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AIM: Congenital hyperinsulinism (CHI) and glycogen storage disease (glycogenosis) are both causing hypoglycemia during infancy, but with different additional clinical features and therapeutic approach. We aimed to identify a genetic cause in a child with an ambiguous phenotype. METHODS AND RESULTS: We present a child with hyperinsulinemic hypoglycemia, physiological 3-OH butyrate, increased triglyceride serum levels, increased level of glycogen in erythrocytes, increased liver transaminases, and increased echogenicity on liver ultrasonography. As both parents of the proband were referred as healthy, we raised a clinical suspicion on glycogenosis with recessive inheritance. However, whole exome sequencing revealed no mutation in genes causing glycogenosis, but a novel heterozygous variant LRG_483t1: c.427-1G>A in the HNF4A gene was identified. Aberrant splicing resulting in in-frame deletion c.429_476del, p.(T144_I159del) was confirmed by sequencing of HNF4A transcripts reverse-transcribed from whole blood RNA. The same variant was found in five of eight tested family relatives (one of them already had diabetes, two had prediabetes). With regard to the results of DNA analysis, we added diazoxide to the therapy. Consequently, the frequency and severity of hypoglycemia in the proband decreased. We have also recommended sulfonylurea treatment after diabetes onset in adult mutation carriers. CONCLUSIONS: We have identified a novel HNF4A gene mutation in our patient with CHI and glycogenosis-like phenotype. The proband and her family members benefited from the genetic testing by WES method and consequently personalized therapy. Nevertheless, the HNF4A gene testing may be considered in selected CHI cases with glycogenosis-like phenotype prior WES analysis.
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Hiperinsulinismo Congênito/genética , Doença de Depósito de Glicogênio/genética , Fator 4 Nuclear de Hepatócito/genética , Adulto , Criança , Feminino , Genótipo , Heterozigoto , Humanos , Masculino , Mutação , FenótipoRESUMO
Congenital hyperinsulinism (CHI) is the most common cause of severe persistent hypoglycemia in neonates and infants. Early diagnosis and effective treatment (based on the principles of pharmacogenetics) play the key role for the prognosis. The DNA anlysis, which can identify mutation in one of the 11 genes causing MODY, is crutial in the diagnostics. Moreover, The genotype determines also the optimal therapy approach (medicaments, diet or rarely surgery). There was a large progress of novel medicaments treating particularly most severe (diazoxide-resistant) forms of CHI.Key words: congenital hyperinsulinism - diazoxid - DNA analysis - hypoglycemia - somatostatine analogues.
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Hiperinsulinismo Congênito/diagnóstico , Hiperinsulinismo Congênito/terapia , Hiperinsulinismo Congênito/genética , Genótipo , Humanos , Recém-Nascido , Mutação , Prognóstico , Resultado do TratamentoRESUMO
Familial hypercholesterolemia (FH) is an autosomal dominant genetic disorder characterized by strikingly elevated low-density lipoprotein (LDL) cholesterol levels and premature atherosclerosis. For individuals with a definite or probable diagnosis of FH, molecular genetic testing is recommended. This can be justified in countries where genetic testing is broadly available and covered. On the other hand, in countries with limited access to genetic testing, it can be argued whether it is necessary and cost-effective to perform genetic testing in patients with a proven clinical diagnosis of FH. This article presents a family with FH where different family members manifested different phenotypes and discusses situations where genetic diagnosis can crucially help physicians in clinical decision-making on how to approach and treat patients.
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Apolipoproteínas B/genética , Testes Genéticos/métodos , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/genética , Pró-Proteína Convertase 9/genética , Receptores de LDL/genética , Adulto , Feminino , Marcadores Genéticos/genética , Humanos , Pessoa de Meia-IdadeRESUMO
OBJECTIVE: Hypertrophic obesity is associated with impaired insulin sensitivity and lipid-mobilizing activity of zinc-α2-glycoprotein. Adipose tissue (AT) of growth hormone (GH) -deficient patients is characterized by extreme adipocyte hypertrophy due to defects in AT lipid metabolism. It was hypothesized that zinc-α2-glycoprotein is regulated by GH and mediates some of its beneficial effects in AT. METHODS: AT from patients with GH deficiency and individuals with obesity-related GH deficit was obtained before and after 5-year and 24-month GH supplementation therapy. GH action was tested in primary human adipocytes. Relationships of GH and zinc-α2-glycoprotein with adipocyte size and insulin sensitivity were evaluated in nondiabetic patients with noncancerous cachexia and hypertrophic obesity. RESULTS: AT in GH-deficient adults displayed a substantial reduction of zinc-α2-glycoprotein. GH therapy normalized AT zinc-α2-glycoprotein. Obesity-related relative GH deficit was associated with almost 80% reduction of zinc-α2-glycoprotein mRNA in AT. GH increased zinc-α2-glycoprotein mRNA in both AT of obese men and primary human adipocytes. Interdependence of GH and zinc-α2-glycoprotein in regulating AT morphology and metabolic phenotype was evident from their relationship with adipocyte size and AT-specific and whole-body insulin sensitivity. CONCLUSIONS: The results demonstrate that GH is involved in regulation of AT zinc-α2-glycoprotein; however, the molecular mechanism linking GH and zinc-α2-glycoprotein in AT is yet unknown.
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Tecido Adiposo/efeitos dos fármacos , Hormônio do Crescimento Humano/administração & dosagem , Obesidade/metabolismo , Proteínas de Plasma Seminal/metabolismo , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Tecido Adiposo/metabolismo , Administração Oral , Adulto , Idoso , Estudos de Casos e Controles , Estudos de Coortes , Suplementos Nutricionais , Feminino , Hormônio do Crescimento Humano/deficiência , Hormônio do Crescimento Humano/farmacologia , Humanos , Metabolismo dos Lipídeos , Masculino , Pessoa de Meia-Idade , Glicoproteína Zn-alfa-2RESUMO
Altered adipose tissue formation is a well-known effectors of obesity and T2D. Here, we describe the role of Lrh1 and its co-repressor Shp in the control of adipocyte formation. Expression of Lrh1 in the pre-adipocyte containing SVF is induced in obese mice models and humans while Shp expression is reduced. We demonstrate, that Lrh1 is an inhibitor of adipogenesis while Shp acts functions as an activator through repression of Lrh1 activity. This regulation is at least in part modulated by estradiol conversion through the regulation of Cyp19a1 gene expression. In vivo, loss of Lrh1 leads to induced adipogenesis, while loss of Shp causes uncontrolled activation of Lrh1 and reduced adipogenesis. As Shp expression has been linked to the development of obesity and metabolic disorders, it is possible that alterations of the Shp/Lrh1 network lead to changes in adipocyte formation, which might contribute to the development of obesity associated T2D.
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Phosphorus magnetic resonance spectroscopy ((31)P-MRS) enables the non-invasive evaluation of muscle metabolism. Resting Pi-to-ATP flux can be assessed through magnetization transfer (MT) techniques, and maximal oxidative flux (Q(max)) can be calculated by monitoring of phosphocreatine (PCr) recovery after exercise. In this study, the muscle metabolism parameters of 13 overweight-to-obese sedentary individuals were measured with both MT and dynamic PCr recovery measurements, and the interrelation between these measurements was investigated. In the dynamic experiments, knee extensions were performed at a workload of 30% of maximal voluntary capacity, and the consecutive PCr recovery was measured in a quadriceps muscle with a time resolution of 2 s with non-localized (31)P-MRS at 3 T. Resting skeletal muscle metabolism was assessed through MT measurements of the same muscle group at 7 T. Significant linear correlations between the Q(max) and the MT parameters k(ATP) (r = 0.77, P = 0.002) and F(ATP) (r = 0.62, P = 0.023) were found in the study population. This would imply that the MT technique can possibly be used as an alternative method to assess muscle metabolism when necessary (e.g. in individuals after stroke or in uncooperative patients).
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Exercício Físico/fisiologia , Espectroscopia de Ressonância Magnética , Obesidade/fisiopatologia , Músculo Quadríceps/fisiopatologia , Descanso/fisiologia , Comportamento Sedentário , Trifosfato de Adenosina/metabolismo , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Oxirredução , Fosfocreatina/metabolismo , Fósforo/metabolismo , Isótopos de Fósforo , Fatores de Tempo , Adulto JovemRESUMO
INTRODUCTION: The role of fat-bone interactions in the pathogenesis of osteoporosis in chronic obstructive pulmonary disease (COPD) is poorly understood. Our aim was to investigate expressions of leptin and osteoprotegerin (OPG) in the adipose tissue, and their relationships to osteoporosis in patients with COPD. METHODS: In 39 patients with stable COPD, bone mineral density (BMD) and body composition was assessed by Dual Energy X-Ray Absorptiometry. Serum leptin was determined by the enzyme-linked immunosorbent assay, and bone turnover markers osteocalcin and ß-crosslaps by the electrochemiluminiscence immunoassays. Subcutaneous adipose tissue samples were analyzed using real-time PCR. RESULTS: Twenty-one patients without, and 18 with osteoporosis were enrolled (35 men; age 62.2 ± 7.3years). Compared to patients without osteoporosis, those with the disease had significantly lower serum levels and adipose tissue expressions of leptin, in association with increased serum ß-crosslaps (p=0.028, p=0.034, p=0.022, respectively). Log adipose tissue leptin was inversely related to serum ß-crosslaps (p=0.015), and directly to serum leptin (p<0.001) and to the total, femoral, and lumbar BMD and T-score (p<0.02 for all relationships). Adipose tissue OPG expression was related to all variables of bone density except for lumbar BMD and T-score (p<0.05 for all relationships). Log adipose tissue leptin and OPG expressions predicted femoral T-score independently of age, gender and pulmonary function (p<0.001, adjusted R(2)=0.383; p=0.008, adjusted R(2)=0.301, respectively). Introducing body mass (or fat mass) index into these models eliminated independent predictive value of leptin and OPG expressions. CONCLUSION: Our results suggest that adipose tissue leptin and OPG expressions are related to osteoporosis in patients with COPD, and appear to act as mediators between fat mass and BMD.
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Leptina/metabolismo , Osteoporose/complicações , Osteoporose/metabolismo , Osteoprotegerina/metabolismo , Doença Pulmonar Obstrutiva Crônica/complicações , Doença Pulmonar Obstrutiva Crônica/metabolismo , Tecido Adiposo/metabolismo , Biomarcadores/sangue , Densidade Óssea , Remodelação Óssea , Feminino , Humanos , Inflamação/sangue , Inflamação/complicações , Leptina/sangue , Leptina/genética , Masculino , Pessoa de Meia-Idade , Osteoporose/sangue , Osteoporose/fisiopatologia , Osteoprotegerina/genética , Doença Pulmonar Obstrutiva Crônica/sangue , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Testes de Função RespiratóriaRESUMO
BACKGROUND: CD40, a transmembrane receptor of the tumor necrosis factor gene superfamily, is activated in response to cellular stress, including hypoxia, and orchestrates the process of inflammation via secondary messengers such as mitogen-activated protein kinase kinase 4 (MKK4) and c-Jun NH(2)-terminal kinases (JNK). OBJECTIVES: We hypothesized that CD40, MKK4 and JNK expression is increased in the adipose tissue of patients with very severe chronic obstructive pulmonary disease (COPD). METHODS: In 20 patients with stable COPD, lung function was assessed using body plethysmography, and samples of subcutaneous adipose tissue were analyzed using real-time PCR. Body composition, including fat mass index (FMI), was assessed by bioelectrical impedance. RESULTS: 12 patients in GOLD stage I-III (age 61.6 ± 8.6 years, 4 females, mean partial pressure of oxygen in arterial blood, PaO(2), 9.38 ± 0.21 kPa) were compared to 8 patients in GOLD stage IV (age 62.6 ± 6.3 years, all male, mean PaO(2) 7.70 ± 0.37 kPa). Compared to patients in GOLD stage I-III, patients in GOLD stage IV had lower FMI (p = 0.004), being associated with significantly higher adipose tissue expression of CD40, MKK4 and JNK [ΔΔCt: 2.55 (1.99, 4.40) vs. 1.87 (1.63, 2.23), p = 0.013; 5.19 (3.13, 5.96) vs. 2.98 (2.82, 3.86), p = 0.002; 9.01 (5.12, 11.41) vs. 4.65 (4.42, 6.26), p = 0.001, respectively]. Log-transformed CD40, MKK4 and JNK expression was significantly inversely related to PaO(2), respectively. CONCLUSIONS: Upregulation of proinflammatory CD40, MKK4 and JNK gene expression in adipose tissue in very severe COPD raises the possibility of a role of chronic systemic hypoxia in the pathogenesis of adipose tissue inflammation in COPD.
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Tecido Adiposo/metabolismo , Antígenos CD40/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , MAP Quinase Quinase 4/metabolismo , Adipócitos/patologia , Composição Corporal , Feminino , Expressão Gênica/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica , Regulação para Cima/fisiologiaRESUMO
Potential links between metabolic derangements and adipose tissue (AT) inflammation in patients with chronic obstructive pulmonary disease (COPD) are unexplored. We investigated AT expressions of interleukin (IL)-6, tumor necrosis factor (TNF)-α, CD68 (macrophage cell surface receptor), caspase-3, and Bax, and their relationships to the metabolic phenotype in nine cachectic, 12 normal-weight, 12 overweight, and 11 obese patients with COPD (age 62.3 ± 7.2 years). With increasing body mass index, increases in AT expressions of IL-6, TNF-α, and CD68 were observed (P < .001; P = .005; P < .001, resp.), in association with reduced insulin sensitivity (P < .001). No differences were observed between cachectic and normal-weight patients in AT expressions of inflammatory or proapoptotic markers. Adipose tissue CD68 and TNF-α expressions predicted insulin sensitivity independently of known confounders (P = .005; P = .025; R(2) = 0.840). Our results suggest that AT inflammation in obese COPD patients relates to insulin resistance. Cachectic patients remain insulin sensitive, with no AT upregulation of inflammatory or proapoptotic markers.
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Tecido Adiposo/patologia , Mediadores da Inflamação/metabolismo , Inflamação/patologia , Doença Pulmonar Obstrutiva Crônica/metabolismo , Doença Pulmonar Obstrutiva Crônica/patologia , Idoso , Antígenos CD/genética , Antígenos de Diferenciação Mielomonocítica/genética , Caquexia/complicações , Caquexia/genética , Caquexia/metabolismo , Caquexia/patologia , Caspase 3/genética , Feminino , Expressão Gênica , Humanos , Resistência à Insulina/fisiologia , Interleucina-6/genética , Masculino , Síndrome Metabólica/complicações , Síndrome Metabólica/genética , Síndrome Metabólica/metabolismo , Pessoa de Meia-Idade , Obesidade/complicações , Obesidade/genética , Obesidade/metabolismo , Obesidade/patologia , Sobrepeso/complicações , Sobrepeso/genética , Sobrepeso/metabolismo , Sobrepeso/patologia , Paniculite/complicações , Paniculite/genética , Paniculite/metabolismo , Paniculite/patologia , Fenótipo , Doença Pulmonar Obstrutiva Crônica/complicações , Doença Pulmonar Obstrutiva Crônica/genética , Receptores Tipo I de Fatores de Necrose Tumoral/genética , Fator de Necrose Tumoral alfa/genética , Proteína X Associada a bcl-2/genéticaRESUMO
OBJECTIVE: Many adipokines, inflammatory cytokines, and other proteins produced by adipose tissue have been shown to be involved in the development of obesity-related insulin resistance. Nevertheless, new factors that play an important role in these processes are still emerging. Therefore, we screened the level of 120 different proteins in biopsies of subcutaneous adipose tissue (ScAT) of lean and obese subjects. RESEARCH METHODS AND PROCEDURES: All studied volunteers (12 obese with BMI >30 and 6 lean with BMI <25 kg/m(2)) were young, clinically healthy, and drug-naive males with normal glucose tolerance. The ScAT was obtained by a needle biopsy from the umbilical region. Protein levels were assessed in adipose tissue lysates using protein arrays; mRNA levels were determined with the aid of real-time reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: The obese subjects had higher fasting plasma glucose (although within the normal range) and insulin levels, increased high sensitivity C-reactive protein (hsCRP) in circulation, and decreased in vivo insulin action. Using the protein array technique, it was shown that of 120 proteins measured, 27 showed higher levels (leptin, HGF, EGF-R, FGF-6, IGF-1sR, Fas/Apo-1, ENA-78, PARC, lymphotactin, HCC-4, IL-10, IL-1a, IL-1R1, IL-1R4, IL-12p70, angiopoietin-2, Axl, Dtk, MIF, MIP-1a, -1b, -3b, MSP-a, osteoprotegerin, TECK, TIMP-1, -2) and only one (RANTES) showed a lower level in ScAT of obese subjects when compared with the lean controls (p < 0.05). The real-time RT-PCR confirmed the results of protein arrays for leptin, MIF, MIP-1a, TIMP-2, adiponectin, IL-6, and TNF-alpha but not for RANTES. DISCUSSION: To our knowledge, this is the first protein array data on a very early dysregulation of ScAT protein levels in insulin-resistant obese, but apparently healthy, subjects with normal glucose tolerance.
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Obesidade/metabolismo , Análise Serial de Proteínas , Proteínas/análise , Gordura Subcutânea/metabolismo , Adulto , Feminino , Humanos , Masculino , Proteínas/genética , Proteínas/metabolismoRESUMO
We examined 2,046 adults (834 males and 1,212 females aged 20-75 years) from polluted district in East Slovakia (POLL) and two neighboring upstream and upwind located districts of background pollution (BCGR). By ultrasound we estimated the thyroid volume (ThV), hypoechogenicity (HYE), nodules and cysts. Serum levels of thyrotropin (TSH), thyroperoxidase antibodies (TPOab) and thyroglobulin were estimated by electrochemiluminiscent assay and these of 15 PCB congeners, p,p'-DDE, p,p'-DDT, hexachlorobenzene (HCB) and hexachlorocyclohexane by high-resolution gas chromatography. In 320 subjects also selected hydroxylated and methylsulfonated PCB metabolites, polychlorinated dibenzo-dioxins (PCDDs), -furans (PCDFs), five dioxin-like coplanar and eight mono-ortho PCB congeners were estimated. Urinary iodine was measured by automatic microplate method. Reciprocal positive association was found between three major POPs (PCBs, DDE and HCB), the levels of these and also PCDDs plus PCDFs in polluted area being considerably higher than in background pollution area. ThV in groups of males and females from POLL with high PCBs level was significantly higher (p<0.001 by t-test) then in age and sex matched groups from BCGR with low PCBs level. In 1,048 males and females aged <60 years with serum PCBs level >1,000 ng g(-1) lipid (median=1,756 ng g(-1)) a significant effect of age on ThV was found (p<0.01 by ANOVA), while in 921 respective subjects with PCBs level <1,000 ng g(-1) (median=661 ng g(-1)) it was not. These findings supported the view on the additional effect of PCBs on ThV other than that of age. Since the urinary iodine in both districts showed optimal range, any interfering effect of unsatisfactory iodine intake on ThV may be excluded. The frequency of autoimmune thyroiditis signs such as HYE, increased serum level of TPOab and TSH resulting in subclinical or overt thyroid hypofunction was positively associated with sex, age and organochlorine levels. The increase of such frequency in males with POPs levels was much more abrupt than that in females. No considerable differences in the frequency of thyroid nodules as related to PCBs level were found.
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Exposição Ambiental/análise , Poluentes Ambientais/sangue , Hidrocarbonetos Clorados/sangue , Glândula Tireoide/diagnóstico por imagem , Adulto , Idoso , Anticorpos/sangue , Autoantígenos/imunologia , Benzofuranos/sangue , Dibenzofuranos Policlorados , Feminino , Humanos , Iodeto Peroxidase/imunologia , Iodo/urina , Proteínas de Ligação ao Ferro/imunologia , Masculino , Pessoa de Meia-Idade , Praguicidas/sangue , Dibenzodioxinas Policloradas/análogos & derivados , Dibenzodioxinas Policloradas/sangue , Eslováquia , Tireoglobulina/sangue , Glândula Tireoide/fisiologia , Tireotropina/sangue , UltrassonografiaRESUMO
The purpose of this work was to study the effects of high environmental exposure to polychlorinated biphenyls (PCBs) and other organochlorines on the thyroid. Thyroid volume, hypoechogenicity and nodules (by ultrasound), presence of antithyroid peroxidase (anti-TPO) antibodies, and abnormal thyroid-stimulating hormone (TSH) levels in serum (by radioimmunoassay) were examined in 101 adults from the PCB-polluted area in 360 controls. Serum levels of PCBs, hexachlorobenzene, gamma-hexachlorocyclohexane (HCH), p,p'-DDT(1,1,1-trichloro-2,2'-bis(p-chlorophenyl)ethane), and p,p'-DDE(1,1-dichloro-2,2'-bis(p-chlorophenyl)ethene) were measured by high-resolution gas chromatography. Very high levels of PCBs were found in the polluted area (7300 +/- 871 ng/g lipids) compared with controls (2045 +/- 147 ng/g). Positive correlations (P < 0.001) were found between the levels of all organochlorines and their total except for hexachlorocyclohexane (HCH). In the polluted area, the highest thyroid volumes (18.7 +/- 2.32 mL; mean +/- SE) were clustered among 23 subjects (17 males and six females) with PCB levels above 10,000 ng/g (range 10,000-58,667 ng/g). In the remaining 438 subjects the thyroid volume was 14.2 +/- 0.29 mL. These data suggest that there might be a threshold serum PCB level of approximately 10,000 ng/g that may influence the thyroid volume. A two-way ANOVA showed that all thyroid volumes in the polluted area were significantly higher (P < 0.001) than in the control area. In males from the polluted area, the frequencies of thyroid hypoechogenicity, thyroid nodules, positive anti-TPO, and abnormal TSH level were higher than in males from the control area, whereas such differences were not observed in females. Increased thyroid volume and indicators of potential thyroid dysfunction were associated with long-term environmental exposure to PCBs. These effects on the thyroid were confined to subjects with PCB levels above 10,000 ng/g of lipid (thyroid volume) and to males from the polluted area (thyroid hypoechogenicity, thyroid nodules, positive anti-TPO, and abnormal TSH).