Correction to: Sex differences in the association between plasma copeptin and incident type 2 diabetes: the Prevention of Renal and Vascular Endstage Disease (PREVEND) study.

The values given for copeptin levels in men in quartiles 1 and 2 (Table 1) were incorrect, and should have read.

Impact of maternal body mass index and gestational weight gain on pregnancy complications: an individual participant data meta-analysis of European, North American and Australian cohorts.

OBJECTIVE: To assess the separate and combined associations of maternal pre-pregnancy body mass index (BMI) and gestational weight gain with the risks of pregnancy complications and their population impact. DESIGN: Individual participant data meta-analysis of 39 cohorts. SETTING: Europe, North America, and Oceania. POPULATION: 265 270 births. METHODS: Information on maternal pre-pregnancy BMI, gestational weight gain, and pregnancy complications was obtained. Multilevel binary logistic regression models were used. MAIN OUTCOME MEASURES: Gestational hypertension, pre-eclampsia, gestational diabetes, preterm birth, small and large for gestational age at birth. RESULTS: Higher maternal pre-pregnancy BMI and gestational weight gain were, across their full ranges, associated with higher risks of gestational hypertensive disorders, gestational diabetes, and large for gestational age at birth. Preterm birth risk was higher at lower and higher BMI and weight gain. Compared with normal weight mothers with medium gestational weight gain, obese mothers with high gestational weight gain had the highest risk of any pregnancy complication (odds ratio 2.51, 95% CI 2.31- 2.74). We estimated that 23.9% of any pregnancy complication was attributable to maternal overweight/obesity and 31.6% of large for gestational age infants was attributable to excessive gestational weight gain. CONCLUSIONS: Maternal pre-pregnancy BMI and gestational weight gain are, across their full ranges, associated with risks of pregnancy complications. Obese mothers with high gestational weight gain are at the highest risk of pregnancy complications. Promoting a healthy pre-pregnancy BMI and gestational weight gain may reduce the burden of pregnancy complications and ultimately the risk of maternal and neonatal morbidity. TWEETABLE ABSTRACT: Promoting a healthy body mass index and gestational weight gain might reduce the population burden of pregnancy complications.

Associations between maternal physical activity in early and late pregnancy and offspring birth size: remote federated individual level meta-analysis from eight cohort studies.

OBJECTIVE: Evidence on the impact of leisure time physical activity (LTPA) in pregnancy on birth size is inconsistent. We aimed to examine the association between LTPA during early and late pregnancy and newborn anthropometric outcomes. DESIGN: Individual level meta-analysis, which reduces heterogeneity across studies. SETTING: A consortium of eight population-based studies (seven European and one US) comprising 72 694 participants. METHODS: Generalised linear models with consistent inclusion of confounders (gestational age, sex, parity, maternal age, education, ethnicity, BMI, smoking, and alcohol intake) were used to test associations between self-reported LTPA at either early (8-18 weeks gestation) or late pregnancy (30+ weeks) and the outcomes. Results were pooled using random effects meta-analyses. MAIN OUTCOME MEASURES: Birth weight, large-for-gestational age (LGA), macrosomia, small-for-gestational age (SGA), % body fat, and ponderal index at birth. RESULTS: Late, but not early, gestation maternal moderate to vigorous physical activity (MVPA), vigorous activity, and LTPA energy expenditure were modestly inversely associated with BW, LGA, macrosomia, and ponderal index, without heterogeneity (all: I2  = 0%). For each extra hour/week of MVPA, RR for LGA and macrosomia were 0.97 (95% CI: 0.96, 0.98) and 0.96 (95% CI: 0.94, 0.98), respectively. Associations were only modestly reduced after additional adjustments for maternal BMI and gestational diabetes. No measure of LTPA was associated with risk for SGA. CONCLUSIONS: Physical activity in late, but not early, pregnancy is consistently associated with modestly lower risk of LGA and macrosomia, but not SGA. TWEETABLE ABSTRACT: In an individual participant meta-analysis, late pregnancy moderate to vigorous physical activity modestly reduced birth size outcomes.

An activity stimulation programme during a child's first year reduces some indicators of adiposity at the age of two-and-a-half.

AIM: Obesity tracks from childhood into adulthood. We evaluated the effect of early stimulation of physical activity on growth, body composition, motor activity and motor development in toddlers. METHODS: We performed a cluster randomised controlled single-blinded trial in Dutch Well Baby Clinics, with seven nurses and 96 children (40% girls) randomised to the intervention group and six nurses and 65 children (57% girls) to the control group. Intervention nurses advised parents on stimulating motor development and physical activity during regular visits at 2 weeks and two, four, eight and 11 months. Baseline characteristics such as birthweight and mode of feeding were comparable. Outcomes at two-and-a-half years included anthropometry, skinfold thicknesses, bioelectrical impedance analyses, motor development and daily physical activity. We used linear mixed models with nurses as cluster. RESULTS: We evaluated 143 children (89 intervention, 54 control) as 18 dropped out. Skinfolds were significantly lower in intervention children (29.6 ± 4.7 mm) than controls (32.4 ± 6.0 mm), without differences in motor development or daily physical activity. Female interventions showed lower weight, skinfolds, waist and hip circumference. CONCLUSION: An activity stimulating programme during the child's first year improved indicators of adiposity when they were toddlers, especially in girls. Further research should determine whether these effects persist.

A multidisciplinary intervention programme has positive effects on quality of life in overweight and obese preschool children.

AIM: Up to 18.1% of Dutch children aged 3-5 are overweight and up to 3.3% are obese, with higher levels in girls. This study assessed the effect of a multidisciplinary intervention programme on health-related quality of life (HRQoL) in this patient group. METHODS: We randomised 75 children to a multidisciplinary intervention, comprising dietary advice, exercise sessions and psychological counselling for parents or the standard care programme, providing healthy lifestyle advice. The parents completed quality of life and child health questionnaires at baseline and after 16 weeks and 12 months. RESULTS: At 16 weeks, children in the intervention group experienced more bodily pain and less mental health than the standard care group, but at 12 months, this difference disappeared and they showed a more positive change in HRQoL than the standard care group, especially for the physical domain. When we combined both groups, a decreased BMIz-score over 12 months was associated with increased global health and reduced visceral fat correlated with increased general health. CONCLUSION: At 12 months, a multidisciplinary intervention programme for overweight and obese children aged 3-5 years had beneficial effects on HRQoL, especially for the physical domain. Reduced obesity parameters correlated with several increased HRQoL parameters.

Longitudinal measurement of physical activity following kidney transplantation.

The purpose of this longitudinal observational study was to (i) examine the change of daily physical activity in 28 adult kidney transplant recipients over the first 12 months following transplantation; and (ii) to examine the change in metabolic characteristics and renal function. Accelerometer-based daily physical activity and metabolic- and clinical characteristics were measured at six wk (T1), three months (T2), six months (T3) and 12 months (T4) following transplantation. Linear mixed effect analyses showed an increase in steps/d (T1 = 6326 ± 2906; T4 = 7562 ± 3785; F = 3.52; p = 0.02), but one yr after transplantation only 25% achieved the recommended 10 000 steps/d. There was no significant increase in minutes per day spent on moderate-to-vigorous intensity physical activity (T1 = 80.4 ± 63.6; T4 = 93.2 ± 55.1; F = 1.71; p = 0.17). Body mass index increased over time (T1 = 25.4 ± 3.2; T4 = 27.2 ± 3.8; F = 12.62; p < 0.001), mainly due to an increase in fat percentage (T1 = 30.3 ± 8.0; T4 = 34.0 ± 7.9; F = 14.63; p < 0.001). There was no significant change in renal function (F = 0.17; p = 0.92). Although the recipients increased physical activity, the majority did not meet the recommended levels of physical activity after one yr. In addition to the weight gain, this may result in negative health consequences. Therefore, it is important to develop strategies to support kidney transplant recipients to comply with healthy lifestyle recommendations, including regular physical activity.

Effects of paternal and maternal lifestyle factors on pregnancy complications and perinatal outcome. A population-based birth-cohort study: the GECKO Drenthe cohort.

STUDY QUESTION: Do paternal and maternal lifestyle factors influence the risk of hypertensive pregnancy complications, gestational diabetes mellitus (GDM), spontaneous preterm birth and small-for-gestational-age (SGA)? SUMMARY ANSWER: Paternal lifestyle factors do not exert an independent effect on the investigated outcomes while maternal prepregnancy BMI and maternal smoking during pregnancy influence the risk of hypertensive pregnancy complications, GDM and SGA. WHAT IS KNOWN ALREADY: Maternal lifestyle factors are associated with perinatal complications, but the impact of paternal lifestyle factors is unclear. STUDY DESIGN, SIZE, DURATION: Data from the GECKO (Groningen Expert Center for Kids with Obesity) Drenthe cohort, a prospective population-based birth-cohort of children born between April 2006 and April 2007 in a northern province of The Netherlands, were analysed. The parents of 2958 children (62% of those approached) gave their consent to participate in the study and the data of 2264 (77%) couples were available for analysis. PARTICIPANTS/MATERIALS, SETTINGS, METHOD: All pregnant women in the Dutch province of Drenthe with an expected date of delivery between April 2006 and April 2007 were invited to participate and included during the third trimester of their pregnancy or within 6 months after delivery. All consenting couples received extensive questionnaires including lifestyle, biological and socio-demographic-related questions covering the period of 6 months prior to conception. Outcome data were obtained from midwives and hospital registries. Univariable and multivariable logistic regression analyses were used to determine the impact of the lifestyle factors on the primary outcome measures. MAIN RESULTS AND THE ROLE OF CHANCE: Of all 2264 women, 241 women (10.6%) developed a hypertensive pregnancy complication, 50 women (2.2%) developed GDM, 79 (3.5%) children were spontaneously delivered preterm and 155 children (6.8%) were SGA. All paternal and maternal lifestyle factors were positively correlated. Multivariable analysis showed that paternal lifestyle factors did not have an independent influence on the investigated outcomes. Of the maternal factors, prepregnancy BMI was independently associated with an increased risk of a hypertensive disorder during pregnancy (odds ratio (OR): 1.12, 95% CI 1.09-1.16), a higher risk of GDM (OR BMI >23 kg/m(2), per BMI unit: 1.13, 95% CI 1.08-1.18) and with a decreased risk of SGA (OR per BMI point 0.94, 95% CI 0.90-0.99). Maternal smoking during pregnancy was significantly associated with SGA (OR 3.00, 95% CI 1.80-4.99) in multivariable analysis. LIMITATIONS, REASONS FOR CAUTION: The retrospective nature of the questionnaire may have induced recall bias. Selection bias might have occurred, as ethnic minorities were less willing to co-operate in the GECKO Drenthe study. The possibility of misclassification bias regarding the primary outcome measures cannot be ruled out. Inclusion bias might have occurred as not all questionnaires of the parents of the children participating in the GECKO Drenthe cohort were completed. WIDER IMPLICATIONS OF THE FINDINGS: Paternal lifestyle factors do not have an independent effect on the investigated adverse pregnancy outcomes. However, as paternal and maternal lifestyles are positively correlated, both partners should be involved in preconception counselling regarding the investigated outcome measures.

Skipping breakfast and overweight in 2- and 5-year-old Dutch children-the GECKO Drenthe cohort.

Skipping breakfast is associated with higher BMI in children aged 5 years and older. However, not much is known about this association in younger children. In the Dutch GECKO Drenthe birth cohort we examined the association between breakfast skipping and objectively measured overweight at the age of 2 (n=1488) and 5 (n=1366) years. At 2 years, 124 (8.3%) children were overweight and 44 (3.0%) did not eat breakfast daily. At 5 years, 180 (13.2%) children were overweight and 73 (5.3%) did not eat breakfast daily. Children belonging to families of non-Dutch origin, those with lower educated parents and those with single parents skipped breakfast more often. Breakfast skipping in 2- and 5-year-olds is rare in the Netherlands. We found no association between skipping breakfast and overweight, neither at age 2 (odds ratio (OR): 1.85 (95% confidence interval (CI): 0.61-5.64)) nor at age 5 (OR: 0.46 (95% CI: 0.19-1.11)). Also the type of breakfast was not related to overweight at 5 years. An explanation for this finding might be that skipping breakfast is not (yet) an issue in these children.

Prevention of the metabolic syndrome in IGT subjects in a lifestyle intervention: results from the SLIM study.

BACKGROUND AND AIMS: The Study on Lifestyle intervention and Impaired glucose tolerance Maastricht (SLIM), a randomized controlled trial, directed at diet and physical activity in impaired glucose tolerant subjects was effective to improve glucose tolerance and prevent type 2 diabetes. The aim of this study was to determine the effects of the SLIM lifestyle intervention on the incidence and prevalence of the metabolic syndrome (MetS) during the active intervention and four years thereafter. METHODS AND RESULTS: MetS was diagnosed according to the NCEP ATP III criteria. At baseline, 66.4% of all participants (n = 146, age 57 ± 7 years, BMI 29.7 ± 3.6, 51.3% female) fulfilled the criteria for MetS. No significant difference in MetS prevalence was observed between the intervention (63.9%) and control group (68.9%). At the end of active intervention (average duration 4.2 ± 2.0 years), prevalence of MetS was significantly lower in the intervention group (52.6%, n = 57) compared to the control group (74.6%, n = 59) (p = 0.014). Furthermore, in participants without MetS at baseline, cumulative incidence of MetS was 18.2% in the intervention group at the end of active intervention, compared to 73.7% in the control group (Log-rank test, p = 0.011). Four years after stopping active intervention, the reduced incidence of MetS was maintained (Log-rank test, p = 0.002). CONCLUSION: In conclusion, a combined diet-and-exercise intervention to improve glucose tolerance, not only prevented type 2 diabetes, but also reduced the prevalence of MetS and prevented MetS development, showing the long-term impact of lifestyle intervention on cardiovascular risk reduction.

Sex differences in the association between plasma copeptin and incident type 2 diabetes: the Prevention of Renal and Vascular Endstage Disease (PREVEND) study.

AIMS/HYPOTHESIS: Vasopressin plays a role in osmoregulation, glucose homeostasis and inflammation. Therefore, plasma copeptin, the stable C-terminal portion of the precursor of vasopressin, has strong potential as a biomarker for the cardiometabolic syndrome and diabetes. Previous results were contradictory, which may be explained by differences between men and women in responsiveness of the vasopressin system. The aim of this study was to evaluate the usefulness of copeptin for prediction of future type 2 diabetes in men and women separately. METHODS: From the Prevention of Renal and Vascular Endstage Disease (PREVEND) study, 4,063 women and 3,909 men without diabetes at baseline were included. A total of 208 women and 288 men developed diabetes during a median follow-up of 7.7 years. RESULTS: In multivariable-adjusted models, we observed a stronger association of copeptin with risk of future diabetes in women (OR 1.49 [95% CI 1.24, 1.79]) than in men (OR 1.01 [95% CI 0.85, 1.19]) (p (interaction) < 0.01). The addition of copeptin to the Data from the Epidemiological Study on the Insulin Resistance Syndrome (DESIR) clinical model improved the discriminative value (C-statistic,+0.007, p = 0.02) and reclassification (integrated discrimination improvement [IDI] = 0.004, p < 0.01) in women. However, we observed no improvement in men. The additive value of copeptin in women was maintained when other independent predictors, such as glucose, high sensitivity C-reactive protein (hs-CRP) and 24 h urinary albumin excretion (UAE), were included in the model. CONCLUSIONS/INTERPRETATION: The association of plasma copeptin with the risk of developing diabetes was stronger in women than in men. Plasma copeptin alone, and along with existing biomarkers (glucose, hs-CRP and UAE), significantly improved the risk prediction for diabetes in women.

Predictors of lifestyle intervention outcome and dropout: the SLIM study.

BACKGROUND/OBJECTIVES: To evaluate the effect of a 4.1-year (range 3-6 years) lifestyle intervention according to general public health recommendations on glucose tolerance and dropout in a Dutch population with impaired glucose tolerance (IGT). SUBJECTS/METHODS: In the Study on Lifestyle intervention and Impaired glucose tolerance Maastricht, 147 Caucasian IGT subjects were randomized to an intervention group (INT: n=74; 38 male, 36 female) and control group (CON: n=73; 37 male, 36 female). Annually, subjects underwent measurements of body weight, anthropometry, glucose tolerance (oral glucose tolerance test), insulin resistance (homeostasis model assessment-insulin resistance), maximal aerobic capacity (VO(2) max), blood lipids and blood pressure. INT received individual advice regarding a healthy diet and physical activity. RESULTS: INT decreased their saturated fat intake, increased their carbohydrate intake (P<0.05) and VO(2) max (P=0.04) compared with CON. Body weight did not change significantly (P=0.20) between the groups. After an initial decrease, 2-h glucose levels overall increased in INT (+0.11 mmol/l), but significantly less than CON (+1.18 mmol/l; P=0.04). Diabetes incidence was lower in INT versus CON (30 versus 56%, P=0.04). Change in body weight was associated with change in 2-h glucose levels (ß=0.399 mmol/l per kg, P=0.02). Dropouts had a lower aerobic fitness and socioeconomic status, and a higher body mass index (BMI) and 2-h glucose compared with non-dropouts. CONCLUSIONS: Prolonged feasible changes in diet and physical activity prevent deterioration of glucose tolerance and reduce diabetes risk. Low socioeconomic status, low aerobic fitness and high BMI and 2-h glucose are indicative of dropout to the program.

Maternal and paternal transmission of type 2 diabetes: influence of diet, lifestyle and adiposity.

OBJECTIVE: Transmission of family history of type 2 diabetes to the next generation is stronger for maternal than paternal diabetes in some populations. The aim of the present study was to investigate whether this difference is explained by diet, lifestyle factors and/or adiposity. METHODS: We analysed 35174 participants from the Dutch contribution to the European Prospective Investigation into Cancer and Nutrition, a prospective population-based cohort (aged 20-70 years) with a median follow-up of 10.2 years. Parental history of diabetes was self-reported. Occurrence of diabetes was mainly identified by self-report and verified by medical records. RESULTS: Amongst 35174 participants, 799 incident cases of diabetes were observed. In age- and sex-adjusted analyses, hazard ratio (HR) and 95% confidence intervals (CIs) for diabetes by maternal and paternal diabetes were 2.66 (2.26-3.14) and 2.40 (1.91-3.02), respectively. Maternal transmission of risk of diabetes was explained by diet (9.4%), lifestyle factors including smoking, alcohol consumption, physical activity and educational level (7.8%) and by adiposity, i.e. body mass index and waist and hip circumference (23.5%). For paternal transmission, the corresponding values were 2.9%, 0.0% and 9.6%. After adjustment for diet, lifestyle factors and adiposity, the HRs for maternal (2.20; 95% CI, 1.87-2.60) and paternal (2.23; 95% CI, 1.77-2.80) transmission of diabetes were comparable. CONCLUSIONS: Both maternal and paternal diabetes are associated with increased risk of type 2 diabetes, independently of diet, lifestyle and adiposity. The slightly higher risk conferred by maternal compared to paternal diabetes was explained by a larger contribution of diet, lifestyle factors and adiposity.

Expression of genes involved in lipid metabolism in men with impaired glucose tolerance: impact of insulin stimulation and weight loss.

BACKGROUND: The impaired glucose tolerance (IGT) state is characterized by insulin resistance. Disturbances in fatty acid (FA) metabolism may underlie this reduced insulin sensitivity. The aim of this study was to investigate whether the prediabetic state is accompanied by changes in the expression of genes involved in FA handling during fasting and in insulin-mediated conditions and to study the impact of weight loss. METHODS: Seven IGT men and 5 men with normal glucose tolerance (NGT), comparable in terms of age and BMI, participated in the study. The 5 IGT men followed a 12-week weight loss program. Muscle biopsies were taken and the expression of 6 genes was investigated. RESULTS: Subjects had a reduction of 15.5 ± 4.3 kg in body weight. Baseline gene expression was not different between NGT and IGT men. After a hyperinsulinemic clamp, there was an overall upregulation of PGC1α, SREBP-1c, SREBP-2, and ACC-2. The upregulation of SREBP-2 was more pronounced in IGT men (p = 0.049). Weight loss significantly increased insulin sensitivity by 71%, which was not reflected in altered gene expression profiles. CONCLUSIONS: SREBP-2 shows altered insulin responsiveness in IGT men compared with NGT men, while there were no differences in basal gene expression.

Markers of the hepatic component of the metabolic syndrome as predictors of mortality in renal transplant recipients.

Cardiovascular disease (CVD) is a leading cause of mortality in renal transplant recipients (RTRs). Metabolic syndrome (MS) is highly prevalent in RTRs. Nonalcoholic fatty liver disease (NAFLD) is considered the hepatic component of MS. We investigated associations of NAFLD markers with MS and mortality. RTRs were investigated between 2001 and 2003. NAFLD markers, alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT) and alkaline phosphatase (AP) were measured. Bone and nonbone fractions of AP were also determined. Death was recorded until August 2007. Six hundred and two RTRs were studied (age 52+/-12 years, 55% men). At baseline 388 RTRs had MS. Prevalence of MS was positively associated with liver enzymes. During follow-up for 5.3[4.5-5.7] years, 95 recipients died (49 cardiovascular). In univariate Cox regression analyses, GGT (HR=1.43[1.21-1.69], p<0.001) and AP (HR=1.34[1.11-1.63], p=0.003) were associated with mortality, whereas ALT was not. Similar associations were found for cardiovascular mortality. Adjustment for potential confounders, including MS, diabetes and traditional risk factors did not materially change these associations. Results for nonbone AP mirrored that for total AP. ALT, GGT and AP are associated with MS. Of these three enzymes, GGT and AP are associated with mortality, independent of MS. These findings suggest that GGT and AP are independently related to mortality in RTRs.

Metabolic flexibility in the development of insulin resistance and type 2 diabetes: effects of lifestyle.

Lipotoxicity in skeletal muscle plays a critical role in the aetiology of insulin resistance and type 2 diabetes mellitus by interference of lipid metabolites with insulin signalling and action. The dynamics of lipid oxidation and fine tuning with fatty acid uptake and intramyocellular triacylglycerol turnover may be very important to limit the accumulation of lipid intermediates. The use of metabolic inflexibility, defined as the impaired capacity to increase fat oxidation upon increased fatty acid availability and to switch between fat and glucose as the primary fuel source after a meal, does more justice to the complexity of changes in fuel oxidation during the day. Fatty acid availability, uptake and oxidation all play a role in metabolic flexibility and insulin resistance. During high fatty acid availability, fatty acid transporters may limit cellular and mitochondrial fatty acid uptake and thus limit fat oxidation. After a meal, when the demand for fatty acids as fuel is low, an increased fractional extraction of lipids from plasma may promote intramyocellular lipid accumulation and insulin resistance. Furthermore, defects in fuel switching cluster together with impaired mitochondrial content and/or function. Lifestyle changes in dietary fat intake, physical activity and weight loss may improve metabolic flexibility in skeletal muscle, and thereby contribute to the prevention of type 2 diabetes.

Impact of 3-year lifestyle intervention on postprandial glucose metabolism: the SLIM study.

OBJECTIVE: To determine the effect of a 3-year diet and exercise lifestyle intervention, based on general public health recommendations, on glucose tolerance, insulin resistance and metabolic cardiovascular risk factors in Dutch subjects with impaired glucose tolerance (IGT). METHODS: The study was a randomized controlled lifestyle intervention over 3 years. A total of 147 IGT subjects (75 male, 72 female) were randomized to the intervention (INT) group or control (CON) group; 106 subjects (52 INT, 54 CON) completed 3 years of intervention. Annually, glucose, insulin and free fatty acid (FFA) concentrations were determined fasting and after an oral glucose tolerance test. Measurements of body weight, serum lipids, blood pressure and maximal aerobic capacity were also performed. RESULTS: Analysis of those who completed the 3-year trial, showed that the lifestyle intervention improved body weight (INT -1.08 +/- 4.30 kg; CON +0.16 +/- 4.91 kg, P = 0.01), homeostatis model assessment index for insulin resistance and 2-h FFA. Two-hour glucose concentrations improved in the INT group, the difference being most pronounced after 1 year, with a return to baseline values after 3 years, from 8.59 +/- 1.55 to 8.55 +/- 0.34 mm; in contrast, 2-h glucose deteriorated in the CON group-from 8.46 +/- 1.84 to 9.35 +/- 2.50 mm (P = 0.02). In the INT group, diabetes incidence was reduced by 58% (P = 0.025). CONCLUSION: Our lifestyle intervention showed a sustained beneficial effect on 2-h glucose concentrations, insulin resistance and 2-h FFA, even after 3 years. Our lifestyle intervention is effective, but for implementation more information is needed about factors influencing adherence.

Insulin acutely upregulates protein expression of the fatty acid transporter CD36 in human skeletal muscle in vivo.

Enhanced fatty acid uptake may lead to the accumulation of lipid intermediates. This is related to insulin resistance and type 2 diabetes mellitus. Rodent studies suggest that fatty acid transporters are acutely regulated by insulin. We investigated differences in fatty acid transporter content before and at the end of a hyperinsulinemic euglycemic clamp in skeletal muscle (m. vastus lateralis) of obese, glucose-intolerant men (IGT) and obese normal glucose tolerant controls (NGT). The fatty acid transporter FAT/CD36 protein content increased 1.5-fold (P < 0.05) after 3-hrs of insulin stimulation with no difference between IGT and control subjects. No change was seen in cytosolic fatty acid binding protein (FABPc) protein content. The increase in FAT/CD36 protein content was positively related to insulin resistance as measured during the clamp (r = 0.56, P < 0.05). An increase in FAT/CD36 protein content in skeletal muscle may result in a higher fractional extraction of fatty acids (larger relative uptake) after a meal, enhancing triglyceride accumulation in the muscle. We conclude that also in obese humans the FAT/CD36 protein content in skeletal muscle is dynamically regulated by insulin in vivo on the short term.

Direct association of a promoter polymorphism in the CD36/FAT fatty acid transporter gene with Type 2 diabetes mellitus and insulin resistance.

AIMS: The membrane-bound fatty acid transporter CD36/FAT may play a role in disturbed fatty acid handling as observed in the metabolic syndrome and Type 2 diabetes mellitus (T2DM). Genetic variation in the CD36 gene may contribute to the aetiology of diabetes. METHODS: A population-based cohort in the Netherlands [age > 40 years and body mass index (BMI) > 25 kg/m2] of 675 subjects was phenotyped with respect to glucose metabolism with an oral glucose tolerance test and was genotyped for a known 478C-->T substitution and a C/T snp in the upstream promoter region (rs1527479) in the CD36 gene. RESULTS: T2DM was more prevalent in the TT genotype than in the CC genotype. This was most pronounced in women and in subjects with a high BMI (BMI > 27 kg/m2). In addition, within the group of diabetic patients, the TT genotype was commoner in subjects with increased homeostasis model assessment (HOMA) index for insulin resistance. The 478C-->T substitution, previously found in the Japanese population, was not found in our caucasian population. CONCLUSIONS: This is the first study to show a direct association of a CD36 snp with T2DM. Moreover, within the diabetic subjects, this CD36 snp was associated with insulin resistance (HOMA index).