Search

Neddylation is a post-translational mechanism that adds a ubiquitin-like protein, namely neural precursor cell expressed developmentally downregulated protein 8 (NEDD8). Here, we show that neddylation in mouse liver is modulated by nutrient availability. Inhibition of neddylation in mouse liver reduces gluconeogenic capacity and the hyperglycemic actions of counter-regulatory hormones. Furthermore, people with type 2 diabetes display elevated hepatic neddylation levels. Mechanistically, fasting or caloric restriction of mice leads to neddylation of phosphoenolpyruvate carboxykinase 1 (PCK1) at three lysine residues—K278, K342, and K387. We find that mutating the three PCK1 lysines that are neddylated reduces their gluconeogenic activity rate. Molecular dynamics simulations show that neddylation of PCK1 could re-position two loops surrounding the catalytic center into an open configuration, rendering the catalytic center more accessible. Our study reveals that neddylation of PCK1 provides a finely tuned mechanism of controlling glucose metabolism by linking whole nutrient availability to metabolic homeostasis.

Neddylation is a post-translational mechanism that adds a ubiquitin-like protein, namely neural precursor cell expressed developmentally downregulated protein 8 (NEDD8). Here, we show that neddylation in mouse liver is modulated by nutrient availability. Inhibition of neddylation in mouse liver reduces gluconeogenic capacity and the hyperglycemic actions of counter-regulatory hormones. Furthermore, people with type 2 diabetes display elevated hepatic neddylation levels. Mechanistically, fasting or caloric restriction of mice leads to neddylation of phosphoenolpyruvate carboxykinase 1 (PCK1) at three lysine residues—K278, K342, and K387. We find that mutating the three PCK1 lysines that are neddylated reduces their gluconeogenic activity rate. Molecular dynamics simulations show that neddylation of PCK1 could re-position two loops surrounding the catalytic center into an open configuration, rendering the catalytic center more accessible. Our study reveals that neddylation of PCK1 provides a finely tuned mechanism of controlling glucose metabolism by linking whole nutrient availability to metabolic homeostasis.

Background: Metastases are the major cause of cancer-related morbidity and mortality. By the time cancer cells detach from their primary site to eventually spread to distant sites, they need to acquire the ability to survive in non-adherent conditions and to proliferate within a new microenvironment in spite of stressing conditions that may severely constrain the metastatic process. In this study, we gained insight into the molecular mechanisms allowing cancer cells to survive and proliferate in an anchorage-independent manner, regardless of both tumor-intrinsic variables and nutrient culture conditions. Methods: 3D spheroids derived from lung adenocarcinoma (LUAD) and breast cancer cells were cultured in either nutrient-rich or -restricted culture conditions. A multi-omics approach, including transcriptomics, proteomics, and metabolomics, was used to explore the molecular changes underlying the transition from 2 to 3D cultures. Small interfering RNA-mediated loss of function assays were used to validate the role of the identified differentially expressed genes and proteins in H460 and HCC827 LUAD as well as in MCF7 and T47D breast cancer cell lines. Results: We found that the transition from 2 to 3D cultures of H460 and MCF7 cells is associated with significant changes in the expression of genes and proteins involved in metabolic reprogramming. In particular, we observed that 3D tumor spheroid growth implies the overexpression of ALDOC and ENO2 glycolytic enzymes concomitant with the enhanced consumption of glucose and fructose and the enhanced production of lactate. Transfection with siRNA against both ALDOC and ENO2 determined a significant reduction in lactate production, viability and size of 3D tumor spheroids produced by H460, HCC827, MCF7, and T47D cell lines. Conclusions: Our results show that anchorage-independent survival and growth of cancer cells are supported by changes in genes and proteins that drive glucose metabolism towards an enhanced lactate pro

The prevalence of obesity is increasing worldwide despite a rise in therapeutic interventions to address this epidemic. However, there is a dearth of evidence-based non-surgical treatment guidelines for severe obesity. The aim of this three-year randomized, controlled trial was to elucidate the role of physical activity (PA) in the treatment of severe obesity. First, we studied the association of lifelong PA, aerobic fitness, and cardiac autonomic function by heart rate variability in severely obese adults. Secondly, we investigated the long-term effects of a three-month intensified behavioral modification (iBM) with exercise on glucose tolerance. Thirdly, we aimed to find out whether the timing of the exercise implemented at the weight loss phase of the intervention affects weight loss and waist circumference reduction (WC) from baseline. Finally, we evaluated whether a three-month exercise intervention combined with iBM has long-term effects on weight loss, weight maintenance, and reduction of WC over a three-year follow-up. 120 volunteers (mean BMI 36.8) were randomized into three intervention groups and a control group. All intervention groups were offered intensified behavioral weight loss guidance. According to previous studies, weight loss often stops and re-weighting begins after six months of intervention; we thus added exercise to the protocol of one group right at the beginning of the intervention and to another group after six months. Supervised three-month heart rate-controlled exercise training was implemented as circuit weight training. The weight loss period lasted 12 months, and the weight maintenance period lasted 24 months. Lifetime physical activity and aerobic fitness were positively associated with cardiac autonomic function. During the trial, iBM alone and combined with exercise led to clinically significant weight loss and long-term weight control. Increasing exercise right at the beginning of the weight loss period reduced abdominal, Tiivistelmä Lihavuus yleistyy huolimatta erilaisten hoitomuotojen kehittymisestä. Vaikean lihavuuden hoitamiseen on vain vähän tutkitusti vaikuttavia ei-leikkauksellisia vaihtoehtoja. Tämän tutkimuksen tavoitteena oli selvittää fyysisen aktiivisuuden roolia vaikean lihavuuden hoidossa. Ensimmäiseksi tutkimme elinaikaisen fyysisen aktiivisuuden ja aerobisen kunnon yhteyksiä sykevaihtelulla mitattuun sydämen autonomiseen säätelyyn vaikeasti lihavilla aikuisilla. Toisessa osatyössä selvitimme 3 kuukauden liikuntaharjoittelun ja tehostetun elintapaohjauksen pitkäaikaisia yhteisvaikutuksia sokeriaineenvaihduntaan. Kolmannessa osatyössä selvitimme, vaikuttaako painonpudotusvaiheessa toteutetun liikuntaharjoittelun ajoitus painonpudotukseen ja vyötärönympärykseen. Lopuksi tutkimme, vaikuttaako elintapaohjaukseen yhdistetty 3 kuukauden harjoittelu pitkällä aikavälillä painonpudotukseen, painonhallintaan ja vyötärönympärykseen kolmen vuoden seurannan aikana. 120 vapaaehtoista aikuista (keskimääräinen BMI 36,8) satunnaistettiin kolmeen interventioryhmään ja kontrolliryhmään. Kaikille interventioryhmien jäsenille tarjottiin tehostettua elintapaohjausta painonpudotukseen. Aiempien interventiotutkimusten perusteella painonlasku usein pysähtyy 6 kuukauden kohdalla. Tämän vuoksi sisällytimme interventioprotokollaan liikuntaharjoittelun yhdelle ryhmälle heti intervention alussa ja toiselle ryhmälle 6 kuukauden kohdalla aloittamisesta. Ohjattu 3 kuukauden liikuntaharjoittelu toteutettiin sykeohjattuna kiertoharjoitteluna. Painonpudotusvaihe kesti 12 kuukautta ja painonhallintavaihe 24 kuukautta. Elinikäinen fyysinen aktiivisuus ja aerobinen kunto olivat positiivisesti yhteydessä sydämen autonomiseen säätelyyn. Tehostettu elintapaohjaus yksin ja yhdessä liikuntaharjoittelun kanssa johti kliinisesti merkittävään painonpudotukseen ja pitkäaikaiseen painonhallintaan. Liikunnan lisääminen heti painonpudotuksen alussa pienensi keskivartalolihavuutta, edisti painonhallintaa ja paransi soke

Except for latitudes close to the equator, seasonal variation in light hours can change dramatically between summer and winter. Yet investigations into the interplay between energy metabolism and circadian rhythms typically use a 12 h light:12 h dark photoperiod corresponding to the light duration at the equator. We hypothesized that altering the seasonal photoperiod affects both the rhythmicity of peripheral tissue clocks and energy homeostasis. Mice were housed at photoperiods representing either light hours in summer, winter, or the equinox. Mice housed at a winter photoperiod exhibited an increase in the amplitude of rhythmic lipid metabolism and a modest reduction in fat mass and liver triglyceride content. Comparing melatonin-proficient and -deficient mice, the effect of seasonal light on energy metabolism was largely driven by differences in the rhythmicity of food intake and not melatonin. Together, these data indicate that seasonal light impacts energy metabolism by modulating the timing of eating.

Background: It has been shown under experimental conditions that cognitive performance, especially working memory, is impaired in patients with type I and type II diabetes mellitus during hyperglycemic and hypoglycemic conditions, perhaps due to altered cerebral glucose metabolism. It is not known if patients with neurodegenerative diseases, who also exhibit pathological cerebral glucose metabolism, are affected in a similar manner by their plasma glucose levels. Objective: We aimed to test if performance on two cognitive screening tests was associated with plasma glucose levels in a memory clinic cohort. Methods: We included patients from the Copenhagen Memory Clinic Cohort with an available Mini Mental-State Examination (MMSE) test score and a plasma glucose measurement performed in conjunction with cognitive testing. We built linear regression models with MMSE and Addenbrooke's Cognitive Examination (ACE) test scores as the outcome and plasma glucose as the explaining variable and adjusted models for age, sex, and diabetes (plasma glucose measurement >11.1 mmol/L). We explored non-linear relationships by adding quadratic terms and by fitting a cubic spline regression model. Results: In total, 2714 patients had an available MMSE score and a plasma glucose measurement. MMSE and ACE total scores were not associated with plasma glucose in a linear or non-linear fashion when we adjusted for age, sex, and diabetes. Conclusion: Plasma glucose levels, predominantly within normal ranges, were not associated with performance on routinely applied cognitive tests and do not need to be taken into consideration when interpreting test results from memory clinic patients.

Dietary interventions modify gut microbiota and clinical outcomes. Weight reduction and improved glucose and lipid homeostasis were observed after adopting an Okinawan-based Nordic diet (O-BN) in individuals with type 2 diabetes. The aim of the present study was to explore changes in metabolomics and gut microbiota during O-BN and correlate changes with clinical outcomes. A total of 30 patients (17 women), aged 57.5 ± 8.2 years, diabetes duration 10.4 ± 7.6 years, 90% over-weight, were included. Participants were provided an O-BN for 12 weeks. Before and after intervention, and 16 weeks afterwards, anthropometry and clinical data were estimated and questionnaires were collected, as well as samples of blood and stool. Plasma metabolomics were determined by gas- (GC-MS) or liquid- (LC-MS) chromatography-based mass spectrometry and fecal microbiota determination was based on 16S rRNA amplicons from regions V1-V2. During the intervention, weight (6.8%), waist circumference (6.1%), and levels of glucose, HbA1c, insulin, triglycerides, and cholesterol were decreased. Of 602 metabolites, 323 were changed for any or both periods; 199 (101 lipids) metabolites were decreased while 58 (43 lipids) metabolites were increased during the intervention. Changes in glucose homeostasis were linked to changes in, e.g., 1,5-anhydroglucitol, thyroxine, and chiro-inositol. Changes of microbe beta diversity correlated positively with food components and negatively with IL-18 (p = 0.045). Abundance differences at phylum and genus levels were found. Abundances of Actinobacteria, Bacteroidetes, Firmicutes, and Verrucomicrobia correlated with anthropometry, HbA1c, lipids, inflammation, and food. Changes in metabolites and microbiota were reversed after the intervention. The O-BN-induced changes in metabolomics and gut microbiota correspond to clinical outcomes of reduced weight and inflammation and improved glucose and lipid metabolism.

External tasks evoke characteristic fMRI BOLD signal deactivations in the default mode network (DMN). However, for the corresponding metabolic glucose demands both decreases and increases have been reported. To resolve this discrepancy, functional PET/MRI data from 50 healthy subjects performing Tetris were combined with previously published data sets of working memory, visual and motor stimulation. We show that the glucose metabolism of the posteromedial DMN is dependent on the metabolic demands of the correspondingly engaged task-positive networks. Specifically, the dorsal attention and frontoparietal network shape the glucose metabolism of the posteromedial DMN in opposing directions. While tasks that mainly require an external focus of attention lead to a consistent downregulation of both metabolism and the BOLD signal in the posteromedial DMN, cognitive control during working memory requires a metabolically expensive BOLD suppression. This indicates that two types of BOLD deactivations with different oxygen-to-glucose index may occur in this region. We further speculate that consistent downregulation of the two signals is mediated by decreased glutamate signaling, while divergence may be subject to active GABAergic inhibition. The results demonstrate that the DMN relates to cognitive processing in a flexible manner and does not always act as a cohesive task-negative network in isolation.

A common observation in fMRI studies using the BOLD signal is that older adults, compared with young adults, show overactivations, particularly during less demanding tasks. The neuronal underpinnings of such overactivations are not known, but a dominant view is that they are compensatory in nature and involve recruitment of additional neural resources. We scanned 23 young (20-37 years) and 34 older (65-86 years) healthy human adults of both sexes with hybrid positron emission tomography/MRI. The radioligand [18F]fluoro-deoxyglucose was used to assess dynamic changes in glucose metabolism as a marker of task-dependent synaptic activity, along with simultaneous fMRI BOLD imaging. Participants performed two verbal working memory (WM) tasks: one involving maintenance (easy) and one requiring manipulation (difficult) of information in WM. Converging activations to the WM tasks versus rest were observed for both imaging modalities and age groups in attentional, control, and sensorimotor networks. Upregulation of activity to WM-demand, comparing the more difficult to the easier task, also converged between both modalities and age groups. For regions in which older adults showed task-dependent BOLD overactivations compared with the young adults, no corresponding increases in glucose metabolism were found. To conclude, findings from the current study show that task-induced changes in the BOLD signal and synaptic activity as measured by glucose metabolism generally converge, but overactivations observed with fMRI in older adults are not coupled with increased synaptic activity, which suggests that these overactivations are not neuronal in origin.

Dietary interventions modify gut microbiota and clinical outcomes. Weight reduction and improved glucose and lipid homeostasis were observed after adopting an Okinawan-based Nordic diet (O-BN) in individuals with type 2 diabetes. The aim of the present study was to explore changes in metabolomics and gut microbiota during O-BN and correlate changes with clinical outcomes. A total of 30 patients (17 women), aged 57.5 ± 8.2 years, diabetes duration 10.4 ± 7.6 years, 90% over-weight, were included. Participants were provided an O-BN for 12 weeks. Before and after intervention, and 16 weeks afterwards, anthropometry and clinical data were estimated and questionnaires were collected, as well as samples of blood and stool. Plasma metabolomics were determined by gas- (GC-MS) or liquid- (LC-MS) chromatography-based mass spectrometry and fecal microbiota determination was based on 16S rRNA amplicons from regions V1-V2. During the intervention, weight (6.8%), waist circumference (6.1%), and levels of glucose, HbA1c, insulin, triglycerides, and cholesterol were decreased. Of 602 metabolites, 323 were changed for any or both periods; 199 (101 lipids) metabolites were decreased while 58 (43 lipids) metabolites were increased during the intervention. Changes in glucose homeostasis were linked to changes in, e.g., 1,5-anhydroglucitol, thyroxine, and chiro-inositol. Changes of microbe beta diversity correlated positively with food components and negatively with IL-18 (p = 0.045). Abundance differences at phylum and genus levels were found. Abundances of Actinobacteria, Bacteroidetes, Firmicutes, and Verrucomicrobia correlated with anthropometry, HbA1c, lipids, inflammation, and food. Changes in metabolites and microbiota were reversed after the intervention. The O-BN-induced changes in metabolomics and gut microbiota correspond to clinical outcomes of reduced weight and inflammation and improved glucose and lipid metabolism.

External tasks evoke characteristic fMRI BOLD signal deactivations in the default mode network (DMN). However, for the corresponding metabolic glucose demands both decreases and increases have been reported. To resolve this discrepancy, functional PET/MRI data from 50 healthy subjects performing Tetris were combined with previously published data sets of working memory, visual and motor stimulation. We show that the glucose metabolism of the posteromedial DMN is dependent on the metabolic demands of the correspondingly engaged task-positive networks. Specifically, the dorsal attention and frontoparietal network shape the glucose metabolism of the posteromedial DMN in opposing directions. While tasks that mainly require an external focus of attention lead to a consistent downregulation of both metabolism and the BOLD signal in the posteromedial DMN, cognitive control during working memory requires a metabolically expensive BOLD suppression. This indicates that two types of BOLD deactivations with different oxygen-to-glucose index may occur in this region. We further speculate that consistent downregulation of the two signals is mediated by decreased glutamate signaling, while divergence may be subject to active GABAergic inhibition. The results demonstrate that the DMN relates to cognitive processing in a flexible manner and does not always act as a cohesive task-negative network in isolation.

Dietary interventions modify gut microbiota and clinical outcomes. Weight reduction and improved glucose and lipid homeostasis were observed after adopting an Okinawan-based Nordic diet (O-BN) in individuals with type 2 diabetes. The aim of the present study was to explore changes in metabolomics and gut microbiota during O-BN and correlate changes with clinical outcomes. A total of 30 patients (17 women), aged 57.5 ± 8.2 years, diabetes duration 10.4 ± 7.6 years, 90% over-weight, were included. Participants were provided an O-BN for 12 weeks. Before and after intervention, and 16 weeks afterwards, anthropometry and clinical data were estimated and questionnaires were collected, as well as samples of blood and stool. Plasma metabolomics were determined by gas- (GC-MS) or liquid- (LC-MS) chromatography-based mass spectrometry and fecal microbiota determination was based on 16S rRNA amplicons from regions V1-V2. During the intervention, weight (6.8%), waist circumference (6.1%), and levels of glucose, HbA1c, insulin, triglycerides, and cholesterol were decreased. Of 602 metabolites, 323 were changed for any or both periods; 199 (101 lipids) metabolites were decreased while 58 (43 lipids) metabolites were increased during the intervention. Changes in glucose homeostasis were linked to changes in, e.g., 1,5-anhydroglucitol, thyroxine, and chiro-inositol. Changes of microbe beta diversity correlated positively with food components and negatively with IL-18 (p = 0.045). Abundance differences at phylum and genus levels were found. Abundances of Actinobacteria, Bacteroidetes, Firmicutes, and Verrucomicrobia correlated with anthropometry, HbA1c, lipids, inflammation, and food. Changes in metabolites and microbiota were reversed after the intervention. The O-BN-induced changes in metabolomics and gut microbiota correspond to clinical outcomes of reduced weight and inflammation and improved glucose and lipid metabolism.

A common observation in fMRI studies using the BOLD signal is that older adults, compared with young adults, show overactivations, particularly during less demanding tasks. The neuronal underpinnings of such overactivations are not known, but a dominant view is that they are compensatory in nature and involve recruitment of additional neural resources. We scanned 23 young (20-37 years) and 34 older (65-86 years) healthy human adults of both sexes with hybrid positron emission tomography/MRI. The radioligand [18F]fluoro-deoxyglucose was used to assess dynamic changes in glucose metabolism as a marker of task-dependent synaptic activity, along with simultaneous fMRI BOLD imaging. Participants performed two verbal working memory (WM) tasks: one involving maintenance (easy) and one requiring manipulation (difficult) of information in WM. Converging activations to the WM tasks versus rest were observed for both imaging modalities and age groups in attentional, control, and sensorimotor networks. Upregulation of activity to WM-demand, comparing the more difficult to the easier task, also converged between both modalities and age groups. For regions in which older adults showed task-dependent BOLD overactivations compared with the young adults, no corresponding increases in glucose metabolism were found. To conclude, findings from the current study show that task-induced changes in the BOLD signal and synaptic activity as measured by glucose metabolism generally converge, but overactivations observed with fMRI in older adults are not coupled with increased synaptic activity, which suggests that these overactivations are not neuronal in origin.

Dietary interventions modify gut microbiota and clinical outcomes. Weight reduction and improved glucose and lipid homeostasis were observed after adopting an Okinawan-based Nordic diet (O-BN) in individuals with type 2 diabetes. The aim of the present study was to explore changes in metabolomics and gut microbiota during O-BN and correlate changes with clinical outcomes. A total of 30 patients (17 women), aged 57.5 ± 8.2 years, diabetes duration 10.4 ± 7.6 years, 90% over-weight, were included. Participants were provided an O-BN for 12 weeks. Before and after intervention, and 16 weeks afterwards, anthropometry and clinical data were estimated and questionnaires were collected, as well as samples of blood and stool. Plasma metabolomics were determined by gas- (GC-MS) or liquid- (LC-MS) chromatography-based mass spectrometry and fecal microbiota determination was based on 16S rRNA amplicons from regions V1-V2. During the intervention, weight (6.8%), waist circumference (6.1%), and levels of glucose, HbA1c, insulin, triglycerides, and cholesterol were decreased. Of 602 metabolites, 323 were changed for any or both periods; 199 (101 lipids) metabolites were decreased while 58 (43 lipids) metabolites were increased during the intervention. Changes in glucose homeostasis were linked to changes in, e.g., 1,5-anhydroglucitol, thyroxine, and chiro-inositol. Changes of microbe beta diversity correlated positively with food components and negatively with IL-18 (p = 0.045). Abundance differences at phylum and genus levels were found. Abundances of Actinobacteria, Bacteroidetes, Firmicutes, and Verrucomicrobia correlated with anthropometry, HbA1c, lipids, inflammation, and food. Changes in metabolites and microbiota were reversed after the intervention. The O-BN-induced changes in metabolomics and gut microbiota correspond to clinical outcomes of reduced weight and inflammation and improved glucose and lipid metabolism.

External tasks evoke characteristic fMRI BOLD signal deactivations in the default mode network (DMN). However, for the corresponding metabolic glucose demands both decreases and increases have been reported. To resolve this discrepancy, functional PET/MRI data from 50 healthy subjects performing Tetris were combined with previously published data sets of working memory, visual and motor stimulation. We show that the glucose metabolism of the posteromedial DMN is dependent on the metabolic demands of the correspondingly engaged task-positive networks. Specifically, the dorsal attention and frontoparietal network shape the glucose metabolism of the posteromedial DMN in opposing directions. While tasks that mainly require an external focus of attention lead to a consistent downregulation of both metabolism and the BOLD signal in the posteromedial DMN, cognitive control during working memory requires a metabolically expensive BOLD suppression. This indicates that two types of BOLD deactivations with different oxygen-to-glucose index may occur in this region. We further speculate that consistent downregulation of the two signals is mediated by decreased glutamate signaling, while divergence may be subject to active GABAergic inhibition. The results demonstrate that the DMN relates to cognitive processing in a flexible manner and does not always act as a cohesive task-negative network in isolation.

A common observation in fMRI studies using the BOLD signal is that older adults, compared with young adults, show overactivations, particularly during less demanding tasks. The neuronal underpinnings of such overactivations are not known, but a dominant view is that they are compensatory in nature and involve recruitment of additional neural resources. We scanned 23 young (20-37 years) and 34 older (65-86 years) healthy human adults of both sexes with hybrid positron emission tomography/MRI. The radioligand [18F]fluoro-deoxyglucose was used to assess dynamic changes in glucose metabolism as a marker of task-dependent synaptic activity, along with simultaneous fMRI BOLD imaging. Participants performed two verbal working memory (WM) tasks: one involving maintenance (easy) and one requiring manipulation (difficult) of information in WM. Converging activations to the WM tasks versus rest were observed for both imaging modalities and age groups in attentional, control, and sensorimotor networks. Upregulation of activity to WM-demand, comparing the more difficult to the easier task, also converged between both modalities and age groups. For regions in which older adults showed task-dependent BOLD overactivations compared with the young adults, no corresponding increases in glucose metabolism were found. To conclude, findings from the current study show that task-induced changes in the BOLD signal and synaptic activity as measured by glucose metabolism generally converge, but overactivations observed with fMRI in older adults are not coupled with increased synaptic activity, which suggests that these overactivations are not neuronal in origin.

A common observation in fMRI studies using the BOLD signal is that older adults, compared with young adults, show overactivations, particularly during less demanding tasks. The neuronal underpinnings of such overactivations are not known, but a dominant view is that they are compensatory in nature and involve recruitment of additional neural resources. We scanned 23 young (20-37 years) and 34 older (65-86 years) healthy human adults of both sexes with hybrid positron emission tomography/MRI. The radioligand [18F]fluoro-deoxyglucose was used to assess dynamic changes in glucose metabolism as a marker of task-dependent synaptic activity, along with simultaneous fMRI BOLD imaging. Participants performed two verbal working memory (WM) tasks: one involving maintenance (easy) and one requiring manipulation (difficult) of information in WM. Converging activations to the WM tasks versus rest were observed for both imaging modalities and age groups in attentional, control, and sensorimotor networks. Upregulation of activity to WM-demand, comparing the more difficult to the easier task, also converged between both modalities and age groups. For regions in which older adults showed task-dependent BOLD overactivations compared with the young adults, no corresponding increases in glucose metabolism were found. To conclude, findings from the current study show that task-induced changes in the BOLD signal and synaptic activity as measured by glucose metabolism generally converge, but overactivations observed with fMRI in older adults are not coupled with increased synaptic activity, which suggests that these overactivations are not neuronal in origin.

Dietary interventions modify gut microbiota and clinical outcomes. Weight reduction and improved glucose and lipid homeostasis were observed after adopting an Okinawan-based Nordic diet (O-BN) in individuals with type 2 diabetes. The aim of the present study was to explore changes in metabolomics and gut microbiota during O-BN and correlate changes with clinical outcomes. A total of 30 patients (17 women), aged 57.5 ± 8.2 years, diabetes duration 10.4 ± 7.6 years, 90% over-weight, were included. Participants were provided an O-BN for 12 weeks. Before and after intervention, and 16 weeks afterwards, anthropometry and clinical data were estimated and questionnaires were collected, as well as samples of blood and stool. Plasma metabolomics were determined by gas- (GC-MS) or liquid- (LC-MS) chromatography-based mass spectrometry and fecal microbiota determination was based on 16S rRNA amplicons from regions V1-V2. During the intervention, weight (6.8%), waist circumference (6.1%), and levels of glucose, HbA1c, insulin, triglycerides, and cholesterol were decreased. Of 602 metabolites, 323 were changed for any or both periods; 199 (101 lipids) metabolites were decreased while 58 (43 lipids) metabolites were increased during the intervention. Changes in glucose homeostasis were linked to changes in, e.g., 1,5-anhydroglucitol, thyroxine, and chiro-inositol. Changes of microbe beta diversity correlated positively with food components and negatively with IL-18 (p = 0.045). Abundance differences at phylum and genus levels were found. Abundances of Actinobacteria, Bacteroidetes, Firmicutes, and Verrucomicrobia correlated with anthropometry, HbA1c, lipids, inflammation, and food. Changes in metabolites and microbiota were reversed after the intervention. The O-BN-induced changes in metabolomics and gut microbiota correspond to clinical outcomes of reduced weight and inflammation and improved glucose and lipid metabolism.

External tasks evoke characteristic fMRI BOLD signal deactivations in the default mode network (DMN). However, for the corresponding metabolic glucose demands both decreases and increases have been reported. To resolve this discrepancy, functional PET/MRI data from 50 healthy subjects performing Tetris were combined with previously published data sets of working memory, visual and motor stimulation. We show that the glucose metabolism of the posteromedial DMN is dependent on the metabolic demands of the correspondingly engaged task-positive networks. Specifically, the dorsal attention and frontoparietal network shape the glucose metabolism of the posteromedial DMN in opposing directions. While tasks that mainly require an external focus of attention lead to a consistent downregulation of both metabolism and the BOLD signal in the posteromedial DMN, cognitive control during working memory requires a metabolically expensive BOLD suppression. This indicates that two types of BOLD deactivations with different oxygen-to-glucose index may occur in this region. We further speculate that consistent downregulation of the two signals is mediated by decreased glutamate signaling, while divergence may be subject to active GABAergic inhibition. The results demonstrate that the DMN relates to cognitive processing in a flexible manner and does not always act as a cohesive task-negative network in isolation.

Background: Dietary sugars are often linked to the development of overweight and type 2 diabetes (T2D) but inconsistencies remain. Objective: We investigated associations of added, free, and total sugars, and glycaemic index (GI) with indices of glucose metabolism (IGM) and indices of body fatness (IBF) during a 3-year weight loss maintenance intervention. Design: The PREVIEW (PREVention of diabetes through lifestyle Intervention and population studies in Europe and around the World) study was a randomised controlled trial designed to test the effects of four diet and physical activity interventions, after an 8-week weight-loss period, on the incidence of T2D. This secondary observational analysis included pooled data assessed at baseline (8), 26, 52, 104 and 156 weeks from 514 participants with overweight/obesity (age 25–70 year; BMI ≥ 25 kg⋅m−2) and with/without prediabetes in centres that provided data on added sugars (Sydney and Helsinki) or free sugars (Nottingham). Linear mixed models with repeated measures were applied for IBF (total body fat, BMI, waist circumference) and for IGM (fasting insulin, HbA1c, fasting glucose, C-peptide). Model A was adjusted for age and intervention centre and Model B additionally adjusted for energy, protein, fibre, and saturated fat. Results: Total sugars were inversely associated with fasting insulin and C-peptide in all centres, and free sugars were inversely associated with fasting glucose and HbA1c (Model B: all p < 0.05). Positive associations were observed between GI and IGM (Model B: fasting insulin, HbA1c, and C-peptide: (all p < 0.01), but not for added sugars. Added sugar was positively associated with body fat percentage and BMI, and GI was associated with waist circumference (Model B: all p < 0.01), while free sugars showed no associations (Model B: p > 0.05). Conclusions: Our findings suggest that ad

The adverse health effects of sedentary behavior and prolonged sedentary bouts are well-known. However, it is still unknown how physical activity can modify adverse health impacts related to sedentary behavior. The purpose of this study was to develop signal analysis methodology for sedentary behavior and physical activity classification from raw data of a hip-worn accelerometer and to investigate associations of patterns of sedentary behavior with lipid and glucose metabolism. A machine learning model was developed and validated using acceleration data, which included nine predefined and controlled typical daily activities ranging in intensity from sedentary to vigorous physical activity. Acceleration data was collected from 22 Finnish adults using a triaxial accelerometer attached to an elastic belt on a hip. The data were classified into five categories (lying down, sitting, and light, moderate, and vigorous physical activity). Thirty-six middle-aged Finnish adults wore an accelerometer for 14 days, and their sedentary behavior and sitting characteristics were determined. In addition, associations of sedentary behavior, sitting, and physical activity with glucose and lipid metabolism were investigated in the Northern Finland Birth Cohort 1966 46-year follow-up (n=5,832). Participants completed health and lifestyle questionnaires and attended clinical examinations and two weeks of sedentary behavior and physical activity measurements. Isotemporal substitution modeling was used for investigating time reallocations from sedentary to physical activities. The developed machine learning model provided acceptable accuracy for sedentary behavior and physical activity classifications. The method can be used for describing characteristics of sedentary behavior and sitting separately. Patterns of SB were more consistently associated with lipid metabolism than those of sitting. Associations between sedentary behavior and cardiometabolic health depended on moderate-t, Tiivistelmä Runsaan paikallaanolon ja pitkien paikallaanolojaksojen haitalliset vaikutukset terveyteen ovat hyvin tiedossa, mutta edelleen puuttuu tietoa, kuinka fyysinen aktiivisuus voi muokata paikallaanolon haitallisia vaikutuksia terveyteen. Työn tarkoituksena oli kehittää signaalinkäsittelymenetelmä paikallaanolon ja fyysisen aktiivisuuden luokittelemiseksi lantiolla pidettävän aktiivisuusmittarin raakakiihtyvyyksistä sekä tutkia paikallaanolon piirteiden yhteyksiä rasva- ja sokeriaineenvaihduntaan. Koneoppimismalli kehitettiin ja validoitiin käyttämällä kiihtyvyysdataa, joka sisälsi yhdeksän ennalta määriteltyä ja kontrolloitua tyypillistä arkiaktiviteettia, joiden intensiteetti vaihteli paikallaanolosta raskaaseen fyysiseen aktiivisuuteen. Kiihtyvyysdata kerättiin 22 suomalaisen aikuisen lantiolta elastiseen vyöhön kiinnitetyllä kolmiakselisella kiihtyvyysanturilla, jonka raakadata luokiteltiin viiteen eri luokkaan (makaaminen, istuminen sekä kevyt, keskiraskas ja raskas fyysinen aktiivisuus). Kolmekymmentäkuusi keski-ikäistä suomalaista käyttivät kiihtyvyysanturia 14 päivän ajan ja heidän paikallaanolonsa ja istumisensa piirteet määritettiin. Paikallaanolon, istumisen ja fyysisen aktiivisuuden yhteyksiä rasva- ja sokeriaineenvaihduntaan tutkittiin Pohjois-Suomen vuoden 1966 syntymäkohortin 46-vuotistutkimuksessa (n = 5832). Tutkittavat täyttivät terveys- ja elämäntapakyselyitä ja osallistuivat kliinisiin tutkimuksiin sekä kahden viikon mittaisiin paikallaanolon ja fyysisen aktiivisuuden mittauksiin. Isotemporaalisella korvausmallilla tutkittiin paikallaanoloajan korvaamista fyysisellä aktiivisuudella. Kehitetyllä koneoppimismenetelmällä voidaan riittävällä tarkkuudella luokitella paikallaanoloa ja fyysistä aktiivisuutta. Menetelmää voidaan käyttää paikallaanolon ja istumisen piirteiden kuvailussa erikseen. Paikallaanolon piirteet olivat selvemmin yhteydessä rasva-aineenvaihduntaan kuin istumisen piirteet. Paikallaanolon yhteydet rasva-aineenvaihduntaan oliva

Alpha-lipoic acid (ALA) is a natural compound with antioxidant and pro-oxidant properties which has effects on the regulation of insulin sensitivity and insulin secretion. ALA is widely prescribed in patients with diabetic polyneuropathy due to its positive effects on nerve conduction and alleviation of symptoms. It is, moreover, also prescribed in other insulin resistance conditions such as metabolic syndrome (SM), polycystic ovary syndrome (PCOS) and obesity. However, several cases of Insulin Autoimmune Syndrome (IAS) have been reported in subjects taking ALA. The aim of the present review is to describe the main chemical and biological functions of ALA in glucose metabolism, focusing on its antioxidant activity, its role in modulating insulin sensitivity and secretion and in symptomatic peripheral diabetic polyneuropathy. We also provide a potential explanation for increased risk for the development of IAS.

External tasks evoke characteristic fMRI BOLD signal deactivations in the default mode network (DMN). However, for the corresponding metabolic glucose demands both decreases and increases have been reported. To resolve this discrepancy, functional PET/MRI data from 50 healthy subjects performing Tetris were combined with previously published data sets of working memory, visual and motor stimulation. We show that the glucose metabolism of the posteromedial DMN is dependent on the metabolic demands of the correspondingly engaged task-positive networks. Specifically, the dorsal attention and frontoparietal network shape the glucose metabolism of the posteromedial DMN in opposing directions. While tasks that mainly require an external focus of attention lead to a consistent downregulation of both metabolism and the BOLD signal in the posteromedial DMN, cognitive control during working memory requires a metabolically expensive BOLD suppression. This indicates that two types of BOLD deactivations with different oxygen-to-glucose index may occur in this region. We further speculate that consistent downregulation of the two signals is mediated by decreased glutamate signaling, while divergence may be subject to active GABAergic inhibition. The results demonstrate that the DMN relates to cognitive processing in a flexible manner and does not always act as a cohesive task-negative network in isolation.

A common observation in fMRI studies using the BOLD signal is that older adults, compared with young adults, show overactivations, particularly during less demanding tasks. The neuronal underpinnings of such overactivations are not known, but a dominant view is that they are compensatory in nature and involve recruitment of additional neural resources. We scanned 23 young (20-37 years) and 34 older (65-86 years) healthy human adults of both sexes with hybrid positron emission tomography/MRI. The radioligand [18F]fluoro-deoxyglucose was used to assess dynamic changes in glucose metabolism as a marker of task-dependent synaptic activity, along with simultaneous fMRI BOLD imaging. Participants performed two verbal working memory (WM) tasks: one involving maintenance (easy) and one requiring manipulation (difficult) of information in WM. Converging activations to the WM tasks versus rest were observed for both imaging modalities and age groups in attentional, control, and sensorimotor networks. Upregulation of activity to WM-demand, comparing the more difficult to the easier task, also converged between both modalities and age groups. For regions in which older adults showed task-dependent BOLD overactivations compared with the young adults, no corresponding increases in glucose metabolism were found. To conclude, findings from the current study show that task-induced changes in the BOLD signal and synaptic activity as measured by glucose metabolism generally converge, but overactivations observed with fMRI in older adults are not coupled with increased synaptic activity, which suggests that these overactivations are not neuronal in origin.

A common observation in fMRI studies using the BOLD signal is that older adults, compared with young adults, show overactivations, particularly during less demanding tasks. The neuronal underpinnings of such overactivations are not known, but a dominant view is that they are compensatory in nature and involve recruitment of additional neural resources. We scanned 23 young (20-37 years) and 34 older (65-86 years) healthy human adults of both sexes with hybrid positron emission tomography/MRI. The radioligand [18F]fluoro-deoxyglucose was used to assess dynamic changes in glucose metabolism as a marker of task-dependent synaptic activity, along with simultaneous fMRI BOLD imaging. Participants performed two verbal working memory (WM) tasks: one involving maintenance (easy) and one requiring manipulation (difficult) of information in WM. Converging activations to the WM tasks versus rest were observed for both imaging modalities and age groups in attentional, control, and sensorimotor networks. Upregulation of activity to WM-demand, comparing the more difficult to the easier task, also converged between both modalities and age groups. For regions in which older adults showed task-dependent BOLD overactivations compared with the young adults, no corresponding increases in glucose metabolism were found. To conclude, findings from the current study show that task-induced changes in the BOLD signal and synaptic activity as measured by glucose metabolism generally converge, but overactivations observed with fMRI in older adults are not coupled with increased synaptic activity, which suggests that these overactivations are not neuronal in origin.

The transcription factor Nrf2 and its repressor Keap1 mediate cell stress adaptation by inducing expression of genes regulating cellular detoxification, antioxidant defence and energy metabolism. Energy production and antioxidant defence employ NADH and NADPH respectively as essential metabolic cofactors; both are generated in distinct pathways of glucose metabolism, and both pathways are enhanced by Nrf2 activation. Here, we examined the role of Nrf2 on glucose distribution and the interrelation between NADH production in energy metabolism and NADPH homeostasis using glio-neuronal cultures isolated from wild-type, Nrf2-knockout and Keap1-knockdown mice. Employing advanced microscopy imaging of single live cells, including multiphoton fluorescence lifetime imaging microscopy (FLIM) to discriminate between NADH and NADPH, we found that Nrf2 activation increases glucose uptake into neurons and astrocytes. Glucose consumption is prioritized in brain cells for mitochondrial NADH and energy production, with a smaller contribution to NADPH synthesis in the pentose phosphate pathway for redox reactions. As Nrf2 is suppressed during neuronal development, this strategy leaves neurons reliant on astrocytic Nrf2 to maintain redox balance and energy homeostasis.

Ca. Accumulibacter was the predominant microorganism (relative FISH bio-abundance of 67 ± 5%) in a lab-scale sequential batch reactor that accomplished enhanced biological phosphorus removal (EBPR) while using glucose and acetate as the carbon sources (1:1 COD-based ratio). Both organic compounds were completely anaerobically consumed. The reactor's performance in terms of P/C ratio, phosphorous release and uptake, and overall kinetic and stoichiometric parameters were on the high end of the reported spectrum for EBPR systems (100:9.3 net mg phosphate removal per mg COD consumed when using glucose and acetate in a 1:1 ratio). The batch tests showed that, to the best of our knowledge, this is the first time a reactor enriched with Ca. Accumulibacter can putatively utilize glucose as the sole carbon source to biologically remove phosphate (COD:P (mg/mg) removal ratio of 100:6.3 when using only glucose). Thus, this research proposes that Ca. Accumulibacter directly anaerobically stored the fed glucose primarily as glycogen by utilizing the ATP provided via the hydrolysis of poly-P and secondarily as PHA by balancing its ATP utilization (glycogen generation) and formation (PHA storage). Alternative hypotheses are also discussed. The reported findings could challenge the conventional theories of glucose assimilation by Ca. Accumulibacter, and can be of significance for the biological removal of phosphorus from wastewaters with high contents of fermentable compounds or low VFAs., BT/Environmental Biotechnology

[Abstract] Purpose: Although some dementia with Lewy bodies (DLB) patients have Alzheimer disease (AD) pathology, there are no reports comparing AD and DLB by amyloid PET and tau PET in the same patient. The aim of this study was to investigate the regional difference of metabolic reduction, amyloid deposition and tau deposition between DLB and AD brain. Methods: Five consecutive subjects with DLB and five age and Mini-mental state examination score matched AD patients, who underwent both fluoro-2-deoxyglucose (FDG)-PET, Pittsburgh compound B (PiB)-amyloid PET and THK5351 (THK)-tau PET, were included in this study. Voxel-based statistical analysis was performed with Statistical Parametric Mapping for comparison with FDG, amyloid and tau accumulation between the DLB and AD brains. Results: FDG PET demonstrated that occipital metabolism in DLB group was significantly lower than that in AD group. PiB PET demonstrated that in the AD group the anterior to posterior cingulate cortices, supplementary motor area, and thalamic amyloid depositions were significantly higher than those in the DLB group. THK PET demonstrated that in the AD group the posterior cingulate cortices, posterior internal capsules, thalamic and peri-brainstem regions tau depositions were significantly higher than those in the DLB group. Conclusions: In the DLB brain, it is suggested that decreased regional glucose metabolism is unrelated to amyloid and tau depositions, and the amyloid and tau depositions in the cingulate gyri and thalamic regions in the AD brain are higher than those in DLB brain., Departmental Bulletin Paper, application/pdf

This thesis investigates the connection between insulin-regulated pathways, connected genes, and hepatocellular carcinoma (HCC) across its different development stages foci, nodule, adenoma, and carcinoma. A Differential Gene Expression Analysis was done, followed by a Term Enrichment Analysis. Furthermore, a Gene Set Variation Analysis was carried out. All gathered results were put into biological context, connected with literature research. Genes and gene sets with significant deregulation across all stages showed a relevant connection to carbohydrate metabolism, cell cycle regulation, proliferation, and cancer cell growth. Some deregulated genes are linked to an increased risk for diabetes and obesity. In contrast, others could be used as biomarkers in the early detection of HCC or as potential drug carriers in its treatment.*****This thesis investigates the connection between insulin-regulated pathways, connected genes, and hepatocellular carcinoma (HCC) across its different development stages foci, nodule, adenoma, and carcinoma. A Differential Gene Expression Analysis was done, followed by a Term Enrichment Analysis. Furthermore, a Gene Set Variation Analysis was carried out. All gathered results were put into biological context, connected with literature research. Genes and gene sets with significant deregulation across all stages showed a relevant connection to carbohydrate metabolism, cell cycle regulation, proliferation, and cancer cell growth. Some deregulated genes are linked to an increased risk for diabetes and obesity. In contrast, others could be used as biomarkers in the early detection of HCC or as potential drug carriers in its treatment.

Low-calorie sweetener (LCS) consumption in children has increased dramatically due to its widespread presence in the food environment and efforts to mitigate obesity through sugar replacement. However, mechanistic studies on the long-term impact of early-life LCS consumption on cognitive function and physiological processes are lacking. Here, we developed a rodent model to evaluate the effects of daily LCS consumption (acesulfame potassium, saccharin, or stevia) during adolescence on adult metabolic, behavioral, gut microbiome, and brain transcriptomic outcomes. Results reveal that habitual early-life LCS consumption impacts normal postoral glucose handling and impairs hippocampal-dependent memory in the absence of weight gain. Furthermore, adolescent LCS consumption yielded long-term reductions in lingual sweet taste receptor expression and brought about alterations in sugar-motivated appetitive and consummatory responses. While early-life LCS consumption did not produce robust changes in the gut microbiome, brain region-specific RNA-Seq analyses reveal LCS-induced changes in collagen- and synaptic signaling-related gene pathways in the hippocampus and nucleus accumbens, respectively, in a sex-dependent manner. Collectively, these results reveal that habitual early-life LCS consumption has long-lasting implications for glucoregulation, sugar-motivated behavior, and hippocampal-dependent memory in rats, which may be based in part on changes in nutrient transporter, sweet taste receptor, and central gene pathway expression.

of the study.

Exploring individual hallmarks of brain ageing is important. Here, we propose the age-related glucose metabolism pattern (ARGMP) as a potential index to characterize brain ageing in cognitively normal (CN) elderly people. We collected 18F-fluorodeoxyglucose (18F-FDG) PET brain images from two independent cohorts: the Alzheimer's Disease Neuroimaging Initiative (ADNI, N = 127) and the Xuanwu Hospital of Capital Medical University, Beijing, China (N = 84). During follow-up (mean 80.60 months), 23 participants in the ADNI cohort converted to cognitive impairment. ARGMPs were identified using the scaled subprofile model/principal component analysis method, and cross-validations were conducted in both independent cohorts. A survival analysis was further conducted to calculate the predictive effect of conversion risk by using ARGMPs. The results showed that ARGMPs were characterized by hypometabolism with increasing age primarily in the bilateral medial superior frontal gyrus, anterior cingulate and paracingulate gyri, caudate nucleus, and left supplementary motor area and hypermetabolism in part of the left inferior cerebellum. The expression network scores of ARGMPs were significantly associated with chronological age (R = 0.808, p < 0.001), which was validated in both the ADNI and Xuanwu cohorts. Individuals with higher network scores exhibited a better predictive effect (HR: 0.30, 95% CI: 0.1340 ~ 0.6904, p = 0.0068). These findings indicate that ARGMPs derived from CN participants may represent a novel index for characterizing brain ageing and predicting high conversion risk into cognitive impairment.

The intracellular pathogen Chlamydia temporally regulates the expression of its genes, but the upstream signals that control transcription are not known. The best-studied regulatory pathway is a partner-switching mechanism that involves an anti-sigma factor, RsbW, which inhibits transcription by binding and sequestering the sigma subunit of RNA polymerase. RsbW is itself regulated by an anti-anti-sigma factor, RsbV, whose phosphorylation state is controlled by the phosphatase RsbU. In this study, we showed that Chlamydia trachomatis RsbU requires manganese or magnesium as a cofactor and dephosphorylates RsbV1 and RsbV2, which are the two chlamydial paralogs of RsbV. The gene for RsbU is adjacent to the enolase gene in a number of Chlamydia genomes, and we showed that eno and rsbU are cotranscribed from the same operon. In other bacteria, there is no known functional connection between the Rsb pathway and enolase, which is an enzyme in the glycolytic pathway. We found, however, that Chlamydia RsbU phosphatase activity was inhibited by phosphoenolpyruvate (PEP), the product of the enolase reaction, but not by 2-phosphoglycerate (2PGA), which is the substrate. These findings suggest that the enolase reaction and, more generally, glucose metabolism, may provide an upstream signal that regulates transcription in Chlamydia through the RsbW pathway. IMPORTANCE The RsbW pathway is a phosphorelay that regulates gene expression in Chlamydia, but its upstream signal has not been identified. We showed that RsbU, a phosphatase in this pathway, is inhibited by phosphoenolpyruvate, which is the product of the enolase reaction. As enolase is an enzyme in the glycolytic pathway, these results reveal an unrecognized link between glucose metabolism and gene regulation in chlamydiae. Moreover, as these intracellular bacteria acquire glucose from the infected host cell, our findings suggest that glucose availability may be an external signal that controls chlamydial gene expression.

Objectives: Subtypes in type 1 diabetes pathogenesis have been implicated based on the first-appearing autoantibody (primary autoantibody). We set out to describe the glucose metabolism in preclinical diabetes in relation to the primary autoantibody in children with HLA-conferred disease susceptibility. Design and methods: Dysglycemic markers are defined as a 10% increase in HbA1c in a 3–12 months interval or HbA1c ≥5.9% (41 mmol/mol) in two consecutive samples, impaired fasting glucose or impaired glucose tolerance, or a random plasma glucose value ≥7.8 mmol/L. A primary autoantibody could be detected in 295 children who later developed at least 1 additional biochemical autoantibody. These children were divided into three groups: insulin autoantibody (IAA) multiple (n = 143), GAD antibody (GADA) multiple (n = 126) and islet antigen 2 antibody (IA-2A) multiple (n = 26). Another 229 children seroconverted to positivity only for a single biochemical autoantibody and were grouped as IAA only (n = 87), GADA only (n = 114) and IA-2A only (n = 28). Results: No consistent differences were observed in selected autoantibody groups during the preclinical period. At diagnosis, children with IAA only showed the highest HbA1c (P < 0.001 between groups) and the highest random plasma glucose (P = 0.005 between groups). Children with IA-2A only progressed to type 1 diabetes as frequently as those with IA-2A multiple (46% vs 54%, P = 0.297) whereas those with IAA only or GADA only progressed less often than children with IAA multiple or GADA multiple (22% vs 62% (P < 0.001) and 7% vs 43% (P < 0.001)), respectively. Conclusions: The phenotype of preclinical diabetes defined by the primary autoantibody is not associated with any discernible differences in glucose metabolism before the clinical disease manifestation.

A fully provided, hypocaloric, carbohydrate-reduced high-protein (CRHP) diet compared to a hypocaloric conventional diabetes (CD) diet for 6 weeks improved glycemic control to a greater extent in face of an intended 6% weight loss in individuals with type 2 diabetes mellitus (T2DM). The present 24-week extension of that study reports on the efficacy of CRHP and CD diets in a real-life setting. Sixty-five individuals with T2DM who completed the initial 6-week fully provided diet period (% energy from carbohydrate, protein, and fat was 30/30/40 in CRHP, and 50/17/33 in CD) continued a free-living, dietician guided 24-week period of which 59 individuals completed. The CRHP compared to CD group reported a 4% lower carbohydrate intake and had higher urea excretion by 22% (both p ≤ 0.05) at week 30, suggesting less difference in carbohydrate and protein intake between groups during the 24-week extension compared to week 6. The loss of body weight during the initial 6 weeks was maintained in both groups during the 24-week extension (−5.5 ± 4.5 and −4.6 ± 4.8 kg) as well as HbA1c (−8.4 ± 6.2 and −8.4 ± 6.9 mmol/mol) with no significant differences between groups. The additional benefits on glucoregulation harnessed by carbohydrate restriction under full diet provision for 6 weeks combined with titrated weight loss could not be maintained in a real-life setting of self-prepared diet aiming on similar diets for 6 months.

type:Departmental Bulletin Paper, [Abstract] Purpose: Although some dementia with Lewy bodies (DLB) patients have Alzheimer disease (AD) pathology, there are no reports comparing AD and DLB by amyloid PET and tau PET in the same patient. The aim of this study was to investigate the regional difference of metabolic reduction, amyloid deposition and tau deposition between DLB and AD brain.Methods: Five consecutive subjects with DLB and five age and Mini-mental state examination score matched AD patients, who underwent both fluoro-2-deoxyglucose (FDG)-PET, Pittsburgh compound B (PiB)-amyloid PET and THK5351 (THK)-tau PET, were included in this study. Voxel-based statistical analysis was performed with Statistical Parametric Mapping for comparison with FDG, amyloid and tau accumulation between the DLB and AD brains.Results: FDG PET demonstrated that occipital metabolism in DLB group was significantly lower than that in AD group. PiB PET demonstrated that in the AD group the anterior to posterior cingulate cortices, supplementary motor area, and thalamic amyloid depositions were significantly higher than those in the DLB group. THK PET demonstrated that in the AD group the posterior cingulate cortices, posterior internal capsules, thalamic and peri-brainstem regions tau depositions were significantly higher than those in the DLB group.Conclusions: In the DLB brain, it is suggested that decreased regional glucose metabolism is unrelated to amyloid and tau depositions, and the amyloid and tau depositions in the cingulate gyri and thalamic regions in the AD brain are higher than those in DLB brain.

Kori-tofu is a frozen soy tofu, and soy consumption is associated with positive effects on cardiometabolic health markers. We aimed to assess the potential of Kori-tofu to improve cardiometabolic health outcomes in humans by repetitive daily consumption. In a double-blind randomized controlled cross-over trial, 45 subjects aged 40–70 years with (mildly) elevated cholesterol levels, received a four week Kori-tofu intervention or whey protein control intervention with a four week wash-out period in between. Cardiometabolic biomarkers were measured before and after both interventions. A significant decrease in total, low-density lipids (LDL), and high-density lipids (HDL) cholesterol, Hemoglobin A1c (HbA1c), fructosamine and systolic blood pressure was observed within the Kori-tofu intervention. However, many of these findings were also observed in the control intervention. Only adiponectin changes were different between treatments but did not change significantly within interventions. Improvements in cardiometabolic markers within the Kori-tofu intervention point toward potential beneficial health effects. Due to the lack of significant effects as compared to control, there is, however, currently no substantiating evidence to claim that Kori-tofu has beneficial effects on cardiometabolic health.

Th17 cells are a subset of effector CD4+ T cells essential for the protection against extracellular bacteria and fungi. At the same time, Th17 cells have been implicated in the progression of autoimmune diseases, including multiple sclerosis, rheumatoid arthritis and psoriasis. Effector T cells require energy and building blocks for their proliferation and effector function. To that end, these cells switch from oxidative and mitochondrial metabolism to fast and short pathways such as glycolysis and glutaminolysis. Pyruvate dehydrogenase (PDH) is the central enzyme connecting cytoplasmic glycolysis to the mitochondrial tricarboxylic acid (TCA) cycle. The specific role of PDH in inflammatory Th17 cells is unknown. To unravel the role of this pivotal enzyme, a mutant mouse line where T cells do not express the catalytic subunit of the PDH complex was generated, using the Cre-Lox recombination system. In this study, PDH was shown to be essential for the generation of an exclusive glucose-derived citrate pool needed for the proliferation, survival, and effector functions of Th17 cells. In vivo, mice harboring a T cell-specific deletion of PDH were less susceptible to experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis, showing lower disease burden and increased survival. In vitro, the absence of PDH in Th17 cells increased glutamine and glucose uptake, as well as glycolysis and glutaminolysis. Similarly, lipid uptake was increased through CD36 in a glutamine-mTOR axis-dependent manner. On the contrary, the TCA cycle was impaired, interfering with oxidative phosphorylation (OXPHOS) and causing levels of cellular citrate to remain critically low in mutant Th17 cells. Citrate is the substrate of ATP citrate synthase (ACLY), an enzyme responsible for the generation of acetyl-CoA, which is essential for lipid synthesis and histone acetylation, crucial for the transcription process. In line, PDH-deficient Th17 cells showed a reduced expression

Th17 cells are a subset of effector CD4+ T cells essential for the protection against extracellular bacteria and fungi. At the same time, Th17 cells have been implicated in the progression of autoimmune diseases, including multiple sclerosis, rheumatoid arthritis and psoriasis. Effector T cells require energy and building blocks for their proliferation and effector function. To that end, these cells switch from oxidative and mitochondrial metabolism to fast and short pathways such as glycolysis and glutaminolysis. Pyruvate dehydrogenase (PDH) is the central enzyme connecting cytoplasmic glycolysis to the mitochondrial tricarboxylic acid (TCA) cycle. The specific role of PDH in inflammatory Th17 cells is unknown. To unravel the role of this pivotal enzyme, a mutant mouse line where T cells do not express the catalytic subunit of the PDH complex was generated, using the Cre-Lox recombination system. In this study, PDH was shown to be essential for the generation of an exclusive glucose-derived citrate pool needed for the proliferation, survival, and effector functions of Th17 cells. In vivo, mice harboring a T cell-specific deletion of PDH were less susceptible to experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis, showing lower disease burden and increased survival. In vitro, the absence of PDH in Th17 cells increased glutamine and glucose uptake, as well as glycolysis and glutaminolysis. Similarly, lipid uptake was increased through CD36 in a glutamine-mTOR axis-dependent manner. On the contrary, the TCA cycle was impaired, interfering with oxidative phosphorylation (OXPHOS) and causing levels of cellular citrate to remain critically low in mutant Th17 cells. Citrate is the substrate of ATP citrate synthase (ACLY), an enzyme responsible for the generation of acetyl-CoA, which is essential for lipid synthesis and histone acetylation, crucial for the transcription process. In line, PDH-deficient Th17 cells showed a reduced expression

Objective: This study aimed to describe the clinical characteristics of children and adolescents with obesity, and the prevalence of cardiometabolic comorbidities over 10 years in this population from a large metropolitan centre in China. Methods: This was a cross-sectional study (2008–2017) of patients aged <18 years with obesity [body mass index (BMI) ≥ 95th percentile for age and sex] enrolled at the Department of Endocrinology, Children’s Hospital of Zhejiang University School of Medicine (Hangzhou, Zhejiang Province). Clinical assessments included anthropometry, blood pressure, liver ultrasound, lipid profile, oral glucose tolerance test, and uric acid. For examination of outcomes, our study cohort was stratified by sex and age bands (<10 vs. ≥10 years), with the study period also split into two strata (2008–2012 and 2013–2017). Results: A total of 2,916 patients (1,954 boys and 962 girls) were assessed at a mean age of 10.5 years. Patients almost invariably presented severe obesity (median BMI SDS = 2.98; Q1 = 2.60, Q3 = 3.39). Obesity-related comorbidities were common among boys and girls, including type 2 diabetes mellitus (2.6% and 3.6%, respectively), abnormal glycaemia (33.6% and 35.5%, respectively), hypertension (33.9% and 32.0%, respectively), dyslipidaemia (35.2% and 39.6%, respectively), hyperuricaemia (16.2% and 8.3%, respectively), acanthosis nigricans (71.9% and 64.0%, respectively), abnormal liver function (66.9% and 47.0%, respectively), and non-alcoholic fatty liver disease (NAFLD) (63.8% and 45.1%, respectively); 38.7% of boys and 44.4% of girls aged ≥10 years had metabolic syndrome. Notably, the incidence of many cardiometabolic comorbidities was in 2013–2017 compared to 2008–2012. For example, rates of hypertension among boys aged <10 years and aged ≥10 years rose from 28.4% and 26.5% to 48.0% and 35.8%, respectively, and in girls from 20.3% and 20.8% to 41.7% and 39.6%, respectively. In 2013–2017, 9.5% of girls in the older group h

Objective: This study aimed to describe the clinical characteristics of children and adolescents with obesity, and the prevalence of cardiometabolic comorbidities over 10 years in this population from a large metropolitan centre in China. Methods: This was a cross-sectional study (2008–2017) of patients aged <18 years with obesity [body mass index (BMI) ≥ 95th percentile for age and sex] enrolled at the Department of Endocrinology, Children’s Hospital of Zhejiang University School of Medicine (Hangzhou, Zhejiang Province). Clinical assessments included anthropometry, blood pressure, liver ultrasound, lipid profile, oral glucose tolerance test, and uric acid. For examination of outcomes, our study cohort was stratified by sex and age bands (<10 vs. ≥10 years), with the study period also split into two strata (2008–2012 and 2013–2017). Results: A total of 2,916 patients (1,954 boys and 962 girls) were assessed at a mean age of 10.5 years. Patients almost invariably presented severe obesity (median BMI SDS = 2.98; Q1 = 2.60, Q3 = 3.39). Obesity-related comorbidities were common among boys and girls, including type 2 diabetes mellitus (2.6% and 3.6%, respectively), abnormal glycaemia (33.6% and 35.5%, respectively), hypertension (33.9% and 32.0%, respectively), dyslipidaemia (35.2% and 39.6%, respectively), hyperuricaemia (16.2% and 8.3%, respectively), acanthosis nigricans (71.9% and 64.0%, respectively), abnormal liver function (66.9% and 47.0%, respectively), and non-alcoholic fatty liver disease (NAFLD) (63.8% and 45.1%, respectively); 38.7% of boys and 44.4% of girls aged ≥10 years had metabolic syndrome. Notably, the incidence of many cardiometabolic comorbidities was in 2013–2017 compared to 2008–2012. For example, rates of hypertension among boys aged <10 years and aged ≥10 years rose from 28.4% and 26.5% to 48.0% and 35.8%, respectively, and in girls from 20.3% and 20.8% to 41.7% and 39.6%, respectively. In 2013–2017, 9.5% of girls in the older group h

Objective: This study aimed to describe the clinical characteristics of children and adolescents with obesity, and the prevalence of cardiometabolic comorbidities over 10 years in this population from a large metropolitan centre in China. Methods: This was a cross-sectional study (2008–2017) of patients aged <18 years with obesity [body mass index (BMI) ≥ 95th percentile for age and sex] enrolled at the Department of Endocrinology, Children’s Hospital of Zhejiang University School of Medicine (Hangzhou, Zhejiang Province). Clinical assessments included anthropometry, blood pressure, liver ultrasound, lipid profile, oral glucose tolerance test, and uric acid. For examination of outcomes, our study cohort was stratified by sex and age bands (<10 vs. ≥10 years), with the study period also split into two strata (2008–2012 and 2013–2017). Results: A total of 2,916 patients (1,954 boys and 962 girls) were assessed at a mean age of 10.5 years. Patients almost invariably presented severe obesity (median BMI SDS = 2.98; Q1 = 2.60, Q3 = 3.39). Obesity-related comorbidities were common among boys and girls, including type 2 diabetes mellitus (2.6% and 3.6%, respectively), abnormal glycaemia (33.6% and 35.5%, respectively), hypertension (33.9% and 32.0%, respectively), dyslipidaemia (35.2% and 39.6%, respectively), hyperuricaemia (16.2% and 8.3%, respectively), acanthosis nigricans (71.9% and 64.0%, respectively), abnormal liver function (66.9% and 47.0%, respectively), and non-alcoholic fatty liver disease (NAFLD) (63.8% and 45.1%, respectively); 38.7% of boys and 44.4% of girls aged ≥10 years had metabolic syndrome. Notably, the incidence of many cardiometabolic comorbidities was in 2013–2017 compared to 2008–2012. For example, rates of hypertension among boys aged <10 years and aged ≥10 years rose from 28.4% and 26.5% to 48.0% and 35.8%, respectively, and in girls from 20.3% and 20.8% to 41.7% and 39.6%, respectively. In 2013–2017, 9.5% of girls in the older group h

Hypoxia-inducible factor (HIF) prolyl 4-hydroxylases (HIF-P4Hs 1–3) are druggable targets in renal anemia, where pan-HIF-P4H inhibitors induce an erythropoietic response. Preclinical data suggest that HIF-P4Hs could also be therapeutic targets for treating metabolic dysfunction, although the contributions of HIF-P4H isoenzymes in various tissues to the metabolic phenotype are inadequately understood. Here, we used mouse lines that were gene-deficient for HIF-P4Hs 1 to 3 and two preclinical pan-HIF-P4H inhibitors to study the contributions of these isoenzymes to the anthropometric and metabolic outcome and HIF response. We show both inhibitors induced a HIF response in wildtype white adipose tissue (WAT), liver, and skeletal muscle and alleviated metabolic dysfunction during a 6-week treatment period, but they did not alter healthy metabolism. Our data indicate that HIF-P4H-1 contributed especially to skeletal muscle and WAT metabolism and that its loss lowered body weight and serum cholesterol levels upon aging. In addition, we found HIF-P4H-3 had effects on the liver and WAT and its loss increased body weight, adiposity, liver weight and triglyceride levels, WAT inflammation, and cholesterol levels and resulted in hyperglycemia and insulin resistance, especially during aging. Finally, we demonstrate HIF-P4H-2 affected all tissues studied; its inhibition lowered body and liver weight and serum cholesterol levels and improved glucose tolerance. We found very few HIF target metabolic mRNAs were regulated by the inhibition of three isoenzymes, thus suggesting a potential for selective therapeutic tractability. Altogether, these data provide specifications for the future development of HIF-P4H inhibitors for the treatment of metabolic diseases.