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

Thiazolidinediones address underlying causes of type 2 diabetes, although their mechanism of action is not clearly understood. The compounds are thought to function as direct activators of the nuclear receptor PPARgamma (peroxisome proliferator-activated receptor-gamma), although pioglitazone, the weaker agonist of the two thiazolidinediones now in clinical use, seems to have more useful effects on circulating lipids. We have used tritiated pioglitazone and a photoaffinity cross-linker to identify a novel binding site in mitochondria. A saturable binding site for [3H]pioglitazone was solubilized from the membranes with CHAPS and migrated as a large complex by size exclusion chromatography. The binding correlated with a <17-kDa protein (m17), marked by a photoaffinity cross-linker, in both subcellular location and selectivity of competition by analogs. The protein was isolated and identified by mass spectrometry analysis and NH2-terminal sequencing. Three synthetic peptides with potential antigenic properties were synthesized from the predicted nontransmembrane sequence to generate antibodies in rabbits. Western blots show that this protein, which we have termed "mitoNEET," is located in the mitochondrial fraction of rodent brain, liver, and skeletal muscle, showing the identical subcellular location and migration on SDS-PAGE as the protein cross-linked specifically by the thiazolidinedione photoprobe. The protein exists in low levels in preadipocytes, and expression increases exponentially in differentiated adipocytes. The synthetic protein bound to solid phase associated with a complex of solubilized mitochondrial proteins, including the trifunctional beta-oxidation protein. It is possible that thiazolidinedione modification of the function of the mitochondrial target may contribute to lipid lowering and/or antidiabetic actions.
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PMID:Identification of a novel mitochondrial protein ("mitoNEET") cross-linked specifically by a thiazolidinedione photoprobe. 1457 Jul 2

Resistin, an adipocyte secreted cysteine rich hormone has been implicated as molecular link between obesity and type 2 diabetes in a murine model. Although, at the protein level mouse and human resistin show remarkable similarities with respect to conserved cysteine residues, the physiological role of human resistin is not yet clear. In the present study we describe the purification and refolding of human recombinant resistin using two different refolding processes. Gel filtration analysis of protein refolded by both the methods revealed that human recombinant resistin, like mouse resistin, has a tendency to form dimers. Interestingly, dimerization of resistin appears to be mediated by both covalent (disulfide bond mediated) and non-covalent interactions as seen on reducing and non-reducing SDS-PAGE. Circular dichroism spectral analysis revealed that human resistin peptide backbone is a mixture of alpha-helical and beta-sheet conformation with significant amounts of unordered structure, similar to the mouse resistin. It is likely that the first cysteine (Cyst22) of human resistin, which is equivalent to mouse Cyst26, may be involved in stabilizing the dimers through covalent interaction.
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PMID:Dimerization of human recombinant resistin involves covalent and noncovalent interactions. 1469 40

Several studies have demonstrated an association between low birth weight and impaired insulin sensitivity or even type 2 diabetes mellitus (DM2) in later life. Growth hormone (GH) is known to increase fasting and postprandial insulin levels. For that reason concern has been expressed regarding possible detrimental effects of GH therapy in children born SGA. In a Dutch trial the possible side effects of GH therapy on carbohydrate metabolism were assessed in short children born SGA after 6 years and at 6 months after discontinuation of GH therapy. This study included 79 prepubertal short children born SGA, participating in a multicenter double-blind, randomized, dose-response GH trial. Inclusion criteria were: 1) birth length SDS below -1.88, 2) age 3-11 years in boys and 3-9 years in girls, 3) height SDS < -1.88, 4) no spontaneous catch-up growth, and 5) an uncomplicated neonatal period. Mean (SD) value for age was 7.3 (2.1) years, birth length SDS -3.6, height SDS -3.0 (0.7) and BMI SDS -1.2 (1.3). All children were randomly assigned to either group A (n = 41) using 1 mg GH/m2/day or group B (n = 38) using 2 mg/m2/ d/ay (approximately 0.1 or 0.2 IU/kg/d, respectively). Standard oral glucose tolerance tests (OGTTs) were performed before and during 6 years of GH therapy and 6 months after discontinuation of GH therapy. Before GH therapy 8% of the children had impaired glucose tolerance (IGT) according to criteria of the WHO. After 6 years of GH therapy, IGT was found in 4% and after stopping GH in 10%. Mean fasting glucose increased significantly with 0.5 mMol/l after 1 year of GH therapy, without a further increase thereafter. GH therapy induced considerably higher fasting and glucose-stimulated insulin levels. None of the observed changes were different between the GH dosage groups. Children who remained prepubertal had similar glucose and insulin levels compared to children who entered puberty. HbA1c levels were always in the normal range and none of the children developed diabetes mellitus. After discontinuation of GH therapy the mean serum glucose levels remained normal and the mean serum insulin levels decreased significantly, to normal age reference values. Before the start of GH the mean systolic blood pressure was significantly higher compared to age-matched peers, whereas during GH therapy a significant decline in mean systolic blood pressure occurred, which remained similar after discontinuation of GH treatment. In conclusion, continuous, long-term GH therapy in short children born SGA has no adverse effects on glucose levels, even with GH dosages up to 2 mg/m2/day. However, as has been reported in other patient groups, GH induced higher fasting and glucose-stimulated insulin levels, indicating insulin resistance. After discontinuation of GH, serum insulin levels declined to normal age-matched reference levels. Since impaired insulin sensitivity and DM2 have been demonstrated in relatively young patients born SGA, long-term follow-up of children born SGA is advised, also after discontinuation of GH therapy.
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PMID:Small for gestational age (SGA): endocrine and metabolic consequences and effects of growth hormone treatment. 1513 8

Many studies have shown that diabetes mellitus is associated with increased whole and blood viscosity and decreased erythrocyte deformability. It has been suggested that these abnormalities in blood rheology may play a causative role in the pathogenesis of diabetic vascular complications. However, less is known about the content and quality of membrane proteins which may contribute to abnormalities in membrane dynamic and decreased erythrocyte deformability. In the present study we analysed various rheological parameters (blood and plasma viscosity, erythrocyte deformability, haemotological parameters), in cats with non-insulin dependent diabetes mellitus (NIDDM). We also investigated alterations in erythrocyte membrane protein content by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). We found that erythrocyte rigidity and plasma and whole blood viscosities were significantly higher in cats with NIDDM compared to controls. SDS-PAGE revealed that the band 5 corresponding to actin was weaker while band 4.5 corresponding to integral membrane proteins (glycophorin A, B and C) had disappeared. Also, band 4.9, which is composed of dematin (a protein with actin-bundling capacity) was lost. We suggest that the observed abnormalities in membrane proteins may play a role in reduced erythrocyte deformability associated with diabetes mellitus.
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PMID:Alterations in rheological properties and erythrocyte membrane proteins in cats with diabetes mellitus. 1615 Dec 55

Abnormal patterns of fetal and infant growth have been associated with an increased risk of cardiovascular disease in adulthood. Catch-up growth during the first year of life has been associated with a higher prevalence of type 2 diabetes mellitus, whereas a lack of catch-up growth tracks with a risk of hypertension. The role of genetic factors influencing both growth and blood pressure have not been explored. We genotyped cord blood samples from 530 singleton, Caucasian, uncomplicated pregnancies, drawn from a larger cohort of 1650 pregnancies, and related polymorphism in the angiotensin converting enzyme (ACE) gene (alleles insertion (I) or deletion (D)) with measures of size at birth and at age of 1 year. ACE genotype did not significantly influence size at birth, although there was a greater proportion of individuals with the D/D genotype born with a birth weight less than the 10th centile (P=0.004). The ACE I/I genotype was significantly associated with higher weight (p=0.001), body mass index (p=0.001) and mid arm circumference (p=0.001) at 1 year of age compared to the ACE D/D and I/D genotypes. Individuals with the I/I genotype displayed catch-up (gain from birth size of >or=0.6 Standard Deviation Score) in weight (p=0.04), body mass index (p=0.03) and mid arm circumference (p=0.03) compared to the D/D group, the majority of which showed no change or catch-down. The I/D genotype was distributed equally across the catch up/catch down/no change categories. The effect was more marked in males, but ACE genotype and sex of the infant contributed independently to mid arm circumference measurements and there was no interaction between the two. There was no effect of maternal or paternal ACE genotype on birth size. In a multiple linear regression model ACE genotype, socioeconomic status and sex of the infant explained 10.9% of the variance in body mass index SDS at 1 year of age. We conclude that the ACE I/I genotype is associated with a higher weight and body mass index SDS at 1 year of age, along with catch-up in terms of these measures from birth to 1 year. The D/D genotype is associated with a greater proportion of babies, born at term, that at small for gestational age. These results suggest that due consideration should be given to the underlying genotype of an individual when evaluating the association of early human growth with the development of risk factors for cardiovascular disease. The observation of independent effects of genotype, sex of the individual and socioeconomic status on postnatal growth suggests the need to develop methodologies for the integration of genetic and environmental factors in causality modelling.
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PMID:Polymorphisms in the angiotensin converting enzyme gene and growth in the first year of life. 1703 88

In Prader-Willi syndrome (PWS) growth hormone therapy (GHT) improves height, body composition, agility and muscular strength. In such patients it is necessary to consider the potential diabetogenic effect of GHT, since they tend to develop type 2 diabetes, particularly after the pubertal age. The aim of our study was to investigate the effects of GHT on glucose and insulin homeostasis in PWS children. An oral glucose tolerance test (OGTT) was performed in 24 prepubertal PWS children (15 male, 9 female, age: 5.8 +/- 2.8 years), 16 were obese (group A) and 8 had normal weight (group B), before and after 2.7 +/- 1.3 years GHT (0.22 +/- 0.03 mg/kg/week) and, only at baseline, in 35 prepubertal children with simple obesity (19 male, 16 female) (group C). Fasting glucose and insulin, glucose tolerance, insulin sensitivity index (ISI), homeostasis model assessment of insulin resistance (HOMA-IR), quick insulin check index (QUICKI), area under the curves (AUC) of glucose and insulin were estimated. At the start of GHT, all PWS children were normoglycaemic and normotolerant but two developed impaired glucose tolerance after 2.2 and 1.9 years of therapy, respectively. At baseline, group A showed lower fasting insulin levels, HOMA-IR and AUC of insulin, higher ISI, QUICKI and AUC of glucose than group C. Comparing groups A and B, AUC of insulin was higher and ISI lower in group A. During GHT, a significant increase of fasting insulin and glucose, a worsening of insulin resistance (HOMA-IR) and insulin sensitivity (QUICKI) was found only in group A while ISI did not change. The AUC of glucose decreased in both groups instead AUC of insulin did not change. BMI-SDS decreased in group A and increased in group B. The increased insulin resistance and decreased insulin sensitivity in obese PWS patients, as well as the occurrence of impaired glucose tolerance during GHT, suggest that a close monitoring of glucose and insulin homeostasis is mandatory, especially in treated obese PWS children.
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PMID:Effects of growth hormone therapy on glucose metabolism and insulin sensitivity indices in prepubertal children with Prader-Willi syndrome. 1733 2

Amylin is an endocrine hormone that regulates metabolism. In patients afflicted with type 2 diabetes, amylin is found in fibrillar deposits in the pancreas. Membranes are thought to facilitate the aggregation of amylin, and membrane-bound oligomers may be responsible for the islet beta-cell toxicity that develops during type 2 diabetes. To better understand the structural basis for the interactions between amylin and membranes, we determined the NMR structure of human amylin bound to SDS micelles. The first four residues in the structure are constrained to form a hairpin loop by the single disulfide bond in amylin. The last nine residues near the C terminus are unfolded. The core of the structure is an alpha-helix that runs from about residues 5-28. A distortion or kink near residues 18-22 introduces pliancy in the angle between the N- and C-terminal segments of the alpha-helix. Mobility, as determined by (15)N relaxation experiments, increases from the N to the C terminus and is strongly correlated with the accessibility of the polypeptide to spin probes in the solution phase. The spin probe data suggest that the segment between residues 5 and 17 is positioned within the hydrophobic lipid environment, whereas the amyloidogenic segment between residues 20 and 29 is at the interface between the lipid and solvent. This orientation may direct the aggregation of amylin on membranes, whereas coupling between the two segments may mediate the transition to a toxic structure.
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PMID:Dynamic alpha-helix structure of micelle-bound human amylin. 1924 49

Insulinoma NIT-1, an insulin-secreting mouse cell line, secretes vesicles in response to glucose or calcium. These vesicles, like exosomes, are relatively homogeneous (30-100 nm). We analyzed their protein profiles employing one-dimensional SDS gel electrophoresis combined with nanoLC-ESI-q-TOF tandem mass spectrometry, and searched for post-translational modifications (PTMs) using MOD(i) algorithm. We identified 270 proteins which matched at least two peptides reproducibly in duplicate runs. These proteins included metabolic proteins, endocytosis/exocytosis related proteins, chaperones, cytoskeletal proteins, membrane transporters/ion channels, signaling molecules, and nucleic acid binding proteins. Over 200 of these are newly identified proteins for the first time in secreted vesicles, and included RNA- and translation-related proteins, ubiquitin- and protein-degradation related proteins and post-translationally modified proteins. The rest of the proteins identified in this study were similar to those reported by others to be present in exosomes of various origins. The present study demonstrates that vesicles secreted from insulinoma NIT-1 cells have some properties, common to exosomes from lymphocytes and cancer cells, and some differing from those of other types of exosomes. We believe that the modified and newly identified proteins we identified in secreted vesicles from insulinoma NIT-1 cells have the potential to provide insights into mechanisms of biogenesis and function of secreted vesicles and may help explain the impairment of insulin secretion in islets from type-2 diabetes.
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PMID:Characterization of vesicles secreted from insulinoma NIT-1 cells. 1935 Nov 51

Connective Tissue Growth Factor (CTGF) expression has been identified in a wide variety of fibrotic disorders; however, the expression of CTGF in carpal tunnel syndrome (CTS) has not yet been described in the literature. Both inflammatory and fibrotic etiologies have been implicated in the pathogenesis of CTS, with current evidence favoring an emphasis on a non-inflammatory fibrosis pathophysiological picture. Our objective was to identify whether CTGF is expressed in the tenosynovium of patients with CTS. Tenosynovial tissue was isolated from human subjects undergoing surgical decompression of the carpal tunnel (carpal tunnel release or CTR) for treatment of CTS following various durations of failed conservative management. Samples tested included patients with "idiopathic" CTS alone or CTS in the presence of associated co-orbidities including Type II Diabetes Mellitus (DM), Rheumatoid Arthritis (RA), and Systemic Lupus Erythematosus (SLE). SDS-PAGE protein analysis of tenosynovial tissue homogenate was performed to assess for differences in overall protein expression amongst all samples. Our findings demonstrate the presence varying levels of CTGF in tenosynovial samples from patients with CTS. Additionally, tenosynovial samples from patients with certain associated comorbidities - specifically RA and SLE - exhibit significant upregulation of CTGF levels relative to the levels observed patients with "idiopathic" CTS. These findings indicate that there is likely to be a role for CTGF in the pathogenesis of CTS.
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PMID:Connective tissue growth factor (ctgf) expression in the tenosynovium of patients with carpal tunnel syndrome - biomed 2009. 1936 35

Epidemiological studies have shown a strong association between type 2 diabetes mellitus and cardiovascular diseases, and hypofibrinolysis may contribute to this phenomenon. The aim of this study was to determine the effect of hyperglycaemia on thrombin-activatable fibrinolysis inhibitor (TAFI). Hyperglycaemia was mimicked in vitro by incubation of TAFI with glyceraldehyde and in vivo by hyperglycaemic clamping of healthy volunteers. The effects of long-term hyperglycaemia in vivo on TAFI were investigated by comparing TAFI from poorly regulated and tightly regulated patients with type 2 diabetes. In vitro glycated TAFI showed an altered migration pattern on SDS-PAGE due to aggregation. Glycated TAFI showed decreased activity after activation by thrombin-thrombomodulin in a glyceraldehyde-dose-dependent manner and a reduced anti-fibrinolytic potential. In vivo, no differences in TAFI parameters were found after hyperglycaemic clamping of healthy volunteers and between tightly and poorly regulated patients with type 2 diabetes. Moreover, TAFI purified from poorly regulated and tightly regulated patients with type 2 diabetes migrated similarly on SDS-PAGE, indicating little or no glycation of the protein. Despite the deleterious effects of glycation of TAFI in vitro on its function, TAFI was neither affected by hyperglycaemic clamping, nor by long-term hyperglycaemia in patients with type 2 diabetes. This is in contrast to fibrinolytic factors as plasminogen-activator inhibitor I and tissue-type plasminogen activator, which are affected. We therefore hypothesise that a normally functioning TAFI under hyperglycaemic conditions may tip the haemostatic balance towards hypofibrinolysis, which may contribute to the development of cardiovascular diseases in type 2 diabetic patients.
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PMID:The effects of hyperglycaemia on thrombin-activatable fibrinolysis inhibitor. 1971 65


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