms of this effect include augmented local growth-factor production, improved neovascularization, enhanced cellular recruitment to wounds, and improved wound contraction.
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PMID:Treatment of diabetic wounds with fetal murine mesenchymal stromal cells enhances wound closure. 1745 45

Diabetic nephropathy (DN) is a frequent complication in patients with diabetes. Although the majority of DN models and human studies have focused on glomeruli, tubulointerstitial damage is a major feature of DN and an important predictor of renal dysfunction. This study sought to investigate molecular markers of pathogenic pathways in the renal interstitium of patients with DN. Microdissected tubulointerstitial compartments from biopsies with established DN and control kidneys were subjected to expression profiling. Analysis of candidate genes, potentially involved in DN on the basis of common hypotheses, identified 49 genes with significantly altered expression levels in established DN in comparison with controls. In contrast to some rodent models, the growth factors vascular endothelial growth factor A (VEGF-A) and epidermal growth factor (EGF) showed a decrease in mRNA expression in DN. This was validated on an independent cohort of patients with DN by real-time reverse transcriptase-PCR. Immunohistochemical staining for VEGF-A and EGF also showed a reduced expression in DN. The decrease of renal VEGF-A expression was associated with a reduction in peritubular capillary densities shown by platelet-endothelial cell adhesion molecule-1/CD31 staining. Furthermore, a significant inverse correlation between VEGF-A and proteinuria, as well as EGF and proteinuria, and a positive correlation between VEGF-A and hypoxia-inducible factor-1alpha mRNA was found. Thus, in human DN, a decrease of VEGF-A, rather than the reported increase as described in some rodent models, may contribute to the progressive disease. These findings and the questions about rodent models in DN raise a note of caution regarding the proposal to inhibit VEGF-A to prevent progression of DN.
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PMID:Interstitial vascular rarefaction and reduced VEGF-A expression in human diabetic nephropathy. 1747 21

Betacellulin is a member of the epidermal growth factor (EGF) family and may play a role in islet neogenesis and regeneration. To evaluate whether polymorphisms in this gene are associated with type 2 diabetes (T2DM) and impaired glucose tolerance (IGT), we genotyped 7 previously identified betacellulin variants in Amish subjects with T2DM (n=150), IGT (n=148) and normal glucose tolerance (NGT) (n=361). There were no significant differences in the allele frequencies of the variants among the 3 groups. In an expanded set of 729 nondiabetic Amish subjects, there was no significant association between the betacellulin variants and levels of glucose or insulin either fasting or during a 3 h oral glucose tolerance test, HOMA or insulin secretion index. These results are consistent with previous studies in Caucasian populations and suggest that variants in the betacellulin gene do not play a major role in the development of T2DM in Caucasian populations.
Exp Clin Endocrinol Diabetes 2007 Apr
PMID:Betacellulin variants and type 2 diabetes in the Old Order Amish. 1747 38

The phenomenon of pancreatic regeneration in mammals has been well documented. It has been shown that pancreatic tissue is able to regenerate in several species of mammal after surgical insult. This tissue is also known to have the potential to maintain or increase its beta-cell mass in response to metabolic demands during pregnancy and obesity. Since deficiency in beta-cell mass is the hallmark of most forms of diabetes, it is worthwhile understanding pancreatic regeneration in the context of this disease. With this view in mind, this article aims to discuss the potential use in clinical strategies of knowledge that we obtained from studies carried out in animal models of diabetes. Approaches to achieve this goal involve the use of biomolecules, adult stem cells and gene therapy. Various molecules, such as glucagon-like peptide-1, beta-cellulin, nicotinamide, gastrin, epidermal growth factor-1 and thyroid hormone, play major roles in the initiation of endogenous islet regeneration in diabetes. The most accepted hypothesis is that these molecules stimulate islet precursor cells to undergo neogenesis or to induce replication of existing beta-cells, emphasizing the importance of pancreas-resident stem/progenitor cells in islet regeneration. Moreover, the potential of adult stem cell population from bone marrow, umbilical cord blood, liver, spleen, or amniotic membrane, is also discussed with regard to their potential to induce pancreatic regeneration.
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PMID:Approaches towards endogenous pancreatic regeneration. 1749 91

Recent success in pancreatic islet transplantation has energized the field to discover an alternative source of stem cells with differentiation potential to beta cells. Generation of glucose-responsive, insulin-producing beta cells from self-renewing, pluripotent human ESCs (hESCs) has immense potential for diabetes treatment. We report here the development of a novel serum-free protocol to generate insulin-producing islet-like clusters (ILCs) from hESCs grown under feeder-free conditions. In this 36-day protocol, hESCs were treated with sodium butyrate and activin A to generate definitive endoderm coexpressing CXCR4 and Sox17, and CXCR4 and Foxa2. The endoderm population was then converted into cellular aggregates and further differentiated to Pdx1-expressing pancreatic endoderm in the presence of epidermal growth factor, basic fibroblast growth factor, and noggin. Soon thereafter, expression of Ptf1a and Ngn3 was detected, indicative of further pancreatic differentiation. The aggregates were finally matured in the presence of insulin-like growth factor II and nicotinamide. The temporal pattern of pancreas-specific gene expression in the hESC-derived ILCs showed considerable similarity to in vivo pancreas development, and the final population contained representatives of the ductal, exocrine, and endocrine pancreas. The hESC-derived ILCs contained 2%-8% human C-peptide-positive cells, as well as glucagon- and somatostatin-positive cells. Insulin content as high as 70 ng of insulin/mug of DNA was measured in the ILCs, representing levels higher than that of human fetal islets. In addition, the hESC-derived ILCs contained numerous secretory granules, as determined by electron microscopy, and secreted human C-peptide in a glucose-dependent manner. Disclosure of potential conflicts of interest is found at the end of this article.
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PMID:Generation of insulin-producing islet-like clusters from human embryonic stem cells. 1751 Feb 17

Recombinant human epidermal growth factor (REGEN-D 150), which was cloned and over expressed in E. coli, has shown enhanced healing of chronic diabetic foot ulcers (DFU) by significantly reducing the duration of healing in addition to providing excellent quality of wound healing and reepithelization. Post-marketing surveillance (PMS) study of REGEN-D 150 in 135 patients of DFU in India was compared with Phase III clinical trial data of REGEN-D 150 in India. Statistical analysis of study data determined that the empirical survival probability distribution, in terms of non-healing of ulcers, was lowest in the case of PMS study, better than that for Phase III; more DFU patients were healed in PMS study. Percentage of patients cured in any given week (e.g., in week 10) is above 90% in PMS study, as compared to 69% in Phase III clinical trial; this percentage was around 18% for the control group with placebo in the Phase III trial. The average wound healing time was significantly lower in PMS study, 4.8 weeks, while it was 9 weeks in Phase III clinical trials while the average wound healing with REGEN-D 150 was found to be 86% in this study. REGEN-D 150 has been found to result in healthy granulation and stimulate epithelization, thus leading to final wound closure. The PMS study has established the efficacy of REGEN-D 150 in faster healing of diabetic foot ulcers.
Diabetes Res Clin Pract 2007 Dec
PMID:Recombinant human epidermal growth factor (REGEN-D 150): effect on healing of diabetic foot ulcers. 1765 64

Independent of the association of obesity with dyslipidemia, hypertension, and increased propensity for diabetes, fatness per se is increasingly recognized as a cardiovascular offender. That adipose tissue releases a wide range of adipokines, growth factors, enzymes, and enzyme substrates linked to vascular injury provides a plausible explanation for the role of fat in vascular disease: tumor necrosis factor-alpha, leptin, resistin, interleukin-1, -6, -8, and -18, serum amyloid A, monocyte chemoattractant protein I, macrophage inhibitory factor, aortic carboxypeptidase, hepa-rin-binding epidermal growth factor-like growth factor, vascular endothelial growth factor, transforming growth factor beta, angiotensinogen, cathepsin S, estradiol, cortisol, mineralocorticoid releasing factor, and calcitonin peptides are probable fat-derived prothrombotic, proinflammatory, and proatherosclerotic agents acting in a paracrine and/or endocrine manner. Other adipocyte products such as adiponectin, transforming growth factor beta, and interleukin-10 exert some antiatherogenic effects. The following is a short overview of how adipose tissue products affect the vasculature.
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PMID:Fat cell-derived modulators of vascular cell pathophysiology: the list keeps growing. 1767 16


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