Longer-term liraglutide administration at the highest dose approved for obesity increases reward-related orbitofrontal cortex activation in response to food cues: Implications for plateauing weight loss in response to anti-obesity therapies.

AIMS: GLP-1 analogs have recently risen to the forefront as effective medications for lowering weight through actions in the central nervous system (CNS). However, their actions in the CNS have not yet been studied in the human brain after longer-term administration at the highest dose approved for obesity (liraglutide 3.0 mg). MATERIALS AND METHODS: A total of 20 participants with obesity were treated with placebo and liraglutide (3.0 mg) in the context of a randomized, placebo-controlled, double-blind, cross-over trial after 5 weeks of dose escalation. Neurocognitive and neuroimaging (fMRI) responses to food cues were examined at the clinical research center of Beth Israel Deaconess Medical Center. RESULTS: While using liraglutide, patients lost more weight (placebo-subtracted -2.7%; P < .001), had decreased fasting glucose (P < .001) and showed improved cholesterol levels. In an uncontrolled analysis, brain activation in response to food images was not altered by liraglutide vs placebo. When controlled for BMI/weight, liraglutide increased activation of the right orbitofrontal cortex (OFC) in response to food cues (P < .016, corrected for multiple comparisons). CONCLUSIONS: In contrast to prior studies, we demonstrate for the first time that liraglutide treatment, administered over a longer period at the highest doses approved for obesity, does not alter brain activation in response to food cues. A counter-regulatory increase in reward-related OFC activation in response to food cues can be observed when neuroimaging data are controlled for BMI changes, indicating changes in CNS that could lead to later plateaus of weight loss. These data point to a promising focus for additional interventions which, by contributing to the CNS reward system, could provide tangible benefits in reversing the plateauing phenomenon and promoting further weight loss.

Long-term outcomes and adverse effects of teduglutide in patients with short bowel syndrome: Highlighting hyperamylasemia and hyperlipasemia.

PURPOSE: Short bowel syndrome is a malabsorptive condition that occurs due to surgical removal or a congenital absence of a significant portion of the small intestine. Patients with short bowel syndrome often rely on parenteral support for extended periods or even their entire lives. Teduglutide, a glucagon-like peptide-2 analog, has shown promising results in reducing dependency on parenteral support in these patients by promoting intestinal adaptation and enhancing nutrient absorption. However, the long-term safety of teduglutide remains a concern, particularly with respect to its potential for the development of hyperamylasemia and hyperlipasemia. METHODS: This study involved patients who received teduglutide from December 2012 to December 2022 at Boston Medical Center. We evaluated outcomes and adverse events, focusing on hyperamylasemia and hyperlipasemia, through chart review. RESULTS: Thirteen eligible patients were identified who had used teduglutide. Of these, the majority (84.6%) experienced a reduction in parenteral support. A high incidence (72.7%) of nonpathological pancreatic enzyme elevation was observed in patients treated with teduglutide. These elevations were often dose dependent and were not associated with any clinical signs of acute pancreatitis or abnormal imaging findings. CONCLUSION: This study highlights the need for further investigations into the long-term safety of teduglutide and the importance of closely monitoring amylase and lipase levels in patients undergoing treatment with teduglutide.

A Case of Abnormal Liver Function Tests in a Patient Receiving Total Parenteral Nutrition.

Hepatic dysfunction is prevalent in patients receiving total parenteral nutrition (TPN), resulting from steatosis, cholestasis, and cholecystitis. Regular assessments and monitoring of TPN patients are essential, even for clinically stable patients on long-term TPN. Furthermore, it is crucial to establish a differential diagnosis for hepatic dysfunction and investigate for other possible causes of elevated liver enzymes and underlying liver conditions. We present the case of a 56-year-old female patient with severe protein-calorie malnutrition on TPN, who exhibited significantly elevated liver enzymes during the routine periodic assessment. Subsequent investigation revealed that the patient had been taking traditional Chinese herbal medications concurrently with TPN. After discontinuing the herbal medications, the patient's liver enzymes returned to normal levels within 3 weeks.

The effect of dietary patterns on non-alcoholic fatty liver disease diagnosed by biopsy or magnetic resonance in adults: a systematic review of randomised controlled trials.

Adhering to specific dietary patterns might hold promise as a lifestyle modification treatment of non-alcoholic fatty liver disease (NAFLD). The aim of this systematic review was to examine the effect of dietary patterns on changes in hepatic fat content, liver enzymes and metabolic syndrome components. We searched Pubmed, Embase, CINAHL and Web of Science for randomised controlled trials published in English until April 2020, comparing a specific dietary pattern with no treatment, usual care, or a different diet in adults with NAFLD. Studies were included if NAFLD had been diagnosed using biopsy, magnetic resonance imaging, or proton magnetic resonance spectroscopy. Data from three trials in adults with NAFLD but without diabetes (n = 128; mean age 49.9 ±â€¯5.0 years, range 42-55 years) were included in the qualitative synthesis; across them, risk of bias was considered low, unclear and high for 33%, 38% and 29% of domains, respectively. There was moderate evidence that a low-carbohydrate, compared to a low-calorie diet (-27%, P = 0.008, one study, n = 18) and the Mediterranean, compared to a low-fat, high-carbohydrate diet (-4.4%, P = 0.030, one study, n = 12) result in greater reductions in hepatic fat content, but no such evidence was found for the Fatty Liver in Obesity dietary pattern (based on the principles of the Mediterranean diet), compared to the American Heart Association diet (-0.6%, P = 0.706, one study, n = 98). No between-group differences were reported for other outcomes across studies. A post hoc analysis, including two eligible studies assessing the effect of the Mediterranean, compared to a low-fat diet, irrespective of baseline presence of diabetes, showed strong evidence that the Mediterranean diet reduces hepatic fat content (-4.1%, 95% CI = -5.8 to -2.3, P < 0.001; I2 = 0%) and triglyceride concentrations (-16.9 mg/dL, 95% CI = -26.3 to -7.7, P < 0.001; I2 = 0%). Well-designed, adequately powered and rigorous randomised controlled trials are needed to provide robust evidence on the effect of these dietary patterns, but also other whole dietary approaches, on NAFLD progression.

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

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 I2 statistic. We identified 2654 reports and included 84 articles reporting 57 trials (n = 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; I2 = 0%), and stroke (RR = 0.67, 95% CI 0.35-0.98; I2 = 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.

Mechanism of Glucagon-Like Peptide 1 Improvements in Type 2 Diabetes Mellitus and Obesity.

PURPOSE OF REVIEW: The purpose of this review is to emphasize the pivotal role of glucagon-like peptide 1 (GLP-1) in tackling the parallel epidemics of obesity and type 2 diabetes (T2DM). RECENT FINDINGS: GLP-1-based therapies and in particular GLP-1 receptor agonists (GLP-1 RA) have proven to be effective in lowering blood glucose and decreasing weight. GLP-1 RA not only mitigate these significant medical burdens but also result in weight loss and weight loss independent factors that decrease cardiovascular disease (CVD) and microvascular complications of T2DM, such as diabetic nephropathy. GLP-1-based therapies are critical for a patient-centered approach in choosing appropriate pharmacotherapy for T2DM and obesity while also taking into consideration comorbidities, such as cardiovascular and chronic kidney diseases.

GEOFFREY HARRIS PRIZE LECTURE 2018: Novel pathways regulating neuroendocrine function, energy homeostasis and metabolism in humans.

The discovery of leptin, an adipocyte-secreted hormone, set the stage for unraveling the mechanisms dictating energy homeostasis, revealing adipose tissue as an endocrine system that regulates appetite and body weight. Fluctuating leptin levels provide molecular signals to the brain regarding available energy reserves modulating energy homeostasis and neuroendocrine response in states of leptin deficiency and to a lesser extent in hyperleptinemic states. While leptin replacement therapy fails to provide substantial benefit in common obesity, it is an effective treatment for congenital leptin deficiency and states of acquired leptin deficiency such as lipodystrophy. Current evidence suggests that regulation of eating behavior in humans is not limited to homeostatic mechanisms and that the reward, attention, memory and emotion systems are involved, participating in a complex central nervous system network. It is critical to study these systems for the treatment of typical obesity. Although progress has been made, further studies are required to unravel the physiology, pathophysiology and neurobehavioral mechanisms underlying potential treatments for weight-related problems in humans.

Pharmacotherapy of obesity: Available medications and drugs under investigation.

Obesity is a chronic disease with a continuously rising prevalence that currently affects more than half a billion people worldwide. Energy balance and appetite are highly regulated via central and peripheral mechanisms, and weight loss triggers a homeostatic response leading to weight regain. Lifestyle and behavioral modifications are the cornerstones of obesity management; however, they often fail to achieve or sustain long-term weight loss. Pharmacotherapy added onto lifestyle modifications results in an additional, albeit limited, weight reduction. Regardless, this weight reduction of 5-10% conveys multiple cardiovascular and metabolic benefits. In this review, evidence on the food and drug administration (FDA)-approved medications, i.e., orlistat, lorcaserin, phentermine/topiramate, liraglutide and naltrexone/bupropion, is summarized. Furthermore, anti-obesity agents in the pipeline for potential future therapeutic use are presented.

Six-Minute Walk Test as a Predictive Measure of Exercise Capacity in Adults with Type 2 Diabetes.

OBJECTIVE: The 6 Minute Walk Test (6MWT) is a measure that is routinely used to assess a response to treatment for cardiopulmonary diseases such as pulmonary fibrosis and congestive heart failure. The measure has never been verified as a valid measure of exercise capacity in the highly prevalent patient population of type 2 diabetes (T2DM). This study investigated the correlation between the 6MWT and graded exercise testing (GXT) in an effort to validate the 6MWT as a quality tool for assessing exercise capacity in adults with T2DM. RESEARCH DESIGN AND METHOD: This is a secondary data analysis of Program ACTIVE II, a randomized controlled trial designed to assess the effectiveness of two behavioral interventions on depression and glycemic outcomes in adults with T2DM. The correlation of 6MWT and predicted VO2 max (PVO2M) using GXT was examined in a subsample of participants at the time of study enrollment and at post-intervention. RESULTS: PVO2M showed a significant correlation with 6MWT distance both at baseline (r=0.57, p=0.014) and post-intervention (r = 0.66, p = 0.037). The regression analysis of baseline data revealed that 6MWT distance alone explained 45% (F = 13.03, p = .0024) of the variability in PVO2M. When combined with the SF-12 physical health component score (PCS), 6MWT explained 66% (F = 13.62, p < .001) of the variance in PVO2M. After adjusting for PCS, 6MWT distance explained an additional 30% variability in PVO2M. CONCLUSIONS: Findings from this study indicate that the 6MWT and predicted exercise capacity are significantly correlated. The 6MWT can be used to estimate exercise capacity in adults with T2DM.