Initial evidence that GLP-1 receptor blockade fails to suppress postprandial satiety or promote food intake in humans.

Glucagon-like peptide 1 (GLP-1) has incretin effects that are well-documented, but the independent role of GLP-1 action in human satiety perception is debated. We hypothesized that blockade of GLP-1 receptors would suppress postprandial satiety and increase voluntary food intake. After an overnight fast, eight normal weight participants (seven men, BMI 19-24.7 kg/m(2), age 19-29 year) were enrolled in a double-blind, placebo-controlled, randomized crossover study of the GLP-1 antagonist Exendin-[9-39] (Ex-9) to determine if the satiating effects of a meal are dependent on GLP-1 signaling in humans. Following a fasting blood draw, iv infusion of Ex-9 (600-750 pmol/kg/min) or saline began. Thirty minutes later, subjects consumed a standardized breakfast followed 90 min later (at the predicted time of maximal endogenous circulating GLP-1) by an ad libitum buffet meal to objectively measure satiety. Infusions ended once the buffet meal was complete. Visual analog scale ratings of hunger and fullness and serial assessments of plasma glucose, insulin, and GLP-1 concentrations were done throughout the experiment. Contrary to the hypothesis, during Ex-9 infusion subjects reported a greater decrease in hunger due to consumption of the breakfast (Ex-9 -62 ± 5; placebo -41 ± 9; P=0.01) than during placebo. There were no differences in ad libitum caloric intake between Ex-9 and placebo. Ex-9 increased glucose, insulin, and endogenous GLP-1, which may have counteracted any effects of Ex-9 infusion to block satiety signaling. Blockade of GLP-1 receptors failed to suppress subjective satiety following a standardized meal or increase voluntary food intake in healthy, normal-weight subjects.

Impact of Students' Scheduling Choice on Clerkship Examination Score Performance in a Time-Varying Competency-Based Curriculum.

PURPOSE: Standardized end-of-clerkship examinations typically occur on the last day of the clerkship. However, recent trends toward time-varying competency-based medical education have offered students more test scheduling flexibility, creating an opportunity to study the impact of student-selected examination timing. METHOD: Starting with the graduating class of 2018, students took the required standardized end-of-core clerkship examinations at any available time they chose during their clinical years. Before this change, these examinations were administered to all students on the last day of the clerkship. Students' examination dates relative to clerkship completion were analyzed between 2017 and 2020 (inclusive of before and after flexible exam timing) to assess the impact that student-selected exam timing had on test performance on National Board of Medical Examiners shelf clinical science examinations for required core clerkships. RESULTS: Data on 146 medical students in 2017 (fixed exam timing) and 466 medical students between 2018 and 2020 (flexible exam timing) were included. Among students offered flexible exam timing, between 2.7% (internal medicine) and 14.6% (psychiatry) took their exam before actually taking clerkship, while between 22.7% (psychiatry) and 40.0% (surgery) took their exam more than 90 days after the clerkship ended. Exam scores were statistically higher for those who took the exam at a time of their choosing compared with those who were required to take it at the end of individual rotations and when the exam scores were combined (fixed exam timing mean = 73.9, standard deviation [SD] = 7.8; flexible exam timing mean = 77.4, SD = 6.0, P < .001). The percent of students with passing scores was statistically higher in internal medicine, pediatrics, and psychiatry. CONCLUSIONS: Self-selection of shelf exam timing appears to increase shelf exam scores. As more medical schools transition to competency-based medical education, providing scheduling flexibility appears not to negatively affect student achievement.

Effects of Levothyroxine Replacement or Suppressive Therapy on Energy Expenditure and Body Composition.

BACKGROUND: Thyrotropin (TSH)-suppressive doses of levothyroxine (LT4) have adverse effects on bone and cardiac function, but it is unclear whether metabolic function is also affected. The objective of this study was to determine whether women receiving TSH-suppressive LT4 doses have alterations in energy expenditure or body composition. METHODS: This study was a cross-sectional comparison between three groups of women: 26 women receiving chronic TSH-suppressive LT4 doses, 80 women receiving chronic replacement LT4 doses, and 16 untreated euthyroid control women. Subjects underwent measurements of resting energy expenditure (REE), substrate oxidation, and thermic effect of food by indirect calorimetry; physical activity energy expenditure by accelerometer; caloric intake by 24-hour diet recall; and body composition by dual X-ray absorptiometry. RESULTS: REE per kilogram lean body mass in the LT4 euthyroid women was 6% lower than that of the LT4-suppressed group, and 4% lower than that of the healthy control group (p = 0.04). Free triiodothyronine (fT3) levels were directly correlated with REE, and were 10% lower in the LT4 euthyroid women compared with the other two groups (p = 0.007). The groups of subjects did not differ in other measures of energy expenditure, caloric intake, or body composition. CONCLUSIONS: LT4 suppression therapy does not adversely affect energy expenditure or body composition in women. However, LT4 replacement therapy is associated with a lower REE, despite TSH levels within the reference range. This may be due to lower fT3 levels, suggesting relative tissue hypothyroidism may contribute to impaired energy expenditure in LT4 therapy.

Effect of Thyroid Function Variations Within the Laboratory Reference Range on Health Status, Mood, and Cognition in Levothyroxine-Treated Subjects.

BACKGROUND: There has been recent debate within the thyroid field regarding whether current upper limits of the thyrotropin (TSH) reference range should be lowered. This debate can be better informed by investigation of whether variations in thyroid function within the reference range have clinical effects. One important target organ for thyroid hormone is the brain, but little is known about variations in neurocognitive measures within the reference range for thyroid function. METHODS: This was a cross-sectional study of 132 otherwise healthy hypothyroid subjects receiving chronic replacement therapy with levothyroxine (LT4) who had TSH levels across the full span of the laboratory reference range (0.34-5.6 mU/L). Subjects underwent detailed tests of health status, mood, and cognitive function, with an emphasis on memory and executive functions. RESULTS: Subjects with low-normal (≤2.5 mU/L) and high-normal (>2.5 mU/L) TSH levels did not differ on most tests of health status, mood, or cognitive function, and there were no correlations between TSH, free T4, or free T3 levels and most outcomes. There was, however, a suggestion that thyroid function affected performance on the Iowa Gambling Task, which mimics real life decision-making. Subjects with low-normal TSH levels made more advantageous decisions than those with high-normal TSH levels. CONCLUSIONS: Variations in thyroid function within the laboratory reference range do not appear to have clinically relevant effects on health status, mood, or memory in LT4 treated subjects. However, decision making, which encompasses many executive functions, may be affected. Unless further studies strengthen this finding, these data do not support narrowing the TSH reference range.

The effects of levothyroxine replacement or suppressive therapy on health status, mood, and cognition.

CONTEXT: TSH-suppressive doses of levothyroxine (L-T4) have adverse effects on bone and cardiac function, but it is unclear whether central nervous system function is also affected. OBJECTIVE: The aim of the study was to determine whether women receiving TSH-suppressive L-T4 doses have decrements in health status, mood, or cognitive function. DESIGN AND SETTING: A cross-sectional comparison was made among three groups of women in an academic medical center research clinic. PATIENTS: Twenty-four women receiving chronic TSH-suppressive L-T4 doses, 35 women receiving chronic replacement L-T4 doses, and 20 untreated control women participated in the study. INTERVENTIONS: Subjects underwent testing at a single outpatient visit. MAIN OUTCOME MEASURES: We measured health status (SF-36), mood (Profile of Mood States, Symptom Checklist 90-R, Affective Lability Scale), and cognitive function (declarative memory [Paragraph Recall], working memory [N-back, Subject Ordered Pointing], motor learning [Pursuit Rotor, Motor Sequence Learning Test], and executive function [Letter Cancellation Test, Trail Making Test, Iowa Gambling Test]). RESULTS: Women receiving TSH-suppressive or replacement L-T4 doses had decrements in health status and mood compared to healthy controls. These decrements were more pronounced in women receiving replacement, rather than suppressive, L-T4 doses. Memory and executive function were not affected in either treated group, compared to healthy controls. CONCLUSIONS: Women receiving TSH-suppressive doses of L-T4 do not have central nervous system dysfunction due to exogenous subclinical thyrotoxicosis, but TSH-suppressed and L-T4-replaced women have slight decrements in health status and mood that may be related to self-knowledge of the presence of a thyroid condition or other uncharacterized factors. These mood alterations do not impair cognitive function.

Change in postprandial substrate oxidation after a high-fructose meal is related to body mass index in healthy men.

Oral fructose decreases fat oxidation and increases carbohydrate oxidation in obese subjects, but the metabolic response to fructose in lean individuals is less well understood. The purpose of this study was to assess the effects of a single fructose-rich mixed meal on substrate oxidation in young healthy nonobese men. We hypothesized that a decrease in fat oxidation and an increase in carbohydrate oxidation would be observed after a fructose-rich mixed meal compared with a glucose-rich mixed meal. Twelve healthy, normal weight to overweight, aged 23 to 31 years participated in a double-blind, crossover study. Each participant completed 2 study visits, eating a mixed meal containing 30% of the calories from either fructose or glucose. Blood samples for glucose, insulin, triglycerides, and leptin as well as gas exchange by indirect calorimetry were measured intermittently for 7 hours. Serum insulin was higher after a fructose mixed meal, but plasma glucose, plasma leptin, and serum triglycerides were not different. Mean postprandial respiratory quotient and estimated fat oxidation did not differ between the fructose and glucose meals. The change in fat oxidation between the fructose- and glucose-rich meals negatively correlated with body mass index (BMI; r = -0.59 [P = .04] and r = -0.59 [P = .04] at the 4- and 7-hour time points, respectively). In healthy nonobese men, BMI correlates with altered postprandial fat oxidation after a high-fructose mixed meal. The metabolic response to a high-fructose meal may be modulated by BMI.

Regional brain response to visual food cues is a marker of satiety that predicts food choice.

BACKGROUND: Neuronal processes that underlie the subjective experience of satiety after a meal are not well defined. OBJECTIVE: We investigated how satiety alters the perception of and neural response to visual food cues. DESIGN: Normal-weight participants (10 men, 13 women) underwent 2 fMRI scans while viewing images of high-calorie food that was previously rated as incompatible with weight loss and "fattening" and low-calorie, "nonfattening" food. After a fasting fMRI scan, participants ate a standardized breakfast and underwent reimaging at a randomly assigned time 15-300 min after breakfast to vary the degree of satiety. Measures of subjective appetite, food appeal, and ad libitum food intake (measured after the second fMRI scan) were correlated with activation by "fattening" (compared with "nonfattening") food cues in a priori regions of interest. RESULTS: Greater hunger correlated with higher appeal ratings of "fattening" (r = 0.46, P = 0.03) but not "nonfattening" (r = -0.20, P = 0.37) foods. Fasting amygdalar activation was negatively associated with fullness (left: r = -0.52; right: r = -0.58; both P ≤ 0.01), whereas postbreakfast fullness was positively correlated with activation in the dorsal striatum (right: r = 0.44; left: r = 0.45; both P < 0.05). After breakfast, participants with greater activation in 4 regions-medial orbital frontal cortex (r = 0.49, P < 0.05), left amygdala (r = 0.49, P < 0.05), left insula (r = 0.47, P < 0.05), and nucleus accumbens (right: r = 0.57, P < 0.01; left: r = 0.43, P < 0.05)-chose buffet foods with higher fat content. CONCLUSIONS: Postmeal satiety is shown in regional brain activation by images of high-calorie foods. Regions including the amygdala, nucleus accumbens, and dorsal striatum may alter perception of, and reduce motivation to consume, energy-rich foods, ultimately driving food choice. This trial was registered at clinicaltrials.gov as NCT01631045.