Effects of Wheat Biscuits Enriched with Plant Proteins Incorporated into an Energy-Restricted Dietary Plan on Postprandial Metabolic Responses of Women with Overweight/Obesity.

This study investigates the effect of daily consumption of wheat biscuits enriched with plant proteins in postprandial metabolic responses of women with overweight/obesity who follow an energy-restricted diet. Thirty apparently healthy women participated in a 12-week randomized controlled trial and were assigned either to a control (CB) or an intervention (PB) group. Participants consumed daily either a conventional (CB) or an isocaloric wheat biscuit enriched with plant proteins (PB) containing high amounts of amino acids with appetite-regulating properties, i.e., BCAAs and L-arg. At baseline and the end of the intervention, a mixed meal tolerance test was performed. The responses of glucose, insulin, ghrelin, GLP-1, and glicentin were evaluated over 180 min. After 12 weeks, both groups experienced significant decreases in body weight, fat mass, and waist circumference. In the PB group, a trend towards higher weight loss was observed, accompanied by lower carbohydrate, fat, and energy intakes (p < 0.05 compared to baseline and CB group), while decreases in fasting insulin and the HOMA-IR index were also observed (p < 0.05 compared to baseline). In both groups, similar postprandial glucose, ghrelin, and GLP-1 responses were detected, while iAUC for insulin was lower (p < 0.05). Interestingly, the iAUC of glicentin was greater in the PB group (p < 0.05 compared to baseline). Subjective appetite ratings were beneficially affected in both groups (p < 0.05). Consumption of wheat biscuits enriched in plant proteins contributed to greater weight loss, lower energy intake, and insulin resistance and had a positive impact on postprandial glicentin response, a peptide that can potentially predict long-term weight loss and decreased food intake.

Update on the Obesity Epidemic: After the Sudden Rise, Is the Upward Trajectory Beginning to Flatten?

PURPOSE OF REVIEW: To provide an update on current obesity prevalence trends and summarize the available evidence suggesting a possible plateau or stabilization in obesity rates after the previous sudden global rise. RECENT FINDINGS: The escalating global obesity epidemic represents one of the most serious public health challenges. There have been some indications that in high-income populations, the rate of obesity increase in adults has been stabilized after the decade 2000-2010, suggesting a possible plateau. Current evidence also suggests that obesity rates have been stabilized in children and adolescents of most economically advanced countries since 2000, which is possibly related to healthier dietary habits and increased levels of physical activity. On the other hand, there is a steady uninterrupted rise in low-income nations, and the universal trend is obesity escalation rather than slowdown, mainly driven by sharp increases in the obesity prevalence of low-income populations. Furthermore, an increasing number of high- and middle-income countries are currently experiencing an epidemic of severe obesity. In high-income populations, severe obesity is expected to double its prevalence from 10 to 20% between 2020 and 2035, posing an enormous threat for healthcare systems. Even if transiently stabilized, the obesity prevalence remains globally at unacceptably high levels, and there is no guarantee that the current stability (if any) will be maintained for long. In this review, we explore the underlying drivers of the global obesity epidemic; we provide possible explanations for the reported slowdown of the obesity rates in some countries; and we overall take a critical perspective on the obesity plateau hypothesis, emphasizing the urgent need for immediate effective actions at population and regional level in order to halt the alarming obesity escalation and its serious health risks.

Novel Dual Incretin Receptor Agonists in the Spectrum of Metabolic Diseases with a Focus on Tirzepatide: Real Game-Changers or Great Expectations? A Narrative Review.

The prevalence of metabolic diseases including type 2 diabetes (T2D), obesity and non-alcoholic fatty liver disease (NAFLD) increases globally. This highlights an unmet need for identifying optimal therapies for the management of these conditions. Tirzepatide is a novel dual incretin receptor agonist (twincretin) that activates both glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors. The aim of this narrative review was to examine the impact of novel twincretins, focusing on tirzepatide, on the management of a wide spectrum of metabolic diseases. Data from preclinical and clinical trials have shown that twincretins significantly reduce blood glucose levels in T2D, and tirzepatide is the first agent of this class that has been approved for the management of T2D. Additionally, the beneficial impact of tirzepatide on weight reduction has been corroborated in several studies, showing that this agent can achieve substantial and sustained weight loss in obese patients with or without T2D. Data also suggest that tirzepatide could be a promising drug for hepatic steatosis reduction in individuals with NAFLD. The remarkable effects of tirzepatide on glycaemic control, weight loss and liver-related outcomes have posed new research questions that are likely to lead to further advancements in the treatment of T2D, obesity and related metabolic disorders.

Non-Classical Aspects of Obesity Pathogenesis and Their Relative Clinical Importance for Obesity Treatment.

Obesity is a chronic disease and a major public health problem due to its association with non-communicable diseases and all-cause mortality. An increased energy intake and decreased physical activity have been long recognized as the classical parameters that contribute to the development of obesity. However, several other, non-classical factors have also been associated with obesity through various complex mechanisms. Some of them are diet related, such as diet quality, dietary habits and speed of eating. Other factors are non-dietary, such as endocrine-disrupting chemicals, sleep quality and quantity, psychotropic medications and light at night. The scope of the present narrative review is to address these non-classical factors that are implicated in the pathogenesis of obesity, to clarify their potential role in the management of obesity and, where possible, to provide some practical clinical recommendations.

Novel Noninvasive Approaches to the Treatment of Obesity: From Pharmacotherapy to Gene Therapy.

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.

Repositioning the Role of Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL) on the TRAIL to the Development of Diabetes Mellitus: An Update of Experimental and Clinical Evidence.

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.

Dietary palmitate and oleate differently modulate insulin sensitivity in human skeletal muscle.

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 < 0.05) but only PAL activated PKCɛ. Moreover, PAL led to increased myocellular ceramides along with stimulated PKCζ translocation (p < 0.05 vs SAF). During clamp, SAF and PAL both decreased insulin-stimulated Rd (p < 0.05 vs VCL), but non-oxidative glucose disposal was lower after PAL compared with SAF (p < 0.05). Muscle serine1101-phosphorylation of IRS-1 was increased upon SAF and PAL consumption (p < 0.05), whereas PAL decreased serine473-phosphorylation of Akt more than SAF (p < 0.05). 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.

The Role of Mitochondrial Adaptation and Metabolic Flexibility in the Pathophysiology of Obesity and Insulin Resistance: an Updated Overview.

PURPOSE OF REVIEW: The term "metabolic flexibility" denotes the dynamic responses of the cellular oxidative machinery in order to adapt to changes in energy substrate availability. A progressive loss of this adaptive capacity has been implicated in the development of obesity-related comorbidities. Mitochondria are dynamic intracellular organelles which play a fundamental role in energy metabolism, and the mitochondrial adaptation to environmental challenges may be viewed as the functional component of metabolic flexibility. Herein, we attempt to comprehensively review the available evidence regarding the role of mitochondrial adaptation and metabolic flexibility in the pathogenesis of obesity and related morbidities, namely insulin resistance states and non-alcoholic fatty liver disease (NAFLD). RECENT FINDINGS: Overall, there is a concrete body of evidence to support the presence of impaired mitochondrial adaptation as a principal component of systemic metabolic inflexibility in conditions related to obesity. There are still many unresolved questions regarding the relationship between the gradual loss of mitochondrial adaptability and the progression of obesity-related complications, such as causality issues, the timely appearance and reversibility of the described disturbances, and the generalizability of the findings to the mitochondrial content of every affected tissue or organ. The evidence regarding the causality between the observed associations remains inconclusive, although most of the available data points towards a bidirectional, potentially mutually amplifying relationship. The spectrum of NAFLD is of particular interest, since functional and pathological changes in the course of its development closely mirror the progression of dysmetabolism, if not constituting a dynamic component of the latter.

Intermittent Energy Restriction, Weight Loss and Cardiometabolic Risk: A Critical Appraisal of Evidence in Humans.

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.

CDATA[The Effect of Oxidative Stress and Antioxidant Therapies on Pancreatic ß-cell Dysfunction: Results from in Vitro and in Vivo Studies.

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 ß-cells dysfunction and apoptosis, as well as in the development and progression of diabetic complications. Considering the vulnerability of pancreatic ß-cells to oxidative damage, the induction of endogenous antioxidant enzymes or exogenous antioxidant administration has been proposed to protect pancreatic ß-cells from damage. OBJECTIVES: The present review aims to provide evidence of the effect of oxidative stress and antioxidant therapies on pancreatic ß-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 ß-cells are extremely sensitive to Reactive Oxygen Species (ROS). Many natural extracts have been tested in vitro in pancreatic ß-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 ß -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 ß-cells dysfunction, as supported by in vitro and in vivo studies. However, more in vitro studies are required for drugs.

The Implication of Gut Hormones in the Regulation of Energy Homeostasis and Their Role in the Pathophysiology of Obesity.

PURPOSE OF REVIEW: 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. RECENT FINDINGS: 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.

Clinical Management of Diabetes Mellitus in the Era of COVID-19: Practical Issues, Peculiarities and Concerns.

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.

Eligibility and Awareness Regarding Metabolic Surgery in Patients With Type 2 Diabetes Mellitus in the Real-World Clinical Setting; Estimate of Possible Diabetes Remission.

Despite high-quality evidence highlighting metabolic surgery as an effective treatment option for type 2 diabetes mellitus (T2DM), the number of patients receiving bariatric surgery (BS) remains low. Since the introduction of the Diabetes Surgery Summit II (DSS-II) eligibility criteria, data on eligibility rates for BS in T2DM cohorts remain scarce. The aims of the present study were to examine in a real-world clinical setting: (i) what is the percentage of T2DM patients visiting diabetes outpatient clinics who meet the DSS-II eligibility criteria, (ii) how many of these have been informed about the option of BS, and (iii) what are the characteristics associated with eligibility and awareness of BS. Demographic, anthropometric, clinical and socioeconomic data were obtained for all patients with T2DM who were consecutively examined in the outpatient clinics of three large-volume university hospitals (n = 1167). A medical registry form was completed to screen for BS eligibility. Patients were considered eligible if the recommendation by DSS-II criteria was either to "consider" or "recommend" BS. Eligible patients were further inquired whether they had ever been informed about the option of BS by their physicians. The advanced DiaRem score (ADRS) was applied to eligible patients to assess their probability of achieving postoperative T2DM remission. A significant percentage of T2DM patients who are routinely assessed in outpatient clinics meet the DSS-II eligibility criteria (15.3%). Eligible patients are younger and more obese, have a shorter T2DM duration, worse glycaemic control and better renal function, compared to non-eligible ones. Among eligible patients, only 39.3% have been medically informed about the option of BS. Informed patients are younger and more severely obese than non-informed ones. A significant percentage of non-informed patients (35%) have an ADRS ≤10, indicating a considerable probability for T2DM remission after BS, and are thus deprived of this opportunity due to lack of appropriate medical counseling. Screening and awareness of BS remain an unmet need in current T2DM management. Future research should focus on intensifying screening for BS eligibility at every medical visit and promoting evidence-based clinical recommendations for patients expected to benefit the most.

Important Considerations for the Treatment of Patients with Diabetes Mellitus and Heart Failure from a Diabetologist's Perspective: Lessons Learned from Cardiovascular Outcome Trials.

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.

Sarcopenic Obesity: Epidemiologic Evidence, Pathophysiology, and Therapeutic Perspectives.

PURPOSE OF REVIEW: 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. RECENT FINDINGS: 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.

Dynamic changes of muscle insulin sensitivity after metabolic surgery.

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.

Remission of Type 2 Diabetes Mellitus after Bariatric Surgery: Fact or Fiction?

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.