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Contains fulltext : 225860.pdf (publisher's version ) (Open Access), Short-term fasting protects tumor-bearing mice against the toxic effects of chemotherapy while enhancing therapeutic efficacy. We randomized 131 patients with HER2-negative stage II/III breast cancer, without diabetes and a BMI over 18 kg m(-2), to receive either a fasting mimicking diet (FMD) or their regular diet for 3 days prior to and during neoadjuvant chemotherapy. Here we show that there was no difference in toxicity between both groups, despite the fact that dexamethasone was omitted in the FMD group. A radiologically complete or partial response occurs more often in patients using the FMD (OR 3.168, P = 0.039). Moreover, per-protocol analysis reveals that the Miller&Payne 4/5 pathological response, indicating 90-100% tumor-cell loss, is more likely to occur in patients using the FMD (OR 4.109, P = 0.016). Also, the FMD significantly curtails chemotherapy-induced DNA damage in T-lymphocytes. These positive findings encourage further exploration of the benefits of fasting/FMD in cancer therapy. Trial number: NCT02126449.

Background: COVID-19 is a global challenge to healthcare. Obesity is common in patients with COVID-19 and seems to aggravate disease prognosis. In this review we explore the link between obesity, chronic disease, lifes

Contains fulltext : 225860.pdf (publisher's version ) (Open Access), Short-term fasting protects tumor-bearing mice against the toxic effects of chemotherapy while enhancing therapeutic efficacy. We randomized 131 patients with HER2-negative stage II/III breast cancer, without diabetes and a BMI over 18 kg m(-2), to receive either a fasting mimicking diet (FMD) or their regular diet for 3 days prior to and during neoadjuvant chemotherapy. Here we show that there was no difference in toxicity between both groups, despite the fact that dexamethasone was omitted in the FMD group. A radiologically complete or partial response occurs more often in patients using the FMD (OR 3.168, P = 0.039). Moreover, per-protocol analysis reveals that the Miller&Payne 4/5 pathological response, indicating 90-100% tumor-cell loss, is more likely to occur in patients using the FMD (OR 4.109, P = 0.016). Also, the FMD significantly curtails chemotherapy-induced DNA damage in T-lymphocytes. These positive findings encourage further exploration of the benefits of fasting/FMD in cancer therapy. Trial number: NCT02126449.

Contains fulltext : 225860.pdf (publisher's version ) (Open Access), Short-term fasting protects tumor-bearing mice against the toxic effects of chemotherapy while enhancing therapeutic efficacy. We randomized 131 patients with HER2-negative stage II/III breast cancer, without diabetes and a BMI over 18 kg m(-2), to receive either a fasting mimicking diet (FMD) or their regular diet for 3 days prior to and during neoadjuvant chemotherapy. Here we show that there was no difference in toxicity between both groups, despite the fact that dexamethasone was omitted in the FMD group. A radiologically complete or partial response occurs more often in patients using the FMD (OR 3.168, P = 0.039). Moreover, per-protocol analysis reveals that the Miller&Payne 4/5 pathological response, indicating 90-100% tumor-cell loss, is more likely to occur in patients using the FMD (OR 4.109, P = 0.016). Also, the FMD significantly curtails chemotherapy-induced DNA damage in T-lymphocytes. These positive findings encourage further exploration of the benefits of fasting/FMD in cancer therapy. Trial number: NCT02126449.

Contains fulltext : 207351.pdf (publisher's version ) (Open Access)

Contains fulltext : 207115.pdf (publisher's version ) (Open Access), Growing preclinical evidence shows that short-term fasting (STF) protects from toxicity while enhancing the efficacy of a variety of chemotherapeutic agents in the treatment of various tumour types. STF reinforces stress resistance of healthy cells, while tumor cells become even more sensitive to toxins, perhaps through shortage of nutrients to satisfy their needs in the context of high proliferation rates and/or loss of flexibility to respond to extreme circumstances. In humans, STF may be a feasible approach to enhance the efficacy and tolerability of chemotherapy. Clinical research evaluating the potential of STF is in its infancy. This review focuses on the molecular background, current knowledge and clinical trials evaluating the effects of STF in cancer treatment. Preliminary data show that STF is safe, but challenging in cancer patients receiving chemotherapy. Ongoing clinical trials need to unravel if STF can also diminish toxicity and increase efficacy of chemotherapeutic regimes in daily practice.

Contains fulltext : 207351.pdf (publisher's version ) (Open Access)

Contains fulltext : 207115.pdf (publisher's version ) (Open Access), Growing preclinical evidence shows that short-term fasting (STF) protects from toxicity while enhancing the efficacy of a variety of chemotherapeutic agents in the treatment of various tumour types. STF reinforces stress resistance of healthy cells, while tumor cells become even more sensitive to toxins, perhaps through shortage of nutrients to satisfy their needs in the context of high proliferation rates and/or loss of flexibility to respond to extreme circumstances. In humans, STF may be a feasible approach to enhance the efficacy and tolerability of chemotherapy. Clinical research evaluating the potential of STF is in its infancy. This review focuses on the molecular background, current knowledge and clinical trials evaluating the effects of STF in cancer treatment. Preliminary data show that STF is safe, but challenging in cancer patients receiving chemotherapy. Ongoing clinical trials need to unravel if STF can also diminish toxicity and increase efficacy of chemotherapeutic regimes in daily practice.

Contains fulltext : 207351.pdf (publisher's version ) (Open Access)

The prevalence of type 2 diabetes (T2D) has increased rapidly. Adopting a heathy diet is suggested as one of the effective behaviors to prevent or delay onset of T2D. Dairy consumption has been recommended as part of a healthy diet, but there remains uncertainty in both the scientific community and the public about the effect of different dairy products on T2D risk. In a recent workshop, the evidence on dairy products and T2D risk was presented and discussed by a group of experts. The main conclusions from the workshop are presented in this position paper and are as follows. 1) Available evidence from large prospective cohort studies and limited randomized controlled trials (RCTs) suggests that total dairy consumption has a neutral or moderately beneficial effect on T2D risk. 2) Increasing evidence from prospective cohort studies indicates that yogurt is most strongly associated with a lower T2D risk, but evidence from RCTs is scarce. 3) Fatty acids from dairy (medium-chain, odd, and very long-chain SFAs as well as trans-palmitoleic acid) are associated with lower T2D risk and improved metabolic health, but more research is needed on studies that explore cause and effect relations to exclude the possibility that the dairy fatty acids simply serve as markers of overall dairy consumption. 4) The food matrix can be a stronger determinant of health effects than SFA content. This review further identifies research gaps in the existing knowledge and highlights key research questions that need to be addressed to better understand the impact of dairy consumption on future T2D risk.

Contains fulltext : 175100.pdf (publisher's version ) (Open Access), BACKGROUND: Activation of the insulin-like growth factor 1 (IGF-1) pathway is involved in cell growth and proliferation and is associated with tumorigenesis, tumor progression, and therapy resistance in solid tumors. We examined whether variability in serum levels of IGF-1, IGF-2, and IGF-binding protein 3 (IGF-BP3) can predict event-free survival (EFS) and overall survival (OS) in Ewing sarcoma patients treated with chemotherapy. PATIENTS AND METHODS: Serum levels of IGF-1, IGF-2, and IGF-BP3 of 22 patients with localized or metastasized Ewing sarcoma treated with six cycles of vincristine/ifosfamide/doxorubicin/etoposide (VIDE) chemotherapy were recorded. Baseline levels were compared with presixth cycle levels using paired t-tests and were tested for associations with EFS and OS. Continuous variables were dichotomized according to the Contal and O'Quigley procedure. Survival analyses were performed using Cox regression analysis. RESULTS: High baseline IGF-1 and IGF-BP3 serum levels were associated with EFS (hazard ratio [HR] 0.075, 95% confidence interval [CI] 0.009-0.602 and HR 0.090, 95% CI 0.011-0.712, respectively) in univariate and multivariate analyses (HR 0.063, 95% CI 0.007-0.590 and HR 0.057, 95% CI 0.005-0.585, respectively). OS was improved, but this was not statistically significant. IGF-BP3 and IGF-2 serum levels increased during treatment with VIDE chemotherapy (P=0.055 and P=0.023, respectively). CONCLUSION: High circulating serum levels of IGF-1 and IGF-BP3 and the molar ratio of IGF-1:IGF-BP3 serum levels were associated with improved EFS and a trend for improved OS in Ewing sarcoma patients treated with VIDE chemotherapy. These findings suggest the need for further investigation of the IGF-1 pathway as a biomarker of disease progression in patients with Ewing sarcoma.

Contains fulltext : 190998.pdf (publisher's version ) (Open Access), From a biological view, most of the processes involved in insulin resistance, which drives the pathobiology of type 2 diabetes, are reversible. This theoretically makes the disease reversible and curable by changing dietary habits and physical activity, particularly when adopted early in the disease process. Yet, this is not fully implemented and exploited in health care due to numerous obstacles. This article reviews the state of the art in all areas involved in a diabetes cure-focused therapy and discusses the scientific and technological advancements that need to be integrated into a systems approach sustainable lifestyle-based healthcare system and economy. The implementation of lifestyle as cure necessitates personalized and sustained lifestyle adaptations, which can only be established by a systems approach, including all relevant aspects (personalized diagnosis and diet, physical activity and stress management, self-empowerment, motivation, participation and health literacy, all facilitated by blended care and ehealth). Introduction of such a systems approach in type 2 diabetes therapy not only requires a concerted action of many stakeholders but also a change in healthcare economy, with new winners and losers. A "call for action" is put forward to actually initiate this transition. The solution provided for type 2 diabetes is translatable to other lifestyle-related disorders.

Item does not contain fulltext, AIMS: Individual indicators of socio-economic status have been associated with glycaemic control in people with Type 2 diabetes, but little is known about the association between partner's socio-economic status and HbA1c levels. We therefore examined the cross-sectional association between individual and partner's level of occupation on HbA1c levels in people with Type 2 diabetes in the Netherlands. METHODS: We included people with Type 2 diabetes with a partner who were treated in primary, secondary and tertiary care in the Diabetes Pearl cohort. Occupational level was classified according to International Standard Classification of Occupations (ISCO)-08 skill levels. Linear regression analyses were performed stratified for sex, and corrected for age, recruitment centre and diabetes medication. RESULTS: In total, 3257 participants (59.8% men, mean 62.2+/-9.4 years) were included. For men, having a partner with an intermediate level of occupation was associated with lower HbA1c levels [e.g. ISCO level 3: -2 mmol/mol (95% CI -4;-1) or -0.2% (95% CI -0.4;-0.1)], compared with having a partner of the highest occupational level (ISCO level 4). In women, having an unemployed partner was associated with higher HbA1c levels [14 mmol/mol (95% CI 6; 22) or 1.3% (95% CI 0.6; 2.0)], compared with having a partner of the highest occupational level. CONCLUSIONS: Partner's occupational status provided additional information on the association between socio-economic status and HbA1c levels in people with Type 2 diabetes. Women seemed to benefit from a partner with a higher occupational status, while men seemed to benefit from a partner with a lower status. Because of the cross-sectional nature of the present study, more research is necessary to explore this association.

_Aims/hypothesis:_ Elevated levels of lipoprotein(a) [Lp(a)] are an independent risk factor for cardiovascular disease (CVD), particularly in individuals with type 2 diabetes. Although weight loss improves conventional risk factors for CVD in type 2 diabetes, the effects on Lp(a) are unknown and may influence the long-term outcome of CVD after diet-induced weight loss. The aim of this clinical study was to determine the effect of diet-induced weight loss on Lp(a) levels in obese individuals with type 2 diabetes. _Methods:_ Plasma Lp(a) levels were determined by immunoturbidimetry in plasma obtained before and after 3–4 months of an energy-restricted diet in four independent study cohorts. The primary cohort consisted of 131 predominantly obese patients with type 2 diabetes (cohort 1), all participants of the Prevent

AimsIndividual indicators of socio-economic status have been associated with glycaemic control in people with Type 2 diabetes, but little is known about the association between partner's socio-economic status and HbA(1c) levels. We therefore examined the cross-sectional association between individual and partner's level of occupation on HbA(1c) levels in people with Type 2 diabetes in the Netherlands.MethodsWe included people with Type 2 diabetes with a partner who were treated in primary, secondary and tertiary care in the Diabetes Pearl cohort. Occupational level was classified according to International Standard Classification of Occupations (ISCO)-08 skill levels. Linear regression analyses were performed stratified for sex, and corrected for age, recruitment centre and diabetes medication.ResultsIn total, 3257 participants (59.8% men, mean 62.29.4 years) were included. For men, having a partner with an intermediate level of occupation was associated with lower HbA(1c) levels [e.g. ISCO level 3: -2 mmol/mol (95% CI -4;-1) or-0.2% (95% CI -0.4;-0.1)], compared with having a partner of the highest occupational level (ISCO level 4). In women, having an unemployed partner was associated with higher HbA(1c) levels [14 mmol/mol (95% CI 6; 22) or 1.3% (95% CI 0.6; 2.0)], compared with having a partner of the highest occupational level.ConclusionsPartner's occupational status provided additional information on the association between socio-economic status and HbA(1c) levels in people with Type 2 diabetes. Women seemed to benefit from a partner with a higher occupational status, while men seemed to benefit from a partner with a lower status. Because of the cross-sectional nature of the present study, more research is necessary to explore this association.

Contains fulltext : 175100.pdf (publisher's version ) (Open Access), BACKGROUND: Activation of the insulin-like growth factor 1 (IGF-1) pathway is involved in cell growth and proliferation and is associated with tumorigenesis, tumor progression, and therapy resistance in solid tumors. We examined whether variability in serum levels of IGF-1, IGF-2, and IGF-binding protein 3 (IGF-BP3) can predict event-free survival (EFS) and overall survival (OS) in Ewing sarcoma patients treated with chemotherapy. PATIENTS AND METHODS: Serum levels of IGF-1, IGF-2, and IGF-BP3 of 22 patients with localized or metastasized Ewing sarcoma treated with six cycles of vincristine/ifosfamide/doxorubicin/etoposide (VIDE) chemotherapy were recorded. Baseline levels were compared with presixth cycle levels using paired t-tests and were tested for associations with EFS and OS. Continuous variables were dichotomized according to the Contal and O'Quigley procedure. Survival analyses were performed using Cox regression analysis. RESULTS: High baseline IGF-1 and IGF-BP3 serum levels were associated with EFS (hazard ratio [HR] 0.075, 95% confidence interval [CI] 0.009-0.602 and HR 0.090, 95% CI 0.011-0.712, respectively) in univariate and multivariate analyses (HR 0.063, 95% CI 0.007-0.590 and HR 0.057, 95% CI 0.005-0.585, respectively). OS was improved, but this was not statistically significant. IGF-BP3 and IGF-2 serum levels increased during treatment with VIDE chemotherapy (P=0.055 and P=0.023, respectively). CONCLUSION: High circulating serum levels of IGF-1 and IGF-BP3 and the molar ratio of IGF-1:IGF-BP3 serum levels were associated with improved EFS and a trend for improved OS in Ewing sarcoma patients treated with VIDE chemotherapy. These findings suggest the need for further investigation of the IGF-1 pathway as a biomarker of disease progression in patients with Ewing sarcoma.

Contains fulltext : 190998.pdf (publisher's version ) (Open Access), From a biological view, most of the processes involved in insulin resistance, which drives the pathobiology of type 2 diabetes, are reversible. This theoretically makes the disease reversible and curable by changing dietary habits and physical activity, particularly when adopted early in the disease process. Yet, this is not fully implemented and exploited in health care due to numerous obstacles. This article reviews the state of the art in all areas involved in a diabetes cure-focused therapy and discusses the scientific and technological advancements that need to be integrated into a systems approach sustainable lifestyle-based healthcare system and economy. The implementation of lifestyle as cure necessitates personalized and sustained lifestyle adaptations, which can only be established by a systems approach, including all relevant aspects (personalized diagnosis and diet, physical activity and stress management, self-empowerment, motivation, participation and health literacy, all facilitated by blended care and ehealth). Introduction of such a systems approach in type 2 diabetes therapy not only requires a concerted action of many stakeholders but also a change in healthcare economy, with new winners and losers. A "call for action" is put forward to actually initiate this transition. The solution provided for type 2 diabetes is translatable to other lifestyle-related disorders.

Item does not contain fulltext, AIMS: Individual indicators of socio-economic status have been associated with glycaemic control in people with Type 2 diabetes, but little is known about the association between partner's socio-economic status and HbA1c levels. We therefore examined the cross-sectional association between individual and partner's level of occupation on HbA1c levels in people with Type 2 diabetes in the Netherlands. METHODS: We included people with Type 2 diabetes with a partner who were treated in primary, secondary and tertiary care in the Diabetes Pearl cohort. Occupational level was classified according to International Standard Classification of Occupations (ISCO)-08 skill levels. Linear regression analyses were performed stratified for sex, and corrected for age, recruitment centre and diabetes medication. RESULTS: In total, 3257 participants (59.8% men, mean 62.2+/-9.4 years) were included. For men, having a partner with an intermediate level of occupation was associated with lower HbA1c levels [e.g. ISCO level 3: -2 mmol/mol (95% CI -4;-1) or -0.2% (95% CI -0.4;-0.1)], compared with having a partner of the highest occupational level (ISCO level 4). In women, having an unemployed partner was associated with higher HbA1c levels [14 mmol/mol (95% CI 6; 22) or 1.3% (95% CI 0.6; 2.0)], compared with having a partner of the highest occupational level. CONCLUSIONS: Partner's occupational status provided additional information on the association between socio-economic status and HbA1c levels in people with Type 2 diabetes. Women seemed to benefit from a partner with a higher occupational status, while men seemed to benefit from a partner with a lower status. Because of the cross-sectional nature of the present study, more research is necessary to explore this association.

Contains fulltext : 190998.pdf (publisher's version ) (Open Access), From a biological view, most of the processes involved in insulin resistance, which drives the pathobiology of type 2 diabetes, are reversible. This theoretically makes the disease reversible and curable by changing dietary habits and physical activity, particularly when adopted early in the disease process. Yet, this is not fully implemented and exploited in health care due to numerous obstacles. This article reviews the state of the art in all areas involved in a diabetes cure-focused therapy and discusses the scientific and technological advancements that need to be integrated into a systems approach sustainable lifestyle-based healthcare system and economy. The implementation of lifestyle as cure necessitates personalized and sustained lifestyle adaptations, which can only be established by a systems approach, including all relevant aspects (personalized diagnosis and diet, physical activity and stress management, self-empowerment, motivation, participation and health literacy, all facilitated by blended care and ehealth). Introduction of such a systems approach in type 2 diabetes therapy not only requires a concerted action of many stakeholders but also a change in healthcare economy, with new winners and losers. A "call for action" is put forward to actually initiate this transition. The solution provided for type 2 diabetes is translatable to other lifestyle-related disorders.

AimsIndividual indicators of socio-economic status have been associated with glycaemic control in people with Type 2 diabetes, but little is known about the association between partner's socio-economic status and HbA(1c) levels. We therefore examined the cross-sectional association between individual and partner's level of occupation on HbA(1c) levels in people with Type 2 diabetes in the Netherlands.MethodsWe included people with Type 2 diabetes with a partner who were treated in primary, secondary and tertiary care in the Diabetes Pearl cohort. Occupational level was classified according to International Standard Classification of Occupations (ISCO)-08 skill levels. Linear regression analyses were performed stratified for sex, and corrected for age, recruitment centre and diabetes medication.ResultsIn total, 3257 participants (59.8% men, mean 62.29.4 years) were included. For men, having a partner with an intermediate level of occupation was associated with lower HbA(1c) levels [e.g. ISCO level 3: -2 mmol/mol (95% CI -4;-1) or-0.2% (95% CI -0.4;-0.1)], compared with having a partner of the highest occupational level (ISCO level 4). In women, having an unemployed partner was associated with higher HbA(1c) levels [14 mmol/mol (95% CI 6; 22) or 1.3% (95% CI 0.6; 2.0)], compared with having a partner of the highest occupational level.ConclusionsPartner's occupational status provided additional information on the association between socio-economic status and HbA(1c) levels in people with Type 2 diabetes. Women seemed to benefit from a partner with a higher occupational status, while men seemed to benefit from a partner with a lower status. Because of the cross-sectional nature of the present study, more research is necessary to explore this association.

Contains fulltext : 165680.pdf (publisher's version ) (Open Access), BACKGROUND: The insulin-like growth factor 1 (IGF-1) pathway is involved in cell growth and proliferation and is associated with tumorigenesis and therapy resistance. This study aims to elucidate whether variation in the IGF-1 pathway is predictive for pathologic response in early HER2 negative breast cancer (BC) patients, taking part in the phase III NEOZOTAC trial, randomizing between 6 cycles of neoadjuvant TAC chemotherapy with or without zoledronic acid. METHODS: Formalin-fixed paraffin-embedded tissue samples of pre-chemotherapy biopsies and operation specimens were collected for analysis of IGF-1 receptor (IGF-1R) expression (n = 216) and for analysis of 8 candidate single nucleotide polymorphisms (SNPs) in genes of the IGF-1 pathway (n = 184) using OpenArray(R) RealTime PCR. Associations with patient and tumor characteristics and chemotherapy response according to Miller and Payne pathologic response were performed using chi-square and regression analysis. RESULTS: During chemotherapy, a significant number of tumors (47.2 %) showed a decrease in IGF-1R expression, while in a small number of tumors an upregulation was seen (15.1 %). IGF-1R expression before treatment was not associated with pathological response, however, absence of IGF-1R expression after treatment was associated with a better response in multivariate analysis (P = 0.006) and patients with a decrease in expression during treatment showed a better response to chemotherapy as well (P = 0.020). Moreover, the variant T allele of 3129G > T in IGF1R (rs2016347) was associated with a better pathological response in multivariate analysis (P = 0.032). CONCLUSIONS: Absent or diminished expression of IGF-1R after neoadjuvant chemotherapy was associated with a better pathological response. Additionally, we found a SNP (rs2016347) in IGF1R as a potential predictive marker for chemotherapy efficacy in BC patients treated with TAC. TRIAL REGISTRATION: ClinicalTrials.gov NCT01099436 . Registered April 6, 20

Contains fulltext : 165680.pdf (publisher's version ) (Open Access), BACKGROUND: The insulin-like growth factor 1 (IGF-1) pathway is involved in cell growth and proliferation and is associated with tumorigenesis and therapy resistance. This study aims to elucidate whether variation in the IGF-1 pathway is predictive for pathologic response in early HER2 negative breast cancer (BC) patients, taking part in the phase III NEOZOTAC trial, randomizing between 6 cycles of neoadjuvant TAC chemotherapy with or without zoledronic acid. METHODS: Formalin-fixed paraffin-embedded tissue samples of pre-chemotherapy biopsies and operation specimens were collected for analysis of IGF-1 receptor (IGF-1R) expression (n = 216) and for analysis of 8 candidate single nucleotide polymorphisms (SNPs) in genes of the IGF-1 pathway (n = 184) using OpenArray(R) RealTime PCR. Associations with patient and tumor characteristics and chemotherapy response according to Miller and Payne pathologic response were performed using chi-square and regression analysis. RESULTS: During chemotherapy, a significant number of tumors (47.2 %) showed a decrease in IGF-1R expression, while in a small number of tumors an upregulation was seen (15.1 %). IGF-1R expression before treatment was not associated with pathological response, however, absence of IGF-1R expression after treatment was associated with a better response in multivariate analysis (P = 0.006) and patients with a decrease in expression during treatment showed a better response to chemotherapy as well (P = 0.020). Moreover, the variant T allele of 3129G > T in IGF1R (rs2016347) was associated with a better pathological response in multivariate analysis (P = 0.032). CONCLUSIONS: Absent or diminished expression of IGF-1R after neoadjuvant chemotherapy was associated with a better pathological response. Additionally, we found a SNP (rs2016347) in IGF1R as a potential predictive marker for chemotherapy efficacy in BC patients treated with TAC. TRIAL REGISTRATION: ClinicalTrials.gov NCT01099436 . Registered April 6, 20

Contains fulltext : 165680.pdf (publisher's version ) (Open Access), BACKGROUND: The insulin-like growth factor 1 (IGF-1) pathway is involved in cell growth and proliferation and is associated with tumorigenesis and therapy resistance. This study aims to elucidate whether variation in the IGF-1 pathway is predictive for pathologic response in early HER2 negative breast cancer (BC) patients, taking part in the phase III NEOZOTAC trial, randomizing between 6 cycles of neoadjuvant TAC chemotherapy with or without zoledronic acid. METHODS: Formalin-fixed paraffin-embedded tissue samples of pre-chemotherapy biopsies and operation specimens were collected for analysis of IGF-1 receptor (IGF-1R) expression (n = 216) and for analysis of 8 candidate single nucleotide polymorphisms (SNPs) in genes of the IGF-1 pathway (n = 184) using OpenArray(R) RealTime PCR. Associations with patient and tumor characteristics and chemotherapy response according to Miller and Payne pathologic response were performed using chi-square and regression analysis. RESULTS: During chemotherapy, a significant number of tumors (47.2 %) showed a decrease in IGF-1R expression, while in a small number of tumors an upregulation was seen (15.1 %). IGF-1R expression before treatment was not associated with pathological response, however, absence of IGF-1R expression after treatment was associated with a better response in multivariate analysis (P = 0.006) and patients with a decrease in expression during treatment showed a better response to chemotherapy as well (P = 0.020). Moreover, the variant T allele of 3129G > T in IGF1R (rs2016347) was associated with a better pathological response in multivariate analysis (P = 0.032). CONCLUSIONS: Absent or diminished expression of IGF-1R after neoadjuvant chemotherapy was associated with a better pathological response. Additionally, we found a SNP (rs2016347) in IGF1R as a potential predictive marker for chemotherapy efficacy in BC patients treated with TAC. TRIAL REGISTRATION: ClinicalTrials.gov NCT01099436 . Registered April 6, 20

Item does not contain fulltext, AIMS/HYPOTHESIS: South Asians have a higher risk of developing type 2 diabetes than Europeans. The underlying cause of this excess risk is still poorly understood but might be related to differences in the regulation of energy/nutrient-sensing pathways in metabolic tissues and subsequent changes in whole-body substrate metabolism. In this study, we investigated the whole-body and skeletal muscle metabolic adaptations to short-term energy restriction in South Asian and European volunteers. METHODS: Twenty-four middle-aged overweight South Asian and European men underwent a two-step hyperinsulinaemic-euglycaemic clamp, with skeletal muscle biopsies and indirect calorimetry before and after an 8 day diet very low in energy (very low calorie diet [VLCD]). Abdominal fat distribution and hepatic triacylglycerol content were assessed using MRI and MR spectroscopy. RESULTS: South Asian men had higher hepatic triacylglycerol content than European men, and exhibited elevated clamp insulin levels that probably reflect a lower insulin clearance rate. Despite higher insulin levels, endogenous glucose production rate was similar and glucose disposal rate (Rd) and nonoxidative glucose disposal rate (NOGD) were significantly lower in South Asian than European men, indicating impaired whole-body insulin sensitivity. Energy restriction decreased abdominal fat mass and hepatic triacylglycerol content in both groups. However, the shift induced by energy restriction from glucose towards lipid oxidation observed in European men was impaired in South Asian men, indicating whole-body metabolic inflexibility. Remarkably, although energy restriction improved hepatic insulin sensitivity in both groups, Rd improved only in South Asian men owing to higher NOGD. At the molecular level, an increase in insulin-induced activation of the skeletal muscle mTOR pathway was found in South Asian men, showing that skeletal muscle energy/nutrient-sensing pathways were differentially affected by energy rest

Contains fulltext : 154173.pdf (publisher's version ) (Closed access), Patients suffering from narcolepsy type 1 show altered skin temperatures, resembling the profile that is related to sleep onset in healthy controls. The aim of the present study is to investigate the effects of sodium oxybate, a widely used drug to treat narcolepsy, on the 24-h profiles of temperature and sleep-wakefulness in patients with narcolepsy and controls. Eight hypocretin-deficient male narcolepsy type 1 patients and eight healthy matched controls underwent temperature measurement of core body and proximal and distal skin twice, and the sleep-wake state for 24 h. After the baseline assessment, 2 x 3 g of sodium oxybate was administered for 5 nights, immediately followed by the second assessment. At baseline, daytime core body temperature and proximal skin temperature were significantly lower in patients with narcolepsy (core: 36.8 +/- 0.05 degrees C versus 37.0 +/- 0.05 degrees C, F = 8.31, P = 0.01; proximal: 33.4 +/- 0.26 degrees C versus 34.3 +/- 0.26 degrees C, F = 5.66, P = 0.03). In patients, sodium oxybate administration increased proximal skin temperature during the day (F = 6.46, P = 0.04) to a level similar as in controls, but did not affect core body temperature, distal temperature or distal-proximal temperature gradient. Sodium oxybate administration normalised the predictive value of distal skin temperature and distal-proximal temperature gradient for the onset of daytime naps (P < 0.01). In conclusion, sodium oxybate administration resulted in a partial normalisation of the skin temperature profile, by increasing daytime proximal skin temperature, and by strengthening the known relationship between skin temperature and daytime sleep propensity. These changes seem to be related to the clinical improvement induced by sodium oxybate treatment. A causal relationship is not proven.

Item does not contain fulltext, BACKGROUND AND AIMS: South Asians have a higher risk of developing cardiovascular disease than white Caucasians. The underlying cause is unknown, but might be related to higher cardiac susceptibility to metabolic disorders. Short-term caloric restriction (CR) can be used as a metabolic stress test to study cardiac flexibility. We assessed whether metabolic and functional cardiovascular flexibility to CR differs between South Asians and white Caucasians. METHODS AND RESULTS: Cardiovascular function and myocardial triglycerides were assessed using a 1.5T-MRI/S-scanner in 12 middle-aged overweight male South Asians and 12 matched white Caucasians before and after an 8-day very low calorie diet (VLCD). At baseline South Asians were more insulin resistant than Caucasians. Cardiac dimensions were smaller, despite correction for body surface area, and pulse wave velocity (PWV) in the distal aorta was higher in South Asians. Systolic and diastolic function, myocardial triglycerides and pericardial fat did not differ significantly between groups. After the VLCD body weight reduced on average by 4.0 +/- 0.2 kg. Myocardial triglycerides increased in both ethnicities by 69 +/- 18%, and diastolic function decreased although this was not significant in South Asians. However, pericardial fat and PWV in the proximal and total aorta were reduced in Caucasians only. CONCLUSION: Myocardial triglyceride stores in middle-aged overweight and insulin resistant South Asians are as flexible and amenable to therapeutic intervention by CR as age-, sex- and BMI-matched but less insulin resistant white Caucasians. However, paracardial fat volume and PWV showed a differential effect in response to an 8-day VLCD in favor of Caucasians. CLINICAL TRIAL REGISTRATION: NTR 2473 (URL: http://www.trialregister.nl/trialreg/admin/rctsearch.asp?Term=2473).

Contains fulltext : 152831.pdf (publisher's version ) (Open Access), BACKGROUND: Preclinical evidence shows that short-term fasting (STF) protects healthy cells against side effects of chemotherapy and makes cancer cells more vulnerable to it. This pilot study examines the feasibility of STF and its effects on tolerance of chemotherapy in a homogeneous patient group with early breast cancer (BC). METHODS: Eligible patients had HER2-negative, stage II/III BC. Women receiving (neo)-adjuvant TAC (docetaxel/doxorubicin/cyclophosphamide) were randomized to fast 24 h before and after commencing chemotherapy, or to eat according to the guidelines for healthy nutrition. Toxicity in the two groups was compared. Chemotherapy-induced DNA damage in peripheral blood mononuclear cells (PBMCs) was quantified by the level of gamma-H2AX analyzed by flow cytometry. RESULTS: Thirteen patients were included of whom seven were randomized to the STF arm. STF was well tolerated. Mean erythrocyte- and thrombocyte counts 7 days post-chemotherapy were significantly higher (P = 0.007, 95 % CI 0.106-0.638 and P = 0.00007, 95 % CI 38.7-104, respectively) in the STF group compared to the non-STF group. Non-hematological toxicity did not differ between the groups. Levels of gamma-H2AX were significantly increased 30 min post-chemotherapy in CD45 + CD3- cells in non-STF, but not in STF patients. CONCLUSIONS: STF during chemotherapy was well tolerated and reduced hematological toxicity of TAC in HER2-negative BC patients. Moreover, STF may reduce a transient increase in, and/or induce a faster recovery of DNA damage in PBMCs after chemotherapy. Larger studies, investigating a longer fasting period, are required to generate more insight into the possible benefits of STF during chemotherapy. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01304251 , March 2011.

Item does not contain fulltext, AIMS/HYPOTHESIS: South Asians have a higher risk of developing type 2 diabetes than Europeans. The underlying cause of this excess risk is still poorly understood but might be related to differences in the regulation of energy/nutrient-sensing pathways in metabolic tissues and subsequent changes in whole-body substrate metabolism. In this study, we investigated the whole-body and skeletal muscle metabolic adaptations to short-term energy restriction in South Asian and European volunteers. METHODS: Twenty-four middle-aged overweight South Asian and European men underwent a two-step hyperinsulinaemic-euglycaemic clamp, with skeletal muscle biopsies and indirect calorimetry before and after an 8 day diet very low in energy (very low calorie diet [VLCD]). Abdominal fat distribution and hepatic triacylglycerol content were assessed using MRI and MR spectroscopy. RESULTS: South Asian men had higher hepatic triacylglycerol content than European men, and exhibited elevated clamp insulin levels that probably reflect a lower insulin clearance rate. Despite higher insulin levels, endogenous glucose production rate was similar and glucose disposal rate (Rd) and nonoxidative glucose disposal rate (NOGD) were significantly lower in South Asian than European men, indicating impaired whole-body insulin sensitivity. Energy restriction decreased abdominal fat mass and hepatic triacylglycerol content in both groups. However, the shift induced by energy restriction from glucose towards lipid oxidation observed in European men was impaired in South Asian men, indicating whole-body metabolic inflexibility. Remarkably, although energy restriction improved hepatic insulin sensitivity in both groups, Rd improved only in South Asian men owing to higher NOGD. At the molecular level, an increase in insulin-induced activation of the skeletal muscle mTOR pathway was found in South Asian men, showing that skeletal muscle energy/nutrient-sensing pathways were differentially affected by energy rest

Contains fulltext : 154173.pdf (publisher's version ) (Closed access), Patients suffering from narcolepsy type 1 show altered skin temperatures, resembling the profile that is related to sleep onset in healthy controls. The aim of the present study is to investigate the effects of sodium oxybate, a widely used drug to treat narcolepsy, on the 24-h profiles of temperature and sleep-wakefulness in patients with narcolepsy and controls. Eight hypocretin-deficient male narcolepsy type 1 patients and eight healthy matched controls underwent temperature measurement of core body and proximal and distal skin twice, and the sleep-wake state for 24 h. After the baseline assessment, 2 x 3 g of sodium oxybate was administered for 5 nights, immediately followed by the second assessment. At baseline, daytime core body temperature and proximal skin temperature were significantly lower in patients with narcolepsy (core: 36.8 +/- 0.05 degrees C versus 37.0 +/- 0.05 degrees C, F = 8.31, P = 0.01; proximal: 33.4 +/- 0.26 degrees C versus 34.3 +/- 0.26 degrees C, F = 5.66, P = 0.03). In patients, sodium oxybate administration increased proximal skin temperature during the day (F = 6.46, P = 0.04) to a level similar as in controls, but did not affect core body temperature, distal temperature or distal-proximal temperature gradient. Sodium oxybate administration normalised the predictive value of distal skin temperature and distal-proximal temperature gradient for the onset of daytime naps (P < 0.01). In conclusion, sodium oxybate administration resulted in a partial normalisation of the skin temperature profile, by increasing daytime proximal skin temperature, and by strengthening the known relationship between skin temperature and daytime sleep propensity. These changes seem to be related to the clinical improvement induced by sodium oxybate treatment. A causal relationship is not proven.

Item does not contain fulltext, BACKGROUND AND AIMS: South Asians have a higher risk of developing cardiovascular disease than white Caucasians. The underlying cause is unknown, but might be related to higher cardiac susceptibility to metabolic disorders. Short-term caloric restriction (CR) can be used as a metabolic stress test to study cardiac flexibility. We assessed whether metabolic and functional cardiovascular flexibility to CR differs between South Asians and white Caucasians. METHODS AND RESULTS: Cardiovascular function and myocardial triglycerides were assessed using a 1.5T-MRI/S-scanner in 12 middle-aged overweight male South Asians and 12 matched white Caucasians before and after an 8-day very low calorie diet (VLCD). At baseline South Asians were more insulin resistant than Caucasians. Cardiac dimensions were smaller, despite correction for body surface area, and pulse wave velocity (PWV) in the distal aorta was higher in South Asians. Systolic and diastolic function, myocardial triglycerides and pericardial fat did not differ significantly between groups. After the VLCD body weight reduced on average by 4.0 +/- 0.2 kg. Myocardial triglycerides increased in both ethnicities by 69 +/- 18%, and diastolic function decreased although this was not significant in South Asians. However, pericardial fat and PWV in the proximal and total aorta were reduced in Caucasians only. CONCLUSION: Myocardial triglyceride stores in middle-aged overweight and insulin resistant South Asians are as flexible and amenable to therapeutic intervention by CR as age-, sex- and BMI-matched but less insulin resistant white Caucasians. However, paracardial fat volume and PWV showed a differential effect in response to an 8-day VLCD in favor of Caucasians. CLINICAL TRIAL REGISTRATION: NTR 2473 (URL: http://www.trialregister.nl/trialreg/admin/rctsearch.asp?Term=2473).

Contains fulltext : 152831.pdf (publisher's version ) (Open Access), BACKGROUND: Preclinical evidence shows that short-term fasting (STF) protects healthy cells against side effects of chemotherapy and makes cancer cells more vulnerable to it. This pilot study examines the feasibility of STF and its effects on tolerance of chemotherapy in a homogeneous patient group with early breast cancer (BC). METHODS: Eligible patients had HER2-negative, stage II/III BC. Women receiving (neo)-adjuvant TAC (docetaxel/doxorubicin/cyclophosphamide) were randomized to fast 24 h before and after commencing chemotherapy, or to eat according to the guidelines for healthy nutrition. Toxicity in the two groups was compared. Chemotherapy-induced DNA damage in peripheral blood mononuclear cells (PBMCs) was quantified by the level of gamma-H2AX analyzed by flow cytometry. RESULTS: Thirteen patients were included of whom seven were randomized to the STF arm. STF was well tolerated. Mean erythrocyte- and thrombocyte counts 7 days post-chemotherapy were significantly higher (P = 0.007, 95 % CI 0.106-0.638 and P = 0.00007, 95 % CI 38.7-104, respectively) in the STF group compared to the non-STF group. Non-hematological toxicity did not differ between the groups. Levels of gamma-H2AX were significantly increased 30 min post-chemotherapy in CD45 + CD3- cells in non-STF, but not in STF patients. CONCLUSIONS: STF during chemotherapy was well tolerated and reduced hematological toxicity of TAC in HER2-negative BC patients. Moreover, STF may reduce a transient increase in, and/or induce a faster recovery of DNA damage in PBMCs after chemotherapy. Larger studies, investigating a longer fasting period, are required to generate more insight into the possible benefits of STF during chemotherapy. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01304251 , March 2011.

Item does not contain fulltext, BACKGROUND AND AIMS: South Asians have a higher risk of developing cardiovascular disease than white Caucasians. The underlying cause is unknown, but might be related to higher cardiac susceptibility to metabolic disorders. Short-term caloric restriction (CR) can be used as a metabolic stress test to study cardiac flexibility. We assessed whether metabolic and functional cardiovascular flexibility to CR differs between South Asians and white Caucasians. METHODS AND RESULTS: Cardiovascular function and myocardial triglycerides were assessed using a 1.5T-MRI/S-scanner in 12 middle-aged overweight male South Asians and 12 matched white Caucasians before and after an 8-day very low calorie diet (VLCD). At baseline South Asians were more insulin resistant than Caucasians. Cardiac dimensions were smaller, despite correction for body surface area, and pulse wave velocity (PWV) in the distal aorta was higher in South Asians. Systolic and diastolic function, myocardial triglycerides and pericardial fat did not differ significantly between groups. After the VLCD body weight reduced on average by 4.0 +/- 0.2 kg. Myocardial triglycerides increased in both ethnicities by 69 +/- 18%, and diastolic function decreased although this was not significant in South Asians. However, pericardial fat and PWV in the proximal and total aorta were reduced in Caucasians only. CONCLUSION: Myocardial triglyceride stores in middle-aged overweight and insulin resistant South Asians are as flexible and amenable to therapeutic intervention by CR as age-, sex- and BMI-matched but less insulin resistant white Caucasians. However, paracardial fat volume and PWV showed a differential effect in response to an 8-day VLCD in favor of Caucasians. CLINICAL TRIAL REGISTRATION: NTR 2473 (URL: http://www.trialregister.nl/trialreg/admin/rctsearch.asp?Term=2473).

Few studies have included subjects with the propensity to reach old age in good health, with the aim to disentangle mechanisms contributing to staying healthier for longer. The hypothalamic-pituitary-thyroid (HPT) axis maintains circulating levels of thyroid stimulating hormone (TSH) and thyroid hormone (TH) in an inverse relationship. Greater longevity has been associated with higher TSH and lower TH levels, but mechanisms underlying TSH/TH differences and longevity remain unknown. The HPT axis plays a pivotal role in growth, development and energy metabolism. We report that offspring of nonagenarians with at least one nonagenarian sibling have increased TSH secretion but similar bioactivity of TSH and similar TH levels compared to controls. Healthy offspring and spousal controls had similar resting metabolic rate and core body temperature. We propose that pleiotropic effects of the HPT axis may favour longevity without altering energy metabolism.

Few studies have included subjects with the propensity to reach old age in good health, with the aim to disentangle mechanisms contributing to staying healthier for longer. The hypothalamic-pituitary-thyroid (HPT) axis maintains circulating levels of thyroid stimulating hormone (TSH) and thyroid hormone (TH) in an inverse relationship. Greater longevity has been associated with higher TSH and lower TH levels, but mechanisms underlying TSH/TH differences and longevity remain unknown. The HPT axis plays a pivotal role in growth, development and energy metabolism. We report that offspring of nonagenarians with at least one nonagenarian sibling have increased TSH secretion but similar bioactivity of TSH and similar TH levels compared to controls. Healthy offspring and spousal controls had similar resting metabolic rate and core body temperature. We propose that pleiotropic effects of the HPT axis may favour longevity without altering energy metabolism.

Item does not contain fulltext, A very low calorie diet (VLCD) results in cardiac remodeling and improved diastolic function. It is unknown how long these effects sustain after reintroduction of a regular diet. We aimed to assess the long-term effects of initial weight loss by VLCD on cardiac dimensions and function in type 2 diabetes mellitus (T2DM) patients. Fourteen insulin-dependent T2DM patients (mean +/- SEM: age 53 +/- 2 years; BMI 35 +/- 1 kg/m(2)) were treated by a VLCD (450 kcal/day) during 16 weeks. Cardiac function and myocardial triglyceride (TG) content were measured by magnetic resonance imaging and spectroscopy at baseline, after a 16-week VLCD and after 14 months of follow-up on a regular diet. BMI decreased from 35 +/- 1 to 28 +/- 1 kg/m(2) after VLCD and increased again to 32 +/- 1 kg/m(2) at 18 months (both P < 0.05 vs. baseline). Left ventricular (LV) end-diastolic volume index increased after the 16-week VLCD (80 +/- 3 to 89 +/- 4 ml/m(2), P < 0.05) and remained increased after follow-up (90 +/- 3 ml/m(2); P < 0.05 vs. baseline) at comparable filling pressures. The improvement in LV diastolic function after the 16-week VLCD, was sustained at 18 months [early (E)/atrial (A) diastolic filling phase ratio: 0.96 +/- 0.07 (baseline); 1.12 +/- 0.06 (after VLCD); 1.06 +/- 0.07 (18 months, P < 0.05 vs. baseline)]. Myocardial TG content decreased after the 16-week VLCD [0.74 (0.41-1.10) to 0.45 (0.31-0.54) %, P < 0.05], but returned to baseline levels at 18 months [0.76 (0.65-1.32) %]. Weight reduction by a 16-week VLCD in T2DM patients results in sustained cardiac remodeling and improved diastolic function after 14 months of follow-up, despite weight regain on a regular diet.

Item does not contain fulltext, OBJECTIVE: Cardiac ectopic fat depositions are thought to play a role in the pathogenesis of cardiovascular disease (CVD), the main cause of death in patients with type 2 diabetes. Diet-induced weight loss results in a decrease in cardiac ectopic fat stores, however if this is the same for surgically induced weight loss is less clear. Therefore, we assessed myocardial triglyceride (TG) content, pericardial fat and cardiac function in obese patients with insulin-dependent type 2 diabetes before and 16 weeks after Roux-en-Y gastric bypass (RYGB) surgery. PATIENTS: Ten obese patients with insulin-dependent type 2 diabetes [40% male, age 53.7 +/- 8.9 years (mean +/- SD)] scheduled to undergo RYGB surgery were included. MEASUREMENTS: Ectopic fat accumulation and cardiovascular function were assessed with magnetic resonance (MR) imaging and myocardial TG content with MR spectroscopy before and 16 weeks after RYGB surgery. RESULTS: Body mass index decreased from 41.3 +/- 4.3 at baseline to 34.1 +/- 2.8 kg/m(2) (P < 0.001) after 16 weeks. Glycemic control improved as well [HbA1c: 7.8 +/- 1.1 to 6.8 +/- 1.3% (62 +/- 12 to 51 +/- 14 mm) (P < 0.05)]. We did not observe an effect of the RYGB surgery on myocardial TG content, cardiac function or pulse wave velocity. There was a greater relative decrease in visceral (-35.5 +/- 9.6%) as compared to subcutaneous fat volume (-25.0 +/- 6.3%) and in paracardial (-17.3 +/-17.2%) as compared to epicardial fat volume (-6.4 +/- 6.0%). CONCLUSIONS: This study shows that surgical-induced weight loss leads to a larger decrease in paracardial than epicardial fat. Myocardial TG and cardiovascular function did not change.

Item does not contain fulltext, South Asians (SAs) develop type 2 diabetes at a younger age and lower BMI compared with Caucasians (Cs). The underlying cause is still poorly understood but might result from an innate inability to adapt to the Westernized diet. This study aimed to compare the metabolic adaptation to a high-fat, high-calorie (HFHC) diet between both ethnicities. Twelve healthy, young lean male SAs and 12 matched Cs underwent a two-step hyperinsulinemic-euglycemic clamp with skeletal muscle biopsies and indirect calorimetry before and after a 5-day HFHC diet. Hepatic triglyceride content (HTG) and abdominal fat distribution were assessed using magnetic resonance imaging and spectroscopy. At baseline, SAs had higher insulin clamp levels than Cs, indicating reduced insulin clearance rate. Despite the higher insulin levels, endogenous glucose production was comparable between groups, suggesting lower hepatic insulin sensitivity in SAs. Furthermore, a 5-day HFHC diet decreased the insulin-stimulated (nonoxidative) glucose disposal rate only in SA. In skeletal muscle, no significant differences were found between groups in insulin/mammalian target of rapamycin signaling, metabolic gene expression, and mitochondrial respiratory chain content. Furthermore, no differences in (mobilization of) HTG and abdominal fat were detected. We conclude that HFHC feeding rapidly induces insulin resistance only in SAs. Thus, distinct adaptation to Western food may partly explain their propensity to develop type 2 diabetes.

Item does not contain fulltext, INTRODUCTION: Narcolepsy is associated with obesity though it is uncertain whether this is caused by changes in glucose and fat metabolism. Therefore, we performed a detailed analysis of systemic energy homeostasis in narcolepsy patients, and additionally, investigated whether it was affected by three months of sodium oxybate (SXB) treatment. METHODS: Nine hypocretin deficient patients with narcolepsy-cataplexy, and nine healthy sex, age, and BMI matched controls were enrolled. A hyperinsulinemic-euglycemic clamp combined with stable isotopes ([6,6-(2)H2]-glucose and [(2)H5]- glycerol) was performed at baseline. In seven patients a second study was performed after three months of SXB treatment. RESULTS: Glucose disposal rate (GDR) per unit serum insulin was significantly higher in narcolepsy patients compared to matched controls (1.6 +/- 0.2 vs. 1.1 +/- 0.3 mumol/kgFFM/min/mUxL; P = 0.024), whereas beta-cell function was similar (P = 0.50). Basal steady state glycerol appearance rate tended to be lower in narcolepsy patients (5.2 +/- 0.4 vs. 7.5 +/- 1.3 mumol/kgFM/min; P = 0.058), suggesting a lower rate of lipolysis. SXB treatment induced a trend in reduction of the GDR (1.4 +/- 0.1 vs. 1.1 +/- 0.2 mumol/kgFFM/min/mUxL; P = 0.063) and a reduction in endogenous glucose production (0.24 +/- 0.03 vs. 0.16 +/- 0.03 mumol/kgFFM/min/mUxL: P = 0.028) per unit serum insulin. After SXB treatment lipolysis increased (4.9 +/- 0.4 vs. 6.5 +/- 0.6 mumol/kgFM/min; P = 0.018), and body weight decreased in narcolepsy patients (99.2 +/- 6.0 vs. 94.0 +/- 5.4 kg; P = 0.044). CONCLUSION: We show that narcolepsy patients are more insulin sensitive and may have a lower rate of lipolysis than matched controls. SXB stimulated lipolysis in narcolepsy patients, possibly accounting for the weight loss after treatment. While sodium oxybate tended to decrease systemic insulin sensitivity, it increased hepatic insulin sensitivity, suggesting tissue-specific effects. CITATION: Donjacour CE; Aziz

Item does not contain fulltext, OBJECTIVE: Obesity and type 2 diabetes mellitus (T2DM) have been associated with increased levels of circulating branched-chain amino acids (BCAAs) that may be involved in the pathogenesis of insulin resistance. However, weight loss has not been consistently associated with the reduction of BCAA levels. RESEARCH DESIGN AND METHODS: We included 30 obese normal glucose-tolerant (NGT) subjects, 32 obese subjects with T2DM, and 12 lean female subjects. Obese subjects underwent either a restrictive procedure (gastric banding [GB], a very low-calorie diet [VLCD]), or a restrictive/bypass procedure (Roux-en-Y gastric bypass [RYGB] surgery). Fasting blood samples were taken for the determination of amine group containing metabolites 4 weeks before, as well as 3 weeks and 3 months after the intervention. RESULTS: BCAA levels were higher in T2DM subjects, but not in NGT subjects, compared with lean subjects. Principal component (PC) analysis revealed a concise PC consisting of all BCAAs, which showed a correlation with measures of insulin sensitivity and glucose tolerance. Only after the RYGB procedure, and at both 3 weeks and 3 months, were circulating BCAA levels reduced. CONCLUSIONS: Our data confirm an association between deregulation of BCAA metabolism in plasma and insulin resistance and glucose intolerance. Three weeks after undergoing RYGB surgery, a significant decrease in BCAAs in both NGT as well as T2DM subjects was observed. After 3 months, despite inducing significant weight loss, neither GB nor VLCD induced a reduction in BCAA levels. Our results indicate that the bypass procedure of RYGB surgery, independent of weight loss or the presence of T2DM, reduces BCAA levels in obese subjects.

Item does not contain fulltext, A very low calorie diet (VLCD) results in cardiac remodeling and improved diastolic function. It is unknown how long these effects sustain after reintroduction of a regular diet. We aimed to assess the long-term effects of initial weight loss by VLCD on cardiac dimensions and function in type 2 diabetes mellitus (T2DM) patients. Fourteen insulin-dependent T2DM patients (mean +/- SEM: age 53 +/- 2 years; BMI 35 +/- 1 kg/m(2)) were treated by a VLCD (450 kcal/day) during 16 weeks. Cardiac function and myocardial triglyceride (TG) content were measured by magnetic resonance imaging and spectroscopy at baseline, after a 16-week VLCD and after 14 months of follow-up on a regular diet. BMI decreased from 35 +/- 1 to 28 +/- 1 kg/m(2) after VLCD and increased again to 32 +/- 1 kg/m(2) at 18 months (both P < 0.05 vs. baseline). Left ventricular (LV) end-diastolic volume index increased after the 16-week VLCD (80 +/- 3 to 89 +/- 4 ml/m(2), P < 0.05) and remained increased after follow-up (90 +/- 3 ml/m(2); P < 0.05 vs. baseline) at comparable filling pressures. The improvement in LV diastolic function after the 16-week VLCD, was sustained at 18 months [early (E)/atrial (A) diastolic filling phase ratio: 0.96 +/- 0.07 (baseline); 1.12 +/- 0.06 (after VLCD); 1.06 +/- 0.07 (18 months, P < 0.05 vs. baseline)]. Myocardial TG content decreased after the 16-week VLCD [0.74 (0.41-1.10) to 0.45 (0.31-0.54) %, P < 0.05], but returned to baseline levels at 18 months [0.76 (0.65-1.32) %]. Weight reduction by a 16-week VLCD in T2DM patients results in sustained cardiac remodeling and improved diastolic function after 14 months of follow-up, despite weight regain on a regular diet.

Item does not contain fulltext, OBJECTIVE: Cardiac ectopic fat depositions are thought to play a role in the pathogenesis of cardiovascular disease (CVD), the main cause of death in patients with type 2 diabetes. Diet-induced weight loss results in a decrease in cardiac ectopic fat stores, however if this is the same for surgically induced weight loss is less clear. Therefore, we assessed myocardial triglyceride (TG) content, pericardial fat and cardiac function in obese patients with insulin-dependent type 2 diabetes before and 16 weeks after Roux-en-Y gastric bypass (RYGB) surgery. PATIENTS: Ten obese patients with insulin-dependent type 2 diabetes [40% male, age 53.7 +/- 8.9 years (mean +/- SD)] scheduled to undergo RYGB surgery were included. MEASUREMENTS: Ectopic fat accumulation and cardiovascular function were assessed with magnetic resonance (MR) imaging and myocardial TG content with MR spectroscopy before and 16 weeks after RYGB surgery. RESULTS: Body mass index decreased from 41.3 +/- 4.3 at baseline to 34.1 +/- 2.8 kg/m(2) (P < 0.001) after 16 weeks. Glycemic control improved as well [HbA1c: 7.8 +/- 1.1 to 6.8 +/- 1.3% (62 +/- 12 to 51 +/- 14 mm) (P < 0.05)]. We did not observe an effect of the RYGB surgery on myocardial TG content, cardiac function or pulse wave velocity. There was a greater relative decrease in visceral (-35.5 +/- 9.6%) as compared to subcutaneous fat volume (-25.0 +/- 6.3%) and in paracardial (-17.3 +/-17.2%) as compared to epicardial fat volume (-6.4 +/- 6.0%). CONCLUSIONS: This study shows that surgical-induced weight loss leads to a larger decrease in paracardial than epicardial fat. Myocardial TG and cardiovascular function did not change.

Item does not contain fulltext, South Asians (SAs) develop type 2 diabetes at a younger age and lower BMI compared with Caucasians (Cs). The underlying cause is still poorly understood but might result from an innate inability to adapt to the Westernized diet. This study aimed to compare the metabolic adaptation to a high-fat, high-calorie (HFHC) diet between both ethnicities. Twelve healthy, young lean male SAs and 12 matched Cs underwent a two-step hyperinsulinemic-euglycemic clamp with skeletal muscle biopsies and indirect calorimetry before and after a 5-day HFHC diet. Hepatic triglyceride content (HTG) and abdominal fat distribution were assessed using magnetic resonance imaging and spectroscopy. At baseline, SAs had higher insulin clamp levels than Cs, indicating reduced insulin clearance rate. Despite the higher insulin levels, endogenous glucose production was comparable between groups, suggesting lower hepatic insulin sensitivity in SAs. Furthermore, a 5-day HFHC diet decreased the insulin-stimulated (nonoxidative) glucose disposal rate only in SA. In skeletal muscle, no significant differences were found between groups in insulin/mammalian target of rapamycin signaling, metabolic gene expression, and mitochondrial respiratory chain content. Furthermore, no differences in (mobilization of) HTG and abdominal fat were detected. We conclude that HFHC feeding rapidly induces insulin resistance only in SAs. Thus, distinct adaptation to Western food may partly explain their propensity to develop type 2 diabetes.

Item does not contain fulltext, INTRODUCTION: Narcolepsy is associated with obesity though it is uncertain whether this is caused by changes in glucose and fat metabolism. Therefore, we performed a detailed analysis of systemic energy homeostasis in narcolepsy patients, and additionally, investigated whether it was affected by three months of sodium oxybate (SXB) treatment. METHODS: Nine hypocretin deficient patients with narcolepsy-cataplexy, and nine healthy sex, age, and BMI matched controls were enrolled. A hyperinsulinemic-euglycemic clamp combined with stable isotopes ([6,6-(2)H2]-glucose and [(2)H5]- glycerol) was performed at baseline. In seven patients a second study was performed after three months of SXB treatment. RESULTS: Glucose disposal rate (GDR) per unit serum insulin was significantly higher in narcolepsy patients compared to matched controls (1.6 +/- 0.2 vs. 1.1 +/- 0.3 mumol/kgFFM/min/mUxL; P = 0.024), whereas beta-cell function was similar (P = 0.50). Basal steady state glycerol appearance rate tended to be lower in narcolepsy patients (5.2 +/- 0.4 vs. 7.5 +/- 1.3 mumol/kgFM/min; P = 0.058), suggesting a lower rate of lipolysis. SXB treatment induced a trend in reduction of the GDR (1.4 +/- 0.1 vs. 1.1 +/- 0.2 mumol/kgFFM/min/mUxL; P = 0.063) and a reduction in endogenous glucose production (0.24 +/- 0.03 vs. 0.16 +/- 0.03 mumol/kgFFM/min/mUxL: P = 0.028) per unit serum insulin. After SXB treatment lipolysis increased (4.9 +/- 0.4 vs. 6.5 +/- 0.6 mumol/kgFM/min; P = 0.018), and body weight decreased in narcolepsy patients (99.2 +/- 6.0 vs. 94.0 +/- 5.4 kg; P = 0.044). CONCLUSION: We show that narcolepsy patients are more insulin sensitive and may have a lower rate of lipolysis than matched controls. SXB stimulated lipolysis in narcolepsy patients, possibly accounting for the weight loss after treatment. While sodium oxybate tended to decrease systemic insulin sensitivity, it increased hepatic insulin sensitivity, suggesting tissue-specific effects. CITATION: Donjacour CE; Aziz

Item does not contain fulltext, OBJECTIVE: Obesity and type 2 diabetes mellitus (T2DM) have been associated with increased levels of circulating branched-chain amino acids (BCAAs) that may be involved in the pathogenesis of insulin resistance. However, weight loss has not been consistently associated with the reduction of BCAA levels. RESEARCH DESIGN AND METHODS: We included 30 obese normal glucose-tolerant (NGT) subjects, 32 obese subjects with T2DM, and 12 lean female subjects. Obese subjects underwent either a restrictive procedure (gastric banding [GB], a very low-calorie diet [VLCD]), or a restrictive/bypass procedure (Roux-en-Y gastric bypass [RYGB] surgery). Fasting blood samples were taken for the determination of amine group containing metabolites 4 weeks before, as well as 3 weeks and 3 months after the intervention. RESULTS: BCAA levels were higher in T2DM subjects, but not in NGT subjects, compared with lean subjects. Principal component (PC) analysis revealed a concise PC consisting of all BCAAs, which showed a correlation with measures of insulin sensitivity and glucose tolerance. Only after the RYGB procedure, and at both 3 weeks and 3 months, were circulating BCAA levels reduced. CONCLUSIONS: Our data confirm an association between deregulation of BCAA metabolism in plasma and insulin resistance and glucose intolerance. Three weeks after undergoing RYGB surgery, a significant decrease in BCAAs in both NGT as well as T2DM subjects was observed. After 3 months, despite inducing significant weight loss, neither GB nor VLCD induced a reduction in BCAA levels. Our results indicate that the bypass procedure of RYGB surgery, independent of weight loss or the presence of T2DM, reduces BCAA levels in obese subjects.