RESUMO
OBJECTIVES: The aim of this study was to characterize diabetes risk in relation to amount and distribution of body fat (environmental factors) and genetic risk defined as having first-degree (FH1) or second-degree relatives with diabetes. DESIGN: We analysed the METSIM population of 10 197 middle-aged, randomly selected men. At baseline, information about family history of diabetes was registered and all individuals underwent extensive phenotyping. A follow-up study was conducted after 6 years. The metabolic consequences of increased visceral versus subcutaneous fat were characterized in a separate cohort of 158 healthy men (the Kuopio Cohort of the EUGENE2 study). RESULTS: At baseline, individuals with a family history of diabetes (FH+) had approximately a twofold increase in the prevalence of type 2 diabetes compared with individuals without a family history of the disease (FH-) (18.0% vs. 9.9%; P = 1.3 × 10(-31) ). FH1 individuals were more commonly overweight and obese compared with FH- (69.2% vs. 64.8%; P = 1.3 × 10(-4) ) and, for a given body mass index, showed an increased risk profile for both type 2 diabetes and cardiovascular disease as well as a greater susceptibility to the negative consequences of increased body fat also when nonobese. Subgroup analyses indicated that the metabolic consequences were due primarily to increased ectopic/visceral fat rather than subcutaneous fat. The increased risk profile in FH+ individuals was not altered by adjusting for 43 major diabetes risk genes. CONCLUSIONS: Family history of type 2 diabetes (particularly FH1) is associated with both increased risk of becoming overweight/obese and with a greater susceptibility to the negative consequences of increasing body fat, probably as a consequence of an increased propensity to accumulate ectopic (nonsubcutaneous) fat.
Assuntos
Diabetes Mellitus Tipo 2/etiologia , Transtornos do Metabolismo dos Lipídeos/etiologia , Sobrepeso/etiologia , Distribuição da Gordura Corporal , Estudos Transversais , Diabetes Mellitus Tipo 2/patologia , Humanos , Insulina/metabolismo , Resistência à Insulina/fisiologia , Secreção de Insulina , Gordura Intra-Abdominal/patologia , Transtornos do Metabolismo dos Lipídeos/patologia , Masculino , Pessoa de Meia-Idade , Obesidade/etiologia , Obesidade/patologia , Sobrepeso/patologia , Linhagem , Fatores de Risco , Gordura Subcutânea/patologia , Circunferência da CinturaRESUMO
AIMS/HYPOTHESIS: Human complex metabolic traits are in part regulated by genetic determinants. Here we applied exome sequencing to identify novel associations of coding polymorphisms at minor allele frequencies (MAFs) >1% with common metabolic phenotypes. METHODS: The study comprised three stages. We performed medium-depth (8×) whole exome sequencing in 1,000 cases with type 2 diabetes, BMI >27.5 kg/m(2) and hypertension and in 1,000 controls (stage 1). We selected 16,192 polymorphisms nominally associated (p < 0.05) with case-control status, from four selected annotation categories or from loci reported to associate with metabolic traits. These variants were genotyped in 15,989 Danes to search for association with 12 metabolic phenotypes (stage 2). In stage 3, polymorphisms showing potential associations were genotyped in a further 63,896 Europeans. RESULTS: Exome sequencing identified 70,182 polymorphisms with MAF >1%. In stage 2 we identified 51 potential associations with one or more of eight metabolic phenotypes covered by 45 unique polymorphisms. In meta-analyses of stage 2 and stage 3 results, we demonstrated robust associations for coding polymorphisms in CD300LG (fasting HDL-cholesterol: MAF 3.5%, p = 8.5 × 10(-14)), COBLL1 (type 2 diabetes: MAF 12.5%, OR 0.88, p = 1.2 × 10(-11)) and MACF1 (type 2 diabetes: MAF 23.4%, OR 1.10, p = 8.2 × 10(-10)). CONCLUSIONS/INTERPRETATION: We applied exome sequencing as a basis for finding genetic determinants of metabolic traits and show the existence of low-frequency and common coding polymorphisms with impact on common metabolic traits. Based on our study, coding polymorphisms with MAF above 1% do not seem to have particularly high effect sizes on the measured metabolic traits.
Assuntos
Exoma/genética , Polimorfismo Genético/genética , Diabetes Mellitus Tipo 2/genética , Frequência do Gene/genética , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Hipertensão/genética , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
AIMS/HYPOTHESIS: This study investigates the role of serine/threonine protein kinase 25 (STK25), a member of the sterile 20 (STE20) superfamily of kinases, in the regulation of skeletal muscle metabolism. METHODS: The effect of depleting STK25 in muscle cells was studied by reducing the mRNA and protein content of this target in the rat myoblast cell line L6 by small interfering (si)RNA. The changes in the mRNA and protein levels of several members of the fatty acid oxidative and glucose metabolic pathways were measured by quantitative real-time (qRT)-PCR and western blot. The rate of palmitate oxidation and glucose uptake was measured after transfection with siRNA for Stk25. Expression of STK25 was also evaluated in skeletal muscle biopsies from 41 white Europid men and women with normal and impaired glucose tolerance and type 2 diabetes using qRT-PCR. RESULTS: We demonstrate that partial depletion of STK25 increases the expression of uncoupling protein 3 (Ucp3), accompanied by increased lipid oxidation, in myoblasts. In addition, a reduced level of STK25 enhances the expression of Slc2a1 (also known as Glut1), Slc2a4 (also known as Glut4) and hexokinase 2, and correspondingly, improves insulin-stimulated glucose uptake in muscle cells. Consistent with these results, significantly higher STK25 levels were observed in the skeletal muscle of type 2 diabetic patients, compared with individuals with normal glucose tolerance. CONCLUSIONS/INTERPRETATION: This is the first study indicating a possible role for STK25 in the regulation of glucose and lipid metabolism in L6 myoblasts. This kinase appears to be an interesting new mediator to be evaluated for therapeutic intervention in type 2 diabetes and related complications, as controlled increase in lipid oxidation and insulin-stimulated glucose uptake in skeletal muscle is favourable and can restore energy balance in metabolically compromised states.
Assuntos
Glucose/metabolismo , Músculo Esquelético/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Animais , Western Blotting , Linhagem Celular , Feminino , Humanos , Imuno-Histoquímica , Técnicas In Vitro , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Metabolismo dos Lipídeos/genética , Masculino , Ácido Palmítico/metabolismo , Proteínas Serina-Treonina Quinases/genética , RNA Interferente Pequeno , Ratos , Reação em Cadeia da Polimerase em Tempo RealRESUMO
OBJECTIVES: The objective of this study was to examine the associations between indices of liver insulin resistance (IR) and whole-body insulin sensitivity and different cardiovascular disease (CVD) risk factors. DESIGN AND SUBJECTS: A total of 8750 nondiabetic men (age 57.2 ± 7.1 years, body mass index 26.8 ± 3.8 kg m(-2) ) were included in this study from the population-based cross-sectional Metabolic Syndrome In Men (METSIM) cohort. Liver IR index and Matsuda insulin sensitivity index (ISI) were used as markers of liver IR and whole-body insulin sensitivity, respectively. Pearson correlation analysis was performed to examine the associations between these indices and various CVD risk factors. RESULTS: Total cholesterol (r = -0.088 vs. r = 0.020; P < 0.0019), high-sensitivity C-reactive protein (CRP) (r = 0.284 vs. r = -0.219; P < 0.0019) and total triglycerides (r = 0.507 vs. r = -0.477; P < 0.05) were more highly correlated with liver IR index than with Matsuda ISI. By contrast, Matsuda ISI was nominally more highly correlated with systolic and diastolic blood pressure (r = -0.234 and r = -0.275 vs. r = 0.202 and r = 0.239, respectively) compared to liver IR index. Furthermore, the variance explained by liver IR index was larger than that explained by Matsuda ISI for the majority of CVD risk factors measured. CONCLUSIONS: Liver IR index correlated more strongly than Matsuda ISI with levels of total cholesterol, CRP and triglycerides. Therefore, liver IR might be a significant indicator of CVD risk amongst men.
Assuntos
Doenças Cardiovasculares/etiologia , Resistência à Insulina , Fígado/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
OBJECTIVES: We investigated serum concentrations of lipoprotein subclass particles and their lipid components determined by proton nuclear magnetic resonance spectroscopy in a population-based study. DESIGN AND METHODS: A total of 9399 Finnish men were included in the study: 3034 men with normal fasting glucose and normal glucose tolerance; 4345 with isolated impaired fasting glucose (IFG); 312 with isolated impaired glucose tolerance (IGT); 1058 with both IFG and IGT; and 650 with newly diagnosed type 2 diabetes (New DM). Lipoprotein subclasses included chylomicrons (CM) and largest VLDL particles, other VLDL particles (five subclasses), intermediate-density lipoprotein (IDL), LDL (three subclasses) and HDL (four subclasses). The phospholipid, triglyceride (TG), cholesterol, free cholesterol and cholesterol ester levels of the lipoprotein particles were measured. RESULTS: Abnormal glucose tolerance (especially IGT and New DM) was significantly associated with increased concentrations of VLDL subclass particles and their components (with the exception of very small VLDL particles). After further adjustment for total TGs and HDL cholesterol, increased lipid concentrations in the CM/largest VLDL particles and in most of the other VLDL particles remained significant in individuals with isolated IGT, IFG+IGT and New DM. There was a consistent trend towards a decrease in large and an increase in small HDL particle concentrations in individuals with hyperglycaemia even after adjustment for serum total TGs and HDL cholesterol. CONCLUSIONS: Abnormal glucose tolerance modifies the concentrations of lipoprotein subclass particles and their lipid components in the circulation and is also related to compositional changes in these particles.
Assuntos
Diabetes Mellitus Tipo 2 , Intolerância à Glucose , Resistência à Insulina , Lipoproteínas VLDL , Lipoproteínas , Antropometria/métodos , Glicemia/análise , Estudos de Coortes , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/epidemiologia , Modificador do Efeito Epidemiológico , Finlândia/epidemiologia , Intolerância à Glucose/sangue , Intolerância à Glucose/diagnóstico , Intolerância à Glucose/epidemiologia , Teste de Tolerância a Glucose/métodos , Teste de Tolerância a Glucose/estatística & dados numéricos , Humanos , Lipoproteínas/sangue , Lipoproteínas/química , Lipoproteínas/classificação , Lipoproteínas VLDL/sangue , Lipoproteínas VLDL/química , Masculino , Estrutura Molecular , Fatores de RiscoRESUMO
AIMS/HYPOTHESIS: In epidemiological and genetic studies surrogate indices are needed to investigate insulin resistance in different insulin-sensitive tissues. Our objective was to develop a surrogate index for hepatic insulin resistance. METHODS: A sample of 368 non-diabetic participants (age 43.0 ± 8.2 years, BMI 26.0 ± 4.0 kg/m(2); mean ± SD) whose endogenous glucose production (EGP) was measured with [6-6(2)H(2)]glucose in the fasting state and during the euglycaemic-hyperinsulinaemic clamp were included in the study. EGP multiplied by fasting plasma insulin (FPI) concentration was the reference measurement for liver insulin resistance (liver IR). Liver IR index was calculated with linear regression analysis including age, obesity indices, lipids, lipoproteins and several variables regulating glucose metabolism. RESULTS: The following variables were significantly associated with liver IR in multiple forward stepwise regression analysis: insulin AUC in an OGTT, fat mass, HDL-cholesterol and BMI. Liver IR index correlated significantly with EGP×FPI (r = 0.65, p < 0.001). In participants with abnormal glucose tolerance, the correlation of liver IR with EGP×FPI was slightly stronger (r = 0.69, p < 0.001) than in those with normal glucose tolerance (r = 0.62, p < 0.001). CONCLUSIONS/INTERPRETATION: We generated a novel surrogate index for liver insulin resistance correlating strongly with EGP × FPI.
Assuntos
Resistência à Insulina/fisiologia , Fígado/metabolismo , Adulto , Biomarcadores/sangue , Biomarcadores/metabolismo , Jejum/sangue , Feminino , Teste de Tolerância a Glucose , Humanos , Insulina/sangue , Fígado/patologia , Masculino , Pessoa de Meia-IdadeRESUMO
AIMS/HYPOTHESIS: Of the confirmed type 2 diabetes susceptibility loci only a few are known to affect insulin sensitivity. We examined the association of indices of hepatic and adipocyte insulin resistance (IR) with 19 confirmed type 2 diabetes risk loci in a large population-based study. METHODS: Non-diabetic participants (n = 8,460, age 57.3 ± 7.0 years, BMI 26.8 ± 3.8 kg/m(2); mean ± SD) from a population-based cohort underwent an OGTT. Of them, 6,733 non-diabetic men were genotyped for single nucleotide polymorphisms (SNPs) in or near PPARG2 (also known as PPARG), KCNJ11, TCF7L2, SLC30A8, HHEX, CDKN2B, IGF2BP2, CDKAL1, HNF1B, WFS1, JAZF1, CDC123, TSPAN8, THADA, ADAMTS9, NOTCH2, KCNQ1, MTNR1B and SNP rs7480010. We investigated hepatic IR with a new index of liver IR. The adipocyte IR index was defined as a product of fasting NEFA and plasma insulin levels. RESULTS: Type 2 diabetes risk SNPs in or near KCNJ11 and HHEX were significantly (p < 0.0013), and those in or near CDKN2B, NOTCH2 and MTNR1B were nominally (p < 0.05), associated with decreased liver IR index. The Pro12 allele of PPARG2 was significantly associated with a high adipocyte IR index and nominally associated with high liver IR. CONCLUSIONS/INTERPRETATION: The Pro12 allele of PPARG2 seems to impair insulin's antilipolytic effect, leading to high NEFA release in the fasting state and IR. In addition, the type 2 diabetes risk alleles of KCNJ11 and HHEX, which are known to impair insulin secretion, were associated with increased hepatic insulin sensitivity.
Assuntos
Adipócitos/fisiologia , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/fisiopatologia , Resistência à Insulina/fisiologia , Fígado/fisiopatologia , Proteínas ADAM/genética , Proteína ADAMTS9 , Adipócitos/metabolismo , Antígenos de Neoplasias/genética , Proteínas de Transporte de Cátions/genética , Proteínas de Ciclo Celular/genética , Proteínas Correpressoras , Quinase 5 Dependente de Ciclina/genética , Inibidor de Quinase Dependente de Ciclina p15/genética , Proteínas de Ligação a DNA , Finlândia , Predisposição Genética para Doença/genética , Fator 1-beta Nuclear de Hepatócito/genética , Proteínas de Homeodomínio/genética , Humanos , Resistência à Insulina/genética , Fígado/metabolismo , Masculino , Glicoproteínas de Membrana/genética , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , PPAR gama/genética , Polimorfismo de Nucleotídeo Único , Canais de Potássio Corretores do Fluxo de Internalização/genética , Proteínas de Ligação a RNA/genética , Receptor Notch2/genética , Tetraspaninas , Proteína 2 Semelhante ao Fator 7 de Transcrição/genética , Fatores de Transcrição/genética , Transportador 8 de Zinco , tRNA MetiltransferasesRESUMO
AIMS/HYPOTHESIS: The aim of this study was to investigate the association of the rs10811661 polymorphism near the CDKN2B/CDKN2A genes with glucose tolerance, insulin sensitivity and insulin release in three samples of white people with European ancestry. METHODS: Sample 1 comprised 845 non-diabetic offspring of type 2 diabetes patients recruited in five European centres participating in the EUGENE2 study. Samples 2 and 3 comprised, respectively, 864 and 524 Italian non-diabetic participants. All individuals underwent an OGTT. Screening for the rs10811661 polymorphism was performed using a TaqMan allelic discrimination assay. RESULTS: The rs10811661 polymorphism did not show a significant association with age, BMI and insulin sensitivity. Participants carrying the TT genotype showed a significant reduction in insulin release, measured by an OGTT-derived index, compared with carriers of the C allele, in the three samples. When these results were pooled with those of three published studies, and meta-analysed with a random-effects model, the T allele was significantly associated with reduced insulin secretion (-35.09 [95% CI 14.68-55.52], p = 0.0008 for CC+CT vs TT; and -29.45 [95% CI 9.51-49.38], p = 0.0038, for the additive model). In addition, in our three samples, participants carrying the TT genotype exhibited an increased risk for impaired glucose tolerance (IGT) compared with carriers of the C allele (OR 1.55 [95% CI 1.20-1.95] for the meta-analysis of the three samples). CONCLUSIONS/INTERPRETATION: Our data, together with the meta-analysis of previously published studies, show that the rs10811661 polymorphism is associated with impaired insulin release and IGT, suggesting that this variant may contribute to type 2 diabetes by affecting beta cell function.
Assuntos
Inibidor de Quinase Dependente de Ciclina p15/genética , Inibidor p16 de Quinase Dependente de Ciclina/genética , Resistência à Insulina/genética , Insulina/metabolismo , Polimorfismo Genético/genética , Adulto , Diabetes Mellitus Tipo 2/genética , Feminino , Predisposição Genética para Doença/genética , Humanos , Secreção de Insulina , Masculino , Pessoa de Meia-Idade , Análise de Sequência de DNARESUMO
BACKGROUND AND AIM: The common single nucleotide polymorphism (SNP) in the FTO (fat mass and obesity associated) gene has been consistently associated with an increased risk of obesity. We investigated whether the SNP rs9939609 (T/A) of the FTO is associated with risk factors of cardiovascular diseases (CVD), including serum levels of C - reactive protein (CRP), the chemokine RANTES (Regulated on Activation, Normal T Cell Expressed and Secreted; CCL5), and serum and lipoprotein lipids in the Finnish Diabetes Prevention Study (DPS). Furthermore, we examined whether the rs9939609 increased the CVD risk in the DPS and if these results could be replicated in a larger cross-sectional population-based random sample of Finnish men (the METSIM). METHODS AND RESULTS: In the DPS, altogether 490 (BMI≥25kg/m(2)) subjects with impaired glucose tolerance were genotyped for rs9939609. Cardiovascular morbidity and mortality data were collected during the median follow-up of 10.2 years. The replication study was a population-based cross-sectional study of 6214 men. In the DPS, the AA genotype of rs9939609 was associated, independently of BMI, with increased RANTES (p=0.002) and decreased HDL cholesterol concentrations (p=0.007) in men. During the follow-up, the AA genotype was associated with an adjusted 2.09-fold risk (95% CI 1.17-3.73, p=0.013) of CVD in men. In the METSIM Study, the association with a history of myocardial infarction was replicated in the subgroup of men with type 2 diabetes. CONCLUSION: We suggest that the variation in the FTO gene may contribute to the development of CVD in men with an abnormal glucose metabolism.
Assuntos
Glicemia/metabolismo , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/genética , Polimorfismo de Nucleotídeo Único , Proteínas/genética , Idoso , Dioxigenase FTO Dependente de alfa-Cetoglutarato , Glicemia/análise , Proteína C-Reativa/análise , Doenças Cardiovasculares/patologia , Estudos Transversais , Feminino , Finlândia/epidemiologia , Seguimentos , Genótipo , Intolerância à Glucose/genética , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas/metabolismo , Fatores de RiscoRESUMO
OBJECTIVES: To examine the relationship between polymorphisms of five candidate genes for type 2 diabetes mellitus (T2DM) and the age at diagnosis of T2DM. METHODS: 538 Slovakian patients with T2DM were included and their age at diagnosis of T2DM retrieved from their medical records. Polymorphisms of genes encoding peroxisome proliferator activated receptor gamma (PPARG), PPARG-coactivator-1 (PGC1), insulin-receptor substrate 1 (IRS1), the subunit Kir 6.2 of the ATP-dependent potassium-channel (KCNJ11) and transcription factor 7-like 2 (TCF7L2) were detected by PCR-RFLP methods. RESULTS: No significant relationship between the risk alleles of the examined gene polymorphisms to the lower mean age at diagnosis of T2DM was observed. The carriers of the TT-genotype of TCF7L2 rs7903146 polymorphism had significantly increased odds ratio for diagnosis of diabetes before the age of 40 years [OR 3.02 (1.34, 6.81), p = 0.008], in comparison with the CC/CT genotype carriers. CONCLUSION: No significant association of PPARG, PGC1, IRS1, KCNJ11 and TCF7L2 gene polymorphisms and the age at diagnosis of T2DM was observed in the present study. Homozygotes for the risk allele of TCF7L2 had more frequently early onset of T2DM, before age of 40 years (Tab. 4, Ref. 15).
Assuntos
Diabetes Mellitus Tipo 2/genética , Polimorfismo Genético , Idade de Início , Diabetes Mellitus Tipo 2/diagnóstico , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , EslováquiaRESUMO
Dyslipidemia in the metabolic syndrome (MS) is considered to be one of the most important risk factors for atherosclerosis. It is characterized by hypertriglyceridemia, low concentration of plasma HDL-cholesterol, predominance of small dense LDL particles and an increased concentration of plasma apolipoprotein B (apoB). The pathogenesis of this type of dyslipidemia is partially explained, but its genetic background is still unknown. To evaluate the influence of cholesterol ester transfer protein (CETP) TaqIB polymorphism, lipoprotein lipase (LPL) PvuII and HindIII polymorphisms, hepatic lipase (LIPC) G-250A polymorphism and apolipoprotein C-III (APOC3) SstI gene polymorphism on lipid levels in dyslipidemia of the metabolic syndrome, 150 patients with dyslipidemia of metabolic syndrome were included. 96 % of patients had type 2 diabetes. The patients did not take any lipid lowering treatment. The exclusion criterion was the presence of any disease that could affect lipid levels, such as thyroid disorder, liver disease, proteinuria or renal failure. Gene polymorphisms were determined using the polymerase chain reaction and restriction fragment length polymorphisms. The genotype subgroups of patients divided according to examined polymorphisms did not differ in plasma lipid levels with the exception of apoB. The apoB level was significantly higher in patients with S1S1 genotype of APOC3 SstI polymorphism when compared with S1S2 group (1.10+/-0.26 vs. 0.98+/-0.21 g/l, p=0.02). Similarly, patients with H-H- genotype of LPL HindIII polymorphism had significantly higher mean apoB, compared with H+H- and H+H+ group (1.35+/-0.30 vs. 1.10+/-0.26 g/l, p=0.02). In the multiple stepwise linear regression analysis, apoB level seemed to be influenced by APOC3 SstI genotype, which explained 6 % of its variance. The present study has shown that the S1 allele of APOC3 SstI polymorphism and the H- allele of LPL HindIII polymorphism might have a small effect on apoB levels in the Central European Caucasian population with dyslipidemia of metabolic syndrome.
Assuntos
Dislipidemias/sangue , Lipoproteínas/sangue , Síndrome Metabólica/sangue , Polimorfismo Genético/genética , Idoso , Apolipoproteína C-III/genética , Apolipoproteínas B/sangue , Colesterol/sangue , Proteínas de Transferência de Ésteres de Colesterol/genética , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Dislipidemias/genética , Feminino , Genótipo , Humanos , Lipase/genética , Lipase Lipoproteica/genética , Masculino , Síndrome Metabólica/genética , Pessoa de Meia-Idade , Triglicerídeos/sangueAssuntos
17-Cetosteroides/urina , Neoplasias da Mama/urina , Cortisona/análogos & derivados , Cortisona/urina , Hidrocortisona/análogos & derivados , Hidrocortisona/urina , Adulto , Androsterona/urina , Neoplasias da Mama/cirurgia , Desidroepiandrosterona/urina , Etiocolanolona/urina , Feminino , Humanos , Pessoa de Meia-Idade , Fatores de TempoRESUMO
AIMS/HYPOTHESIS: We examined the phenotype of individuals with impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) with regard to insulin release and insulin resistance. METHODS: Non-diabetic offspring (n=874; mean age 40+/-10.4 years; BMI 26.6+/-4.9 kg/m(2)) of type 2 diabetic patients from five different European Centres (Denmark, Finland, Germany, Italy and Sweden) were examined with regard to insulin sensitivity (euglycaemic clamps), insulin release (IVGTT) and glucose tolerance (OGTT). The levels of glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP) were measured during the OGTT in 278 individuals. RESULTS: Normal glucose tolerance was found in 634 participants, while 110 had isolated IFG, 86 had isolated IGT and 44 had both IFG and IGT, i.e. about 28% had a form of reduced glucose tolerance. Participants with isolated IFG had lower glucose-corrected first-phase (0-10 min) and higher second-phase insulin release (10-60 min) during the IVGTT, while insulin sensitivity was reduced in all groups with abnormal glucose tolerance. Similarly, GLP-1 but not GIP levels were reduced in individuals with abnormal glucose tolerance. CONCLUSIONS/INTERPRETATION: The primary mechanism leading to hyperglycaemia in participants with isolated IFG is likely to be impaired basal and first-phase insulin secretion, whereas in isolated IGT the primary mechanism leading to postglucose load hyperglycaemia is insulin resistance. Reduced GLP-1 levels were seen in all groups with abnormal glucose tolerance and were unrelated to the insulin release pattern during an IVGTT.
Assuntos
Glicemia/metabolismo , Diabetes Mellitus Tipo 2/sangue , Peptídeo 1 Semelhante ao Glucagon/sangue , Intolerância à Glucose/sangue , Insulina/sangue , Insulina/metabolismo , Adulto , Diabetes Mellitus Tipo 2/genética , Família , Jejum , Feminino , Polipeptídeo Inibidor Gástrico/sangue , Intolerância à Glucose/genética , Teste de Tolerância a Glucose , Humanos , Secreção de Insulina , Masculino , Pessoa de Meia-Idade , Valores de ReferênciaRESUMO
The 24 hour urinary free cortisol and cortisone excretion after an oral 100 g glucose load was measured in 60 males (aged 22-56) divided into three groups. G-I consisted of 10 healthy men, G-II of 37 surgical patients and G-III comprised 23 patients with atherosclerotic peripheral vascular disease. The followed subjects responded to the glucose ingestion accordingly to their cortisol excretion. Subjects with an urinary cortisol excretion up to 200 micrograms/24 h responded to the glucose load with an increase of excretion in free cortisol and cortisone. Subjects with the excretion of cortisol above 200 micrograms/24 h responded unambiguously with a decrease in their excretion. We suggest that these changes in both directions can be explained by the available amount of NADPH in the liver. In patients with atherosclerotic peripheral vascular disease, in whom disturbances in lipid and carbohydrate metabolism can be proposed, the response of free corticoids, namely the respond of cortisone, are unequal.
Assuntos
Glucose/farmacologia , Hidrocortisona/metabolismo , Adulto , Arteriosclerose/urina , Cortisona/urina , Humanos , Hidrocortisona/urina , Fígado/metabolismo , Masculino , Pessoa de Meia-Idade , NADP/metabolismoRESUMO
The relationship of hexuronic acid and monosaccharide concentrations in serum to the excretion of urinary free cortisol and cortisone was studied in 14 healthy subjects, in 16 patients with diabetes mellitus, and in 14 patients with atherosclerotic peripheral vascular disease. In both groups of patients increased values of hexuronic acids, reducing monosaccharides and keto-sugars were registered. In diabetics the relative proportion of monosaccharides was increased, the proportion of hexuronic acids was lowered. In atherosclerotic peripheral vascular disease a significant preponderance of hexuronic acid and keto-sugar amounts in the composition of total sugar components was observed in comparison with healthy subjects. In healthy subjects there is a close correlation of urinary free cortisol and cortisone with reducing monosaccharides in blood, measured on the same day. In diabetes not any correlation of the increased values of free corticoids with the sugar components was registered. In atherosclerotic peripheral vascular disease a highly significant correlation between urinary free cortisol and cortisone and the hexuronic acid content in serum was observed. In patients with atherosclerotic peripheral vascular disease the results suggest an altered metabolism of glucose, which is shunted into insulin-insensitive glucuronate pathway in conditions of endogenous hypercortisolism.
Assuntos
Arteriosclerose/metabolismo , Cortisona/urina , Diabetes Mellitus/metabolismo , Ácidos Hexurônicos/sangue , Hidrocortisona/urina , Monossacarídeos/sangue , Ácidos Urônicos/sangue , Doenças Vasculares/metabolismo , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
The levels of serum monosaccharides (SMO) and hexuronic acids (SHA) were measured in subjects without any metabolic or endocrine disease after a short-time administration of cortisol, dexamethasone and ACTH. The effects of the three hormones were evaluated in regard to the urinary excretion of free cortisol and cortisone at basal conditions. In thirteen subjects a significant increase of SMO during cortisol treatment was registered after 24 hours. A distinct difference in the response of SMO to cortisol treatment was observed in patients with normal or increased cortisol excretion, respectively. In the subjects with high urinary free corticoids a peak of SMO occurred soon after 4 hours after cortisol administration, in the next 48 hours no tendency of return towards basal levels was observed. In the subjects with normal urinary free cortisol excretion only a slight increment was seen after 24 hours. Soon after 4 hours in eight subjects dexamethasone administration resulted in an increase of SMO without regard to the excretion of urinary free corticoids. The highest values were obtained after 28 hours of dexamethasone treatment. Ten hours after cessation of dexamethasone the levels of SMO reached the basal values. In the study in which ACTH was administered, an increment of SMO was registered only in the first four hours. In the group of subjects treated with ACTH a slight difference between subjects with normal and increased corticoid excretion was seen. The levels of SHA successively increased after the administration of all three hormones, without regard to the basal excretion of urinary free corticoids. This increase persisted also 10 hours after cessation of cortisol and dexamethasone, and 40 hours after the last dosis of ACTH, respectively. The possibility of an altered metabolism of glucose through the glucuronate pathway under conditions of glucocorticoid excess is discussed.
Assuntos
Hormônio Adrenocorticotrópico/farmacologia , Dexametasona/farmacologia , Ácidos Hexurônicos/sangue , Hidrocortisona/farmacologia , Transtornos Mentais/sangue , Monossacarídeos/sangue , Ácidos Urônicos/sangue , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
In four groups of persons, 1/healthy individuals, 2/ patients with diabetes mellitus, 3/ patients with peripheral vascular disease, and 4/ patients with hyperthyroidism, the urinary excretion of free cortisol, cortisone, cortisol sulfate and cortisone sulfate was estimated. In groups 2 and 3 the excretion of all four substances was elevated. In hyperthyroidism a preponderance of free cortisone over cortisol was registered. The ratios of the followed substances suggest in patients with peripheral vascular disease a detoriation in the normal excretion of the followed corticoids, based on a preponderance of 11-OH-corticosteroids over their 11-oxo-derivatives. This observation could be implicated in the mild hyperglycemia or decreased glucose tolerance, that is often found in atherosclerotic disease.