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)

beta 3-adrenoceptors have been described through both molecular and pharmacological studies. In this context, it has been characterized the beta 3-adrenoceptor agonist activity of a new compound (Trecadrine), and evaluated whether it exhibits additional activity at beta 1- and beta 2-adrenoceptor subtypes. In addition, it has been tested its potential anti-diabetic properties in a model of alloxan-induced diabetes in rats. Our data show that Trecadrine induces oesophageal muscularis mucosae relaxation, indicating a putative action on beta 3-adrenoceptors. In the absence of beta 3-adrenoceptor antagonists, assays with beta 1- and beta 2-adrenergic antagonists reveal a quite remarkable selectivity for beta 3-adrenoceptors. Furthermore, it has been suggested that this molecule has hypoglycaemic and lipomobilizing effects, although hypoglycaemia was not related to an increase in insulin secretion in diabetic rats. It is concluded that Trecadrine mainly acts through beta 3-adrenoceptors, and it may constitute a potential drug in the treatment of diabetes.
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PMID:Potential anti-diabetic applications of a new molecule with affinity for beta 3-adrenoceptors. 879 8

Alteration in mesangial volume, due to an increase of the matrix surrounding mesangial cells, is a hallmark indicator of nephropathy in diabetes. Mesangial cells may also play a significant role in the development of nephropathy. Therefore, we examined the effect of glucose on the expression of integrins by cultured human mesangial cells and their ability to interact with collagen IV, a major component of the mesangial matrix. Human mesangial cells were grown in 5 and 25 mM glucose and their integrin profile was examined by immunoprecipitation and flow cytometry in each experimental condition. The results indicate that when mesangial cells were grown in 25 mM glucose, the expression of integrin subunit alpha 2, was increased, while the alpha 1 subunit was considerably decreased, as compared to cells grown in 5 mM glucose. Additionally, mesangial cells were tested for their ability to adhere to collagen IV in a solid-phase assay in the presence of neutralizing antibodies to integrin subunits. The results of these experiments indicate that both alpha 1 and alpha 2 complexed to beta 1 (alpha 2 beta 1 and alpha 1 beta 1) are major mesangial cell receptors for adhesion to collagen IV both in 5 and 25 mM glucose. The two receptors act in concert to mediate adhesion of mesangial cells to type IV collagen. When cell surface expression of the alpha 1 subunit in 25 mM glucose was reduced, the alpha 2 subunit was involved in adhesion to a greater extent than it was in 5 mM glucose. Immunoperoxidase histochemical studies localized both alpha 1 and alpha 2 integrin subunits in the mesangium of normal adult kidneys, suggesting that in vivo interaction with collagen IV could involve both of these receptors. These observations suggest that glucose-induced alterations in integrin expression may modify the ability of mesangial cells to interact with collagen IV.
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PMID:Glucose-induced alteration of integrin expression and function in cultured human mesangial cells. 884 21

The maximal capacity of low affinity ouabain binding sites in kidney medulla was found to be increased by 20 +/- 3.8% after 2 weeks, and by 35 +/- 4.5% in 4 weeks diabetes. However, in kidney cortex no similar changes could be detected. Western blot analysis of Na+/K(+)-ATPase subunits in kidney medulla indicated a significant enhancement of both the alpha 1 and beta 1 subunit in two and four weeks diabetic rats (alpha 1: 35 +/- 3.1, 51 +/- 5.8% and beta 1: 31.3 +/- 5.2 and 43.2 +/- 6.8%, respectively). However, kidney cortex showed no significant change in any condition tested. In diabetes we could detect a significant change only in the medulla in case of the b subunit mRNA transcript, which showed 1.69 +/- 0.59 and 2.89 +/- 0.81 times increased in two and four weeks diabetic state, respectively. There was no change in the alpha 1 subunit mRNA abundance. Insulin treatment of diabetic animals did not result in a complete reversal of diabetes-induced changes in ouabain binding capacity or in the amount of Na+/K(+)-ATPase alpha 1 and beta 1 subunit protein and mRNA levels. Our data indicate a good correlation between changes in low affinity ouabain binding capacity and the level of alpha 1 isoform in diabetic rats, and suggest an important role of the b subunit in the regulation of enzyme quantity.
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PMID:Effect of streptozotocin-induced diabetes on kidney Na+/K(+)-ATPase. 886 95

1. An atypical non beta 1/beta 2-adrenoceptor (AR) subtype (beta 3-AR) has been identified which is selectively stimulated by a group of ligands which mediate lipolytic and thermic responses in brown and white adipose tissue. 2. Molecular studies have shown that beta 3-AR in man are mainly expressed in visceral adipocytes, and to a lesser extent in gall-bladder and colon. In vitro studies with beta 3-AR agonists have shown activity at other sites including skeletal muscle and myocardium. 3. Regulation of beta 3-AR may differ from beta 1/beta 2-AR subtypes in that continuous agonist exposure does not result in receptor down-regulation. 4. A polymorphism of the human beta 3-AR gene (Trp64Arg) has been identified which is associated with obesity, insulin resistance and an earlier onset of non-insulin-dependent diabetes mellitus (NIDDM). Studies are required to establish whether expression of the mutant gene results in altered metabolic responses to beta 3-AR stimulation in man. 5. There is accumulating evidence to support a therapeutic role of beta 3-AR agonists in NIDDM because of anti-obesity and anti-diabetic activity, as a consequence of thermogenic effects as well as increased insulin sensitivity and glucose tolerance. 6. Selectivity studies with BRL35135 and isoprenaline in humans have demonstrated a beta 3-AR mediated component to thermogenesis which is dissociated from beta 1/beta 2-mediated effects on carbohydrate and fat metabolism. Similar studies have suggested a functional beta 3-AR mediating cardiac but not airway responses in humans. An evaluation of beta 3-AR agonists in irritable bowel syndrome may be warranted in view of colonic antimotility properties in vitro.
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PMID:Clinical pharmacology of beta 3-adrenoceptors. 887 18

The submitted review draws attention to advantages and pitfalls of the use of betablockers in the treatment of arterial hypertension. Despite certain metabolically adverse effects which are reduced to a minimum in small doses and more recent betablockers, the latter are along with diuretics the only antihypertensive agents where unequivocally the the long-term favourable effect on the general and cardiovascular mortality was proved. In other hypertensive agents results are expected after completion of multicentric studies which are underway. Beta-blockers, as monotherapy or combined with other drugs, are the drug of choice in the treatment of essential hypertension in young hypertonic patients with hyperkinetic circulation, a tendency for tachycardia, in hypertonic patients with ischaemic heart disease after myocardial infarction or with angina pectoris. In these subjects they quite obviously reduce the general as well as cardiovascular mortality, sudden death and myocardial re-infarction. Betablockers are effective also in elderly hypertonic patients where preparations with ISA or beta 1-selective preparations are more useful. With a certain amount of care similar types of beta-blockers or beta-blockers with a dual effect can be used in hypertension associated with diabetes mellitus, hyperlipoproteinaemia or ischaemia of the lower extremities. Beta-blockers are irreplaceable among antihypertensives of first choice and are experiencing their revival being effective, safe, cheap and well tolerated antihypertensive drugs. Their other properties such as the degree of selectivity, the presence of internal sympathetic activity, combined dual effect, lipophilic or hydrophilic character, enable us to indicate different preparations "tailored" with regard to the severity of hypertension, organ complications and associated diseases.
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PMID:[Do beta-blockers have a role in the modern treatment of arterial hypertension?]. 892 15

The cloning, sequencing and expression in model systems of the previously unidentified beta 3-adrenoceptor recently led to an extensive functional characterization. Ligand binding and adenylate cyclase activation studies helped define a specific profile that is quite distinct from that of the beta 1- and beta 2-adrenoceptors, but strongly reminiscent of most of the 'atypical' beta-adrenoceptor-mediated responses reported in earlier pharmacological studies. More recently, a naturally occurring variation in the human beta 3-adrenoceptor has been correlated with hereditary obesity and with increased dynamic capacity to add on weight and develop non-insulin dependent diabetes in Western obese patients. Donny Strosberg and France Pietri-Rouxel describe how results now provide a consistent picture of an important role for the human beta 3-adrenoceptor in the regulation of lipid metabolism and as an obvious target for drugs to treat some forms of obesity and diabetes.
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PMID:Function and regulation of the beta 3-adrenoceptor. 965 87

We report a point mutation in the ligand-binding domain of the TR beta 1 gene in an affected patient and his daughter. The phenotype was borderline hyperthyroid with periodic aggravation of symptoms. In the cognate variant TR beta (TR beta-CN) amino acid codon 322 was exchanged from aspartic acid to asparagine. TR beta-CN revealed strongly decreased T3-binding activity. At low T3 levels TR beta-CN transactivated a palindromic thyroid hormone response element (TRE-PAL) only to a limited extend, whereas full activity was retained at a high T3 concentration. At low T3 levels, TR beta-CN exerted a dominant negative effect on wild-type TR beta, whereas this effect was diminished in the presence of high T3 concentrations. TR beta-CN could not be activated by retinoid X receptor (RXR) beta in the presence of T3, whereas addition of 9cis-retinoic acid (9c-RA) resulted in the transactivation of TRE-PAL through RXR beta independently of the presence of TR beta-CN. In conclusion, the time dependent variable THR phenotype of patient CN might be influenced by the differential expression of RXRs and the T3 and 9c-RA hormonal status.
Exp Clin Endocrinol Diabetes 1996
PMID:Periodically hyperthyroid phenotype in thyroid hormone resistance is associated with mutation D322N in the thyroid hormone receptor beta gene: transcriptional properties of the mutant and the role of retinoid X receptor. 898 Oct 16

Protein kinase C (PKC) is known to be activated in experimental model systems by elevated glucose and may play an important role in the pathogenesis of diabetic complications. Since there is no information about its role in humans in vivo we investigated the activation of PKC in human thrombocytes during infusion of glucose and insulin in normal controls and in 19 NIDDM patients by determining membrane and cytosol levels of PKC beta 2 using immune blots. In the 27 subjects investigated (8 controls, 19 NIDDM) membrane-associated levels of PKC beta 2 increased significantly after 60 and 150 min (p < 0.005). In controls an increase of membrane and of cytosolic PKC beta 2 occurred upon elevation of glucose by 5.5 mmol/L or more and the membrane association persisted for at least 60 min. In NIDDM glucose was elevated by 7.5-10 mmol/L during infusions. Increases of both membrane and cytosolic PKC beta 2 (< 20%-300%) occurred in 10 NIDDM patients suggesting that both, translocation and increased synthesis of PKC beta 2 were stimulated by glucose. Nine other patients showed no alteration (i.e. < 20%) of PKC beta 2. The 2 groups were similar regarding parameters of diabetes control, baseline glucose and glucose elevation during the test. However, the PKC beta 2 responsive group had lower levels of serum triglycerides (1.39 +/- 0.19 vs. 2.32 +/- 0.34 g/L; p = 0.038). To assess whether absolute levels of PKC were altered in human diabetes, platelet levels of PKC alpha, beta 1 and beta 2 were determined in 22 controls and 25 NIDDM subjects with poorly controlled diabetes (HbA1c = 9.8 +/- 0.36%). Cytosolic levels of PKC alpha were significantly decreased by 27% compared to controls in NIDDM but there was no change of PKC beta 1 or PKC beta 2. We conclude that 1. acute elevation of glucose by 5.5 mmol/L or more can activate PKC beta 2 translocation in controls and NIDDM patients in vivo irrespective of parameters of metabolic control. 2. NIDDM patients differ in their PKC beta 2-responses to glucose and 3. poor metabolic control leads to moderate downregulation of PKC alpha suggesting continued activation.
Exp Clin Endocrinol Diabetes 1996
PMID:Activation of human platelet protein kinase C-beta 2 in vivo in response to acute hyperglycemia. 902 43

In view of the major alterations which take place at the level of the extracellular matrix of the glomerular wall in diabetes mellitus and the key roles played by beta 1 integrins in cell-to-matrix interactions, it is imperative to understand the role played by integrins in the development of diabetic glomerulosclerosis. In the present study, we revealed by immunocytochemistry the ultrastructural distribution of the alpha 3 beta 1 at the level of the plasma membrane of the different renal glomerular cells from short- and long-term diabetic rats. For the endothelial cells, the labelling present on both the luminal and abluminal plasma membranes was low. For the podocyte epithelial cells, the labelling was present on both the luminal and basal plasma membranes, the former being concentrated at points of contact between podocyte foot processes. The labelling on the basal plasma membrane was more significant and similar in domains facing either the glomerular basement membrane or the mesangial matrix. The plasma membrane of mesangial cells also exhibited alpha 3 beta 1. The labelling was recorded under diabetic conditions, at the same sites, with similar intensities, alongside that of the basal plasma membrane of podocytes facing the glomerular basement membrane, the density of which decreased significantly. This decrease in labelling was similar in renal tissues from short- and long-term diabetic animals. These results demonstrate that alpha 3 beta 1 present at the podocyte basal plasma membrane facing the glomerular basement membrane, which undergoes important alterations in diabetes, could be involved in the major dysfunctions of the glomerular wall characteristic of diabetic glomerulosclerosis. Since the changes in integrin were found to occur as early as after 1 month of hyperglycaemia, when morphological alterations of the glomerular basement membrane are not yet established, we propose that they constitute an early event which precedes the onset of diabetic nephropathy.
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PMID:Alterations in the expression of the alpha 3 beta 1 integrin in certain membrane domains of the glomerular epithelial cells (podocytes) in diabetes mellitus. 902 13

Hypertension, diabetes mellitus and chronic glomerular diseases reportedly cause in excess of 80% of the incident cases of end-stage renal disease (ESRD) in the U.S. The factors that initiate progressive renal failure in patients with these disorders remain unknown. Several investigators have reported enhanced synthesis and activity of cytokines in the kidneys of patients with renal failure. The ensuing inflammation and fibrosis have been postulated to contribute to the development of progressive renal failure. There is also abundant evidence supporting the contribution of genetic factors in ESRD susceptibility based upon the strong familial clustering of ESRD, particularly in African Americans. Therefore, genetic linkage analysis may be useful to evaluate the role of candidate genes in several cytokine cascades that could contribute to the pathogenesis of chronic renal failure. We tested for genetic linkage between eight cytokine candidate genes and chronic renal failure in a collection of African American sibling pairs concordant for ESRD. Epidermal growth factor (EGF), platelet-derived growth factor (PDGF), transforming growth factor (TGF) beta 1, TGF-beta 2 and TGF-beta 3, and tumor necrosis factor (TNF)-alpha and TNF-beta candidate genes were selected for analysis due to their putative roles in diabetic renal disease and chronic glomerulonephritis. The interleukin-1 receptor antagonist gene (IL1RN) was also genotyped due to its reported association with diabetic nephropathy. Non-parametric (genetic model independent) affected sib pair linkage analysis was used to evaluate evidence for linkage. In order to genotype TGF-beta 3, we identified four closely linked, previously unidentified, highly polymorphic microsatellite loci near the TGF-beta 3 gene. Linkage of ESRD and transforming growth factor beta 2 polymorphisms on human chromosome 1 approached significance for non-diabetic nephropathy (predominantly chronic glomerular disease, hypertensive nephrosclerosis and unknown etiology) (P = 0.08), but showed no linkage to diabetic nephropathy. The other candidate loci did not demonstrate linkage to ESRD in the total population or in the subgroups with diabetic or non-diabetic etiologies of ESRD. The IL1RN gene did not show significant evidence for linkage to ESRD; however, we did confirm an association between allele 2 of IL1RN and ESRD (as reported in diabetic nephropathy). Overall, these results suggest that these growth factor loci do not make major contributions to the pathogenesis of ESRD in African Americans.
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PMID:Genetic linkage analysis of growth factor loci and end-stage renal disease in African Americans. 906 16


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