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Biomedical subjects

F Machicao

Publications and source records attributed to F Machicao.

At least 19 recordsLinked to original sources
PubMed2006

Paraadrenal Castleman disease presenting with adrenal hyperandrogenism.

Castleman disease, or angiofollicular lymph node hyperplasia, is a rare benign lymphoproliferative disorder. We report an uncommon case of retroperitoneal Castleman syndrome associated with adrenal hyperandrogenism and with interleukin-6 as the possible link in the pathophysiology of both disturbances. Four years after surgical resection of the paraadrenal mass, the patient is free of signs of recurrence of Castleman disease and adrenal hyperandrogenism.

Adrenal Glands↗
PubMed2005

Polymorphisms in the gene encoding adiponectin receptor 1 are associated with insulin resistance and high liver fat.

AIMS/HYPOTHESIS: The adipokine adiponectin has insulin-sensitising, anti-atherogenic and anti-inflammatory properties. Recently, the genes for mouse and human adiponectin receptor-1 (ADIPOR1) and -2 (ADIPOR2) have been cloned. The aim of this study was to investigate whether genetic variants of the genes encoding ADIPOR1 and ADIPOR2 play a role in human metabolism. MATERIALS AND METHODS: We screened ADIPOR1 and ADIPOR2 for polymorphisms and determined their association with glucose metabolism, lipid metabolism, an atherogenic lipid profile and inflammatory markers in 502 non-diabetic subjects. A subgroup participated in a longitudinal study; these subjects received diet counselling and increased their physical activity. RESULTS: We identified six variants of ADIPOR1 and seven variants of ADIPOR2. A single-nucleotide polymorphism (SNP) in the putative promoter region 8503 bp upstream of the translational start codon (-8503 G/A) of ADIPOR1 (frequency of allele A=0.31) was in almost complete linkage disequilibrium with another SNP (-1927 T/C) in intron 1. Subjects carrying the -8503 A and -1927 C alleles had lower insulin sensitivity, as estimated from a 75 g OGTT (p=0.04) and determined during a euglycaemic clamp (n=295, p=0.04); they also had higher HbA(1)c levels (p=0.02) and, although the difference was not statistically significant, higher liver fat (n=85, determined by proton magnetic resonance spectroscopy, p=0.056) (all p values are adjusted for age, sex and percentage of body fat). In the longitudinal study (n=45), the -8503 A and -1927 C alleles were associated with lower insulin sensitivity (p=0.03) and higher liver fat (p=0.02) at follow-up compared with the -8503 G and -1927 T alleles, independently of basal measurements, sex and baseline and follow-up percentage of body fat. CONCLUSIONS/INTERPRETATION: The present findings suggest that the -8503 G/A SNP in the promoter or the -1927 T/C SNP in intron 1 of ADIPOR1 may affect insulin sensitivity and liver fat in humans.

Adipose Tissue↗
PubMed2005

Adiponectin is functionally active in human islets but does not affect insulin secretory function or beta-cell lipoapoptosis.

CONTEXT: The adipokine adiponectin has insulin-sensitizing, antiatherogenic, and antiinflammatory properties. Mouse and human adiponectin receptor-1 and -2 have been cloned, both of which are expressed in various tissues and mediate effects of globular and full-length adiponectin. Whether adiponectin affects insulin secretion and beta-cell apoptosis and whether plasma adiponectin is associated with beta-cell function in humans is under investigation. DESIGN AND METHODS: In human islets from multiorgan donors, we investigated expression of adiponectin receptor-1 and -2. Furthermore, glucose-stimulated insulin secretion was determined by RIA. In addition, we investigated fatty acid-induced beta-cell apoptosis by terminal dUTP nick end labeling and flow-cytometric cell cycle analysis (sub-G1 formation). In humans in vivo, insulin secretory function was measured during hyperglycemic clamps in 65 normal glucose-tolerant subjects. We determined first and second phase of glucose-stimulated, glucagon-like peptide-1-stimulated, and arginine-stimulated insulin secretion. RESULTS: Adiponectin receptor-1 and -2 are expressed in human islets at the mRNA and protein level. Moreover, full-length adiponectin induces phosphorylation of acetyl coenzyme A carboxylase. However, adiponectin did not affect basal or glucose-stimulated insulin secretion or basal or fatty acid-induced beta-cell apoptosis. In vivo, fasting plasma adiponectin concentrations were not associated with glucose-stimulated first- and second-phase insulin secretion or with glucagon-like peptide-1- or arginine-stimulated insulin secretion (all P > 0.42). CONCLUSIONS: These data support a regulatory role of adiponectin in human islets; however, adiponectin does not seem to affect insulin secretion or basal/fatty acid-induced beta-cell apoptosis in humans.

Adiponectin↗
PubMed2005

Fatty acid-induced differential regulation of the genes encoding peroxisome proliferator-activated receptor-gamma coactivator-1alpha and -1beta in human skeletal muscle cells that have been differentiated in vitro.

AIMS/HYPOTHESIS: The transcriptional coactivator peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) enhances metabolically relevant pathways, such as gluconeogenesis, fatty acid oxidation, thermogenesis, oxidative phosphorylation and mitochondrial biogenesis. Since regulation of the expression of the gene encoding PGC-1alpha (PPARGC1A) by nutrients/metabolites has not been assessed in detail, the aim of this study was to determine whether PPARGC1A (and PPARGC1B) expression is modulated by common plasma fatty acids in human skeletal muscle cells. METHODS: Human myotubes that had been differentiated in vitro were treated with 0.5 mmol/l myristate (C14:0), palmitate (C16:0), stearate (C18:0), palmitoleate (C16:1omega7), oleate (C18:1omega9) or linoleate (C18:2omega6). PPARGC1A/B mRNA was quantified by RT-PCR. Mitochondrial activity was determined by formazan formation. RESULTS: Untreated cells expressed 28-fold more PPARGC1B mRNA than PPARGC1A mRNA (13.33+/-2.86 vs 0.47+/-0.08 fg/mug total RNA, n=5). PPARGC1A expression was increased two- to three-fold by all unsaturated fatty acids (UFAs) tested (p<0.05 each, n=5). In contrast, saturated fatty acids (SFAs) did not modulate PPARGC1A expression. Furthermore, the effect of linoleate was not blunted by palmitate. PPARGC1B mRNA expression was not increased by either the UFAs or the SFAs. SFAs reduced PPARGC1B expression (p<0.05 for palmitate and stearate, n=5). Notably, linoleate reversed palmitate's repressive effect on PPARGC1B. Myotube mitochondrial activity was increased by all UFAs (p<0.01 each, n=5), but was impaired by the SFA stearate (p<0.001, n=5). CONCLUSIONS/INTERPRETATION: We report here that fatty acids differentially regulated expression of the genes encoding the PGC-1 isoforms. Since these effects were accompanied by significant changes in mitochondrial activity, we suggest that the fatty acid-induced regulation of expression of these genes plays an important role in muscle oxidative metabolism.

Carrier Proteins↗
PubMed2005

A novel functional polymorphism (-336A/G) in the promoter of the partitioning-defective protein-6alpha gene is associated with increased glucose tolerance and lower concentrations of serum non-esterified fatty acids.

AIMS/HYPOTHESIS: Partitioning-defective protein-6alpha (Par6alpha) has recently been demonstrated to negatively regulate insulin signalling in murine myoblasts. To address whether Par6alpha plays a role in human physiology, the present study investigated whether mutations exist in the Par6alpha gene and whether these mutations, if present, are associated with pre-diabetic phenotypes in non-diabetic subjects. METHODS: The complete gene (part of the promoter [2.1 kb], all exons/introns and the 3' untranslated region) encoding Par6alpha was analysed in 664 non-diabetic subjects. We investigated possible associations between single nucleotide polymorphisms and percentage of body fat, glucose tolerance (as determined by OGTT), serum NEFA concentrations and whole-body insulin sensitivity (estimated during the OGTT, and for a subgroup of 242 subjects determined by the euglycaemic-hyperinsulinaemic clamp). RESULTS: A rare A/G polymorphism was found 336-bp upstream of the translational start codon (allele frequency 0.03). The data for subjects homozygous and heterozygous for -336G (R/G, n=43) were combined and compared with those for subjects homozygous for -336A (A/A, n=621). Subjects with the R/G genotype had lower fasting (4.84+/-0.09 mmol/l, means+/-SEM, p=0.049) and 2-h (5.50+/-0.02 mmol/l, p=0.050) plasma glucose concentrations than subjects with the A/A genotype (5.02+/-0.02 and 5.94+/-0.06 mmol/l, respectively). Subjects with the R/G genotype also had lower fasting (448+/-31 micromol/l, p=0.018) and 2-h serum NEFA concentrations (61+/-7 micromol/l, p=0.015) than subjects with the A/A genotype (529+/-9 and 75+/-2 micromol/l, respectively), adjusted for age, sex and percentage of body fat. There were no differences in adiposity or whole-body insulin sensitivity between the two genotype groups (all p>0.36). A luciferase reporter gene assay revealed that the -336G promoter variant had a significantly lower (-22.8%, p=0.006) transcriptional activity in transfected C2C12 murine myoblasts than the -336A promoter variant. CONCLUSIONS/INTERPRETATION: A novel functional variant in the promoter of the Par6alpha gene is associated with reduced fasting glycaemia, increased glucose tolerance and reduced serum NEFA concentrations.

Adult↗
PubMed2005

Adiponectin receptor gene expression in human skeletal muscle cells is not regulated by fibrates and thiazolidinediones.

BACKGROUND: Thiazolidinediones as PPARgamma agonists and fibrates as PPARalpha agonists improve insulin sensitivity in insulin-responsive tissues. Recent data show an induction of adiponectin receptor 2 (AdipoR2) by PPARalpha and PPARgamma agonists in human macrophages. OBJECTIVE: In this study, we examined the effects of thiazolidinediones and fibrates on the expression of adiponectin receptors in human skeletal muscle cells, an important cell type in the context of insulin resistance. RESULTS AND METHODS: In vitro differentiated human myotubes treated with troglitazone or rosiglitazone (20 h) showed no significant changes in AdipoR1 and AdipoR2 mRNA expression. PPARgamma activation was controlled by determination of PPARgamma mRNA induction. Likewise, differentiated myotubes treated with Wy-14,643 or fenofibrate (20 h) revealed no significant regulation of AdipoR1 and AdipoR2 mRNA. PPARalpha activation was assessed by measuring PDHK4 mRNA expression. CONCLUSION: Induction of AdipoR gene expression in human skeletal muscle cells is not involved in the insulin-sensitizing effects of thiazolidinediones or fibrates.

Adult↗
PubMed2005

Genetic determinants of insulin action in polycystic ovary syndrome.

INTRODUCTION: Insulin resistance is associated with both type 2 diabetes (T2 D) and polycystic ovary syndrome (PCOS). There is an association of T2 D with several polymorphisms in candidate genes related to insulin resistance. However, there is limited information about the association of these polymorphisms with PCOS. METHODS: 57 non-diabetic women with PCOS and a control group of 567 healthy non-diabetic women underwent an oral glucose tolerance test (OGTT). They were genotyped for the polymorphisms Gly972Arg in IRS-1, Gly1057Asp in IRS-2, SNP 43, 44, and 45 in CAPN10, Pro12Ala in PPAR(gamma)2, C-512 T in FOXC2, and T45 G in adiponectin. RESULTS: Women with PCOS had higher 2-h blood glucose levels (6.5 +/- 0.2 vs. 6.0 +/- 0.06 mmol/l, p = 0.03) compared to control women, higher fasting insulin (79 +/- 7 vs. 53 +/- 2 pmol/l, p = 0.02), and a lower insulin sensitivity estimated from the OGTT (12.4 +/- 1.1 vs. 19.1 +/- 0.5 U, p = 0.0001). More homozygous G allele carriers of the T45 G polymorphism in the adiponectin gene were found in women with PCOS compared to controls (13.2 % vs. 2.6 %, p = 0.008). In women with PCOS, G-allele carriers had lower fasting insulin levels than TT carriers (61 +/- 9 vs. 88 +/- 10, p = 0.02) in contrast to controls (p = 0.03 for interaction genotype x PCOS). The other polymorphisms were distributed equally among women with PCOS and controls (all p > 0.5). SUMMARY: We found a higher prevalence of the T45 G polymorphism in the adiponectin gene in women with PCOS compared to controls. This was not associated with a more insulin resistant phenotype in PCOS, however. Other frequent polymorphisms in genes related to insulin resistance and type 2 diabetes showed no association with PCOS.

Adiponectin↗
PubMed2004

Association of the -514C-->T polymorphism in the hepatic lipase gene (LIPC) promoter with elevated fasting insulin concentrations, but not insulin resistance, in non-diabetic Germans.

Hepatic lipase hydrolyses triglycerides and phospholipids in all major classes of lipoproteins. The -514C-->T genetic variation in the hepatic lipase gene promoter was found to be associated with diminished lipase activity, dyslipidemia, and atherosclerosis. We investigated whether this polymorphism associates with hyperinsulinemia and insulin resistance in 535 normal glucose-tolerant Germans. Only in homozygous individuals (22 subjects), the T allele (frequency: 18.1 %) was significantly associated with elevated glucose concentrations after 120 min of oral glucose tolerance test (p = 0.05) and with elevated fasting concentrations of insulin (p = 0.03), triglycerides (p < 0.01), total and HDL-cholesterol (p = 0.02), as determined by multivariate linear regression analysis. In a recessive model (C/C+C/T vs. T/T), T/T was associated with decreased insulin sensitivity index (p = 0.03) as calculated from oral glucose tolerance test data (n = 535), but not with the glucose infusion rate during hyperinsulinemic euglycemic clamp (n = 218). In conclusion, we have provided evidence that, among the metabolic parameters tested, the hepatic lipase -514C-->T gene polymorphism correlates with elevated fasting insulin concentrations in a German population. Since no corresponding difference in insulin sensitivity was seen in the clamp-subgroup, an effect of this polymorphism on insulin clearance has to be considered.

Adult↗
PubMed2004

The Gly482Ser variant in the peroxisome proliferator-activated receptor gamma coactivator-1 is not associated with diabetes-related traits in non-diabetic German and Dutch populations.

The peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1) is involved in regulation of fatty acid oxidation, skeletal muscle fiber type specificity, and gluconeogenesis. The prevalent Gly482Ser variant in PGC-1 was shown to be associated with type 2 diabetes in some but not all studies. Moreover, it is unclear whether it influences prediabetic subphenotypes in non-diabetic populations. We studied the association of this variant with glucose tolerance (oral glucose tolerance test), insulin sensitivity (euglycemic hyperinsulinemic clamp) of glucose disposal and antilipolysis, insulin secretion (hyperglycemic clamp, 10 mM), maximal oxygen consumption (VO(2)max, bicycle ergometry), and intramyocellular lipids (magnetic resonance spectroscopy, tibialis and soleus muscle) in a normal glucose tolerant German cohort (n = 423) and a normal (n = 65) and impaired glucose tolerant (n = 94) cohort from the Netherlands. No statistically significant association with an examined phenotype was detected in any of the study cohorts. Specifically, VO(2)max and the soleus-to-tibialis ratio of intramyocellular lipid contents as a surrogate parameter of fiber type specificity was not different between the genotype groups. We conclude, that the Gly482Ser variant in PGC-1 is not associated with diabetes-related traits or skeletal muscle fiber type composition in a non-diabetic German and Dutch population.

Adult↗
PubMed2003

Induction of adiponectin gene expression in human myotubes by an adiponectin-containing HEK293 cell culture supernatant.

AIMS/HYPOTHESIS: Adiponectin, an adipocytokine known to be down-regulated in obesity-linked disorders, is considered to be a potential key mediator of insulin sensitivity. In this study, we asked whether adiponectin is able to regulate ten selected genes possibly associated with insulin sensitivity in human skeletal muscle cells. METHODS: To this end, we treated in vitro differentiated human myotubes with the culture supernatant of HEK293 cells stably transfected with human recombinant adiponectin and assessed gene expression by RT-PCR. Intracellular adiponectin protein was quantified by radioimmunoassay and visualized by Western blotting. RESULTS: In contrast to the control supernatant, the adiponectin-containing supernatant consistently induced expression of adiponectin mRNA in human myotubes from eight different donors (mean increase: 90-fold over control; n=8, p<0.001). This increase in mRNA was paralleled by a rise in intracellular adiponectin protein (mean increase: 8.3-fold over control; n=4, p<0.05). Expression of the other nine candidate genes was not altered. In human skin fibroblasts and HepG2 cells, the adiponectin-enriched supernatant did not induce relevant amounts of adiponectin mRNA. CONCLUSIONS/INTERPRETATION: In conclusion, we show here that adiponectin gene expression is specifically inducible in skeletal muscle cells.

Adiponectin↗
PubMed2003

Glucose oversupply increases Delta9-desaturase expression and its metabolites in rat skeletal muscle.

AIM/HYPOTHESIS: Previous studies have shown that prolonged glucose infusion causes insulin resistance and triglyceride accumulation in rat skeletal muscle. In this study, we investigated a possible relationship between insulin resistance and the composition of different accumulated lipid fractions in rat skeletal muscle. METHODS: Continuous glucose infusion was carried out in rats for 7 days. Lipids were extracted from skeletal muscle, separated by thin layer chromatography and fatty acid composition of phospholipids, triglycerides, diglycerides, free fatty acids and cholesterol esters fractions was analysed by gas chromatography. Delta9-Desaturase mRNA was measured by real time polymerase chain reaction. The enzyme activity was measured in the microsomal fractions. RESULTS: Prolonged glucose infusion (5 days) increased the relative content of palmitoleic acid (16:1 N7) several-fold (2.3- to 5.8-fold) in four out of five lipid fractions and enhanced oleic acid (18:1 N9) two-fold in three lipid fractions suggesting increased Delta9-desaturase activity while the content of several polyunsaturated fatty acids was reduced. In parallel, Delta9-Desaturase mRNA contents and enzyme activities in skeletal muscle were increased 10-fold, 75-fold, 2.6-fold and 7.7-fold after 2 and 5 days of glucose infusion, respectively. CONCLUSION/INTERPRETATION: Our results suggest that long-term glucose oversupply induces a rapid increase in Delta9-desaturase expression and enzyme activity in skeletal muscle which leads to fast and specific changes in fatty acid metabolism possibly contributing to the insulin resistance in this animal model.

Animals↗
PubMed2003

Insulin-like effect of low-dose leptin on glucose transport in Langendorff rat hearts.

BACKGROUND: In a murine myotube cell line (C 2 C 12 myotubes), leptin at low physiological concentrations (1 ng/ml) has been shown to stimulate glucose transport and glycogen synthesis. The aim of the present study was to test whether an analogous leptin effect on glucose transport is detectable in the heart. METHODS AND RESULTS: We used the isolated Langendorff rat heart preparation with hemodynamic function control. Using polymerase chain reaction (RT-PCR), a 346- and 375-base fragment indicative for the short and long leptin receptor isoform was detected in the rat heart. Glucose transport rates were calculated using equimolar double tracer perfusion with the non-metabolizable glucose analog 3-O-methylglucose (3-O-MG) and the non-transportable tracer mannitol and two-compartimental modeling. 3-O-MG uptake at a perfusate glucose concentration of 11 mM was measured over 15 minutes in control hearts, hearts perfused with insulin (10 mU/ml), leptin (1 ng/ml) or insulin (10 mU/ml) plus leptin (1 ng/ml; n = 8 in each group). The basal 3-O-MG transport rate of 0,7351 +/- 0,051 micro mol/min/g wet weight was increased 4.18 fold with insulin, 2.69 fold with leptin, and 4.2 fold with leptin plus insulin. Simultaneous monitoring of hemodynamic function revealed a minor and transient effect of leptin on left ventricular pressure, which was strongly augmented in coperfusion with insulin. CONCLUSIONS: The data suggest that leptin at low physiological concentrations is able to exert a partial insulin like effect on glucose uptake. We speculate that the effect might be mediated by both leptin receptor isoforms. This leptin effect is additive to the effect of insulin and might therefore contribute to the insulin independent basal glucose supply of the heart. It can not be completely excluded that the observed leptin effect on glucose transport is secondary to altered myocardial function.

Animals↗
PubMed2002

Insulin sensitivity of glucose disposal and lipolysis: no influence of common genetic variants in IRS-1 and CAPN10.

AIMS/HYPOTHESIS: This study aimed to assess the physiologic relationships between insulin sensitivity of lipolysis and that of glucose disposal and whether two common genetic polymorphisms associated with insulin resistance partially explained the remaining variation. METHODS: We measured suppression of lipolysis (isotopically [primed-continuous infusion of d5 glycerol] measured glycerol rate of appearance) and glucose disposal during a three-step (n = 24) or standard (n = 57) hyperinsulinaemic euglycaemic clamp in 81 healthy subjects. We also compared insulin sensitivity of lipolysis in carriers (vs. wildtype controls) of the CAPN10 UCSNP43 G/A and IRS-1 Gly972Arg polymorphisms. RESULTS: We observed a significant correlation between insulin sensitivity of glucose disposal and insulin sensitivity of lipolysis ( r = -0.39, p < 0.001) which was retained, albeit weaker, after adjusting for BMI ( r = -0.27, p = 0.002). No significant difference in insulin sensitivity of lipolysis was found between Gly/Gly compared with X/Arg ( IRS-1) and G/G compared with G/A + A/A ( CAPN10) (all p values > 0.15). CONCLUSION/INTERPRETATION: Insulin sensitivity of lipolysis has a considerable variation in healthy human beings and independently explains about 10% of the variation in insulin sensitivity of glucose disposal (or vice versa). It is possible that mediated through NEFAs, insulin resistance of glucose disposal is secondary to that of lipolysis. Alternatively, the biological variation in insulin sensitivity, to some extent, affects both systems in parallel. Neither of the two putatively insulin resistance-related polymorphisms that were tested contributed measurably to the biological variation of insulin sensitivity of lipolysis.

Adult↗