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Background Digital health interventions are effective for hypertension self-management, but a comparison of the effectiveness and implementation of the different modes of interventions is not currently available. This study aimed to compare the effectiveness of SMS, smartphone application, and website interventions on improving blood pressure in adults with hypertension, and to report on their reach, uptake, and feasibility. Methods In this systematic review and meta-analysis we searched CINAHL Complete, Cochrane Central Register of Controlled Trials, Ovid Embase, Ovid MEDLINE, and APA PsycInfo on May 25, 2022, for randomised controlled trials (RCTs) published in English from Jan 1, 2009, that examined the effectiveness of digital health interventions on reducing blood pressure in adults with hypertension. Screening was carried out using Covidence, and data were extracted following Cochrane's guidelines. The primary endpoint was change in the mean of systolic blood pressure. Risk of bias was assessed with Cochrane Risk of Bias 2. Data on systolic and diastolic blood pressure reduction were synthesised in a meta-analysis, and data on reach, uptake and feasibility were summarised narratively. Grading of Recommendations, Assessment, Development, and Evaluation criteria were used to evaluate the level of evidence. The study was registered with PROSPERO CRD42021247845. Findings Of the 3235 records identified, 29 RCTs from 13 regions (n=7592 participants) were included in the systematic review, and 28 of these RCTs (n=7092 participants) were included in the meta-analysis. 11 studies used SMS as the primary mode of delivery of the digital health intervention, 13 used smartphone applications, and five used websites. Overall, digital health intervention group participants had a –3·62 mm Hg (95% CI –5·22 to –2·02) greater reduction in systolic blood pressure, and a –2·45 mm Hg (–3·83 to –1·07) greater reduction in diastolic blood pressure, compared with control group participants. No statistically significant differences between the three different modes of delivery were observed for both the systolic (p=0·73) and the diastolic blood pressure (p=0·80) outcomes. Smartphone application interventions had a statistically significant reduction in diastolic blood pressure (–2·45 mm Hg [–4·15 to –0·74]); however, there were no statistically significant reductions for SMS interventions (–1·80 mm Hg [–4·60 to 1·00]) or website interventions (–3·43 mm Hg [–7·24 to 0·38]). Due to the considerable heterogeneity between included studies and the high risk of bias in some, the level of evidence was assigned a low overall score. Interventions were more effective among people with greater severity of hypertension at baseline. SMS interventions reported higher reach and smartphone application studies reported higher uptake, but differences were not statistically significant. Interpretation SMS, smartphone application, and website interventions were associated with statistically and clinically significant systolic and diastolic blood pressure reductions, compared with usual care, regardless of the mode of delivery of the intervention. This conclusion is tempered by the considerable heterogeneity of included studies and the high risk of bias in most. Future studies need to describe in detail the mediators and moderators of the effectiveness and implementation of these interventions, to both further improve their effectiveness as well as increase their reach, uptake, and feasibility.

Aims/hypothesis Energy-dense nutrition generally induces insulin resistance, but dietary composition may differently affect glucose metabolism. This study investigated initial effects of monounsaturated vs saturated lipid meals on basal and insulin-stimulated myocellular glucose metabolism and insulin signalling. Methods In a randomised crossover study, 16 lean metabolically healthy volunteers received single meals containing safflower oil (SAF), palm oil (PAL) or vehicle (VCL). Whole-body glucose metabolism was assessed from glucose disposal (Rd) before and during hyperinsulinaemic–euglycaemic clamps with d-[6,6-2H2]glucose. In serial skeletal muscle biopsies, subcellular lipid metabolites and insulin signalling were measured before and after meals. Results SAF and PAL raised plasma oleate, but only PAL significantly increased plasma palmitate concentrations. SAF and PAL increased myocellular diacylglycerol and activated protein kinase C (PKC) isoform θ (p p Rd (p p 1101-phosphorylation of IRS-1 was increased upon SAF and PAL consumption (p 473-phosphorylation of Akt more than SAF (p Conclusions/interpretation Lipid-induced myocellular insulin resistance is likely more pronounced with palmitate than with oleate and is associated with PKC isoforms activation and inhibitory insulin signalling. Trial registration ClinicalTrials.gov.NCT01736202. Funding German Federal Ministry of Health, Ministry of Culture and Science of the State North Rhine-Westphalia, German Federal Ministry of Education and Research, European Regional Development Fund, German Research Foundation, German Center for Diabetes Research. Graphical abstract

Recent insights into the pathophysiologic underlying mechanisms of obesity have led to the discovery of several promising drug targets and novel therapeutic strategies to address the global obesity epidemic and its comorbidities. Current pharmacologic options for obesity management are largely limited in number and of modest efficacy/safety profile. Therefore, the need for safe and more efficacious new agents is urgent. Drugs that are currently under investigation modulate targets across a broad range of systems and tissues, including the central nervous system, gastrointestinal hormones, adipose tissue, kidney, liver, and skeletal muscle. Beyond pharmacotherapeutics, other potential antiobesity strategies are being explored, including novel drug delivery systems, vaccines, modulation of the gut microbiome, and gene therapy. The present review summarizes the pathophysiology of energy homeostasis and highlights pathways being explored in the effort to develop novel antiobesity medications and interventions but does not cover devices and bariatric methods. Emerging pharmacologic agents and alternative approaches targeting these pathways and relevant research in both animals and humans are presented in detail. Special emphasis is given to treatment options at the end of the development pipeline and closer to the clinic (ie, compounds that have a higher chance to be added to our therapeutic armamentarium in the near future). Ultimately, advancements in our understanding of the pathophysiology and interindividual variation of obesity may lead to multimodal and personalized approaches to obesity treatment that will result in safe, effective, and sustainable weight loss until the root causes of the problem are identified and addressed.

The mechanisms underlying improved insulin sensitivity after surgically-induced weight loss are still unclear. We monitored skeletal muscle metabolism in obese individuals before and over 52 weeks after metabolic surgery. Initial weight loss occurs in parallel with a decrease in muscle oxidative capacity and respiratory control ratio. Persistent elevation of intramyocellular lipid intermediates, likely resulting from unrestrained adipose tissue lipolysis, accompanies the lack of rapid changes in insulin sensitivity. Simultaneously, alterations in skeletal muscle expression of genes involved in calcium/lipid metabolism and mitochondrial function associate with subsequent distinct DNA methylation patterns at 52 weeks after surgery. Thus, initial unfavorable metabolic changes including insulin resistance of adipose tissue and skeletal muscle precede epigenetic modifications of genes involved in muscle energy metabolism and the long-term improvement of insulin sensitivity., Surgical weight-loss interventions improve insulin sensitivity via incompletely understood mechanisms. Here the authors assess skeletal muscle epigenetic changes in individuals with obesity following metabolic surgery and compare them with data from individuals without obesity.

A wealth of clinical and epidemiological evidence has linked obesity to a broad spectrum of cardiovascular diseases (CVD) including coronary heart disease, heart failure, hypertension, stroke, atrial fibrillation and sudden cardiac death. Obesity can increase CVD morbidity and mortality directly and indirectly. Direct effects are mediated by obesity-induced structural and functional adaptations of the cardiovascular system to accommodate excess body weight, as well as by adipokine effects on inflammation and vascular homeostasis. Indirect effects are mediated by co-existing CVD risk factors such as insulin resistance, hyperglycemia, hypertension and dyslipidemia. Adipose tissue (AT) quality and functionality are more relevant aspects for cardiometabolic risk than its total amount. The consequences of maladaptive AT expansion in obesity are local and systemic: the local include inflammation, hypoxia, dysregulated adipokine secretion and impaired mitochondrial function; the systemic comprise insulin resistance, abnormal glucose/lipid metabolism, hypertension, a pro-inflammatory and pro-thrombotic state and endothelial dysfunction, all of which provide linking mechanisms for the association between obesity and CVD. The present narrative review summarizes the major pathophysiological links between obesity and CVD (traditional and novel concepts), analyses the heterogeneity of obesity-related cardiometabolic consequences, and provides an overview of the cardiovascular impact of weight loss interventions.

Dietary patterns with intermittent energy restriction (IER) have been proposed as an attractive alternative to continuous energy restriction (CER) for the management of obesity and its associated comorbidities. The most widely studied regimens of IER comprise energy restriction on two days per week (5:2), alternate-day energy restriction by 60–70% (ADF), and timely restriction of energy intake during a specific time window within the day (TRF; time-restricted feeding). Although there is some evidence to suggest that IER can exert beneficial effects on human cardiometabolic health, yet is apparently not superior compared to CER, there are still some critical issues/questions that warrant further investigation: (i) high-quality robust scientific evidence regarding the long-term effects of IER (safety, efficacy, compliance) is limited since the vast majority of intervention studies had a duration of less than 6 months; (ii) whether the positive effects of IER are independent of or actually mediated by weight loss remains elusive; (iii) it remains unknown whether IER protocols are a safe recommendation for the general population; (iv) data concerning the impact of IER on ectopic fat stores, fat-free mass, insulin resistance and metabolic flexibility are inconclusive; (v) the cost-effectiveness of IER dietary regimens has not been adequately addressed; (vi) direct head-to-head studies comparing different IER patterns with variable macronutrient composition in terms of safety and efficacy are scarce; and (vii) evidence is limited with regard to the efficacy of IER in specific populations, including males, the elderly and patients with morbid obesity and diabetes mellitus. Until more solid evidence is available, individualization and critical perspective are definitely warranted to determine which patients might benefit the most from an IER intervention, depending on their personality traits and most importantly comorbid health conditions.

This review provides an update on the role of gut hormones and their interactions in the regulation of energy homeostasis, describes gut hormone adaptations in obesity and in response to weight loss, and summarizes the current evidence on the role of gut hormone-based therapies for obesity treatment. Gut hormones play a key role in regulating eating behaviour, energy and glucose homeostasis. Dysregulated gut hormone responses have been proposed to be pathogenetically involved in the development and perpetuation of obesity. Summarizing the major gut hormone changes in obesity, obese individuals are characterized by blunted postprandial ghrelin suppression, loss of premeal ghrelin peaks, impaired diurnal ghrelin variability and reduced fasting and postprandial levels of anorexigenic peptides. Adaptive alterations of gut hormone levels are implicated in weight regain, thus complicating hypocaloric dietary interventions, and can further explain the profound weight loss and metabolic improvement following bariatric surgery. A plethora of compounds mimicking gut hormone changes after bariatric surgery are currently under investigation, introducing a new era in the pharmacotherapy of obesity. The current trend is to combine different gut hormone receptor agonists and target multiple systems simultaneously, in order to replicate as closely as possible the gut hormone milieu after bariatric surgery and circumvent the counter-regulatory adaptive changes associated with dietary energy restriction. An increasing number of preclinical and early-phase clinical trials reveal the additive benefits obtained with dual or triple gut peptide receptor agonists in reducing body weight and improving glycaemia. Gut hormones act as potent regulators of energy and glucose homeostasis. Therapeutic strategies targeting their levels or receptors emerge as a promising approach to treat patients with obesity and hyperglycaemia.

The management of patients with diabetes mellitus (DM) in the era of the COVID-19 pandemic can be challenging. Even if they are not infected, they are at risk of dysregulated glycemic control due to the restrictive measures which compromise and disrupt healthcare delivery. In the case of infection, people with DM have an increased risk of developing severe complications. The major principles of optimal care for mild outpatient cases include a patient-tailored therapeutic approach, regular glucose monitoring and adherence to medical recommendations regarding lifestyle measures and drug treatment. For critically ill hospitalized patients, tight monitoring of glucose, fluids, electrolytes, pH and blood ketones is of paramount importance to optimize outcomes. All patients with DM do not have an equally increased risk for severity and mortality due to COVID-19. Certain clinical and biological characteristics determine high-risk phenotypes within the DM population and such prognostic markers need to be characterized in future studies. Further research is needed to examine which subgroups of DM patients are expected to benefit the most from specific antiviral, immunomodulatory and other treatment strategies in the context of patient-tailored precision medicine, which emerges as an urgent priority in the era of COVID-19.

Hypercaloric diets cause dyslipidemia, insulin resistance and contribute to the development of type 2 diabetes. Nevertheless, the degree of fatty acid (FA) saturation may differently affect metabolism and risk of cardiovascular diseases, with saturated FA (SAFA) considered to be harmful and polyunsaturated FA (PUFA) considered to be beneficial. Thus, we aimed at characterizing the acute effects of palm oil (POL, SAFA-rich) and safflower oil (SOL, PUFA-rich) on tissue-specific insulin sensitivity and skeletal muscle mitochondrial function in glucose-tolerant volunteers (10 m/6 f; age 24±2 years; BMI 23.1±0.9 kg/m2), who ingested 1.2 g/kg BW of POL, SOL or control (CON, water) on three occasions. Whole-body glucose disposal (Rd) was assessed with [2H2]glucose before and during hyperinsulinemic-euglycemic clamps. Skeletal muscle biopsies were performed to assess protein kinase C (PKC) ԑ and θ translocation and oxygen fluxes by high-resolution respirometry at 1 h before and 2, 4 and 7 h after the interventions. Before the clamp, POL but not SOL ingestion raised plasma palmitic acid levels by 102% (p In conclusion, oral ingestion of palmitate-enriched lipids rapidly induces whole-body insulin resistance, which is likely mediated through skeletal muscle lipid-mediated PKCԑ activation and possibly accelerated by impaired mitochondrial function. Thus, the amount of dietary lipids determines acute insulin resistance, but its composition may differentially regulate skeletal muscle oxidative capacity. Disclosure T. Sarabhai: None. C. Koliaki: None. S. Kahl: None. D. Pesta: None. L. Mastrototaro: None. M. Apostolopoulou: None. D.F. Markgraf: None. C. Herder: Research Support; Self; Sanofi-Aventis. M. Roden: Advisory Panel; Self; Servier. Board Member; Self; Poxel SA. Consultant; Self; Eli Lilly and Company, Gilead Sciences, Inc., ProSciento, TARGET PharmaSolutions. Research Support; Self; Boehringer Ingelheim International GmbH, Novartis Pharma K.K., Sanofi US. Speaker’s Bureau; Self; Novo Nordisk A/S. Funding German Federal Ministry of Health and Ministry of Culture and Science of the State North Rhine-Westphalia; German Federal Ministry of Education and Research by the European Regional Development Fund (KomIT, EFRE-0400191); German Research Foundation (DFG; SFB 1116/2)

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), a member of the TNF protein superfamily, represents a multifaceted cytokine with unique biological features including both proapoptotic and pro-survival effects in different cell types depending on receptor interactions and local stimuli. Beyond its extensively studied anti-tumor and immunomodulatory properties, a growing body of experimental and clinical evidence over the past two decades suggests a protective role of TRAIL in the development of type 1 (T1DM) and type 2 (T2DM) diabetes mellitus. This evidence can be briefly summarized by the following observations: (i) acceleration and exacerbation of T1DM and T2DM by TRAIL blockade or genetic deficiency in animal models, (ii) prevention and amelioration of T1DM and T2DM with recombinant TRAIL treatment or systemic TRAIL gene delivery in animal models, (iii) significantly reduced circulating soluble TRAIL levels in patients with T1DM and T2DM both at disease onset and in more advanced stages of diabetes-related complications such as cardiovascular disease and diabetic nephropathy, (iv) increase of serum TRAIL levels in diabetic patients after initiation of antidiabetic treatment and metabolic improvement. To explore the underlying mechanisms and provide mechanistic links between TRAIL and diabetes, a number of animal and in vitro studies have reported direct effects of TRAIL on several tissues involved in diabetes pathophysiology such as pancreatic islets, skeletal muscle, adipose tissue, liver, kidney, and immune and vascular cells. Residual controversy remains regarding the effects of TRAIL on adipose tissue homeostasis. Although the existing evidence is encouraging and paves the way for investigating TRAIL-related interventions in diabetic patients with cardiometabolic abnormalities, caution is warranted in the extrapolation of animal and in vitro data to the clinical setting, and further research in humans is imperative in order to uncover all aspects of the TRAIL-diabetes relationship and delineate its therapeutic implications in metabolic disease.

OBJECTIVE Insulin resistance and nonalcoholic fatty liver disease have been linked to several lipid metabolites in animals, but their role in humans remains unclear. This study examined the relationship of sphingolipids with hepatic and peripheral metabolism in 21 insulin-resistant obese patients without (NAFL−) or with (NAFL+) nonalcoholic fatty liver and nonalcoholic steatohepatitis (NASH) and 7 healthy lean individuals undergoing tissue biopsies during bariatric or elective abdominal surgery. RESEARCH DESIGN AND METHODS Hyperinsulinemic-euglycemic clamps with d-[6,6-2H2]glucose were performed to quantify tissue-specific insulin sensitivity. Hepatic oxidative capacity, lipid peroxidation, and the phosphorylated-to-total c-Jun N-terminal kinase (pJNK-to-tJNK) ratio were measured to assess mitochondrial function, oxidative stress, and inflammatory activity. RESULTS Hepatic total ceramides were higher by 50% and 33% in NASH compared with NAFL+ and NAFL−, respectively. Only in NASH were hepatic dihydroceramides (16:0, 22:0, and 24:1) and lactosylceramides increased. Serum total ceramides and dihydroceramides (hepatic dihydroceramides 22:0 and 24:1) correlated negatively with whole-body but not with hepatic insulin sensitivity. Hepatic maximal respiration related positively to serum lactosylceramide subspecies, hepatic sphinganine, and lactosylceramide 14:0. Liver lipid peroxides (total ceramides, sphingomyelin 22:0) and the pJNK-to-tJNK ratio (ceramide 24:0; hexosylceramides 22:0, 24:0, and 24:1) all positively correlated with the respective hepatic sphingolipids. CONCLUSIONS Sphingolipid species are not only increased in insulin-resistant humans with NASH but also correlate with hepatic oxidative stress and inflammation, suggesting that these lipids may play a role during progression of simple steatosis to NASH in humans.

Heart failure (HF) represents an important cardiovascular complication of type 2 diabetes mellitus (T2DM) associated with substantial morbidity and mortality, and is emphasized in recent cardiovascular outcome trials (CVOTs) as a critical outcome for patients with T2DM. Treatment of T2DM in patients with HF can be challenging, considering that these patients are usually elderly, frail and have extensive comorbidities, most importantly chronic kidney disease. The complexity of medical regimens, the high risk clinical characteristics of patients and the potential of HF therapies to interfere with glucose metabolism, and conversely the emerging potential of some antidiabetic agents to modulate HF outcomes, are only some of the challenges that need to be addressed in the framework of a team-based personalized approach. The presence of established HF or the high risk of developing HF in the future has influenced recent guideline recommendations and can guide therapeutic decision making. Metformin remains first-line treatment for overweight T2DM patients at moderate cardiovascular risk. Although not contraindicated, metformin is no longer considered as first-line therapy for patients with established HF or at risk for HF, since there is robust scientific evidence that treatment with other glucose-lowering agents such as sodium-glucose cotransporter 2 inhibitors (SGLT2i) should be prioritized in this population due to their strong and remarkably consistent beneficial effects on HF outcomes.

Background: Oxidative stress is a hallmark of many diseases. A growing body of evidence suggests that hyperglycemia-induced oxidative stress plays an important role in pancreatic β-cells dysfunction and apoptosis, as well as in the development and progression of diabetic complications. Considering the vulnerability of pancreatic β-cells to oxidative damage, the induction of endogenous antioxidant enzymes or exogenous antioxidant administration has been proposed to protect pancreatic β-cells from damage. Objectives: The present review aims to provide evidence of the effect of oxidative stress and antioxidant therapies on pancreatic β-cell function, based on in vitro and in vivo studies. Methods: The MEDLINE and EMBASE databases were searched to retrieve available data. Results: Due to poor endogenous antioxidant mechanisms, pancreatic β-cells are extremely sensitive to Reactive Oxygen Species (ROS). Many natural extracts have been tested in vitro in pancreatic β-cell lines in terms of their antioxidant and diabetes mellitus ameliorating effects, and the majority of them have shown a dose-dependent protective role. On the other hand, there is relatively limited evidence regarding the in vitro antioxidant effects of antidiabetic drugs on pancreatic β -cells. Concerning in vivo studies, several natural extracts have shown beneficial effects in the setting of diabetes by decreasing blood glucose and lipid levels, increasing insulin sensitivity, and by up-regulating intrinsic antioxidant enzyme activity. However, there is limited evidence obtained from in vivo studies regarding antidiabetic drugs. Conclusion: Antioxidants hold promise for developing strategies aimed at the prevention or treatment of diabetes mellitus associated with pancreatic β-cells dysfunction, as supported by in vitro and in vivo studies. However, more in vitro studies are required for drugs.

This review provides a comprehensive update on the definition, assessment, epidemiology, pathophysiology, clinical implications, and therapeutic approach of sarcopenic obesity (SO) and highlights the challenges, limitations, and knowledge gaps in SO research. The confluence of a rapidly aging population with rising obesity rates has led to the phenotype of SO, defined as the concurrent presence of sarcopenia and obesity. Despite efforts, a standardized definition of SO is still lacking. Its prevalence varies widely between studies, depending on population characteristics and different definitions. The major pathogenetic mechanisms include age-related changes in body composition and hormonal milieu, positive energy balance, pro-inflammatory pathways, and insulin resistance. Lifestyle interventions, including caloric restriction and physical activity, are the cornerstones of SO treatment. SO is a multifaceted syndrome with serious clinical implications. The development and implementation of effective prevention and treatment strategies is a top priority based on its dramatically increasing health impact.

Although type 2 diabetes mellitus (T2DM) has been traditionally viewed as an intractable chronic medical condition, accumulating evidence points towards the notion that a complete remission of T2DM is feasible following a choice of medical and/or surgical interventions. This has been paralleled by increasing interest in the establishment of a universal definition for T2DM remission which, under given circumstances, could be considered equivalent to a “cure”. The efficacy of bariatric surgery in particular for achieving glycemic control has highlighted surgery as a candidate curative intervention for T2DM. Herein, available evidence regarding available surgical modalities and the mechanisms that drive metabolic amelioration after bariatric surgery are reviewed. Furthermore, reports from observational and randomized studies with regard to T2DM remission are reviewed, along with concepts relevant to the variety of definitions used for T2DM remission and other potential sources of discrepancy in success rates among different studies.

Mitochondrial function refers to a broad spectrum of features such as resting mitochondrial activity, (sub)maximal oxidative phosphorylation capacity (OXPHOS), and mitochondrial dynamics, turnover, and plasticity. The interaction between mitochondria and insulin sensitivity is bidirectional and varies depending on tissue, experimental model, methodological approach, and features of mitochondrial function tested. In human skeletal muscle, mitochondrial abnormalities may be inherited (e.g., lower mitochondrial content) or acquired (e.g., impaired OXPHOS capacity and plasticity). Abnormalities ultimately lead to lower mitochondrial functionality due to or resulting in insulin resistance and type 2 diabetes mellitus. Similar mechanisms can also operate in adipose tissue and heart muscle. In contrast, mitochondrial oxidative capacity is transiently upregulated in the liver of obese insulin-resistant humans with or without fatty liver, giving rise to oxidative stress and declines in advanced fatty liver disease. These data suggest a highly tissue-specific interaction between insulin sensitivity and oxidative metabolism during the course of metabolic diseases in humans.

We aimed to compare the effects of Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) on postprandial glucose and lipid metabolism in addition to weight loss and fasting metabolic profile, in non-diabetic patients undergoing bariatric surgery. Seventy-one patients were consecutively recruited and studied preoperatively, 3 and 6 months after surgery. Of these, 28 underwent RYGB (7 males, age 38 ± 9 years, BMI 46.9 ± 5.0 kg/m2), and 43 SG (9 males, age 38 ± 9 years, BMI 50.2 ± 7.0 kg/m2). A semi-liquid mixed meal was consumed, and blood samples were taken before, and every 30 min after meal ingestion up to 180 min postprandially, for measurement of glucose, insulin, and lipids. The overall postprandial response was assessed as area under the concentration-time curve (AUC). Baseline metabolic parameters were similar between RYGB and SG. Both groups experienced comparable weight loss, and a similar improvement in fasting glucose, insulin, and insulin resistance. Total and LDL cholesterol levels were lower at 6 months after RYGB compared to SG, while there was no difference in HDL cholesterol or triglycerides. Glucose AUC was lower after RYGB compared to SG at both 3 (p = 0.008) and 6 months (p = 0.016), without any difference in postprandial insulin response. Triglyceride AUC was also lower in RYGB vs. SG at 3 and 6 months (p ≤ 0.001). RYGB is superior to SG in improving postprandial glycaemia and lipaemia and cholesterol profile 6 months postoperatively in non-diabetic, severely obese patients. These findings imply procedure-specific effects, such as the malabsorptive nature of RYGB, and less likely a different incretin postoperative response.

Weight loss-induced improvement in insulin sensitivity (IS) has been related to enhanced muscle energy metabolism. Thus, we hypothesized that weight loss due to bariatric surgery may induce epigenomic changes, which in turn modify mitochondrial function and intracellular lipids. We previously reported that IS fails to improve at 2 weeks (2 w), but then continuously increases until 52 weeks (52 w) after surgery. Now, we monitored muscle mitochondrial function and lipid intermediates in 49 obese humans (OBE; 40±10 years, BMI 51±7 kg/m2) before and for 52 w after bariatric surgery. Genome-wide gene expression and DNA methylation were analyzed in a subgroup of 16 OBE. Initial weight loss increases muscle oxidative capacity by 11% at 2 w, but transient elevation of certain muscle diacylglycerols resulting from unrestrained adipose lipolysis prevents from rapid improvement in IS. At 52 w, both mitochondrial function and intracellular lipids are comparable to lean humans. Acute alterations in expression of 1287 genes involved primarily in mitochondrial function, transcriptional regulation, protein transport, fatty acid metabolism and inflammatory processes, but not changes in DNA methylation, underlie the transient upregulation of mitochondrial function and lipolysis. At 52 w, 1091CpGs are differentially methylated, which relates to improved IS. Specifically, epigenetic alterations at 52 w in FTO gene, encoding an α-ketoglutarate dependent dioxygenase, and TOMM7 gene, encoding a translocase of the outer mitochondrial membrane, contribute to reprogramming transient changes in mRNA expression at 2 w. In conclusion, initial metabolic changes after weight loss induce epigenetic modification of genes involved in muscle energy metabolism, which in turn leads to long-term beneficial changes in gene expression. Disclosure S. Gancheva: None. M. Ouni: None. C. Koliaki: None. T. Jelenik: None. D.F. Markgraf: None. J. Szendroedi: None. M. Schlensak: None. A. Schuermann: None. M. Roden: Speaker's Bureau; Self; Boehringer Ingelheim GmbH. Research Support; Self; Boehringer Ingelheim GmbH. Consultant; Self; Poxel SA. Research Support; Self; Danone Nutricia Early Life Nutrition, GlaxoSmithKline plc., Nutricia Advanced Medical Nutrition, Sanofi.

High field MR scanners can resolve a metabolite resonating at 2.06 ppm in the in vivo proton-decoupled liver 31P MR spectrum. Traditionally this peak has been assigned to phosphoenolpyruvate (PEP), the key metabolite for gluconeogenesis. However, recent evidence supported the assignment to biliary phosphatidylcholine (PtdCh), which is produced in the liver and stored in the gall bladder. To elucidate the respective contributions of PtdCh and PEP to the in vivo resonance at 2.06 ppm (PEP–PtdCh), we made phantom measurements that confirmed that both biliary PtdCh and PEP resonate approximately at 2 ppm. The absolute quantification of PEP–PtdCh yielded concentrations ranging from 0.6 to 2.0 mmol/l, with mean coefficients of variation of 4.8% for intraday and 7.2% for interday reproducibility in healthy volunteers. The T1 relaxation time of PEP–PtdCh was 0.97 ± 0.30 s in the liver and 0.44 ± 0.11 s in the gallbladder. Ingestion of a mixed meal decreased the concentration of PtdCh-PEP by approximately 12%. In the retrospective analysis, PEP–PtdCh was 68% higher in the liver of subjects with gallbladder infiltration of the volume of interest (VOI) compared with those without gallbladder infiltration. PEP–PtdCh was also significantly higher in the liver of cholecystectomy patients compared with volunteers without gallbladder infiltration, which suggests increased intrahepatic bile fluid as a compensation for gall bladder removal. These results show that liver PtdCh is the major component of the resonance at 2.06 ppm and that careful VOI positioning is mandatory to avoid interference from the gallbladder. Copyright © 2015 John Wiley & Sons, Ltd.

This study aimed to perform a comprehensive analysis of interlobular, intralobular and parenchymal pancreatic fat in order to assess their respective effects on beta cell function.Fifty-six participants (normal glucose tolerance [NGT] (n = 28), impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) (n = 14) and patients with type 2 diabetes (n = 14)) underwent a frequent-sampling OGTT and non-invasive magnetic resonance imaging (MRI; whole-body and pancreatic) and proton magnetic resonance spectroscopy ((1)H-MRS; liver and pancreatic fat). Total pancreatic fat was assessed by a standard 2 cm(3) (1)H-MRS method, intralobular fat by 1 cm(3) (1)H-MRS that avoided interlobular fat within modified DIXON (mDIXON) water images, and parenchymal fat by a validated mDIXON-MRI fat-fraction method.Comparison of (1)H-MRS techniques revealed an inhomogeneous distribution of interlobular and intralobular adipose tissue, which increased with decreasing glucose tolerance. mDIXON-MRI measurements provided evidence against uniform steatosis, revealing regions of parenchymal tissue void of lipid accumulation in all participants. Total (r = 0.385, p0.01) and intralobular pancreas adipose tissue infiltration (r = 0.310, p0.05) positively associated with age, but not with fasting or 2 h glucose levels, BMI or visceral fat content (all p0.5). Furthermore, no associations were found between total and intralobular pancreatic adipose tissue infiltration and insulin secretion or beta cell function within NGT, IFG/IGT or patients with type 2 diabetes (all p0.2).The pancreas does not appear to be another target organ for abnormal endocrine function because of ectopic parenchymal fat storage. No relationship was found between pancreatic adipose tissue infiltration and beta cell function, regardless of glucose tolerance status.

Studies in rodents suggest that insulin controls hepatic glucose metabolism through brain-liver crosstalk, but human studies using intranasal insulin to mimic central insulin delivery provided conflicting results. In this randomized controlled cross-over trial we investigated effects of intranasal insulin on hepatic insulin sensitivity and energy metabolism in 10 patients with type 2 diabetes and 10 lean healthy participants (CON). Endogenous glucose production (EGP) was monitored with [6,6-(2)H2]glucose, hepatocellular lipids (HCL), adenosine triphosphate (ATP) and inorganic phosphate concentrations with (31)P/(1)H magnetic resonance spectroscopy. Intranasal insulin transiently increased serum insulin, followed by gradual lowering of blood glucose in CON only. Fasting hepatic insulin sensitivity index (HIS) was not affected by intranasal insulin in CON and patients. Only in CON, HCL decreased by 35%, whereas absolute hepatic ATP concentrations increased by 18% after three hours. A subgroup of CON received intravenous insulin to mimic the changes in serum insulin and blood glucose levels observed after intranasal insulin. This resulted in a 34% increase in HCL, without altering hepatic ATP concentrations. In conclusion, intranasal insulin does not affect HIS but rapidly improves hepatic energy metabolism in healthy humans, which is independent of peripheral insulinemia. These effects are blunted in patients with type 2 diabetes.

OBJECTIVE Altered immune reactivity precedes and accompanies type 1 and type 2 diabetes. We hypothesized that the metabolic phenotype relates to the systemic cellular immune status. RESEARCH DESIGN AND METHODS A total of 194 metabolically well-controlled patients with type 1 diabetes (n = 62, mean diabetes duration 1.29 years) or type 2 diabetes (n = 132, 1.98 years) and 60 normoglycemic persons underwent blood sampling for automated white blood cell counting (WBC) and flow cytometry. Whole-body insulin sensitivity was measured with hyperinsulinemic-euglycemic clamp tests. RESULTS Patients with type 2 diabetes had higher WBC counts than control subjects along with a higher percentage of T cells and activated T helper (Th) and cytotoxic T (Tc) cells but lower proportions of natural killer (NK) cells. In type 1 diabetes, the percentage of activated Th and Tc cells was also higher compared with control subjects, whereas the ratio of regulatory T (Treg) cells to activated Th cells was lower, suggesting diminished regulatory capacity. Parameters of glycemic control related positively to Treg cells only in type 2 diabetes. Upon age, sex, and body mass adjustments, insulin sensitivity correlated positively with monocytes, while circulating lipids correlated positively with T cell subsets in type 1 diabetes. CONCLUSIONS Immune cell phenotypes showed distinct frequencies of occurrence in both diabetes types and associate with insulin sensitivity, glycemia, and lipidemia.

Objective: Although obesity is typically associated with increased cardiovascular risk, a subset of obese individuals display a normal metabolic profile (“metabolically healthy obese,” MHO) and conversely, a subset of nonobese subjects present with obesity-associated cardiometabolic abnormalities (“metabolically obese nonobese,” MONO). The aim of this cross-sectional study was to identify the most important body composition determinants of metabolic phenotypes of obesity in nonobese and obese healthy postmenopausal women. Design and Methods: We studied a total of 150 postmenopausal women (age 54 ± 7 years, mean ± 1 SD). Based on a cardiometabolic risk score, nonobese (body mass index [BMI] ≤ 27) and obese women (BMI > 27) were classified into “metabolically healthy” and “unhealthy” phenotypes. Total and regional body composition was assessed with dual-energy X-ray absorptiometry (DXA). Results: In both obese and nonobese groups, the “unhealthy” phenotypes were characterized by frequent bodyweight fluctuations, higher biochemical markers of insulin resistance, hepatic steatosis and inflammation, and higher anthropometric and DXA-derived indices of central adiposity, compared with “healthy” phenotypes. Indices of total adiposity, peripheral fat distribution and lean body mass were not significantly different between “healthy” and “unhealthy” phenotypes. Despite having increased fat mass, MHO women exhibited comparable cardiometabolic parameters with healthy nonobese, and better glucose and lipid levels than MONO. Two DXA-derived indices, trunk-to-legs and abdominal-to-gluteofemoral fat ratio were the major independent determinants of the “unhealthy” phenotypes in our cohort. Conclusions: The “metabolically obese phenotype” is associated with bodyweight variability, multiple cardiometabolic abnormalities and an excess of central relative to peripheral fat in postmenopausal women. DXA-derived centrality ratios can discriminate effectively between metabolic subtypes of obesity in menopause.

Medical history and clinical examination: We report on a 52-year-old lean female patient with diabetes mellitus, treated with various glucose-lowering medications including insulin for 6 years. Both her mother and great-grandmother were also diagnosed with diabetes. At admission, she presents with good glycemic control and no signs of diabetes-related comorbidities.HbA1c is 6 %. On the basis of positive family history for diabetes, normal body weight and negative antibodies against islet-cell antigens, we perform blood molecular genetic analyses with the suspicion of a genetic form of diabetes. Genetic tests reveal a monogenic form of diabetes (MODY, Maturity Onset Diabetes of the Young) due to an heterozygous mutation in exon 6 of the glucokinase (GCK) gene. The same mutation is subsequently detected in the patient's mother.We diagnose MODY2 diabetes due to a glucokinase gene mutation. Repaglinide therapy is withdrawn due to lack of solid literature data showing beneficial cardiometabolic outcomes in patients with diabetes. Based on the MODY diagnosis, we recommend sulfonylurea treatment, which is however rejected by the patient due to a history of hypoglycemic episodes under the lowest dose. Thus, sitagliptin-treatment is continued under regular visits in our outpatient clinic.The joint presence of a positive family history, age under 25 years at diagnosis of diabetes, normal bodyweight, negative diabetes-specific autoantibodies and mild hyperglycaemia should raise the suspicion of a monogenic form of diabetes such as MODY and result in molecular-genetic testing.

Combination therapies are a widely accepted approach to type 2 diabetes treatment, considering that monotherapies fail to provide adequate glycemic control in the majority of cases. The combination of oral antidiabetic agents into a single tablet would significantly simplify the therapeutic regimen and maximize patients' adherence to treatment. Recently, a fixed-dose, single-tablet, combined formulation of linagliptin (a dipeptidyl peptidase-4 inhibitor) and metformin has been approved for use in type 2 diabetic patients, and is indicated as an adjunct to diet and exercise for those patients who remain inadequately controlled despite maximal tolerated doses of metformin, metformin and sulfonylurea, or linagliptin and metformin monotherapies. The combination tablet is administered twice daily and can be used either alone or combined with sulfonylureas. Clinical trials suggest that this fixed-dose combination provides significantly superior glycemic control compared to linagliptin and metformin monotherapy, in terms of improving key parameters of glucose homeostasis such as glycosylated hemoglobin, fasting and postprandial glucose levels. It also exhibits an excellent tolerability profile, without promoting weight gain and hypoglycemic episodes. The compounds of this formulation do not display clinically relevant pharmacokinetic interactions with each other, and exert synergistic (complementary) pharmacodynamic effects, including an enhanced incretin effect, suppressed hepatic glucose production, and improved peripheral insulin sensitivity. As a result, a linagliptin/metformin fixed-dose combination offers the potential to address multiple defects of type 2 diabetes pathophysiology (pancreatic islet dysfunction, insulin resistance, increased hepatic glucose output), and most importantly, in the context of a safe, efficacious, flexible, and convenient therapeutic regimen.

In this issue of Molecular Metabolism, Martin et al. addressed the intensively debated term “mitochondrial dysfunction” in the context of insulin resistance using a comprehensive cell-autonomous approach, which allowed constant substrate delivery to distinct insulin-sensitive cell types circumventing confounding effects of in vivo inter-tissue crosstalk [1]. The authors provoked and titrated the reduction of oxidative phosphorylation (OXPHOS) by inhibiting respiratory complexes I and V in 3T3L1 adipocyte and FAO hepatoma cell cultures, and assessed the effects on insulin sensitivity. Inhibition of OXPHOS reduced the insulin action in adipocytes but had insulin-sensitizing effects in hepatocytes. Interestingly, these effects occurred independently of the production of reactive oxygen species (ROS). Although using the misleading term “mitochondrial dysfunction”, which should be avoided as it implies one unifying abnormality of mitochondria, the authors took effort to assess several interdependent aspects of mitochondrial function such as respiration, membrane potential, and ROS production. An even more comprehensive assessment of mitochondrial function could have been obtained by integrating additional features into this multi-component analysis, such as β-oxidation, tricarboxylic acid (TCA) cycle activity, and mitochondrial content or density. Of note, it is of interest to examine whether their findings would also hold true for other cell types, such as the β-cell or the skeletal muscle cell, which is mainly responsible for insulin-mediated whole-body glucose disposal and oxidative adaptation to physical training as well as a key player in the pathogenesis of insulin resistance and type 2 diabetes mellitus (T2DM). The finding of tissue-specific functional characteristics of mitochondria is not unexpected, as mitochondrial metabolism is tailored to meet the metabolic and bioenergetic demands of divergent tissues such as brain, heart, liver, adipose tissue, or skeletal muscle by means of their broad range of OXPHOS capacity. This diversity results from different combinations of mitochondrial content, amount of electron transport chain complexes, and their intrinsic activities, which can be viewed as an adaptation to the variable substrate fluxes and may further account for tissue-specific interference of mitochondrial function with insulin sensitivity. The relationship between mitochondrial function and insulin sensitivity is influenced by various factors: (i) the tissue or cell type, as pointed by the study by Martin et al. [1], (ii) the mitochondrial features examined, (iii) the mode of insulin resistance, and (iv) time-dependent interaction. First, the postulate that reduced mitochondrial function uniformly associates with insulin resistance is based on studies in human skeletal muscle in vivo and in vitro [2]. Nevertheless, upregulated OXPHOS gene expression has been already found in liver of T2DM patients [3]. Second, inhibition of individual mitochondrial features such as β-oxidation vs. OXPHOS might cause opposing effects on insulin sensitivity. For example, mice exhibiting genetic defects related to impaired β-oxidation exhibit reduced hepatic insulin sensitivity [4], whereas mice with inherited OXPHOS defects can present with improved insulin sensitivity [5]. It is also important to differentiate between the distinct components of one mitochondrial feature such as the respiratory complexes I–V. Martin et al. contribute to unraveling this diversity, by showing differential effects on insulin sensitivity in hepatocytes and adipocytes depending on selective inhibition of complex I or V [1]. These findings might pave the way to novel individualized therapeutic approaches for improving insulin sensitivity, by targeting not only specific tissues and mitochondrial features, but also distinct mitochondrial proteins and their bioactive subunits. Third, the choice of model of insulin resistance likely affects the results of studies on a relationship between mitochondrial features and insulin sensitivity. In highly insulin resistant first-degree relatives of T2DM patients, reduction of muscle mitochondrial density and function tightly associates with insulin resistance [6], while muscle mitochondrial function is not necessarily impaired in all T2DM patients [7]. Similarly, hepatic mitochondrial function could be enhanced in obese humans with fatty liver, but impaired in patients with T2DM and non-alcoholic steatohepatitis [8]. In this context, the cellular models of insulin resistance such as used in the present study, i.e. tumor necrosis factor-α or chronic insulin exposure, might further influence the results due to their different mechanisms of action. Finally, opposing alterations of mitochondrial features may occur during the time course of the development of insulin resistance under in vivo conditions. At the onset of diabetes, NOD mice become insulin resistant at the level of both muscle and liver, while oxidative capacity decreases in muscle and transiently rises in the liver [9]. This might result from sequential activation of tissue-specific pathways linked to glucolipotoxicity. Although the underlying mechanisms remain still unresolved, it has been postulated that the insulin-dependent vs. -independent glucose carriers in myocytes and hepatocytes might render these cells differentially susceptible to the regulatory effects of fasting glycemia on mitochondrial function [3] (Figure 1). Furthermore, the unique mitochondrial characteristics such as the semi-autonomous hepatic TCA cycle, which is not tightly coupled to β-oxidation, need to be considered. On the other hand, greater lipid availability can induce insulin resistance via toxic lipid intermediates such as the diacylglycerol-protein kinase C or the ceramide-toll-like receptor-4 pathway, but maybe also via incomplete fat oxidation (Figure 1). Conversely, lipid exposure can decrease ATP production at least in human skeletal muscle [7]. Figure 1 This figure illustrates the major interactions between features of mitochondrial function and insulin action in an unspecified insulin-sensitive cell (hepatocyte or myocyte). Red color denotes liver- and blue color muscle-specific pathways and mediators. ... Another interesting finding of Martin et al. is the uniform absence of any effect of ROS on the relationship between impairment of mitochondrial OXPHOS and insulin sensitivity. This seems counterintuitive, as ROS has been proposed to mediate insulin resistance in the face of lower mitochondrial function. However, at least certain forms of oxidative stress, i.e. exercise training, ameliorate insulin resistance, and induce adaptive responses promoting endogenous antioxidant defense capacity, in line with the concept of mitohormesis [10]. Nevertheless, further research is warranted to re-examine the role of oxidant and anti-oxidant pathways with regard to mitochondrial function and insulin sensitivity. Taken together, the study by Martin et al. highlights that the interaction between mitochondria and insulin sensitivity is not only tissue-specific, but also site-specific. Although supporting the contention of mitochondrial diversity, many questions remain unanswered: (i) is the relationship between mitochondrial function and insulin resistance bidirectional, or in other words what are causes and consequences in different tissues, (ii) what are the precise mechanisms accounting for the peculiar relationship of hepatic mitochondria with insulin sensitivity, when compared to other tissues, and (iii) which other – if not ROS – are the downstream effectors mediating the interference between mitochondrial function and insulin sensitivity? To elucidate these issues, further cell or organelle-based studies such as the one by Martin et al. will remain important, but clinical studies are also needed to assess simultaneously multiple mitochondrial features in different tissues of well-phenotyped insulin resistant humans.

Various dietary approaches with different caloric content and macronutrient composition have been recommended to treat obesity in adults. Although their safety and efficacy profile has been assessed in numerous randomized clinical trials, reviews and meta-analyses, the characteristics of the optimal dietary weight loss strategy remain controversial. This mini-review will provide general principles and practical recommendations for the dietary management of obesity and will further explore the components of the optimal dietary intervention. To this end, various dietary plans are critically discussed, including low-fat diets, low-carbohydrate diets, high-protein diets, very low-calorie diets with meal replacements, Mediterranean diet, and diets with intermittent energy restriction. As a general principle, the optimal diet to treat obesity should be safe, efficacious, healthy and nutritionally adequate, culturally acceptable and economically affordable, and should ensure long-term compliance and maintenance of weight loss. Setting realistic goals for weight loss and pursuing a balanced dietary plan tailored to individual needs, preferences, and medical conditions, are the key principles to facilitate weight loss in obese patients and most importantly reduce their overall cardiometabolic risk and other obesity-related comorbidities.

We evaluated the relationship between coronary artery stenosis status and established cardiovascular risk factors in a large population of 1228 patients who consecutively underwent coronary angiography. Smoking proved to be the most important predictive factor for angiographically significant coronary artery disease (CAD), followed by dyslipidemia, diabetes, family history, and hypertension in a descending order of significance. Obesity rates did not differ significantly between the CAD positive and negative groups, nor changed significantly as the number of affected vessels increased. Smoking, dyslipidemia, and diabetes were positively associated with atherosclerotic involvement of all 3 major coronary arteries, whereas hypertension related only to significant stenosis of left anterior descending and left circumflex artery. The only established risk factors that could reliably predict left main stem disease were diabetes and age. Furthermore, large-scale studies will delineate the implications of the existing interrelationship between clinical and angiographic features.

Ghrelin is a powerful orexigenic gut hormone with growth hormone releasing activity. It plays a pivotal role for long-term energy balance and short-term food intake. It is also recognized as a potent signal for meal initiation. Ghrelin levels rise sharply before feeding onset, and are strongly suppressed by food ingestion. Postprandial ghrelin response is totally macronutrient specific in normal weight subjects, but is rather independent of macronutrient composition in obese. In rodents and lean individuals, isoenergetic meals of different macronutrient content suppress ghrelin to a variable extent. Carbohydrate appears to be the most effective macronutrient for ghrelin suppression, because of its rapid absorption and insulin-secreting effect. Protein induces prolonged ghrelin suppression and is considered to be the most satiating macronutrient. Fat, on the other hand, exhibits rather weak and insufficient ghrelin-suppressing capacity. The principal mediators involved in meal-induced ghrelin regulation are glucose, insulin, gastrointestinal hormones released in the postabsorptive phase, vagal activity, gastric emptying rate, and postprandial alterations in intestinal osmolarity.

We summarize the existing literature data concerning the involvement of skeletal muscle (SM) in whole body glucose homeostasis and the contribution of SM insulin resistance (IR) to the metabolic derangements observed in several endocrine disorders, including polycystic ovary syndrome (PCOS), adrenal disorders and thyroid function abnormalities. IR in PCOS is associated with a unique postbinding defect in insulin receptor signaling in general and in SM in particular, due to a complex interaction between genetic and environmental factors. Adrenal hormone excess is also associated with disrupted insulin action in peripheral tissues, such as SM. Furthermore, both hyper- and hypothyroidism are thought to be insulin resistant states, due to insulin receptor and postreceptor defects. Further studies are definitely needed in order to unravel the underlying pathogenetic mechanisms. In summary, the principal mechanisms involved in muscle IR in the endocrine diseases reviewed herein include abnormal phosphorylation of insulin signaling proteins, altered muscle fiber composition, reduced transcapillary insulin delivery, decreased glycogen synthesis, and impaired mitochondrial oxidative metabolism.

Background: Impaired energy metabolism is a possible mechanism that contributes to insulin resistance and ectopic fat storage. Objective: We examined whether meal ingestion differently affects hepatic phosphorus metabolites in insulin-sensitive and insulinresistant humans. Design: Young, lean, insulin-sensitive humans (CONs) [mean 6 SD body mass index (BMI; in kg/m 2 ): 23.2 6 1.5]; insulin-resistant, glucose-tolerant, obese humans (OBEs) (BMI: 34.3 6 1.7); and type 2 diabetes patients (T2Ds) (BMI: 32.0 6 2.4) were studied (n = 10/group). T2Ds (61 6 7 y old) were older (P , 0.001) than were OBEs (31 6 7 y old) and CONs (28 6 3 y old). We quantified hepatic gATP, inorganic phosphate (Pi), and the fat content [hepatocellular lipids (HCLs)] with the use of 31 P/ 1 H magnetic resonance spectroscopy before and at 160 and 240 min after a high-caloric mixed meal. In a subset of volunteers, we measured the skeletal muscle oxidative capacity with the use of high-resolution respirometry. Whole-body insulin sensitivity (M value) was assessed with the use of hyperinsulinemic-euglycemic clamps. Results: OBEs and T2Ds were similarly insulin resistant (M value: 3.5 6 1.4 and 1.9 6 2.5 mg $ kg 21 $ min 21 , respectively; P = 0.9) and had 12-fold (P = 0.01) and 17-fold (P = 0.002) higher HCLs, respectively, than those of lean persons. Despite comparable fasting hepatic gATP concentrations, the maximum postprandial increase of gATP was 6-fold higher in OBEs (0.7 6 0.2 mmol/L; P = 0.03) but only tended to be higher in T2Ds (0.6 6 0.2 mmol/L; P = 0.09) than in CONs (0.1 6 0.1 mmol/L). However, in the fasted state, muscle complex I activity was 53% lower (P = 0.01) in T2Ds but not in OBEs (P = 0.15) than in CONs. Conclusions: Young, obese, nondiabetic humans exhibit augmented postprandial hepatic energy metabolism, whereas elderly T2Ds have impaired fasting muscle energy metabolism. These findings support the concept of a differential and tissue-specific regulation of energy metabolism, which can occur independently of insulin resistance. This trial was registered at clinicaltrials.gov as NCT01229059. Am J Clin Nutr 2015;102:1051–8.

Summary The association of hepatic mitochondrial function with insulin resistance and non-alcoholic fatty liver (NAFL) or steatohepatitis (NASH) remains unclear. This study applied high-resolution respirometry to directly quantify mitochondrial respiration in liver biopsies of obese insulin-resistant humans without (n = 18) or with (n = 16) histologically proven NAFL or with NASH (n = 7) compared to lean individuals (n = 12). Despite similar mitochondrial content, obese humans with or without NAFL had 4.3- to 5.0-fold higher maximal respiration rates in isolated mitochondria than lean persons. NASH patients featured higher mitochondrial mass, but 31%–40% lower maximal respiration, which associated with greater hepatic insulin resistance, mitochondrial uncoupling, and leaking activity. In NASH, augmented hepatic oxidative stress (H 2 O 2 , lipid peroxides) and oxidative DNA damage (8-OH-deoxyguanosine) was paralleled by reduced anti-oxidant defense capacity and increased inflammatory response. These data suggest adaptation of the liver ("hepatic mitochondrial flexibility") at early stages of obesity-related insulin resistance, which is subsequently lost in NASH.

High field MR scanners can resolve a metabolite resonating at 2.06 ppm in the in vivo proton-decoupled liver (31) P MR spectrum. Traditionally this peak has been assigned to phosphoenolpyruvate (PEP), the key metabolite for gluconeogenesis. However, recent evidence supported the assignment to biliary phosphatidylcholine (PtdCh), which is produced in the liver and stored in the gall bladder. To elucidate the respective contributions of PtdCh and PEP to the in vivo resonance at 2.06 ppm (PEP-PtdCh), we made phantom measurements that confirmed that both biliary PtdCh and PEP resonate approximately at 2 ppm. The absolute quantification of PEP-PtdCh yielded concentrations ranging from 0.6 to 2.0 mmol/l, with mean coefficients of variation of 4.8% for intraday and 7.2% for interday reproducibility in healthy volunteers. The T1 relaxation time of PEP-PtdCh was 0.97 ± 0.30 s in the liver and 0.44 ± 0.11 s in the gallbladder. Ingestion of a mixed meal decreased the concentration of PtdCh-PEP by approximately 12%. In the retrospective analysis, PEP-PtdCh was 68% higher in the liver of subjects with gallbladder infiltration of the volume of interest (VOI) compared with those without gallbladder infiltration. PEP-PtdCh was also significantly higher in the liver of cholecystectomy patients compared with volunteers without gallbladder infiltration, which suggests increased intrahepatic bile fluid as a compensation for gall bladder removal. These results show that liver PtdCh is the major component of the resonance at 2.06 ppm and that careful VOI positioning is mandatory to avoid interference from the gallbladder.

Muscle insulin resistance is a key feature of obesity and type 2 diabetes and is strongly associated with increased intramyocellular lipid content and inflammation. However, the cellular and molecular mechanisms responsible for causing muscle insulin resistance in humans are still unclear. To address this question, we performed serial muscle biopsies in healthy, lean subjects before and during a lipid infusion to induce acute muscle insulin resistance and assessed lipid and inflammatory parameters that have been previously implicated in causing muscle insulin resistance. We found that acute induction of muscle insulin resistance was associated with a transient increase in total and cytosolic diacylglycerol (DAG) content that was temporally associated with protein kinase (PKC)θ activation, increased insulin receptor substrate (IRS)-1 serine 1101 phosphorylation, and inhibition of insulin-stimulated IRS-1 tyrosine phosphorylation and AKT2 phosphorylation. In contrast, there were no associations between insulin resistance and alterations in muscle ceramide, acylcarnitine content, or adipocytokines (interleukin-6, adiponectin, retinol-binding protein 4) or soluble intercellular adhesion molecule-1. Similar associations between muscle DAG content, PKCθ activation, and muscle insulin resistance were observed in healthy insulin-resistant obese subjects and obese type 2 diabetic subjects. Taken together, these data support a key role for DAG activation of PKCθ in the pathogenesis of lipid-induced muscle insulin resistance in obese and type 2 diabetic individuals.