Publications by authors named "Christos S Mantzoros"

425 Publications

Molecular modelling of novel ADCY3 variant predicts a molecular target for tackling obesity.

Int J Mol Med 2022 Jan 25;49(1). Epub 2021 Nov 25.

Department of Pharmacy, School of Health Sciences, Frederick University Cyprus, 1036 Nicosia, Cyprus.

Severe early‑onset obesity is mainly attributed to single gene variations of the hypothalamic leptin‑melanocortin system, which is critical for controlling the balance between appetite and energy expenditure. Adenylate cyclase 3 (ADCY3), a transmembrane enzyme localized in primary neuronal cilia, is a key genetic candidate, which appears to have an essential role in regulating body weight. The present study aimed to identify ADCY3 genetic variants in severely obese young patients of Greek‑Cypriot origin by genomic sequencing. Apart from previously reported variants, the novel and probably pathogenic variant c.349T>A, causing a p.Leu117Met substitution within one of the two pseudo‑symmetric halves of the transmembrane part of the protein, was reported. Molecular modelling analysis used to delineate bonding interactions within the mutated protein structure strongly suggested a change in interactive forces and energy levels affecting the pseudo‑twofold symmetry of the transmembrane domain of the protein and probably its catalytic function. These results support the involvement of ADCY3 in the pathology of the disease and point towards the requirement of defining protein function and evaluating the clinical significance of the detected variants.
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http://dx.doi.org/10.3892/ijmm.2021.5065DOI Listing
January 2022

Serum adipokine levels in patients with type 1 diabetes are associated with degree of obesity but only resistin is independently associated with atherosclerosis markers.

Hormones (Athens) 2021 Oct 30. Epub 2021 Oct 30.

2nd Propedeutic Department of Internal Medicine, Aristotle University, Konstantinoupoleos 49, Thessaloniki, Greece.

Purpose: The role of adipokines in causing inflammation and insulin resistance in normal weight and obese patients is generally well studied. However, there are often conflicting results regarding their levels in type 1 diabetes mellitus (T1DM) patients and their relationship to micro- and macrovascular disease. We therefore investigated which serum adipokine levels are independently associated with markers of early atherosclerosis and microvascular complications in patients with T1DM.

Methods: A cross-sectional study was performed in the Diabetes Outpatient Clinic of Hippokrateion General Hospital, Thessaloniki, Greece. Sixty T1DM patients (30 females, mean age 38.8 ± 10.6 years, mean diabetes duration 17.4 ± 9.9 years) were included. Plasma adiponectin, leptin, and resistin, carotid artery intima media thickness (cIMT), and arterial stiffness (pulse wave velocity, PWV/SpygmoCor CP System and Mobil-O-Graph 24 h PWA) were assessed.

Results: Leptin and resistin levels were significantly higher in overweight and obese patients (p = 0.002 and p = 0.039, respectively). Adiponectin was the only adipokine negatively correlated with BMI (r =  - 0.41, p = 0.001). We report a bivariate association between serum adiponectin levels and retinopathy (p = 0.007). Resistin was the only adipokine that showed significant correlation with systolic (r = 0.42, p = 0.001) and diastolic (r = 0.29, p = 0.024) hypertension and PWV (p = 0.035).

Conclusions: Serum adipokine levels demonstrate similar bivariate associations with anthropometric variables in patients with T1DM to those in normal weight subjects. Although microvascular complications are associated with serum adipokine levels by bivariate analysis, only resistin, an inflammatory marker, is independently associated with arterial stiffness in patients with T1DM.
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http://dx.doi.org/10.1007/s42000-021-00328-9DOI Listing
October 2021

Novel Non-invasive Approaches to the Treatment of Obesity: From Pharmacotherapy to Gene Therapy.

Endocr Rev 2021 Oct 26. Epub 2021 Oct 26.

Section of Endocrinology, VA Boston Healthcare System, Harvard Medical School, Boston, USA.

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 which 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, i.e., 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.
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http://dx.doi.org/10.1210/endrev/bnab034DOI Listing
October 2021

Daily transient coating of the intestine leads to weight loss and improved glucose tolerance.

Metabolism 2022 Jan 21;126:154917. Epub 2021 Oct 21.

Laboratory for Surgical and Metabolic Research, Department of Surgery, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Division of General and GI Surgery, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. Electronic address:

Introduction: Roux-en-Y gastric bypass surgery (RYGB) has been shown to be the gold standard treatment for obesity associated type-2-diabetes (T2D), however many T2D patients do not qualify or are reluctant to proceed with surgery due to its potential risks and permanent changes to GI anatomy. We have previously described a novel oral formulation, LuCI, that provides a transient coating of the proximal bowel and mimics the effects of RYGB. Herein, we aim to investigate the outcome of chronic LuCI administration on weight and glucose homeostasis.

Methods: Sprague-Dawley rats on a high fat diet achieving diet-induced obesity (DIO) received 5 weeks of daily LuCI or normal saline as control (n = 8/group). Daily weights and glucose tolerance were monitored throughout the experiment. At 5 weeks, systemic blood was sampled through a surgically placed jugular vein catheter, before and during an intestinal glucose bolus, to investigate changes in key hormones involved in glucose metabolism. To elucidate the effects of LuCI on nutrient absorption, fecal output and food intake were measured simultaneously with the analysis of homogenized stool samples performed using bomb calorimetry.

Results: At 5 weeks, LuCI animals weighted 8.3% less and had lower fasting glucose levels than Controls (77.6 ± 3.8 mg/dl vs. 99.1 ± 2.7 mg/dl, P < 0.001). LuCI-treated animals had lower baseline insulin and HOMA-IR. Post-prandially, LuCI group had increased GLP-1 and GIP secretion following a glucose challenge. Serum lipid analysis revealed lowered LDL levels highlighting the potential to not only improve glucose control but also modify cardiovascular risk. We then investigated whether LuCI's effect on proximal bowel exclusion may play a role in energy balance. Bomb calorimetry analysis suggested that LuCI reduced calorie absorption with no difference in caloric consumption.

Conclusion: We demonstrated that LuCI recapitulates the physical and hormonal changes seen after RYGB and can ameliorate weight gain and improve insulin sensitivity in a DIO rat model. Since LuCI's effect is transient and without systemic absorption, LuCI has the potential to be a novel therapy for overweight or obese T2D patients.
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http://dx.doi.org/10.1016/j.metabol.2021.154917DOI Listing
January 2022

Clinical Care Pathway for the Risk Stratification and Management of Patients With Nonalcoholic Fatty Liver Disease.

Gastroenterology 2021 Nov 20;161(5):1657-1669. Epub 2021 Sep 20.

University of Florida, Gainesville, Florida; Malcom Randall Veterans Affairs Medical Center, Gainesville, Florida. Electronic address:

Find AGA's NASH Clinical Care Pathway App for iOS and Android mobile devices at nash.gastro.org. Scan this QR code to be taken directly to the website.Nonalcoholic fatty liver disease (NAFLD) is becoming increasingly common, currently affecting approximately 37% of US adults. NAFLD is most often managed in primary care or endocrine clinics, where clinicians must determine which patients might benefit from secondary care to address hepatic manifestations, comorbid metabolic traits, and cardiovascular risks of the disease. Because NAFLD is largely asymptomatic, and because optimal timing of treatment depends on accurate staging of fibrosis risk, screening at the primary care level is critical, together with consistent, timely, evidence-based, widely accessible, and testable management processes. To achieve these goals, the American Gastroenterological Association assembled a multidisciplinary panel of experts to develop a Clinical Care Pathway providing explicit guidance on the screening, diagnosis, and treatment of NAFLD. This article describes the NAFLD Clinical Care Pathway they developed and provides a rationale supporting proposed steps to assist clinicians in diagnosing and managing NAFLD with clinically significant fibrosis (stage F2-F4) based on the best available evidence. This Pathway is intended to be applicable in any setting where care for patients with NAFLD is provided, including primary care, endocrine, obesity medicine, and gastroenterology practices.
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http://dx.doi.org/10.1053/j.gastro.2021.07.049DOI Listing
November 2021

The presence of NAFLD influences the transition of metabolically healthy to metabolically unhealthy obesity and the ten-year cardiovascular disease risk: A population-based cohort study.

Metabolism 2021 Sep 30:154893. Epub 2021 Sep 30.

Department of Medicine, Boston VA Healthcare System and Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.

Background/objectives: We evaluated the role of the presence of non-alcoholic fatty liver disease (NAFLD) at baseline in the transition from metabolically healthy to metabolically unhealthy obesity (MHO to MUO) ten years later.

Methods: A prospective cohort study (ATTICA study, Greece) was performed between 2002 and 2012 studying a sample from the greater metropolitan Athens area. In total, 1514 (49·8%) men and 1528 (50.2%) women (aged >18 years old) free-of-CVD were included. Healthy metabolic status was defined as absence of all NCEP ATP III (2005) metabolic syndrome components. NAFLD was defined according to validated liver steatosis indices. Follow-up CVD assessment (2011-2012) was achieved in n = 2020 participants (n = 317 cases).

Results: NAFLD prevalence among MHO participants ranged from 29% to 39% according to the specific NAFLD score used. MHO participants who developed metabolically unhealthy status had about two times higher odds to have NAFLD at baseline compared with their metabolically healthy normal weight counterparts whereas stable MHO was not associated significantly with NAFLD. Moreover, MHO status accompanied by NAFLD was associated with increased CVD risk (Hazard Ratio = 2.90 95% Confidence Interval (1.35, 5.40)) in comparison to their non-NAFLD MHO counterparts. Further analysis revealed that in the obese, NAFLD indices and not simply visceral adiposity increased significantly the ability of metabolic status (using standard definition) to predict long-term CVD incidence.

Conclusions: Considering NAFLD, even when assessed using validated indices only, in the clinical assessment of apparently healthy obese individuals predicts who is to develop MUO and contributes independently and more accurately to defining future cardiometabolic risk.
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http://dx.doi.org/10.1016/j.metabol.2021.154893DOI Listing
September 2021

CYP1A2 polymorphisms modify the association of habitual coffee consumption with appetite, macronutrient intake, and body mass index: results from an observational cohort and a cross-over randomized study.

Int J Obes (Lond) 2021 Sep 25. Epub 2021 Sep 25.

Department of Biology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.

Background/objectives: Evidence regarding the influence of coffee on appetite and weight control is equivocal and the influence of covariates, such as genetic variation in caffeine metabolism, remains unknown. Herein, we addressed the novel hypothesis that genetic variation in CYP1A2, a gene responsible for more than 95% of caffeine metabolism, differentially impacts the association of coffee consumption with appetite and BMI among individuals with different genetic predispositions to obesity.

Subjects/methods: A cross-over randomized intervention study involving 18 volunteers assessed the effects of coffee consumption on dietary intake, appetite, and levels of the appetite-controlling hormones asprosin and leptin. Data on habitual coffee intake, BMI, and perceived appetite were obtained from an observational cohort of 284 volunteers using validated questionnaires. Participants were stratified according to a validated genetic risk score (GRS) for obesity and to the -163C > A (rs762551) polymorphism of CYP1A2 as rapid (AA), intermediate (AC), or slow (CC) caffeine metabolizers.

Results: Coffee consumption led to lower energy and dietary fat intake and circulating asprosin levels (P for interaction of rs762551 genotype*coffee consumption=0.056, 0.039, and 0.043, respectively) as compared to slow/intermediate metabolizers. High coffee consumption was more prevalent in rapid compared to slow metabolizers (P = 0.008 after adjustment for age, sex, and BMI) and was associated with lower appetite perception and lower BMI only in rapid metabolizers (P for interaction of rs762551 genotype*coffee consumption = 0.002 and 0.048, respectively). This differential association of rs762551 genotype and coffee consumption with BMI was more evident in individuals at higher genetic risk of obesity (mean adjusted difference in BMI = -5.82 kg/m for rapid versus slow/intermediate metabolizers who consumed more than 14 cups of coffee per week).

Conclusions: CYP1A2 rs762551 polymorphism modifies the association of habitual coffee consumption with BMI, in part by influencing appetite, energy intake and circulating levels of the orexigenic hormone asprosin. This association is more evident in subjects with high genetic predisposition to obesity. ClinicalTrials.gov: registered Clinical Trial NCT04514588.
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http://dx.doi.org/10.1038/s41366-021-00972-6DOI Listing
September 2021

Incretin-based therapies in 2021 - Current status and perspectives for the future.

Metabolism 2021 09 30;122:154843. Epub 2021 Jul 30.

Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA; Section of Endocrinology, VA Boston Healthcare System, Harvard Medical School, Boston, MA, USA.

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http://dx.doi.org/10.1016/j.metabol.2021.154843DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8321622PMC
September 2021

Deep transfer learning and data augmentation improve glucose levels prediction in type 2 diabetes patients.

NPJ Digit Med 2021 Jul 14;4(1):109. Epub 2021 Jul 14.

Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA.

Accurate prediction of blood glucose variations in type 2 diabetes (T2D) will facilitate better glycemic control and decrease the occurrence of hypoglycemic episodes as well as the morbidity and mortality associated with T2D, hence increasing the quality of life of patients. Owing to the complexity of the blood glucose dynamics, it is difficult to design accurate predictive models in every circumstance, i.e., hypo/normo/hyperglycemic events. We developed deep-learning methods to predict patient-specific blood glucose during various time horizons in the immediate future using patient-specific every 30-min long glucose measurements by the continuous glucose monitoring (CGM) to predict future glucose levels in 5 min to 1 h. In general, the major challenges to address are (1) the dataset of each patient is often too small to train a patient-specific deep-learning model, and (2) the dataset is usually highly imbalanced given that hypo- and hyperglycemic episodes are usually much less common than normoglycemia. We tackle these two challenges using transfer learning and data augmentation, respectively. We systematically examined three neural network architectures, different loss functions, four transfer-learning strategies, and four data augmentation techniques, including mixup and generative models. Taken together, utilizing these methodologies we achieved over 95% prediction accuracy and 90% sensitivity for a time period within the clinically useful 1 h prediction horizon that would allow a patient to react and correct either hypoglycemia and/or hyperglycemia. We have also demonstrated that the same network architecture and transfer-learning methods perform well for the type 1 diabetes OhioT1DM public dataset.
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http://dx.doi.org/10.1038/s41746-021-00480-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8280162PMC
July 2021

Empagliflozin Improves Metabolic and Hepatic Outcomes in a Non-Diabetic Obese Biopsy-Proven Mouse Model of Advanced NASH.

Int J Mol Sci 2021 Jun 13;22(12). Epub 2021 Jun 13.

Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Ave, Boston, MA 02215, USA.

Empagliflozin, an established treatment for type 2 diabetes (T2DM), has shown beneficial effects on liver steatosis and fibrosis in animals and in humans with T2DM, non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH). However, little is known about the effects of empagliflozin on liver function in advanced NASH with liver fibrosis and without diabetes. This study aimed to assess the effects of empagliflozin on hepatic and metabolic outcomes in a diet-induced obese (DIO) and insulin-resistant but non-diabetic biopsy-confirmed mouse model of advanced NASH. Male C57BL/6JRj mice with a biopsy-confirmed steatosis and fibrosis on AMLN diet (high fat, fructose and cholesterol) for 36-weeks were randomized to receive for 12 weeks: (a) Empagliflozin (10 mg/kg/d p.o.), or (b) vehicle. Metabolic outcomes, liver pathology, markers of Kupffer and stellate cell activation and lipidomics were assessed at the treatment completion. Empagliflozin did not affect the body weight, body composition or insulin sensitivity (assessed by intraperitoneal insulin tolerance test), but significantly improved glucose homeostasis as assessed by oral glucose tolerance test in DIO-NASH mice. Empagliflozin improved modestly the NAFLD activity score compared with the vehicle, mainly by improving inflammation and without affecting steatosis, the fibrosis stage and markers of Kupffer and stellate cell activation. Empagliflozin reduced the hepatic concentrations of pro-inflammatory lactosylceramides and increased the concentrations of anti-inflammatory polyunsaturated triglycerides. Empagliflozin exerts beneficial metabolic and hepatic (mainly anti-inflammatory) effects in non-diabetic DIO-NASH mice and thus may be effective against NASH even in non-diabetic conditions.
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http://dx.doi.org/10.3390/ijms22126332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8232001PMC
June 2021

Maternal Midpregnancy Leptin and Adiponectin Levels as Predictors of Autism Spectrum Disorders: A Prenatal Cohort Study.

J Clin Endocrinol Metab 2021 09;106(10):e4118-e4127

Harvard Medical School, Boston, Massachusetts 02115, USA.

Context: Autism spectrum disorders (ASDs) are a group of conditions characterized by impaired social function and repetitive behaviors. Their etiology is largely unknown.

Objective: This work aims to examine the associations of maternal second-trimester and cord blood leptin and adiponectin levels with ASDs in offspring.

Methods: We used data from 1164 mother-child pairs enrolled in Project Viva, a prospective prebirth cohort. We used logistic regression analysis to examine the associations of leptin and adiponectin levels in maternal second-trimester blood and cord blood obtained at birth with ASDs. Additionally, we examined the association of maternal prepregnancy body mass index (BMI) as an exposure. Main outcome measures included doctor-diagnosed ASDs reported by mothers using questionnaires in midchildhood and early adolescence.

Results: The cumulative incidence of ASDs was 3.4%. Maternal prepregnancy BMI (per 5 points) was positively associated with ASDs in a logistic regression model adjusted for maternal race/ethnicity, education, smoking status and child sex (adjusted odds ratio [OR] 1.38; 95% CI, 1.06-1.79). Higher second-trimester adiponectin was associated with lower odds of ASD in offspring (unadjusted OR 0.49; 95% CI, 0.30-0.78; and OR 0.54; 95% CI, 0.32-0.91 after adjusting for maternal race/ethnicity, education, child sex, OR 0.55; 95% CI, 0.33-0.93 after adjusting for BMI, gestational weight gain, gestational diabetes, and smoking status). Maternal leptin and cord blood leptin and adiponectin levels were not associated with ASDs.

Conclusion: Prepregnancy BMI and adiponectin during pregnancy may be useful as a tool to monitor the risk of autism. Increasing adiponectin levels prenatally may play a role in the prevention of ASDs.
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http://dx.doi.org/10.1210/clinem/dgab378DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8475238PMC
September 2021

Long-term statin treatment for hepatic fibrosis in patients with nonalcoholic fatty liver disease: Is it time to give the emperor a statin robe?

Metabolism 2021 08 11;121:154796. Epub 2021 May 11.

Section of Endocrinology, Boston VA Healthcare System and Harvard Medical School, Boston, MA, USA; Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. Electronic address:

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http://dx.doi.org/10.1016/j.metabol.2021.154796DOI Listing
August 2021

Addressing the epidemic of fatty liver disease: A call to action, a call to collaboration, a call to moving the field forward.

Metabolism 2021 09 24;122:154781. Epub 2021 Apr 24.

Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA; Department of Medicine, Boston VA Healthcare System, Boston, MA, USA. Electronic address:

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http://dx.doi.org/10.1016/j.metabol.2021.154781DOI Listing
September 2021

Elafibranor and liraglutide improve differentially liver health and metabolism in a mouse model of non-alcoholic steatohepatitis.

Liver Int 2021 08 21;41(8):1853-1866. Epub 2021 Apr 21.

Department of Medicine, Boston VA Healthcare System and Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.

Background & Aims: This study aimed to assess and compare the effects of the GLP-1 analog liraglutide and the PPARα/δ agonist elafibranor on liver histology and their impact on hepatic lipidome, metabolome, Kupffer and hepatic stellate cell activation in a model of advanced non-alcoholic fatty liver disease (NAFLD).

Methods: Male C57BL/6JRj mice with biopsy-confirmed hepatosteatosis and fibrosis induced by 36-week Amylin liver NASH (AMLN) diet (high-fat, fructose and cholesterol) were randomized to receive for 12 weeks: (a) liraglutide (0.4 mg/kg/day s.c.), (b) elafibranor (30 mg/kg/day p.o.) and (c) vehicle. Metabolic status, liver pathology, markers of inflammation, Kupffer and stellate cell activation, and metabolomics/lipidomics were assessed at study completion.

Results: Elafibranor and liraglutide improved weight, insulin sensitivity, glucose homeostasis and NAFLD activity score (pre-to-post biopsy). Elafibranor had a profound effect on hepatic lipidome, demonstrated by reductions in glycerides, increases in phospholipids, and by beneficial regulation of mediators of fatty acid oxidation, inflammation and oxidative stress. Liraglutide had a major impact on inflammatory and fibrogenic markers of Kupffer and hepatic stellate cell activation (Galectin-3, Collagen type I alpha 1, alpha-smooth muscle actin). Liraglutide exerted beneficial effects on bile acid and carbohydrate metabolism, demonstrated by restorations of the concentrations of bile acids, glycogen metabolism by-products and pentoses, thus facilitating glycogen utilization turnover and nucleic acid formation.

Conclusions: Liraglutide and elafibranor robustly but through different pathways improve overall metabolic health and liver status in NAFLD. These data indicate important differences in the respective mechanisms of action and support the notion for their evaluation as combination therapies in the future.
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http://dx.doi.org/10.1111/liv.14888DOI Listing
August 2021

COVID-19 editorial: mechanistic links and therapeutic challenges for metabolic diseases one year into the COVID-19 pandemic.

Metabolism 2021 06 26;119:154769. Epub 2021 Mar 26.

Section of Endocrinology, VA Boston Healthcare System and Harvard Medical School, Boston, MA, USA. Electronic address:

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http://dx.doi.org/10.1016/j.metabol.2021.154769DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7997260PMC
June 2021

Diabetes type 1: Can it be treated as an autoimmune disorder?

Rev Endocr Metab Disord 2021 Mar 17. Epub 2021 Mar 17.

Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias, 11527, Athens, Goudi, Greece.

Type 1 Diabetes Mellitus (T1DM) is characterized by progressive autoimmune-mediated destruction of the pancreatic beta-cells leading to insulin deficiency and hyperglycemia. It is associated with significant treatment burden and necessitates life-long insulin therapy. The role of immunotherapy in the prevention and management of T1DM is an evolving area of interest which has the potential to alter the natural history of this disease.In this review, we give insight into recent clinical trials related to the use of immunotherapeutic approaches for T1DM, such as proinflammatory cytokine inhibition, cell-depletion and cell-therapy approaches, autoantigen-specific treatments and stem cell therapies. We highlight the timing of intervention, aspects of therapy including adverse effects and the emergence of a novel lymphocyte crucial in T1DM autoimmunity. We also discuss the role of cardiac autoimmunity and its link to excess CVD risk in T1DM.We conclude that significant advances have been made in development of immunotherapeutic targets and agents for the treatment and prevention of T1DM. These immune-based therapies promise preservation of beta-cells and decreasing insulin dependency. In their current state, immunotherapeutic approaches cannot yet halt the progression from a preclinical state to overt T1DM nor can they replace standard insulin therapy in existing T1DM. It remains to be seen whether immunotherapy will ultimately play a key role in the prevention of progression to overt T1DM and whether it may find a place in our therapeutic armamentarium to improve clinical outcomes and quality of life in established T1DM.
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http://dx.doi.org/10.1007/s11154-021-09642-4DOI Listing
March 2021

Vitamin D Status Is Associated With In-Hospital Mortality and Mechanical Ventilation: A Cohort of COVID-19 Hospitalized Patients.

Mayo Clin Proc 2021 04 9;96(4):875-886. Epub 2021 Jan 9.

Department of Medicine, Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, MA; Section of Endocrinology, VA Boston Healthcare System, Harvard Medical School, Boston, MA. Electronic address:

Objective: To explore the possible associations of serum 25-hydroxyvitamin D [25(OH)D] concentration with coronavirus disease 2019 (COVID-19) in-hospital mortality and need for invasive mechanical ventilation.

Patients And Methods: A retrospective, observational, cohort study was conducted at 2 tertiary academic medical centers in Boston and New York. Eligible participants were hospitalized adult patients with laboratory-confirmed COVID-19 between February 1, 2020, and May 15, 2020. Demographic and clinical characteristics, comorbidities, medications, and disease-related outcomes were extracted from electronic medical records.

Results: The final analysis included 144 patients with confirmed COVID-19 (median age, 66 years; 64 [44.4%] male). Overall mortality was 18%, whereas patients with 25(OH)D levels of 30 ng/mL (to convert to nmol/L, multiply by 2.496) and higher had lower rates of mortality compared with those with 25(OH)D levels below 30 ng/mL (9.2% vs 25.3%; P=.02). In the adjusted multivariable analyses, 25(OH)D as a continuous variable was independently significantly associated with lower in-hospital mortality (odds ratio, 0.94; 95% CI, 0.90 to 0.98; P=.007) and need for invasive mechanical ventilation (odds ratio, 0.96; 95% CI, 0.93 to 0.99; P=.01). Similar data were obtained when 25(OH)D was studied as a continuous variable after logarithm transformation and as a dichotomous (<30 ng/mL vs ≥30 ng/mL) or ordinal variable (quintiles) in the multivariable analyses.

Conclusion: Among patients admitted with laboratory-confirmed COVID-19, 25(OH)D levels were inversely associated with in-hospital mortality and the need for invasive mechanical ventilation. Further observational studies are needed to confirm these findings, and randomized clinical trials must be conducted to assess the role of vitamin D administration in improving the morbidity and mortality of COVID-19.
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http://dx.doi.org/10.1016/j.mayocp.2021.01.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7834253PMC
April 2021

Diabetes mellitus: 100 years since the discovery of insulin.

Metabolism 2021 05 18;118:154737. Epub 2021 Feb 18.

Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA; Section of Endocrinology, Boston VA Healthcare System, Harvard Medical School, Boston, MA, USA. Electronic address:

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http://dx.doi.org/10.1016/j.metabol.2021.154737DOI Listing
May 2021

Severe insulin resistance syndromes.

J Clin Invest 2021 02;131(4)

Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.

Severe insulin resistance syndromes are a heterogeneous group of rare disorders characterized by profound insulin resistance, substantial metabolic abnormalities, and a variety of clinical manifestations and complications. The etiology of these syndromes may be hereditary or acquired, due to defects in insulin potency and action, cellular responsiveness to insulin, and/or aberrations in adipose tissue function or development. Over the past decades, advances in medical technology, particularly in genomic technologies and genetic analyses, have provided insights into the underlying pathophysiological pathways and facilitated the more precise identification of several of these conditions. However, the exact cellular and molecular mechanisms of insulin resistance have not yet been fully elucidated for all syndromes. Moreover, in clinical practice, many of the syndromes are often misdiagnosed or underdiagnosed. The majority of these disorders associate with an increased risk of severe complications and mortality; thus, early identification and personalized clinical management are of the essence. This Review aims to categorize severe insulin resistance syndromes by disease process, including insulin receptor defects, signaling defects, and lipodystrophies. We also highlight several complex syndromes and emphasize the need to identify patients, investigate underlying disease mechanisms, and develop specific treatment regimens.
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http://dx.doi.org/10.1172/JCI142245DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880309PMC
February 2021

Leptin in Leanness and Obesity: JACC State-of-the-Art Review.

J Am Coll Cardiol 2021 02;77(6):745-760

Department of Medicine, Boston VA Healthcare System, Boston, Massachusetts, USA; Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA. Electronic address:

Leptin has emerged over the past 2 decades as a key hormone secreted by adipose tissue that conveys information on energy stores. Leptin is considered an important regulator of both neuroendocrine function and energy homeostasis. Numerous studies (mainly preclinical and much less in humans) have investigated the mechanisms of leptin's actions both in the healthy state as well as in a wide range of metabolic diseases. In this review, the authors present leptin physiology and review the main findings from animal studies, observational and interventional studies, and clinical trials in humans that have investigated the role of leptin in metabolism and cardiometabolic diseases (energy deficiency, obesity, diabetes, cardiovascular diseases, nonalcoholic fatty liver disease). The authors discuss the similarities and discrepancies between animal and human biology and present clinical applications of leptin, directions for future research, and current approaches for the development of the next-generation leptin analogs.
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http://dx.doi.org/10.1016/j.jacc.2020.11.069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8483570PMC
February 2021

Branched-Chain Amino Acids in relation to food preferences and insulin resistance in obese subjects consuming walnuts: A cross-over, randomized, double-blind, placebo-controlled inpatient physiology study.

Clin Nutr 2021 05 23;40(5):3032-3036. Epub 2021 Jan 23.

Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center/Harvard Medical School, 330 Brookline Avenue, SL-419, Boston, MA, 02215, USA. Electronic address:

Background&aims: To assess whether the concentrations of circulating Branched-Chain Amino Acids (BCAAs) change after walnut consumption and, whether these changes are associated with alterations in markers of insulin resistance and food preferences.

Methods: In a crossover, randomized, double-blind, placebo-controlled study, ten subjects participated in two 5-day inpatient study admissions, during which they had a smoothie containing 48 g walnuts or a macronutrient-matched placebo smoothie without nuts every morning. Between the two phases there was a 1-month washout period.

Results: Fasting valine and isoleucine levels were reduced (p = .047 and p < .001) and beta-hydroxybutyrate levels were increased after 5-days of walnut consumption compared to placebo (p = .023). Fasting valine and isoleucine correlated with HOMA-IR while on walnut (r = 0.709, p = .032 and r = 0.679, p = .044). The postprandial area under the curve (AUC) of leucine in response to the smoothie consumption on day 5 was higher after walnut vs placebo (p = .023) and correlated negatively with the percentage of Kcal from carbohydrate and protein consumed during an ad libitum buffet meal consumed the same day for lunch (r = -0.661, p = .037; r = -0.628, p = .05, respectively).

Conclusion: The fasting and postabsorptive profiles of BCAAs are differentially affected by walnut consumption. The reduction in fasting valine and isoleucine may contribute to the longer-term benefits of walnuts on insulin resistance, cardiovascular risk and mortality, whereas the increase in postabsorptive profiles with walnuts may influence food preference. TRIAL REGISTRATION CLINICALTRIALS.GOV: Number: NCT02673281, Website: https://clinicaltrials.gov/ct2/show/NCT02673281.
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http://dx.doi.org/10.1016/j.clnu.2021.01.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8172419PMC
May 2021

Adipokines and Metabolic Regulators in Human and Experimental Pulmonary Arterial Hypertension.

Int J Mol Sci 2021 Feb 1;22(3). Epub 2021 Feb 1.

Department of Pediatric Newborn Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.

Pulmonary hypertension (PH) is associated with meta-inflammation related to obesity but the role of adipose tissue in PH pathogenesis is unknown. We hypothesized that adipose tissue-derived metabolic regulators are altered in human and experimental PH. We measured circulating levels of fatty acid binding protein 4 (FABP-4), fibroblast growth factor -21 (FGF-21), adiponectin, and the mRNA levels of FABP-4, FGF-21, and peroxisome proliferator-activated receptor γ (PPARγ) in lung tissue of patients with idiopathic PH and healthy controls. We also evaluated lung and adipose tissue expression of these mediators in the three most commonly used experimental rodent models of pulmonary hypertension. Circulating levels of FABP-4, FGF-21, and adiponectin were significantly elevated in PH patients compared to controls and the mRNA levels of these regulators and PPARγ were also significantly increased in human PH lungs and in the lungs of rats with experimental PH compared to controls. These findings were coupled with increased levels of adipose tissue mRNA of genes related to glucose uptake, glycolysis, tricarboxylic acid cycle, and fatty acid oxidation in experimental PH. Our results support that metabolic alterations in human PH are recapitulated in rodent models of the disease and suggest that adipose tissue may contribute to PH pathogenesis.
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http://dx.doi.org/10.3390/ijms22031435DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867052PMC
February 2021

Integrating blood cell mechanics, platelet adhesive dynamics and coagulation cascade for modelling thrombus formation in normal and diabetic blood.

J R Soc Interface 2021 02 3;18(175):20200834. Epub 2021 Feb 3.

Division of Applied Mathematics, Brown University, Providence, RI 02912, USA.

Normal haemostasis is an important physiological mechanism that prevents excessive bleeding during trauma, whereas the pathological thrombosis especially in diabetics leads to increased incidence of heart attacks and strokes as well as peripheral vascular events. In this work, we propose a new multiscale framework that integrates seamlessly four key components of blood clotting, namely transport of coagulation factors, coagulation kinetics, blood cell mechanics and platelet adhesive dynamics, to model the development of thrombi under physiological and pathological conditions. We implement this framework to simulate platelet adhesion due to the exposure of tissue factor in a three-dimensional microchannel. Our results show that our model can simulate thrombin-mediated platelet activation in the flowing blood, resulting in platelet adhesion to the injury site of the channel wall. Furthermore, we simulate platelet adhesion in diabetic blood, and our results show that both the pathological alterations in the biomechanics of blood cells and changes in the amount of coagulation factors contribute to the excessive platelet adhesion and aggregation in diabetic blood. Taken together, this new framework can be used to probe synergistic mechanisms of thrombus formation under physiological and pathological conditions, and open new directions in modelling complex biological problems that involve several multiscale processes.
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http://dx.doi.org/10.1098/rsif.2020.0834DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8086870PMC
February 2021

Serum Follistatin Is Increased in Thyroid Cancer and Is Associated With Adverse Tumor Characteristics in Humans.

J Clin Endocrinol Metab 2021 04;106(5):e2137-e2150

Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.

Context: Obesity and classical growth factors are associated with thyroid cancer (TC). However, less is known regarding novel hormones such as follistatins and activins. We hypothesized that serum follistatin but not activins would be increased in TC.

Objective: This work aimed to assess circulating levels of follistatins, activins, and growth factors in patients with a history of TC vs patients with nonmalignant thyroid diseases.

Methods: A hospital-based, unmatched case-control study was conducted with 170 thyroidectomized patients due to well-differentiated TC and 106 thyroidectomized patients without history of malignancy. Anthropometric, biochemical, and histological parameters were recorded. Serum samples were collected in the steady state 45 days after surgery. Multivariate models were used to adjust for baseline differences of the unmatched variables. Serum levels of follistatin (FST), follistatin like-3, activin A, activin B, bioactive insulin-like growth factor-1, and stanniocalcin-2 were assayed with novel, highly specific ELISA kits.

Results: In unmatched univariate models, TC patients had higher FST serum levels compared to cancer-free individuals, independently of histological subtype. In multivariate models adjusting for covariates, individuals in the highest tertile of FST levels were associated with an increased risk for the presence of any type of TC or specific histological subtypes, including papillary, follicular and Hürthle-cell carcinoma, and medullary TC. Higher postoperative FST concentrations were found in patients with vascular invasion and distant metastases and associated with TNM staging at diagnosis.

Conclusion: FST serum levels are increased in TC patients and correlate with advanced tumor aggressiveness. Future longitudinal studies are needed to confirm and extend our observations.
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http://dx.doi.org/10.1210/clinem/dgab041DOI Listing
April 2021

Empagliflozin Attenuates Non-Alcoholic Fatty Liver Disease (NAFLD) in High Fat Diet Fed ApoE Mice by Activating Autophagy and Reducing ER Stress and Apoptosis.

Int J Mol Sci 2021 Jan 15;22(2). Epub 2021 Jan 15.

Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece.

Aims/hypothesis: SGLT-2 inhibitors (SGLT-2i) have been studied as potential treatments against NAFLD, showing varying beneficial effects. The molecular mechanisms mediating these effects have not been fully clarified. Herein, we investigated the impact of empagliflozin on NAFLD, focusing particularly on ER stress, autophagy and apoptosis.

Methods: Five-week old ApoE mice were switched from normal to a high-fat diet (HFD). After five weeks, mice were randomly allocated into a control group (HFD + vehicle) and Empa group (HFD + empagliflozin 10 mg/kg/day) for five weeks. At the end of treatment, histomorphometric analysis was performed in liver, mRNA levels of , , , , , , , , , , , , , , , , , , , , , and were measured by qRT-PCR, and protein levels of p-EIF2α, EIF2a, CHOP, LC3II, P62, BECLIN-1 and cleaved CASPASE-8 were assessed by immunoblotting.

Results: Empagliflozin-treated mice exhibited reduced fasting glucose, total cholesterol and triglyceride serum levels, as well as decreased NAFLD activity score, decreased expression of lipogenic enzymes (, and ) and inflammatory molecules ( and ), compared to the Control group. Empagliflozin significantly decreased the expression of ER stress molecules , , , , , , , and ; whilst activating autophagy via increased AMPK phosphorylation, decreased and increased expression. Finally, empagliflozin increased the ratio and inhibited CASPASE-8 cleavage, reducing liver cell apoptosis. Immunoblotting analysis confirmed the qPCR results.

Conclusion: These novel findings indicate that empagliflozin treatment for five weeks attenuates NAFLD progression in ApoE mice by promoting autophagy, reducing ER stress and inhibiting hepatic apoptosis.
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http://dx.doi.org/10.3390/ijms22020818DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7829901PMC
January 2021

Fasting oxyntomodulin, glicentin, and gastric inhibitory polypeptide levels are associated with activation of reward- and attention-related brain centres in response to visual food cues in adults with obesity: A cross-sectional functional MRI study.

Diabetes Obes Metab 2021 05 22;23(5):1202-1207. Epub 2021 Jan 22.

Division of Endocrinology, Beth Israel Deaconess Medical Centre/Harvard Medical School, Boston, Massachusetts.

Postprandial increases in gastrointestinal hormones are associated with reduced energy intake, partially through direct effects on the brain. However, it remains unknown whether the fasting levels of gastrointestinal hormones are associated with altered brain activity in response to visual food stimuli. We therefore performed a whole-brain regression cross-sectional analysis to assess the association between fasting brain activations according to functional magnetic resonance imaging, performed during viewing of highly desirable versus less desirable food images, with fasting levels of five gastrointestinal hormones (glucagon-like peptide [GLP]-1, GLP-2, oxyntomodulin, glicentin and gastric inhibitory polypeptide [GIP]) in 36 subjects with obesity. We observed that fasting blood levels of GIP were inversely associated with the activation of attention-related areas (visual cortices of the occipital lobe, parietal lobe) and of oxyntomodulin and glicentin with reward-related areas (insula, putamen, caudate for both, and additionally orbitofrontal cortex for glicentin) and the hypothalamus when viewing highly desirable as compared to less desirable food images. Future studies are needed to confirm whether fasting levels of oxyntomodulin, glicentin and GIP are associated with the activation of brain areas involved in appetite regulation and with energy intake in people with obesity.
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http://dx.doi.org/10.1111/dom.14315DOI Listing
May 2021

Commentary: Nonalcoholic or metabolic dysfunction-associated fatty liver disease? The epidemic of the 21st century in search of the most appropriate name.

Metabolism 2020 12 22;113:154413. Epub 2020 Oct 22.

Section of Endocrinology, Boston VA Healthcare System, Harvard Medical School, Boston, MA, USA; Department of Internal Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. Electronic address:

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http://dx.doi.org/10.1016/j.metabol.2020.154413DOI Listing
December 2020

The Effect of the Mediterranean Diet on Metabolic Health: A Systematic Review and Meta-Analysis of Controlled Trials in Adults.

Nutrients 2020 Oct 30;12(11). Epub 2020 Oct 30.

Division of Endocrinology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.

The Mediterranean diet (MD) may provide metabolic benefits but no systematic review to date has examined its effect on a multitude of outcomes related to metabolic health. This systematic review with meta-analysis (International Prospective Register of Systematic Reviews, PROSPERO; number CRD42019141459) aimed to examine the MD's effect on metabolic syndrome (MetSyn) incidence, components and risk factors (primary outcomes), and incidence and/or mortality from MetSyn-related comorbidities and receipt of pharmacologic treatment for MetSyn components and comorbidities (secondary outcomes). We searched Pubmed, Embase, Cumulative Index to Nursing and Allied Health Literature (CINAHL), and Web of Science for controlled trials published until June 2019, comparing the MD with no treatment, usual care, or different diets in adults. Studies not published in English and not promoting the whole MD were excluded. Two authors independently extracted data and assessed risk of bias using the Cochrane Collaboration's and Risk of Bias in non-randomised studies (ROBINS-I) tools. Reporting followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Random-effects meta-analyses, subgroup analyses and meta-regressions were performed, and heterogeneity was quantified using the I statistic. We identified 2654 reports and included 84 articles reporting 57 trials ( = 36,983). In random effects meta-analyses, the MD resulted in greater beneficial changes in 18 of 28 MetSyn components and risk factors (body weight, body mass index, waist circumference, systolic and diastolic blood pressure, glucose, insulin, homeostatic model assessment of insulin resistance (HOMA-IR) index, total-, low-density lipoprotein (LDL)- and high-density lipoprotein (HDL)-cholesterol, triglycerides, alanine transaminase, hepatic fat mass, C-reactive protein, interleukin-6, tumour necrosis factor-a, and flow-mediated dilatation) and lower risk of cardiovascular disease incidence (risk ratio (RR) = 0.61, 95% confidence intervals (CI) 0.42-0.80; I = 0%), and stroke (RR = 0.67, 95% CI 0.35-0.98; I = 0%). Only six studies reported effects on pharmacotherapy use, and pooled analysis indicated no differences between diet groups. Lack of consistency in comparator groups and other study characteristics across studies resulted in high heterogeneity for some outcomes, which could not be considerably explained by meta-regressions. However, a consistent direction of beneficial effect of the MD was observed for the vast majority of outcomes examined. Findings support MD's beneficial effect on all components and most risk factors of the MetSyn, in addition to cardiovascular disease and stroke incidence. More studies are needed to establish effects on other clinical outcomes and use of pharmacotherapy for MetSyn components and comorbidities. Despite the high levels of heterogeneity for some outcomes, this meta-analysis enabled the comparison of findings across studies and the examination of consistency of effects. The consistent direction of effect, suggesting the MD's benefits on metabolic health, supports the need to promote this dietary pattern to adult populations.
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http://dx.doi.org/10.3390/nu12113342DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692768PMC
October 2020

Effect of the glucagon-like peptide-1 analogue liraglutide versus placebo treatment on circulating proglucagon-derived peptides that mediate improvements in body weight, insulin secretion and action: A randomized controlled trial.

Diabetes Obes Metab 2021 02 19;23(2):489-498. Epub 2020 Nov 19.

Department of Medicine, Boston VA Healthcare System and Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.

Aim: To examine how circulating glucagon-like peptide-1 (GLP-1) concentrations during liraglutide treatment relate to its therapeutic actions on glucose and weight, and to study the effects of liraglutide on other proglucagon-derived peptides (PGDPs), including endogenous GLP-1, glucagon-like peptide-2, glucagon, oxyntomodulin, glicentin and major proglucagon fragment, which also regulate metabolic and weight control.

Materials And Methods: Adults who were overweight/obese (body mass index 27-40 kg/m ) with prediabetes were randomized to liraglutide (1.8 mg/day) versus placebo for 14 weeks. We used specific assays to measure exogenous (liraglutide, GLP-1 agonist [GLP-1A]) and endogenous (GLP-1E) GLP-1, alongside five other PGDP concentrations during a mixed meal tolerance test (MMTT) completed at baseline and at week 14 (liraglutide, n = 16; placebo, n = 19). Glucose during MMTT, steady-state plasma glucose (SSPG) concentration for insulin resistance and insulin secretion rate (ISR) were previously measured. MMTT area-under-the-curve (AUC) was calculated for ISR, glucose and levels of PGDPs.

Results: Participants on liraglutide versus placebo had significantly (P ≤ .004) decreased weight (mean -3.6%, 95% CI [-5.2% to -2.1%]), SSPG (-32% [-43% to -22%]) and glucose AUC (-7.0% [-11.5% to -2.5%]) and increased ISR AUC (30% [16% to 44%]). GLP-1A AUC at study end was significantly (P ≤ .04) linearly associated with % decrease in weight (r = -0.54) and SSPG (r = -0.59) and increase in ISR AUC (r = 0.51) in the liraglutide group. Treatment with liraglutide significantly (P ≤ .005) increased exogenous GLP-1A AUC (median 310 vs. 262 pg/mL × 8 hours at baseline but decreased endogenous GLP-1E AUC [13.1 vs. 24.2 pmol/L × 8 hours at baseline]), as well as the five other PGDPs. Decreases in the PGDPs processed in the intestines are independent of weight loss, indicating a probable direct effect of GLP-1 receptor agonists to decrease their endogenous production in contrast to weight loss-dependent changes in glucagon and major proglucagon fragment that are processed in pancreatic alpha cells.

Conclusions: Circulating GLP-1A concentrations, reflecting liraglutide levels, predict improvement in weight, insulin action and secretion in a linear manner. Importantly, liraglutide also downregulates other PGDPs, normalization of the levels of which may provide additional metabolic and weight loss benefits in the future.
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http://dx.doi.org/10.1111/dom.14242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7856054PMC
February 2021

Mediterranean diet as a nutritional approach for COVID-19.

Metabolism 2021 01 17;114:154407. Epub 2020 Oct 17.

Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Section of Endocrinology, VA Boston Healthcare System, Harvard Medical School, Boston, MA 02115, USA. Electronic address:

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http://dx.doi.org/10.1016/j.metabol.2020.154407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7833284PMC
January 2021
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