RESUMO
In this review, we aim to summarize knowledge about gestational diabetes mellitus (GDM) after delivery; with special focus on the potential of preventing Type 2 diabetes in a family context. The review expands on the key messages from a symposium held in Copenhagen in May 2017 and highlights avenues for future research. A narrative review of the symposium presentations and related literature is given. GDM is associated with increased short- and long-term adverse outcomes including Type 2 diabetes for both mother and offspring. Interestingly, GDM in mothers also predicts diabetes in the fathers. Thus, although GDM is diagnosed in pregnant women, the implications seem to affect the whole family. Structured lifestyle intervention can prevent or delay the onset of Type 2 diabetes. In this review, we show how numerous challenges are present in the target group, when such interventions are sought and implemented in real-world settings. Although interlinked and interacting, barriers to maintaining a healthy lifestyle post-partum can be grouped into those pertaining to diabetes beliefs, the family context and the healthcare system. Health literacy level and perceptions of health and disease risk may modify these barriers. There is a need to identify effective approaches to health promotion and health service delivery for women with prior GDM and their families. Future efforts may benefit from involving the target group in the development and execution of such initiatives as one way of ensuring that approaches are tailored to the needs of individual women and their families.
Assuntos
Diabetes Mellitus Tipo 2/prevenção & controle , Diabetes Gestacional/prevenção & controle , Dinamarca , Diabetes Mellitus Tipo 2/psicologia , Diabetes Gestacional/psicologia , Saúde da Família , Pai , Feminino , Doenças Fetais/etiologia , Doenças Fetais/prevenção & controle , Previsões , Conhecimentos, Atitudes e Prática em Saúde , Nível de Saúde , Estilo de Vida Saudável , Humanos , Masculino , Mães , Gravidez , Efeitos Tardios da Exposição Pré-Natal/etiologia , Efeitos Tardios da Exposição Pré-Natal/prevenção & controle , Recidiva , Fatores de Risco , Saúde da MulherRESUMO
AIMS: To assess young healthy men from rural India, who had normal or low birth weights, using magnetic resonance spectroscopy to determine the potential differences in ectopic fat storage between birth weight groups, and to determine if ectopic fat storage was associated with insulin resistance in this population. METHODS: A total of 54 lean men with normal birth weight and 49 lean men with low birth weight (age range 18-22 years) from rural India were recruited. All the men underwent anthropometry, magnetic resonance spectroscopy, a hyperinsulinaemic-euglycaemic clamp and a dual-energy X-ray absorptiometry. RESULTS: The median (interquartile range) values for hepatic cellular lipids, intramyocellular lipids and extramyocellular lipids, measured using magnetic resonance spectroscopy were 0.76 (0.1-1.8)%, 1.27 (1.0-2.3)% and 1.89 (1.3-3.2)%, respectively, for the normal birth weight group and 0.4 (0.1-1.3)%, 1.38 (0.9-2.2)% and 2.07 (1.2-2.8)%, respectively, for the low birth weight group (P > 0.05). No difference in ectopic fat storage was observed between the low and normal birth weight groups, with or without adjustment for age and total fat percentage. Homeostatic model assessment of insulin resistance values were not associated with hepatic cellular, intramyocellular or extramyocellular lipid content in any of the groups. Total fat percentage was the only independent predictor of intramyocellular and extramyocellular lipid content. CONCLUSION: Young and lean men from rural India with low birth weight were not observed to have ectopic fat storage in the liver or muscle, and the amount of liver and muscle fat was unrelated to insulin resistance. Older age and/or an urban affluent lifestyle may be required to show a potential role of ectopic fat storage on insulin resistance in Indian people with low or normal birth weight.
Assuntos
Adiposidade , Recém-Nascido de Baixo Peso/fisiologia , Resistência à Insulina/fisiologia , Fígado/metabolismo , Músculo Esquelético/metabolismo , Adolescente , Adulto , Humanos , Índia , Recém-Nascido , Metabolismo dos Lipídeos , Lipídeos/análise , Fígado/química , Espectroscopia de Ressonância Magnética , Masculino , Músculo Esquelético/química , População Rural , Adulto JovemRESUMO
Twenty years ago, Hales and Barker along with their co-workers published some of their pioneering papers proposing the 'thrifty phenotype hypothesis' in Diabetologia (4;35:595-601 and 3;36:62-67). Their postulate that fetal programming could represent an important player in the origin of type 2 diabetes, the metabolic syndrome and cardiovascular disease (CVD) was met with great scepticism.More recently, their observations have been confirmed and expanded in many epidemiological and animal experimental studies, and human integrative physiological studies have provided insights into some of the underlying molecular mechanisms. Type 2 diabetes is a multiple-organ disease, and developmental programming, with its idea of organ plasticity, is a plausible hypothesis for a common basis for the widespread organ dysfunctions in type 2 diabetes and the metabolic syndrome. Only two among the 45 known type 2 diabetes susceptibility genes are associated with low birthweight, indicating that the association between low birthweight and type 2 diabetes is mainly non-genetic. Prevention programmes targeting adult lifestyle factors seems unable to stop the global propagation of type 2 diabetes, and intensive glucose control is inadequate to reduce the excess CVD mortality in type 2 diabetic patients. Today, the thrifty phenotype hypothesis has been established as a promising conceptual framework for a more sustainable intergenerational prevention of type 2 diabetes.
Assuntos
Doenças Cardiovasculares/genética , Diabetes Mellitus Tipo 2/genética , Desenvolvimento Fetal/genética , Resistência à Insulina/genética , Síndrome Metabólica/genética , Fenótipo , Doenças Cardiovasculares/prevenção & controle , Diabetes Mellitus Tipo 2/prevenção & controle , Epigênese Genética , Feminino , Humanos , Masculino , Síndrome Metabólica/prevenção & controle , GravidezRESUMO
AIMS/HYPOTHESIS: Histone deacetylases (HDACs) are promising pharmacological targets in cancer and autoimmune diseases. All 11 classical HDACs (HDAC1-11) are found in the pancreatic beta cell, and HDAC inhibitors (HDACi) protect beta cells from inflammatory insults. We investigated which HDACs mediate inflammatory beta cell damage and how the islet content of these HDACs is regulated in recent-onset type 1 diabetes. METHODS: The rat beta cell line INS-1 and dispersed primary islets from rats, either wild type or HDAC1-3 deficient, were exposed to cytokines and HDACi. Molecular mechanisms were investigated using real-time PCR, chromatin immunoprecipitation and ELISA assays. Pancreases from healthy children and children with type 1 diabetes were assessed using immunohistochemistry and immunofluorescence. RESULTS: Screening of 19 compounds with different HDAC selectivity revealed that inhibitors of HDAC1, -2 and -3 rescued INS-1 cells from inflammatory damage. Small hairpin RNAs against HDAC1 and -3, but not HDAC2, reduced pro-inflammatory cytokine-induced beta cell apoptosis in INS-1 and primary rat islets. The protective properties of specific HDAC knock-down correlated with attenuated cytokine-induced iNos expression but not with altered expression of the pro-inflammatory mediators Il1α, Il1ß, Tnfα or Cxcl2. HDAC3 knock-down reduced nuclear factor κB binding to the iNos promoter and HDAC1 knock-down restored insulin secretion. In pancreatic sections from children with type 1 diabetes of recent onset, HDAC1 was upregulated in beta cells whereas HDAC2 and -3 were downregulated in comparison with five paediatric controls. CONCLUSIONS/INTERPRETATION: These data demonstrate non-redundant functions of islet class I HDACs and suggest that targeting HDAC1 and HDAC3 would provide optimal protection of beta cell mass and function in clinical islet transplantation and recent-onset type 1 diabetic patients.
Assuntos
Apoptose , Diabetes Mellitus Tipo 1/metabolismo , Histona Desacetilase 1/metabolismo , Inibidores de Histona Desacetilases/metabolismo , Histona Desacetilases/metabolismo , Células Secretoras de Insulina/metabolismo , Pâncreas/metabolismo , Animais , Apoptose/genética , Criança , Pré-Escolar , Citocinas , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/patologia , Feminino , Humanos , Lactente , Masculino , NF-kappa B/metabolismo , Pâncreas/patologia , RNA Interferente Pequeno , Ratos , Reação em Cadeia da Polimerase em Tempo Real , Regulação para CimaRESUMO
AIMS/HYPOTHESIS: Cytokine-induced beta cell toxicity is abrogated by non-selective inhibitors of lysine deacetylases (KDACs). The KDAC family consists of 11 members, namely histone deacetylases HDAC1 to HDAC11, but it is not known which KDAC members play a role in cytokine-mediated beta cell death. The aim of the present study was to examine the KDAC gene expression profile of the beta cell and to investigate whether KDAC expression is regulated by cytokines. In addition, the protective effect of the non-selective KDAC inhibitor ITF2357 and interdependent regulation of four selected KDACs were investigated. METHODS: The beta cell line INS-1 and intact rat and human islets were exposed to cytokines with or without ITF2357. Expression of mRNA was assessed by real-time PCR and selected targets validated at the protein level by immunoblotting. Effects on cytokine-induced toxicity were investigated by in vitro assays. RESULTS: Hdac1 to Hdac11 were expressed and differentially regulated by cytokines in INS-1 cells and rat islets. HDAC1, -2, -6 and -11 were found to be expressed and regulated by cytokines in human islets. ITF2357 protected against cytokine-induced beta cell apoptosis and counteracted cytokine-induced attenuation of basal insulin secretion. In addition, cytokine-induced regulation of Hdac2 and Hdac6, but not Hdac1 and Hdac11, was reduced by KDAC inhibition. CONCLUSIONS/INTERPRETATION: All classical KDAC genes are expressed by beta cells and differentially regulated by cytokines. Based on the relative expression levels and degree of regulation by cytokines, we propose that HDAC1, -2, -6 and -11 are of particular importance for beta cell function. These observations may help in the design of specific KDAC inhibitors to prevent beta cell destruction in situ and in islet grafts.
Assuntos
Citocinas/farmacologia , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Mediadores da Inflamação/farmacologia , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Lisina/metabolismo , Animais , Animais Recém-Nascidos , Apoptose/efeitos dos fármacos , Células Cultivadas , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Humanos , Ratos , Ratos Wistar , Fatores de TempoRESUMO
Individuals born small have an increased risk for developing type 2 diabetes. Altered food preferences in these subjects seem to play a role; however, limited evidence is available on the association between being born small-for-gestational-age (SGA) at term and food intake in adolescence. Alterations in leptin, ghrelin and dopamine levels are suggested mechanisms linking SGA with later food intake. From a large prospective Danish National Birth Cohort, we compared dietary intake of adolescents being born SGA with normal-for-gestational-age (NGA) adolescents. Intake of foods and nutrients was assessed by a validated food frequency questionnaire in a subsample of 15,607 14-year-old individuals born at term. SGA was defined by birth weight (BW) <10th percentile (n = 1470) and NGA as BW between 10 and 90th percentile (n = 14,137) according to sex and gestational age-specific BW standard curves. Girls born SGA had a 7% (95% CI: 3-12%, P = 0.002) higher intake of added sugar and a 2-8% lower intake of dietary fibre, vegetables, polyunsaturated fatty acids, and total n-6, compared with NGA girls (P < 0.05). Adjusting for parental socio-occupational status, maternal smoking and diet in pregnancy did not substantially change the differences in dietary intake, except from dietary fibre, which were no longer statistically significant. No significant differences in dietary intake between SGA and NGA boys were found. In summary, girls born SGA had an unfavourable dietary intake compared with NGA girls. These differences persisted after controlling for potential confounders, thus supporting a fetal programming effect on dietary intake in girls born SGA at term. However, residual confounding by other factors operating early in childhood cannot be excluded.
Assuntos
Comportamento do Adolescente/fisiologia , Dieta , Ingestão de Energia , Comportamento Alimentar/fisiologia , Desenvolvimento Fetal , Recém-Nascido Pequeno para a Idade Gestacional/crescimento & desenvolvimento , Adolescente , Adulto , Peso ao Nascer , Feminino , Humanos , Recém-Nascido , Masculino , Gravidez , Estudos ProspectivosRESUMO
Telomeres are protein-bound regions of repetitive nucleotide sequences (TTAGGG) at the end of human chromosomes, and their length is a marker of cellular aging. Intrauterine growth restriction is associated with shorter blood cell telomeres at birth and individuals with type 2 diabetes have shorter telomeres. Individuals with a low birth weight (LBW) have an increased risk of metabolic disease and type 2 diabetes. Therefore, we aimed to investigate the relationship between birth weight and telomere length and the association between birth weight, telomere length and cardiometabolic phenotype in adulthood. Young, healthy men with LBW (n = 55) and normal birth weight (NBW) (n = 65) were examined including blood pressure, blood samples and body composition. Leukocyte telomere length was determined using a high-throughput qPCR method. The LBW men were more insulin resistant as determined by the HOMA-IR index. There was no difference in telomere length between LBW and NBW subjects. When adjusting for birth weight and cohort effect, significant negative associations between telomere length and fasting glucose (P = 0.003) and HbA1c (P = 0.0008) were found. In conclusion, no significant difference in telomere length was found between LBW and NBW men. The telomere length was negatively associated with glucose concentrations and HbA1c levels within the normal non-diabetic range independent of birth weight.
Assuntos
Peso ao Nascer , Glicemia/genética , Hemoglobinas Glicadas/genética , Síndrome Metabólica/genética , Homeostase do Telômero , Adulto , Glicemia/metabolismo , Hemoglobinas Glicadas/metabolismo , Humanos , Recém-Nascido de Baixo Peso , Recém-Nascido , Leucócitos/metabolismo , Masculino , Síndrome Metabólica/sangue , Síndrome Metabólica/epidemiologiaAssuntos
Serpinas/sangue , Tecido Adiposo/metabolismo , Idoso , Idoso de 80 Anos ou mais , Envelhecimento , Dinamarca , Feminino , Genótipo , Intolerância à Glucose , Teste de Tolerância a Glucose , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Genéticos , RNA Mensageiro/metabolismo , Análise de Regressão , Gêmeos Dizigóticos , Gêmeos MonozigóticosRESUMO
AIM: Phosphatase and tensin homologue (PTEN) reduces insulin sensitivity by inhibiting the phosphatidylinositol 3-kinase (PI3K)/v-akt murine thymoma viral oncogene homologue (Akt) pathway. This study investigated how a common single nucleotide polymorphism near PTEN, previously associated with fasting levels of plasma insulin and glucose, influences in vivo glucose metabolism and insulin signalling. The primary outcome measure was the gene variant's association with peripheral glucose disposal rate and, secondarily, whether this association was explained by altered activities of PTEN targets PI3K and Akt. METHODS: A total of 183 normoglycaemic Danes, including 158 twins and 25 singletons, were genotyped for PTEN rs11202614, which is in complete linkage disequilibrium with rs2142136 and rs10788575, which have also been reported in association with glycaemic traits and type 2 diabetes (T2D). Hepatic and peripheral insulin sensitivity was measured using tracer and euglycaemic-hyperinsulinaemic clamp techniques; insulin secretion was assessed by intravenous glucose tolerance test; and muscle biopsies were taken during insulin infusion from 150 twins for measurement of PI3K and Akt activities. RESULTS: The minor G allele of PTEN rs11202614 was associated with elevated fasting plasma insulin levels and a decreased peripheral glucose disposal rate, but not with the hepatic insulin resistance index or insulin secretion measured as the first-phase insulin response and disposition index. The single nucleotide polymorphism was not associated with either PI3K or Akt activities. CONCLUSION: A common PTEN variation is associated with peripheral insulin resistance and subsequent risk of developing T2D. However, the association with insulin resistance is not explained by decreased proximal insulin signalling in skeletal muscle.
Assuntos
Resistência à Insulina/genética , PTEN Fosfo-Hidrolase/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Diabetes Mellitus Tipo 2/genética , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Técnica Clamp de Glucose , Teste de Tolerância a Glucose , Humanos , Insulina/metabolismo , Secreção de Insulina , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Cônjuges , GêmeosRESUMO
Physical inactivity and low birth weight (LBW) may lead to an increased risk for developing type 2 diabetes. The extent to which LBW individuals may benefit from physical exercise training when compared with those with normal birth weight (NBW) controls is uncertain. We assessed the impact of an outdoor exercise intervention on body composition, insulin secretion and action in young men born with LBW and NBW in rural India. A total of 61 LBW and 56 NBW healthy young men were recruited into the study. The individuals were instructed to perform outdoor bicycle exercise training for 45 min every day. Fasting blood samples, intravenous glucose tolerance tests and bioimpedance body composition assessment were carried out. Physical activity was measured using combined accelerometry and heart rate monitoring during the first and the last week of the intervention. Following the exercise intervention, the LBW group displayed an increase in physical fitness [55.0 ml (O2)/kg min (52.0-58.0)-57.5 ml (O2)/kg min (54.4-60.5)] level and total fat-free mass [10.9% (8.0-13.4)-11.4% (8.0-14.6)], as well as a corresponding decline in the ratio of total fat mass/fat-free mass. In contrast, an increase in total fat percentage as well as total fat mass was observed in the NBW group. After intervention, fasting plasma insulin levels, homoeostasis model assessments (HOMA) of insulin resistance (HOMA-IR) and insulin secretion (HOMA-IS), improved to the same extent in both the groups. In summary, young men born with LBW in rural India benefit metabolically from exercise training to an extent comparable with NBW controls.
Assuntos
Composição Corporal , Exercício Físico , Recém-Nascido de Baixo Peso , Resistência à Insulina , Acelerometria/métodos , Adolescente , Ciclismo , Diabetes Mellitus Tipo 2/epidemiologia , Frequência Cardíaca/fisiologia , Humanos , Índia/epidemiologia , Recém-Nascido , Masculino , População Rural , Adulto JovemRESUMO
OBJECTIVES: Using a unique twin approach, we examined the extent to which birth weight is determined by genetic and nongenetic factors and whether associations between birth weight and measures of glucose metabolism are of genetic or nongenetic origin. SETTING/SUBJECTS: An oral glucose tolerance test (OGTT) was performed in a population-based cohort of twins including 138 same-sex monozygotic (MZ) and 214 dizygotic (DZ) twin pairs aged 55-73 years whose birth weight was known. Heritability of birth weight was determined and regression analyses with intra-twin pair differences of birth weight and measures of glucose metabolism, with and without adjustment for adult obesity, were performed. RESULTS: The heritability of birth weight was estimated to be 38%. We demonstrated significant nongenetic associations between birth weight and measures of glucose homeostasis in MZ twins, with a reduction in fasting plasma glucose, 120 min post-OGTT plasma glucose, fasting plasma insulin and HOMA-IR index of 15.7%, 25.5%, 26.4% and 37.2%, respectively, for every 1 kg increase in birth weight. The nongenetic negative associations between birth weight and measures of glucose intolerance were independent of adult obesity, whereas the nongenetic association between birth weight and insulin resistance persisted, although not as strongly, after adjusting for current body size. CONCLUSIONS: We demonstrated a genetic component to birth weight in elderly twins. When adjusting for this influence, we found a nongenetic negative association between birth weight and glucose tolerance as well as insulin resistance that was partially independent of adult obesity. This implies that the foetal environment influences glucose homeostasis in elderly twins.
Assuntos
Peso ao Nascer/fisiologia , Doenças em Gêmeos/etiologia , Intolerância à Glucose/etiologia , Idoso , Antropometria , Peso ao Nascer/genética , Glicemia/metabolismo , Estudos de Coortes , Doenças em Gêmeos/embriologia , Doenças em Gêmeos/genética , Feminino , Intolerância à Glucose/embriologia , Intolerância à Glucose/genética , Teste de Tolerância a Glucose , Humanos , Recém-Nascido , Resistência à Insulina/genética , Resistência à Insulina/fisiologia , Masculino , Pessoa de Meia-Idade , Obesidade/complicações , Gêmeos Dizigóticos , Gêmeos MonozigóticosRESUMO
AIMS/HYPOTHESIS: We studied the impact of genetic versus pre- and postnatal environmental factors on the plasma levels of IL6, TNF and the soluble TNF receptor superfamily, member 1A (TNFRSF1A, previously known as TNF receptor type1 [TNFR1]). MATERIALS AND METHODS: Using the hyperinsulinaemic-euglycaemic clamp, we assessed the association between cytokine levels and both peripheral insulin sensitivity and hepatic glucose production. Fasting plasma IL6, TNF and soluble TNFRSF1A levels were measured using ELISA in 55 young and 43 elderly twin pairs. RESULTS: Plasma IL6 and TNF were influenced by genetic factors in young and elderly twins respectively, while no significant impact of genetics was found for soluble TNFRSF1A. Significant intra-twin pair correlations between birthweight and both IL6 and soluble TNFRSF1A levels were found. In addition to the effect of birthweight on IL6, age and fat % also significantly influenced IL6 levels, whereas soluble TNFRSF1A levels were significantly influenced by zygosity, age, fat % and sex. Plasma soluble TNFRSF1A was associated with higher plasma NEFA and to some extent with reduced insulin sensitivity. Plasma IL6 was associated positively with basal NEFA. TNF level was not associated with in vivo glucose or fat metabolism after correction for known confounders. CONCLUSIONS/INTERPRETATION: Plasma IL6 and soluble TNFRSF1A are influenced by the intrauterine environment. We found some evidence of a genetic component for TNF and IL6 in young and elderly twins respectively. Plasma IL6 may influence basal lipolysis, but neither plasma TNF nor IL6 levels are independently associated with hepatic or peripheral insulin action. Nevertheless, plasma soluble TNFRSF1A may play some role in the control of insulin action.
Assuntos
Envelhecimento/sangue , Insulina/fisiologia , Interleucina-6/sangue , Receptores Tipo I de Fatores de Necrose Tumoral/sangue , Fator de Necrose Tumoral alfa/análise , Adulto , Idoso , Envelhecimento/genética , Peso ao Nascer , Ensaio de Imunoadsorção Enzimática , Ácidos Graxos não Esterificados/sangue , Feminino , Glucose/metabolismo , Técnica Clamp de Glucose , Humanos , Insulina/genética , Resistência à Insulina/genética , Interleucina-6/genética , Fígado/metabolismo , Masculino , Pessoa de Meia-Idade , Gravidez , Receptores Tipo I de Fatores de Necrose Tumoral/genética , Caracteres Sexuais , Fator de Necrose Tumoral alfa/genética , Gêmeos Dizigóticos , Gêmeos MonozigóticosRESUMO
Numerous studies have shown an association between low weight at birth and being born small for gestational age (SGA) on the one hand and risk of developing insulin resistance and type 2 diabetes on the other. Our studies in twins have indicated a non-genetic age-dependent origin of insulin resistance and type 2 diabetes associated with being born SGA. In order to gain insight into the molecular metabolic defects and mechanisms linking SGA with insulin resistance and type 2 diabetes, we performed a series of experiments in young and elderly twins, and, in particular, in young men (aged 19-23 years) with a weight at birth at term in the lowest 10th percentile with no family history of diabetes. The control group included age-matched men with birth weights at term in the upper normal range. While body mass index and waist-to-hip ratios were similar in the individuals born SGA and controls, dual-energy X-ray absorptiometry studies documented a higher degree of abdominal obesity in the men who had a low weight at birth. Using the gold standard hyperinsulinaemic-euglycaemic clamp technique combined with glucose tracers and studies of forearm glucose uptake, we found an impairment of insulin-stimulated glycolytic flux and reduced forearm (muscle) glucose uptake in the face of normal whole-body glucose uptake. In addition, we found a significantly decreased insulin secretion rate during oral glucose ingestion after correction for insulin action (disposition index), a paradoxical enhanced insulin suppression of hepatic glucose production and lower fasting plasma glycerol levels, suggesting impaired lipolysis. Finally, analysis of skeletal muscle biopsies showed reduced muscle expression of several key proteins involved in insulin signalling and glucose transport, including protein kinase C-zeta, the two subunits of phosphoinositol 3-kinase (i.e., p85alpha and p110beta) and the insulin-sensitive glucose transporter, Glut-4, in individuals of low birth weight. In conclusion, being born SGA and of low birth weight is associated with type 2 diabetes in a non-genetic manner, and programming of muscle insulin action and signalling represents an early mechanism responsible for this association.
Assuntos
Recém-Nascido Pequeno para a Idade Gestacional/fisiologia , Resistência à Insulina/fisiologia , Tecido Adiposo/metabolismo , Adulto , Diabetes Mellitus Tipo 2/fisiopatologia , Feminino , Glucose/metabolismo , Homeostase , Humanos , Recém-Nascido , Fígado/metabolismo , Masculino , Músculo Esquelético/metabolismo , Gravidez , Estudos em Gêmeos como AssuntoRESUMO
AIMS/HYPOTHESIS: Individuals with low birthweight are at increased risk of type 2 diabetes mellitus. However, the underlying molecular mechanisms are unknown. Previously we have shown that low birthweight is associated with changes in muscle insulin signalling proteins. Here we determined whether low birthweight is associated with changes in insulin signalling proteins in adipose tissue. METHODS: Men (age 23 years) with either a low (bottom 10th percentile) (n = 17) or a normal (50th-90th percentile) (n = 17) birthweight were recruited from the Danish Medical Birth Registry and subcutaneous adipose biopsies were taken. RESULTS: Between the two groups there was no difference in protein level of the insulin receptor, protein kinase C zeta, glycogen synthase kinase-3 (GSK3) alpha, GSK3 beta, protein kinase B alpha and beta, peroxisome proliferative activated receptor gamma coactivator 1 or Src-homology-2-containing protein. However, the levels of GLUT4 (also known as solute carrier family 2 [facilitated glucose transporter], member 4 [SLC2A4]) (52 +/- 10.9% reduction, p < 0.01), p85alpha subunit of phosphoinositide 3-kinase (PI3K) (45 +/- 9% reduction, p < 0.01), p110ss subunit of PI3K (48 +/- 17% reduction, p = 0.06) and IRS1 (59 +/- 24% reduction, p < 0.05) were reduced in men of low birthweight. CONCLUSIONS/INTERPRETATION: These findings show that low birthweight is associated with reduced levels of adipose insulin signalling proteins, thus providing a potential molecular framework to explain why people with low birthweight are at increased risk of developing type 2 diabetes. These differences precede the development of diabetes and thus may help predict disease risk.
Assuntos
Proteínas Sanguíneas/metabolismo , Diabetes Mellitus Tipo 2/epidemiologia , Recém-Nascido de Baixo Peso , Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Adulto , Biópsia , Peso ao Nascer , Transportador de Glucose Tipo 4/genética , Quinase 3 da Glicogênio Sintase/genética , Humanos , Recém-Nascido , Masculino , Fosfatidilinositol 3-Quinases/genética , RNA Mensageiro/genética , Medição de RiscoRESUMO
Exercise-induced translocation of Na+-K+ pump subunits to the sarcolemmal membrane was studied using sarcolemmal giant vesicles as a membrane purification procedure. The subunit content was quantified by Western blotting or by ouabain labeling. Low-intensity treadmill running increased (P<0.01) the alpha1, alpha2, beta1, and beta2 subunit contents by 19-32% in membranes from oxidative muscle fibers and the alpha1, alpha2, and beta2 contents increased by 13-25% in membranes from glycolytic muscle fibers. Ouabain labeling of membranes from mixed fibers was increased by 29% after exercise. A similar increase in subunit content could be induced by 5 min of fatiguing, high-intensity electrical stimulation of isolated soleus muscles. An increased subunit content was just detectable in vesicles produced 30 min after exercise, and the content was completely back to control levels 3 h after exercise. It is concluded that both low-intensity long-lasting running and short-lasting high-intensity contractions are able to induce a translocation of pump subunits to the sarcolemmal membrane. The post-exercise disappearance of the extra subunits (half-time approximately 20 min) from the membrane demonstrates the reversible nature of the translocation process.