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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Various stimuli have been used in clinical practice to test islet function, including intravenous glucose, arginine--both at basal glucose levels and with the hyperglycaemic clamp, tolbutamide, glucagon and glucagon-like peptide 1. The subsequent first phase insulin response (also termed acute insulin response or AIR) to intravenous glucose or arginine has been quantified in a variety of ways, from the mean serum insulin measured at multiple times after glucose injection to the mean value above baseline of serum insulin at 2 to 10 min. The purpose of this study was to review the different protocols of AIR calculation and their pitfalls, and to assess the results of AIR in the islet transplantation field. By investigating the first phase of insulin secretion, AIR provides both a qualitative and a quantitative approach to insulin secretion. In islet transplantation, post-glucose AIR (AIRg) may predict graft survival while post-arginine AIR (AIRa) may be better correlated with engrafted beta cell mass, despite these facts need to be confirmed. AIRa also limits intravenous hyperglycaemia glucotoxicity. In conclusion, AIR could help to predict the need for a second or third islet injection in islet transplantation. These specific indications, however, need to be confirmed by future studies and completed by other approaches such as insulin sensitivity studies and in vivo morphological assessment of islet mass.
Diabetes Metab 2006 Sep
PMID:Acute insulin response (AIR): review of protocols and clinical interest in islet transplantation. 1697 56

The current goal in the treatment of diabetes is not only to enhance the glycemic control but also to improve the associated cardiovascular risk factors. Among many of the strategies available, a co-ligand of PPARalpha and gamma in a single molecule which combines the insulin sensitizing potential of PPARgamma and the beneficial lipid modulating properties of PPARalpha agonism, has gained attention in the recent past. Here we report the biochemical mechanism by which a dual PPAR alpha/gamma agonist Ragaglitazar (Raga) achieves this goal. The PPARalpha component of Raga appears to contribute to a significant increase in beta oxidation, ApoA1 secretion and inhibition of TG biosynthesis in HepG2 cells. These effects of Raga at 60 microM were similar to that shown by Fenofibrate (Feno) at 250 microM. The PPARgamma component of Raga showed significant G3PDH activity and TG accumulation with a corresponding increase in aP2 expression in 3T3L1 cells. Significantly reduced levels of IL-6 and TNFalpha were observed in the culture supernatants of Raga treated 3T3L1 cells. Raga resulted in significant insulin dependent glucose uptake in 3T3L1 with a corresponding increase in GLUT4 expression. Further, Raga showed a significant cholesterol efflux with a corresponding increase in ABCA1 protein expression in THP-1 macrophages. In conclusion, Raga activates both PPARalpha and gamma regulated pathway in adipocytes as well as in hepatocytes which together contributes for its insulin sensitizing and lipid lowering activity. In addition the dual activation of PPAR alpha/gamma also shows an athero-protective potential by inducing reverse cholesterol efflux and inhibiting the pro-inflammatory cytokines.
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PMID:Biochemical mechanism of insulin sensitization, lipid modulation and anti-atherogenic potential of PPAR alpha/gamma dual agonist: Ragaglitazar. 1701 68

The nicotinamide adenine dinucleotide (NAD(+))-dependent protein deacetylase SIRT1 has been linked to fatty acid metabolism via suppression of peroxysome proliferator-activated receptor gamma (PPAR-gamma) and to inflammatory processes by deacetylating the transcription factor NF-kappaB. First, modulation of SIRT1 activity affects lipid accumulation in adipocytes, which has an impact on the etiology of a variety of human metabolic diseases such as obesity and insulin-resistant diabetes. Second, activation of SIRT1 suppresses inflammation via regulation of cytokine expression. Using high-throughput screening, the authors identified compounds with SIRT1 activating and inhibiting potential. The biological activity of these SIRT1-modulating compounds was confirmed in cell-based assays using mouse adipocytes, as well as human THP-1 monocytes. SIRT1 activators were found to be potent lipolytic agents, reducing the overall lipid content of fully differentiated NIH L1 adipocytes. In addition, the same compounds have anti-inflammatory properties, as became evident by the reduction of the proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha). In contrast, a SIRT1 inhibitory compound showed a stimulatory activity on the differentiation of adipocytes, a feature often linked to insulin sensitization.
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PMID:SIRT1 modulating compounds from high-throughput screening as anti-inflammatory and insulin-sensitizing agents. 1709 46

Methylglyoxal (MG) is a highly reactive alpha-oxoaldehyde formed endogenously in numerous enzymatic and nonenzymatic reactions. It modifies arginine and lysine residues in proteins forming advanced glycation end-products such as N(delta)-(5-methyl-4-imidazolon-2-yl)-L-ornithine (MG-H1), 2-amino-5-(2-amino-5-hydro-5-methyl-4-imidazolon-1-yl)pentanoic acid (MG-H2), 2-amino-5-(2-amino-4-hydro-4-methyl-5-imidazolon-1-yl)pentanoic acid (MG-H3), argpyrimidine, N(delta)-(4-carboxy-4,6-dimethyl-5,6-dihydroxy-1,4,5,6-tetrahydropyrimidine-2-yl)-L-ornithine (THP), N(epsilon)-(1-carboxyethyl)lysine (CEL), MG-derived lysine dimer (MOLD), and 2-ammonio-6-({2-[4-ammonio-5-oxido-5-oxopently)amino]-4-methyl-4,5-dihydro-1H-imidazol-5-ylidene}amino)hexanoate (MODIC), which have been identified in vivo and are associated with complications of diabetes and some neurodegenerative diseases. In foodstuffs and beverages, MG is formed during processing, cooking, and prolonged storage. Fasting and metabolic disorders and/or defects in MG detoxification processes cause accumulation of this reactive dicarbonyl in vivo. In addition, the intake of low doses of MG over a prolonged period of time can cause degenerative changes in different tissues, and can also exert anticancer activity. MG in biological samples can be quantified by HPLC or GC methods with preliminary derivatization into more stable chromophores and/or fluorophores, or derivatives suitable for determination by MS by use of diamino derivatives of benzene and naphthalene, 6-hydroxy-2,4,5-triaminopyrimidine, cysteamine, and o-(2,3,4,5,6-pentafluorobenzyl) hydroxylamine. The methods include three basic steps: deproteinization, incubation with derivatization agent, and chromatographic analysis with or without preliminary extraction of the formed products.
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PMID:Methylglyoxal in food and living organisms. 1710 72

Peroxisome Proliferator-Activate Receptors (PPARs) are transcription factors belonging to the nuclear receptor superfamily. The three PPARs (alpha, beta/delta, and gamma) are distributed differently in the different organs. PPARalpha is most common in the liver, but also found in kidney, gut, skeletal muscle and adipose tissue, while PPARbeta/delta, is fairly ubiquitous; it may be found in body tissues and brain (for myelination process and lipid metabolism in the brain). PPARgamma has 3 isoforms, such as PPARgamma 1, PPARgamma 2, and PPARgamma 3. The syndrome-X was firstly coined by Reaven in 1988 and then to be provided in 1999 by the name : the metabolic syndrome-X. This metabolic syndrome represents a "Cluster" of metabolic disorders and cardiovascular risk factors which has been collected and summarized by the author and such a cluster includes: insulin resistance/hyperinsulinemia, central obesity, glucose intolerance/DM, atherogenic dyslipidemia (increase TG, decrease HDL-cholesterol, increase Apo-B, increase small dense LDL), hypertension, prothrombotic state (increase PAI-1, increase F-VII, increase fibrinogen, increase vWF, increase adhesion molecules), endothelial dysfunction, hyperuricemia, and increased hsC-RP and cytokines. The metabolic syndrome-X may lead to the development of T2DM and coronary heart disease (CHD); insulin resistance plays pivotal roles in the progression of such a syndrome and cardiovascular diseases. Improvement of Insulin Resistance, therefore, is most likely to reduce the high cardiovascular event rate in T2DM. It has been generally accepted that Insulin Resistance (detected by HOMA-R) and Acute Insulin Response = AIR (by HOMA-B) are both usually present in T2DM. The Thiazolidinedions (TZDs) are Insulin Sensitizers (e.g Rosiglitazone = ROS, Pioglitazone = PIO) introduced into clinical practice in 1997; clinical evidence data showed that TZDs improved both HOMA-R, and HOMA-B. PPARgamma can be activated by TZDs and it appears to be fundamental to the pathophysiology of diabetes mellitus i.e increase GLUT-4, increase glucokinase, decrease PEPCK, increase GLUT-4, and decreases production by fat cell of several mediators that may cause insulin resistance, such as TNFalpha and resistin. PPARgamma also mediates increased production of Adiponectin and the insulin signaling intermediate PI3K, and both actions lead to increase insulin sensitivity. A "dual PPARgamma-PPARalpha agonists" (e.g PIO, but ROS poorly activate PPARalpha) might lower glucose and modulate lipids. Thus, PIO, as a stronger "dual PPARgamma-PPARalpha agonists", shows an important therapeutic pathway in diabetes mellitus and cardiovascular diseases, even in metabolic syndrome. Current evidence suggests a close relationship between activation of PPARgamma and restoration of insulin sensitivity by reductions in TNFalpha and FFAs, and the enhancement of insulin stimulation of PI3-K Pathway and also increase adiponectin & decrease resistin.
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PMID:New approach in the treatment of T2DM and metabolic syndrome (focus on a novel insulin sensitizer). 1711 68

Recently, the transcription factor 7-like 2 (TCF7L2) gene on chromosome 10q25.2 has been linked with type 2 diabetes among Caucasians, with disease associations noted for single nucleotide polymorphisms (SNPs) rs12255372 and rs7903146. To investigate mechanisms by which TCF7L2 could contribute to type 2 diabetes, we examined the effects of these SNPs on clinical and metabolic traits affecting glucose homeostasis in 256 nondiabetic female subjects (138 European Americans and 118 African Americans) aged 7-57 years. Outcomes included BMI, percent body fat, insulin sensitivity (S(i)), acute insulin response to glucose (AIR(g)), and the disposition index (DI). Homozygosity for the minor allele (TT) of SNP rs12255372 occurred in 9% of individuals and was associated with a 31% reduction in DI values in a recessive model. The at-risk allele TT was also associated with lower AIR(g) adjusted for S(i) in both ethnic groups, whereas rs12255372 genotype was not associated with measures of adiposity or with S(i). The T allele of rs12255372 was also associated with increased prevalence of impaired fasting glucose. Genotypes at rs7903146 were not associated with any metabolic trait. Lower S(i) and higher AIR(g) observed in the African-American compared with the European-American subgroup could not be explained by the TCF7L2 genotype. Our data suggest that the TCF7L2 gene is an important factor regulating insulin secretion, which could explain its association with type 2 diabetes.
Diabetes 2006 Dec
PMID:Polymorphism in the transcription factor 7-like 2 (TCF7L2) gene is associated with reduced insulin secretion in nondiabetic women. 1713 May 14

Atherosclerosis, an inflammatory disease, is closely associated with hyperglycemia, major sign of diabetes mellitus. Caveolae are vesicular invaginations of the plasma membrane that mediate the intracellular transport of lipids such as cholesterol. We evaluated the relationship between the expression of caveolin-1 and the number of caveolae in macrophages under conditions of high glucose concentration. Increased superoxide production, induction of inducible nitric oxide synthase (iNOS), and decreased caveolin-1 were observed in a concentration-dependent manner in THP-1 derived macrophages with high glucose concentrations. Mannitol, used as an osmotic control, showed no effects. Furthermore, co-localization of the NADPH oxidase component, p47(phox), and caveolin was confirmed by confocal microscopy. An atomic force microscopy (AFM) study showed that high glucose concentrations reduced the number and size of the caveolae. The percentage of cells with fragmented DNA was increased in cells grown in hyperglycemic media. Taken together, high glucose concentrations suppress the levels of caveolin-1 expression and reduce the number of caveolae. This might be due to the actions of superoxide via the activation of NADPH oxidase by translocation of its component and uncoupling of induced iNOS in macrophages. Furthermore, the apoptosis of macrophages might occur with high glucose concentrations, leading to the spreading of lipids from macrophages into intracellular spaces in the vessel wall.
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PMID:High glucose downregulates the number of caveolae in monocytes through oxidative stress from NADPH oxidase: implications for atherosclerosis. 1724 Jan 21

Ligation of advanced glycation end products (AGEs) with their receptor (RAGE) plays an important role in the development of various diabetes complications, including atherosclerosis. Monocyte activation, adhesion, and migration are key events in the pathogenesis of atherosclerosis. Previous studies showed that AGEs and S100b, a specific RAGE ligand, could augment monocyte inflammatory responses via RAGE. In this study, we examined whether LR-90, a compound belonging to a new class of AGE inhibitor, could inhibit inflammatory responses in human monocytes. Human THP-1 cells were pretreated with LR-90 and then stimulated with S100b. LR-90 significantly inhibited S100b-induced expression of RAGE and other proinflammatory genes including monocyte chemoattractant protein-1, interferon-gamma-inducible protein-10, and cyclooxygenase-2 in a dose-dependent manner. These inhibitory effects may be exerted via inhibition of nuclear factor-kappaB (NF-kappaB) activation, as LR-90 suppressed both S100b-and tumor necrosis factor-alpha-induced IkappaB-alpha degradation as well as NF-kappaB promoter transcriptional activity. LR-90 also prevented oxidative stress in activated monocytes, as demonstrated by its inhibitory effects on S100b-induced expression of NADPH oxidase and intracellular superoxide production. In addition, LR-90 blocked S100b-induced monocyte adhesion to human umbilical vein endothelial cell. These new data show that, in addition to its AGE inhibitory effects, LR-90 has novel anti-inflammatory properties and might therefore have additional protective effects against diabetic vascular complications.
Diabetes 2007 Mar
PMID:Anti-inflammatory effects of the advanced glycation end product inhibitor LR-90 in human monocytes. 1732 32

Aberrant histone lysine methylation patterns that change chromatin structure can promote dysregulated gene transcription and disease progression. Diabetic conditions such as high glucose (HG) are known to alter key pathologic pathways. However, their impact on cellular histone lysine methylation is unknown. We hypothesized that chronic HG can induce aberrant changes in histone H3 lysine 4 and lysine 9 dimethylation (H3K4me2 and H3K9me2) within target cells. Chromatin immunoprecipitation linked to microarrays (ChIP-on-chip) is currently a widely used approach for acquiring genome-wide information on histone modifications. We adopted this approach to profile and compare the variations in H3K4me2 and H3K9me2 in human gene coding and CpG island regions in THP-1 monocytes cultured in normal glucose and HG. Subsequently, we identified key relevant candidate genes displaying differential changes in H3K4me2 and H3K9me2 in HG versus normal glucose and also validated them with follow-up conventional ChIPs. Relevance to human diabetes was demonstrated by noting that H3K9me2 at the coding and promoter regions of two candidate genes was significantly greater in blood monocytes of diabetic patients relative to normal controls similar to the THP-1 data. In addition, regular mRNA profiling with cDNA arrays revealed correlations between mRNA and H3K9me2 levels. These novel results show histone methylation variations, for the first time, under diabetic conditions at a genome-wide level.
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PMID:Genome-wide analysis of histone lysine methylation variations caused by diabetic conditions in human monocytes. 1733 27

The diabetes epidemic and lack of adequate glycemic control in patients with diabetes emphasize the need for alternative diabetes treatment strategies. Although many new compounds have been developed, insulin remains the most potent agent for controlling glycemia. Inhaled insulin systems have been developed to alleviate the fear of insulin injections and to improve the convenience of insulin administration. The AIR Inhaled Insulin System being developed by Eli Lilly (Indianapolis, IN) and Alkermes (Cambridge, MA) uses AIR particle technology to deliver dry powder insulin to the deep lung. Pharmacokinetic and glucodynamic data in Phase 1 clinical trials have demonstrated that AIR Insulin is rapidly absorbed with prolonged insulin exposure and action compared to insulin lispro. AIR Insulin has also been shown to have dose equivalence and dose reproducibility across a range of doses, and it has been shown that three inhalations of the 2 U-equivalent dose can be interchanged with one 6 U-equivalent dose. A Phase 2 study demonstrated preference for AIR Insulin over subcutaneous injectable insulins, and a recent study reported that the system is easy to teach and use. Several Phase 3 studies are currently underway to further investigate the safety and efficacy and to evaluate the system's intention to meet provider and patient expectations.
Diabetes Technol Ther 2007 Jun
PMID:The AIR inhaled insulin system: system components and pharmacokinetic/glucodynamic data. 1756 3


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