RESUMO
BACKGROUND: Although the ability of glucose to mediate its own in vivo metabolism is long documented, the quantitative measurement of whole body glucose-mediated glucose disposal at basal insulin levels (glucose effectiveness [GE]), followed the introduction of the Minimal Model intravenous glucose tolerance test technique. METHODS: A literature review, combined with our own studies, of the role of GE in glucose metabolism in normal and "at risk" individuals, was undertaken to determine GE's contribution to glucose homeostasis. RESULTS: GE accounts for ~45% to 65% of glucose disposal in man. A negative association between GE and insulin meditated glucose disposal (Si), is present in normal subjects without a family history of type 2 diabetes mellitus but is absent in normoglycaemic "at risk" relatives with a positive family history of diabetes mellitus. Intracellular GE disposal is mediated by mass action of glucose through the skeletal muscle membrane via facilitated Glut 4 transporters. However, GE is frequently forgotten as a significant contributor to the development of glucose intolerance in "at risk" individuals. Only limited studies have examined the role of a lower GE in such normoglycemic subjects with preexisting mild insulin resistance and ß-cell dysfunction. These studies demonstrate that in "at risk" individuals, an initial low GE is a key contributor and predictor of future glucose intolerance, whereas an initial raised GE is protective against future glucose intolerance. CONCLUSION: In "at risk" individuals, a low GE and genetically determined vulnerable ß-cell function are more critical determinants of future glucose intolerance than their preexisting insulin-resistant state.
Assuntos
Glicemia/metabolismo , Diabetes Mellitus Tipo 2/epidemiologia , Intolerância à Glucose/epidemiologia , Estado Pré-Diabético/epidemiologia , Austrália/epidemiologia , Diabetes Mellitus Tipo 2/metabolismo , Intolerância à Glucose/metabolismo , Teste de Tolerância a Glucose , Humanos , Resistência à Insulina , Estado Pré-Diabético/metabolismoRESUMO
AIM: To examine the association between early onset of type 2 diabetes mellitus (DM) and clinical and behavioural risk factors for later complications of diabetes. METHODS: We conducted a cross-sectional study of 5115 persons with incident type 2 DM enrolled during 2010-2015 in the Danish Centre for Strategic Research in Type 2 Diabetes-cohort. We compared risk factors at time of diagnosis among those diagnosed at ≤45 years (early onset) with diagnosis age 46 to 55, 56 to 65 (average onset = reference), 66 to 75, and >75 years (late onset). Prevalence ratios (PRs) were computed by using Poisson regression. RESULTS: Poor glucose control, ie, HbA1c ≥ 75 mmol/mol (≥9.0%) in the early-, average-, and late-onset groups was observed in 12%, 7%, and 1%, respectively (PR 1.70 [95% confidence intervals (CI) 1.27, 2.28] and PR 0.17 [95% CI 0.06, 0.45]). A similar age gradient was observed for severe obesity (body mass index > 40 kg/m2 : 19% vs. 8% vs. 2%; PR 2.41 [95% CI 1.83, 3.18] and 0.21 (95% CI 0.08, 0.57]), dyslipidemia (90% vs. 79% vs. 68%; PR 1.14 [95% CI 1.10, 1.19] and 0.86 [95% CI 0.79, 0.93]), and low-grade inflammation (C-reactive protein > 3.0 mg/L: 53% vs. 38% vs. 26%; PR 1.41 [95% CI 1.12, 1.78] and 0.68 [95% CI 0.42, 1.11]). Daily smoking was more frequent and meeting physical activity recommendations less likely in persons with early-onset type 2 DM. CONCLUSIONS: We found a clear age gradient, with increasing prevalence of clinical and behavioural risk factors the younger the onset age of type 2 DM. Younger persons with early-onset type 2 DM need clinical awareness and support.
Assuntos
Índice de Massa Corporal , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/epidemiologia , Fatores Etários , Idade de Início , Idoso , Estudos Transversais , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores de RiscoRESUMO
AIMS: To assess the difference between analogue and human insulin with regard to nocturnal glucose profiles and risk of hypoglycaemia in people with recurrent severe hypoglycaemia. METHODS: A total of 72 people [46 men, mean ± sd age 54 ± 12 years, mean ± sd HbA1c 65 ± 12 mmol/mol (8.1 ± 1.1%), mean ± sd duration of diabetes 30 ± 14 years], who participated in a 2-year randomized, crossover trial of basal-bolus therapy with insulin detemir/insulin aspart or human NPH insulin/human regular insulin (the HypoAna trial) were studied for 2 nights during each treatment. Venous blood was drawn hourly during sleep. Primary endpoints were nocturnal glucose profiles and occurrence of hypoglycaemia (blood glucose ≤ 3.9 mmol/l). RESULTS: During insulin analogue treatment, the mean nocturnal plasma glucose level was significantly higher than during treatment with human insulin (10.6 vs 8.1 mmol/l). The fasting plasma glucose level was similar between the treatments. Nocturnal hypoglycaemia was registered during 41/101 nights (41%) in the human insulin arm and 19/117 nights (16%) in the insulin analogue arm, corresponding to a hazard ratio of 0.26 (95% CI 0.14 to 0.45; P < 0.0001) with insulin analogue. CONCLUSIONS: Treatment with insulin analogue reduces the occurrence of nocturnal hypoglycaemia assessed by nocturnal glucose profiles in people with Type 1 diabetes prone to severe hypoglycaemia. Nocturnal glucose profiles provide a more comprehensive assessment of clinical benefit of insulin regimens as compared to conventional recording of hypoglycaemia.
Assuntos
Glicemia/efeitos dos fármacos , Diabetes Mellitus Tipo 1/tratamento farmacológico , Hipoglicemia/prevenção & controle , Insulina/análogos & derivados , Insulina/administração & dosagem , Adulto , Idoso , Glicemia/metabolismo , Ritmo Circadiano/efeitos dos fármacos , Estudos Cross-Over , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/epidemiologia , Feminino , Humanos , Hipoglicemia/induzido quimicamente , Hipoglicemia/epidemiologia , Insulina/efeitos adversos , Insulina Aspart/administração & dosagem , Insulina Aspart/efeitos adversos , Insulina Isófana/administração & dosagem , Insulina Isófana/efeitos adversos , Insulina de Ação Prolongada/administração & dosagem , Insulina de Ação Prolongada/efeitos adversos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Adulto JovemAssuntos
Biomarcadores/sangue , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/metabolismo , Inflamação/imunologia , Inflamação/metabolismo , Antígenos CD/sangue , Antígenos de Diferenciação Mielomonocítica/sangue , Proteína C-Reativa/análise , Criança , Feminino , Seguimentos , Humanos , Masculino , Lectina de Ligação a Manose/sangue , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Receptores de Superfície Celular/sangueRESUMO
AIM: Insulin analogues reduce the risk of hypoglycaemia compared with human insulin in patients with type 1 diabetes (T1D) and minor hypoglycaemia problems. The HypoAna trial showed that, in patients with recurrent severe hypoglycaemia, treatment based on insulin analogues reduces the risk of severe hypoglycaemia. The present study aims to assess whether this also applies to non-severe hypoglycaemia events during the day and at night. METHODS: This 2-year investigator-initiated multicentre, prospective, randomized, open, blinded endpoint (PROBE) trial involved patients with T1D and at least two episodes of severe hypoglycaemia during the previous year. Using a balanced crossover design, patients were randomized to basal-bolus therapy based on analogue (detemir/aspart) or human (NPH/regular) insulins. A total of 114 participants were included. Endpoints were the number of severe hypoglycaemic events and non-severe events, including documented symptomatic and asymptomatic episodes occurring during the day and at night (ClinicalTrials.gov number: NCT00346996). RESULTS: Analogue-based treatment resulted in a 6% (2-10%; P=0.0025) overall relative risk reduction of non-severe hypoglycaemia. This was due to a 39% (32-46%; P<0.0001) reduction of non-severe nocturnal hypoglycaemia, seen for both symptomatic (48% [36-57%]; P<0.0001) and asymptomatic (28% [14-39%]; P=0.0004) nocturnal hypoglycaemia episodes. No clinically significant differences in hypoglycaemia occurrence were observed between the insulin regimens during the day. The time needed to treat one patient with insulin analogues to avoid one episode (TNT1) of non-severe nocturnal hypoglycaemia was approximately 3 months. CONCLUSION: In T1D patients prone to severe hypoglycaemia, treatment with analogue insulin reduced the risk of non-severe nocturnal hypoglycaemia compared with human insulin.
Assuntos
Diabetes Mellitus Tipo 1/tratamento farmacológico , Hipoglicemia/induzido quimicamente , Hipoglicemia/epidemiologia , Hipoglicemiantes/efeitos adversos , Insulina/análogos & derivados , Insulina/efeitos adversos , Adulto , Idoso , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Estudos Cross-Over , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/epidemiologia , Suscetibilidade a Doenças , Feminino , Humanos , Hipoglicemiantes/administração & dosagem , Incidência , Insulina/administração & dosagem , Insulina Aspart/administração & dosagem , Insulina Aspart/efeitos adversos , Insulina Detemir/administração & dosagem , Insulina Detemir/efeitos adversos , Insulina Isófana/administração & dosagem , Insulina Isófana/efeitos adversos , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de DoençaRESUMO
Objective. Microvesicles (MVs) are small cell-derived particles shed upon activation. Familial hypercholesterolemia (FH) particularly when associated with Achilles tendon xanthomas (ATX) predisposes to atherosclerosis, possibly through oxLDL-C interaction with the CD36 receptor. To investigate the hypothesis that MVs derived from cells involved in atherosclerosis are increased in FH and that CD36 expressing MVs (CD36+ MVs) may be markers of oxLDL-C-induced cell activation, cell-specific MVs were measured in FH patients with and without ATX and their association with atherogenic lipid profile was studied. Approach and Results. Thirty FH patients with and without ATX and twenty-three controls were included. Plasma concentrations of MVs and CD36+ MVs derived from platelets (PMVs), erythrocytes (ErytMVs), monocytes (MMVs), and endothelial cells (EMVs), as well as tissue factor-positive cells (TF+ MVs), were measured by flow cytometry. Total MVs, MMVs, EMVs, ErytMVs, and TF+ MVs were significantly increased in FH patients, compared to controls. CD36+ MVs derived from endothelial cells and monocytes were significantly higher in FH patients and oxLDL-C predicted all the investigated cell-specific CD36+ MVs in FH patients with ATX. Conclusions. MVs derived from cells involved in atherosclerosis were increased in FH and may contribute to elevated atherothrombosis risk. The increased cell-specific CD36+ MVs observed in FH may represent markers of oxLDL-C-induced cell activation.
Assuntos
Micropartículas Derivadas de Células/metabolismo , Hiperlipoproteinemia Tipo II/metabolismo , Lipoproteínas/metabolismo , Estresse Oxidativo , Tendão do Calcâneo/patologia , Antígenos CD36/metabolismo , Feminino , Citometria de Fluxo , Humanos , Hiperlipoproteinemia Tipo II/complicações , Hiperlipoproteinemia Tipo II/patologia , Lipoproteínas LDL/metabolismo , Masculino , Pessoa de Meia-Idade , Análise de Regressão , Xantomatose/complicações , Xantomatose/patologiaRESUMO
AIM: To examine prescribing practices and predictors of glucose-lowering therapy within the first year following diagnosis of Type 2 diabetes mellitus in a clinical care setting. METHODS: We followed people enrolled in the Danish Centre for Strategic Research in Type 2 Diabetes (DD2) cohort from outpatient hospital clinics and general practices throughout Denmark in 2010-2013. We used Poisson regression to compute age- and gender-adjusted risk ratios (RRs). RESULTS: Among 1158 new Type 2 diabetes mellitus patients, 302 (26%) did not receive glucose-lowering therapy within the first year, 723 (62%) received monotherapy [685 (95%) with metformin], and 133 (12%) received more than one drug. Predictors of receiving any vs. no therapy and combination vs. monotherapy were: age < 40 years [RR: 1.29 (95% CI: 1.16-1.44) and 3.60 (95% CI: 2.36-5.50)]; high Charlson Comorbidity Index [RRs: 1.20 (95% CI: 1.05-1.38) and 2.08 (95% CI: 1.16-3.72)]; central obesity [RRs: 1.23 (95% CI: 1.04-1.44) and 1.93 (95% CI: 0.76-4.94)]; fasting blood glucose of ≥ 7.5 mmol/l [RRs: 1.25 (95% CI: 1.10-1.42) and 1.94 (95% CI: 1.02-3.71)]; and HbA1c ≥ 59 mmol/mol (≥ 7.5%) [RR: 1.26 (95% CI: 1.20-1.32) and 2.86 (95% CI: 1.97-4.14)]. Weight gain ≥ 30 kg since age 20, lack of physical exercise and C-peptide of < 300 pmol/l also predicted therapy. CONCLUSIONS: Comorbidity, young age, central obesity and poor baseline glycaemic control are important predictors of therapy one year after Type 2 diabetes mellitus debut.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hiperglicemia/prevenção & controle , Hipoglicemiantes/uso terapêutico , Padrões de Prática Médica , Adulto , Fatores Etários , Idoso , Índice de Massa Corporal , Estudos de Coortes , Dinamarca , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Quimioterapia Combinada , Feminino , Seguimentos , Clínicos Gerais , Médicos Hospitalares , Humanos , Masculino , Metformina/uso terapêutico , Pessoa de Meia-Idade , Obesidade Abdominal/complicações , Ambulatório Hospitalar , Estudos Prospectivos , Sistema de RegistrosAssuntos
Insuficiência Adrenal/sangue , Hormônio Adrenocorticotrópico , Diabetes Mellitus Tipo 1/sangue , Hipoglicemia/sangue , Insuficiência Adrenal/epidemiologia , Adulto , Idoso , Comorbidade , Diabetes Mellitus Tipo 1/epidemiologia , Feminino , Humanos , Hipoglicemia/epidemiologia , Masculino , Pessoa de Meia-IdadeRESUMO
OBJECTIVE: To examine mortality and hospitalisations among infant twins and singletons after the perinatal period in Guinea-Bissau. METHODS: The study was conducted from September 2009 to November 2012 by the Bandim Health Project (BHP). Newborn twins and unmatched singleton controls were included at the National Hospital Simão Mendes in the capital Bissau. Children were examined clinically at enrolment. Maternal, pregnancy and obstetric information was collected and HIV testing offered at birth. Follow-up occurred at home at 2, 6 and 12 months and through linkage with the paediatric admission register at the National Hospital. RESULTS: About 495 twins and 333 singletons were alive on day 7 after birth. In total, 36 twins and 12 singletons died during follow-up, the post-perinatal infant mortality rate being 91/1000 person-years for twins and 42/1000 for singletons (HR = 2.11, 95% CI: 1.09-4.07). In a multivariable analysis among twins only, birth weight <2000 g [3.32, (1.36-8.07)], death of the cotwin perinatally [2.54, (1.16-5.57)] and severe maternal illness during pregnancy [2.35, (1.00-5.51)] were significant risk factors for twin death. In the subgroup with available HIV status, maternal HIV infection was strongly associated with twin mortality [3.16, (1.24-8.05)]. Death occurred at home for 60% of twins and 67% of singletons. During follow-up, 90 first-time hospital admissions were registered, with similar rates observed for twins (139/1000) and singletons (143/1000) [0.97, (0.61-1.52)]. CONCLUSION: The post-perinatal infant mortality rate of twins was double that of singletons. No excess in twin hospitalisations was observed, possibly implying obstacles to hospital admission for twins in case of severe illness.
Assuntos
Hospitalização , Mortalidade Infantil , Gêmeos , Adulto , Peso ao Nascer , Feminino , Guiné-Bissau/epidemiologia , Infecções por HIV/complicações , Humanos , Lactente , Recém-Nascido , Masculino , Mortalidade Perinatal , Gravidez , Complicações na Gravidez , Estudos Prospectivos , Fatores de Risco , Adulto JovemRESUMO
AIMS: The Lifestyle in Pregnancy intervention in obese pregnant women resulted in significantly lower gestational weight gain compared with the control group, but without improvement in rates of clinical pregnancy complications. The impact of the lifestyle intervention on metabolic measurements in the study participants is now reported. METHODS: The Lifestyle in Pregnancy study was a randomized controlled trial among 360 obese women (BMI 30-45 kg/m²) who were allocated in early pregnancy to lifestyle interventions with diet counselling and physical activities or to the control group. Fasting blood samples, including plasma glucose, insulin, lipid profile and capillary blood glucose during a 2-h oral glucose tolerance test were carried out three times throughout pregnancy. Insulin resistance was estimated with the homeostasis model assessment of insulin resistance. RESULTS: Three hundred and four women (84%) were followed until delivery. Women in the intervention group had a significantly lower change in insulin resistance (HOMA-IR) from randomization to 28-30 weeks' gestation compared with control subjects (mean ± SD: 0.7 ± 1.3 vs. 1.0 ± 1.3, P = 0.02). Despite a significantly lower gestational weight gain in the intervention group, there was no difference between the groups with respect to total cholesterol, HDL, LDL or triglycerides. CONCLUSIONS: Lifestyle intervention in obese pregnant women resulted in attenuation of the physiologic pregnancy-induced insulin resistance. Despite restricted gestational weight gain, there were no changes in glucose or lipid metabolism between the groups.
Assuntos
Promoção da Saúde , Estilo de Vida , Obesidade Mórbida/terapia , Obesidade/terapia , Complicações na Gravidez/terapia , Adolescente , Adulto , Índice de Massa Corporal , Terapia Combinada , Dinamarca/epidemiologia , Diabetes Gestacional/epidemiologia , Diabetes Gestacional/etiologia , Diabetes Gestacional/prevenção & controle , Feminino , Humanos , Hiperlipidemias/epidemiologia , Hiperlipidemias/etiologia , Hiperlipidemias/prevenção & controle , Resistência à Insulina , Fenômenos Fisiológicos da Nutrição Materna , Atividade Motora , Política Nutricional , Obesidade/sangue , Obesidade/metabolismo , Obesidade/fisiopatologia , Obesidade Mórbida/sangue , Obesidade Mórbida/metabolismo , Obesidade Mórbida/fisiopatologia , Educação de Pacientes como Assunto , Gravidez , Complicações na Gravidez/metabolismo , Complicações na Gravidez/fisiopatologia , Complicações na Gravidez/prevenção & controle , Risco , Aumento de Peso , Adulto JovemRESUMO
AIMS: Reduced glucose effectiveness is a predictor of future glucose tolerance in individuals with a family history of type 2 diabetes. We examined retrospectively at 10 years in normoglycemic relatives of diabetic subjects (RELs) the pathophysiological role of glucose effectiveness in the development of isolated impaired fasting glucose, glucose intolerance, and acute insulin release. METHODS: At 0 years, 19 RELs and 18 matched control subjects had glucose effectiveness (GE), insulin sensitivity, acute insulin release (AIR)IVGTT, and disposition index measured during an iv glucose tolerance test (IVGTT), using the minimal model analysis. At 0 and 10 years, oral glucose tolerance (OGTT) and AIROGTT were determined. RESULTS: At 0 years, fasting glucose (FG) and GE were raised in RELs, but insulin sensitivity and AIROGTT were reduced (P ≤ .05) compared with controls. At 10 years, RELs developed raised fasting and 2-hour OGTT glucose. FG10y correlated significantly with FG0y and body mass index0y and negatively with âGE and 2-hour OGTT glucose10y with FG0y and negatively with AIRIVGTT0y and AIROGTT0y. Log AIROGTT10y correlated with âGE, log AIRIVGTT0y and log AIROGTT0y. Multiple regression analyses demonstrated the following: REL FG10y was predicted by combined FG0y, âGE and body mass index0y (radj(2) = 56%; P ≤ .001) and 2-hour OGTT glucose10y weakly related by FG0y,and âGE (r(adj)(2) = 25%; P = .06). Log AIROGTT10y was predicted by AIRIVGTT0y and âGE (r(adj)(2) = 46%; P ≤ .004). CONCLUSION: In normoglycemic RELs, a relative reduction of glucose effectiveness is an important contributor over 10 years to the development of isolated impaired fasting glucose and reduced acute insulin secretion.
Assuntos
Glicemia/metabolismo , Diabetes Mellitus Tipo 2 , Intolerância à Glucose/epidemiologia , Células Secretoras de Insulina/fisiologia , Adulto , Estudos de Casos e Controles , Família , Feminino , Seguimentos , Intolerância à Glucose/metabolismo , Teste de Tolerância a Glucose , Humanos , Resistência à Insulina , Masculino , Estado Pré-Diabético/epidemiologia , Estado Pré-Diabético/metabolismo , Estudos RetrospectivosRESUMO
AIMS/HYPOTHESIS: This study is a 19 year observational follow-up of a pragmatic open multicentre cluster-randomised controlled trial of 6 years of structured personal diabetes care starting from diagnosis. METHODS: A total of 1,381 patients aged ≥ 40 years and newly diagnosed with type 2 diabetes were followed up in national registries for 19 years. Clinical follow-up was at 6 and 14 years after diabetes diagnosis. The original 6 year intervention included regular follow-up and individualised goal setting, supported by prompting of doctors, clinical guidelines, feedback and continuing medical education (ClinicalTrials.gov NCT01074762). The registry-based endpoints were: incidence of any diabetes-related endpoint; diabetes-related death; all-cause mortality; myocardial infarction (MI); stroke; peripheral vascular disease; and microvascular disease. RESULTS: At 14 year clinical follow-up, group differences in risk factors from the 6 year follow-up had levelled out, although the prevalence of (micro)albuminuria and level of triacylglycerols were lower in the intervention group. During 19 years of registry-based monitoring, all-cause mortality was not different between the intervention and comparison groups (58.9 vs 62.3 events per 1,000 patient-years, respectively; for structured personal care, HR 0.94, 95% CI 0.83, 1.08, p = 0.40), but a lower risk emerged for fatal and non-fatal MI (27.3 vs 33.5, HR 0.81, 95% CI 0.68, 0.98, p = 0.030) and any diabetes-related endpoint (69.5 vs 82.1, HR 0.83, 95% CI 0.72, 0.97, p = 0.016). These differences persisted after extensive multivariable adjustment. CONCLUSIONS/INTERPRETATION: In concert with features such as prompting, feedback, clinical guidelines and continuing medical education, individualisation of goal setting and drug treatment may safely be applied to treat patients newly diagnosed with type 2 diabetes to lower the risk of diabetes complications.
Assuntos
Diabetes Mellitus Tipo 2/terapia , Autocuidado , Adulto , Idoso , Complicações do Diabetes/diagnóstico , Diabetes Mellitus Tipo 2/mortalidade , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Infarto do Miocárdio/complicações , Infarto do Miocárdio/diagnóstico , Sistema de Registros , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Triglicerídeos/sangueRESUMO
OBJECTIVES: To examine the impact of maternal pregestational body mass index (BMI) and smoking on neonatal abdominal circumference (AC) and weight at birth. To define reference curves for birth AC and weight in offspring of healthy, nonsmoking, normal weight women. DESIGN: Population-based study. SETTING: Data from the Danish Medical Birth Registry. POPULATION: All live singletons without congenital malformations in Denmark 2004-10. METHODS: Data on 366,886 singletons at 35(+0) to 41(+6) weeks(+days) of gestation were extracted and analysed using multivariate linear regressions. MAIN OUTCOME MEASURES: Birth AC and weight in relation to pregestational maternal BMI, maternal smoking and medical conditions (any). RESULTS: Birth AC and weight increased with increasing pregestational BMI, and decreased with smoking (P < 0.0001). Reference curves were created for offspring of healthy, nonsmoking mothers with normal pregestational BMI. Mean AC ranged from 30.1 cm and 30.2 cm at 35 weeks of gestation to 33.9 cm and 34.1 cm at 41 weeks of gestation, for girls and boys, respectively. Mean birthweight ranged from 2581 and 2666 g at 35 weeks to 3705 and 3852 g at 41 weeks of gestation for girls and boys, respectively. Pregestational BMI correlated more to the Z score of birthweight than to the Z score of AC (P < 0.0001). CONCLUSION: Birth AC and weight are affected by maternal smoking status and pregestational BMI. Pregestational BMI correlated more to birthweight than to AC. Using data from healthy, nonsmoking mothers with normal pregestational BMI we have provided new reference curves for birth AC and birthweight.
Assuntos
Índice de Massa Corporal , Circunferência da Cintura/fisiologia , Peso ao Nascer/fisiologia , Dinamarca/epidemiologia , Feminino , Idade Gestacional , Humanos , Recém-Nascido , Masculino , Obesidade/epidemiologia , Cuidado Pré-Concepcional , Gravidez , Complicações na Gravidez/epidemiologia , Valores de Referência , Sistema de Registros , Fumar/epidemiologiaRESUMO
AIMS/HYPOTHESIS: Low birthweight (BW) is associated with increased risk of type 2 diabetes. We compared glucose metabolism in adult BW-discordant monozygotic (MZ) twins, thereby controlling for genetic factors and rearing environment. METHODS: Among 77,885 twins in the Danish Twin Registry, 155 of the most BW-discordant MZ twin pairs (median BW difference 0.5 kg) were assessed using a 2 h oral glucose tolerance test with sampling of plasma (p-)glucose, insulin, C-peptide, glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1. HOMA for beta cell function (HOMA-ß) and insulin resistance (HOMA-IR), and also insulin sensitivity index (BIGTT-SI) and acute insulin response (BIGTT-AIR), were calculated. Subgroup analyses were performed in those with: (1) double verification of BW difference; (2) difference in BW >0.5 kg; and (3) no overt metabolic disease (type 2 diabetes, hyperlipidaemia or thyroid disease). RESULTS: No intra-pair differences in p-glucose, insulin, C-peptide, incretin hormones, HOMA-ß, HOMA-IR or BIGTT-SI were identified. p-Glucose at 120 min was higher in the twins with the highest BW without metabolic disease, and BIGTT-AIR was higher in those with the highest BW although not in pairs with a BW difference of >0.5 kg. CONCLUSIONS/INTERPRETATION: BW-discordant MZ twins provide no evidence for a detrimental effect of low BW on glucose metabolism in adulthood once genetic factors and rearing environment are controlled for.
Assuntos
Peso ao Nascer , Glicemia/metabolismo , Peptídeo C/sangue , Diabetes Mellitus Tipo 2/sangue , Suscetibilidade a Doenças/sangue , Peptídeo 1 Semelhante ao Glucagon/sangue , Gêmeos Monozigóticos , Adulto , Idoso , Análise de Variância , Dinamarca/epidemiologia , Diabetes Mellitus Tipo 2/epidemiologia , Suscetibilidade a Doenças/epidemiologia , Feminino , Intolerância à Glucose , Teste de Tolerância a Glucose , Humanos , Recém-Nascido de Baixo Peso , Recém-Nascido , Resistência à Insulina , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Inquéritos e QuestionáriosRESUMO
BACKGROUND AND PURPOSE: Oral salmon calcitonin (sCT), a dual-action amylin and calcitonin receptor agonist, improved glucose homeostasis in diet-induced obese rats. Here, we have evaluated the anti-diabetic efficacy of oral sCT using parameters of glycaemic control and beta-cell morphology in male Zucker diabetic fatty (ZDF) rats, a model of type 2 diabetes. EXPERIMENTAL APPROACH: Male ZDF rats were treated with oral sCT (0.5, 1.0 or 2 mg·kg(-1) ) or oral vehicle twice daily from age 8 to 18 weeks. Zucker lean rats served as control group. Fasting and non-fasted blood glucose, glycosylated haemoglobin (HbA1c) and levels of pancreas and incretin hormones were determined. Oral glucose tolerance test and i.p. glucose tolerance test were compared, and beta-cell area and function were evaluated. KEY RESULTS: Oral sCT treatment dose-dependently attenuated fasting and non-fasted hyperglycaemia during the intervention period. At the end of the study period, oral sCT treatment by dose decreased diabetic hyperglycaemia by â¼9 mM and reduced HbA1c levels by 1.7%. Furthermore, a pronounced reduction in glucose excursions was dose-dependently observed for oral sCT treatment during oral glucose tolerance test. In addition, oral sCT treatment sustained hyperinsulinaemia and attenuated hyperglucagonaemia and hypersecretion of total glucagon-like peptide-1 predominantly in the basal state. Lastly, oral sCT treatment dose-dependently improved pancreatic beta-cell function and beta-cell area at study end. CONCLUSIONS AND IMPLICATIONS: Oral sCT attenuated diabetic hyperglycaemia in male ZDF rats by improving postprandial glycaemic control, exerting an insulinotropic and glucagonostatic action in the basal state and by preserving pancreatic beta-cell function and beta-cell area.
Assuntos
Calcitonina/administração & dosagem , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hiperglicemia/tratamento farmacológico , Hipoglicemiantes/administração & dosagem , Células Secretoras de Insulina/efeitos dos fármacos , Administração Oral , Animais , Glicemia/análise , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Polipeptídeo Inibidor Gástrico/sangue , Peptídeo 1 Semelhante ao Glucagon/sangue , Teste de Tolerância a Glucose , Hemoglobinas Glicadas/análise , Hiperglicemia/metabolismo , Hiperglicemia/patologia , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patologia , Masculino , Ratos , Ratos ZuckerRESUMO
AIMS/HYPOTHESIS: In type 2 diabetes, reduced insulin-stimulated glucose disposal, primarily glycogen synthesis, is associated with defective insulin activation of glycogen synthase (GS) in skeletal muscle. Hyperglycaemia may compensate for these defects, but to what extent it involves improved insulin signalling to glycogen synthesis remains to be clarified. METHODS: Whole-body glucose metabolism was studied in 12 patients with type 2 diabetes, and 10 lean and 10 obese non-diabetic controls by means of indirect calorimetry and tracers during a euglycaemic-hyperinsulinaemic clamp. The diabetic patients underwent a second isoglycaemic-hyperinsulinaemic clamp maintaining fasting hyperglycaemia. Muscle biopsies from m. vastus lateralis were obtained before and after the clamp for examination of GS and relevant insulin signalling components. RESULTS: During euglycaemia, insulin-stimulated glucose disposal, glucose oxidation and non-oxidative glucose metabolism were reduced in the diabetic group compared with both control groups (p < 0.05). This was associated with impaired insulin-stimulated GS and AKT2 activity, deficient dephosphorylation at GS sites 2 + 2a, and reduced Thr308 and Ser473 phosphorylation of AKT. When studied under hyperglycaemia, all variables of insulin-stimulated glucose metabolism were normalised compared with the weight-matched controls. However, insulin activation and dephosphorylation (site 2 + 2a) of GS as well as activation of AKT2 and phosphorylation at Thr308 and Ser473 remained impaired (p < 0.05). CONCLUSIONS/INTERPRETATIONS: These data confirm that hyperglycaemia compensates for decreased whole-body glucose disposal in type 2 diabetes. In contrast to previous less well-controlled studies, we provide evidence that the compensatory effect of hyperglycaemia in patients with type 2 diabetes does not involve normalisation of insulin action on GS or upstream signalling in skeletal muscle.
Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Glucose/metabolismo , Glicogênio Sintase/metabolismo , Hiperglicemia/metabolismo , Insulina/administração & dosagem , Músculo Esquelético/enzimologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Feminino , Técnica Clamp de Glucose , Humanos , Masculino , Pessoa de Meia-Idade , Fosforilação , Serina/metabolismo , Treonina/metabolismoRESUMO
AIMS/HYPOTHESIS: The molecular mechanisms underlying insulin resistance in skeletal muscle are incompletely understood. Here, we aimed to obtain a global picture of changes in protein abundance in skeletal muscle in obesity and type 2 diabetes, and those associated with whole-body measures of insulin action. METHODS: Skeletal muscle biopsies were obtained from ten healthy lean (LE), 11 obese non-diabetic (OB), and ten obese type 2 diabetic participants before and after hyperinsulinaemic-euglycaemic clamps. Quantitative proteome analysis was performed by two-dimensional differential-gel electrophoresis and tandem-mass-spectrometry-based protein identification. RESULTS: Forty-four protein spots displayed significant (p < 0.05) changes in abundance by at least a factor of 1.5 between groups. Several proteins were identified in multiple spots, suggesting post-translational modifications. Multiple spots containing glycolytic and fast-muscle proteins showed increased abundance, whereas spots with mitochondrial and slow-muscle proteins were downregulated in the OB and obese type 2 diabetic groups compared with the LE group. No differences in basal levels of myosin heavy chains were observed. The abundance of multiple spots representing glycolytic and fast-muscle proteins correlated negatively with insulin action on glucose disposal, glucose oxidation and lipid oxidation, while several spots with proteins involved in oxidative metabolism and mitochondrial function correlated positively with these whole-body measures of insulin action. CONCLUSIONS/INTERPRETATION: Our data suggest that increased glycolytic and decreased mitochondrial protein abundance together with a shift in muscle properties towards a fast-twitch pattern in the absence of marked changes in fibre-type distribution contribute to insulin resistance in obesity with and without type 2 diabetes. The roles of several differentially expressed or post-translationally modified proteins remain to be elucidated.
Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Resistência à Insulina/fisiologia , Mitocôndrias/metabolismo , Músculo Esquelético/metabolismo , Obesidade/metabolismo , Feminino , Técnica Clamp de Glucose , Glicólise , Humanos , Insulina/metabolismo , Masculino , Pessoa de Meia-Idade , Proteômica , Espectrometria de Massas em TandemRESUMO
OBJECTIVES: Insulin resistance is associated with increased CD36 expression in a number of tissues. Moreover, excess macrophage CD36 may initiate atherosclerotic lesions. The aim of this study was to determine whether plasma soluble CD36 (sCD36) was associated with insulin resistance, fatty liver and carotid atherosclerosis in nondiabetic subjects. METHODS: In 1296 healthy subjects without diabetes or hypertension recruited from 19 centres in 14 European countries (RISC study), we determined the levels of sCD36, adiponectin, lipids and liver enzymes, insulin sensitivity (M/I) by euglycaemic-hyperinsulinaemic clamp, carotid atherosclerosis as intima-media thickness (IMT) and two estimates of fatty liver, the fatty liver index (FLI) and liver fat percentage (LF%). RESULTS: IMT, FLI, LF%, presence of the metabolic syndrome, impaired glucose regulation, insulin and triglycerides increased across sCD36 quartiles (Q2-Q4), whereas adiponectin and M/I decreased (P ≤ 0.01). sCD36 was lower in women than in men (P = 0.045). Log sCD36 showed a bimodal distribution, and amongst subjects with sCD36 within the log-normal distribution (log-normal population, n = 1029), sCD36 was increased in subjects with impaired glucose regulation (P = 0.045), metabolic syndrome (P = 0.006) or increased likelihood of fatty liver (P < 0.001). sCD36 correlated significantly with insulin, triglycerides, M/I and FLI (P < 0.05) after adjustment for study centre, gender, age, glucose tolerance status, smoking habits and alcohol consumption. In the log-normal population, these relationships were stronger than in the total study population and, additionally, sCD36 was significantly associated with LF% and IMT (P < 0.05). CONCLUSIONS: In this cross-sectional study of nondiabetic subjects, sCD36 was significantly associated with indices of insulin resistance, carotid atherosclerosis and fatty liver. Prospective studies are needed to further evaluate the role of sCD36 in the inter-relationship between atherosclerosis, fatty liver and insulin resistance.
Assuntos
Aterosclerose/sangue , Antígenos CD36/sangue , Diabetes Mellitus/sangue , Fígado Gorduroso/sangue , Resistência à Insulina/fisiologia , Adulto , Algoritmos , Biomarcadores/sangue , Índice de Massa Corporal , Estudos de Coortes , Estudos Transversais , Ensaio de Imunoadsorção Enzimática , Europa (Continente) , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos ProspectivosRESUMO
INTRODUCTION: The effect of insulin analogues on glycaemic control is well-documented, whereas the effect on avoidance of severe hypoglycaemia remains tentative. We studied the frequency of severe hypoglycaemia in unselected patients with type 1 diabetes treated with insulin analogues, human insulin, or mixed regimens. METHODS: A questionnaire was posted from six Danish diabetes clinics to 6112 unselected patients with type 1 diabetes and filled in by 3861 patients (63.2%). Primary endpoint was number of episodes of severe hypoglycaemia in the preceding year. Mild hypoglycaemia was also reported. RESULTS: The frequency of severe hypoglycaemic episodes per patient-year in patients receiving long-acting insulin analogues was 1.47±0.18 versus 1.09±0.10 in patients on long-acting human insulin (p=0.01). The frequency of severe hypoglycaemic episodes per patient-year was 1.09±0.11 in patients on short-acting insulin analogues versus 1.26±0.13 in patients on short-acting human insulin (p=0.15), which was statistically significant in an adjusted analysis. CONCLUSIONS: Severe hypoglycaemia is more frequent in patients with type 1 diabetes treated with long-acting insulin analogues. Confounding by indication may be involved. Clinical intervention trials using insulin analogues in patients prone to severe hypoglycaemia are highly needed.
Assuntos
Hipoglicemia/induzido quimicamente , Hipoglicemiantes/efeitos adversos , Insulina/análogos & derivados , Insulina/uso terapêutico , Adulto , Glicemia/efeitos dos fármacos , Estudos Transversais , Diabetes Mellitus Tipo 1 , Feminino , Humanos , Insulina/efeitos adversos , Insulina de Ação Prolongada/efeitos adversos , Insulina de Ação Prolongada/uso terapêutico , Masculino , Pessoa de Meia-IdadeRESUMO
AIMS/HYPOTHESIS: There is substantial evidence that mitochondrial dysfunction is linked to insulin resistance and is present in several tissues relevant to the pathogenesis of type 2 diabetes. Here, we examined whether common variation in genes involved in oxidative phosphorylation (OxPhos) contributes to type 2 diabetes susceptibility or influences diabetes-related metabolic traits. METHODS: OxPhos gene variants (n = 10) that had been nominally associated (p < 0.01) with type 2 diabetes in a recent genome-wide meta-analysis (n = 10,108) were selected for follow-up in 3,599 type 2 diabetic and 4,956 glucose-tolerant Danish individuals. A meta-analysis of these variants was performed in 11,729 type 2 diabetic patients and 43,943 non-diabetic individuals. The impact on OGTT-derived metabolic traits was evaluated in 5,869 treatment-naive individuals from the Danish Inter99 study. RESULTS: The minor alleles of COX10 rs9915302 (p = 0.02) and COX5B rs1466100 (p = 0.005) showed nominal association with type 2 diabetes in our Danish cohort. However, in the meta-analysis, none of the investigated variants showed a robust association with type 2 diabetes after correction for multiple testing. Among the alleles potentially associated with type 2 diabetes, none negatively influenced surrogate markers of insulin sensitivity in non-diabetic participants, while the minor alleles of UQCRC1 rs2228561 and COX10 rs10521253 showed a weak (p < 0.01 to p < 0.05) negative influence on indices of glucose-stimulated insulin secretion. CONCLUSIONS/INTERPRETATION: We cannot rule out the possibility that common variants in or near OxPhos genes may influence beta cell function in non-diabetic individuals. However, our quantitative trait studies and a sufficiently large meta-analysis indicate that common variation in proximity to the examined OxPhos genes is not a major cause of insulin resistance or type 2 diabetes.