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Objective: The objective of this study was to explore how dietary macronutrient composition influences postprandial appetite hormone responses and subsequent energy intake. Methods: A total of 20 adults (mean [SEM], age 30 [1] years, BMI 27.8 [1.3] kg/m2, n = 8 with normal weight, n = 6 with overweight, n = 6 with obesity) consumed a low‐fat (LF) diet (10% fat, 75% carbohydrate) and a low‐carbohydrate (LC) diet (10% carbohydrate, 75% fat) for 2 weeks each in an inpatient randomized crossover design. At the end of each diet, participants consumed isocaloric macronutrient‐representative breakfast test meals, and 6‐h postprandial responses were measured. Ad libitum energy intake was measured for the rest of the day. Results: The LC meal resulted in greater mean postprandial plasma active glucagon‐like peptide‐1 (GLP‐1; LC: 6.44 [0.78] pg/mL, LF: 2.46 [0.26] pg/mL; p < 0.0001), total glucose‐dependent insulinotropic polypeptide (GIP; LC: 578 [60] pg/mL, LF: 319 [37] pg/mL; p = 0.0004), and peptide YY (PYY; LC: 65.6 [5.6] pg/mL, LF: 50.7 [3.8] pg/mL; p = 0.02), whereas total ghrelin (LC: 184 [25] pg/mL, LF: 261 [47] pg/mL; p = 0.0009), active ghrelin (LC: 91 [9] pg/mL, LF: 232 [28] pg/mL; p < 0.0001), and leptin (LC: 26.9 [6.5] ng/mL, LF: 35.2 [7.5] ng/mL; p = 0.01) were lower compared with LF. Participants ate more during LC at lunch (244 [85] kcal; p = 0.01) and dinner (193 [86] kcal; p = 0.04), increasing total subsequent energy intake for the day compared with LF (551 [103] kcal; p < 0.0001). Conclusions: In the short term, endogenous gut‐derived appetite hormones do not necessarily determine ad libitum energy intake. [ABSTRACT FROM AUTHOR]

Objective Elevated rates of gluconeogenesis are an early pathogenic feature of youth-onset type 2 diabetes (Y-T2D), but targeted first-line therapies are suboptimal, especially in African American (AA) youth. We evaluated glucose-lowering mechanisms of metformin and liraglutide by measuring rates of gluconeogenesis and β-cell function after therapy in AA Y-T2D. Methods In this parallel randomized clinical trial, 22 youth with Y-T2D—age 15.3 ± 2.1 years (mean ± SD), 68% female, body mass index (BMI) 40.1 ± 7.9 kg/m2, duration of diagnosis 1.8 ± 1.3 years—were randomized to metformin alone (Met) or metformin + liraglutide (Lira) (Met + Lira) and evaluated before and after 12 weeks. Stable isotope tracers were used to measure gluconeogenesis [2H2O] and glucose production [6,6-2H2]glucose after an overnight fast and during a continuous meal. β-cell function (sigma) and whole-body insulin sensitivity (mSI) were assessed during a frequently sampled 2-hour oral glucose tolerance test. Results At baseline, gluconeogenesis, glucose production, and fasting and 2-hour glucose were comparable in both groups, though Met + Lira had higher hemoglobin A1C. Met + Lira had a greater decrease from baseline in fasting glucose (−2.0 ± 1.3 vs −0.6 ± 0.9 mmol/L, P =.008) and a greater increase in sigma (0.72 ± 0.68 vs −0.05 ± 0.71, P =.03). The change in fractional gluconeogenesis was similar between groups (Met + Lira: −0.36 ± 9.4 vs Met: 0.04 ± 12.3%, P =.9), and there were no changes in prandial gluconeogenesis or mSI. Increased glucose clearance in both groups was related to sigma (r = 0.63, P =.003) but not gluconeogenesis or mSI. Conclusion Among Y-T2D, metformin with or without liraglutide improved glycemia but did not suppress high rates of gluconeogenesis. Novel therapies that will enhance β-cell function and target the elevated rates of gluconeogenesis in Y-T2D are needed. [ABSTRACT FROM AUTHOR]

BACKGROUND. Postreceptor insulin resistance (IR) is associated with hyperglycemia and hepatic steatosis. However, receptor-level IR (e.g., insulin receptor pathogenic variants, INSR) causes hyperglycemia without steatosis. We examined 4 pathologic conditions of IR in humans to examine pathways controlling lipid metabolism and gluconeogenesis. METHODS. Cross-sectional study of severe receptor IR (INSR, n = 7) versus postreceptor IR that was severe (lipodystrophy, n = 14), moderate (type 2 diabetes, n = 9), or mild (obesity, n = 8). Lipolysis (glycerol turnover), hepatic glucose production (HGP), gluconeogenesis (deuterium incorporation from body water into glucose), hepatic triglyceride (magnetic resonance spectroscopy), and hepatic fat oxidation (plasma [beta]-hydroxybutyrate) were measured. RESULTS. Lipolysis was 2- to 3-fold higher in INSR versus all other groups, and HGP was 2-fold higher in INSR and lipodystrophy versus type 2 diabetes and obesity (P < 0.001), suggesting severe adipose and hepatic IR. INSR subjects had a higher contribution of gluconeogenesis to HGP, approximately 77%, versus 52% to 59% in other groups (P = 0.0001). Despite high lipolysis, INSR subjects had low hepatic triglycerides (0.5% [interquartile range 0.1%-0.5%]), in contrast to lipodystrophy (10.6% [interquartile range 2.8%-17.1%], P < 0.0001). [beta]-hydroxybutyrate was 2- to 7-fold higher in INSR versus all other groups (P < 0.0001), consistent with higher hepatic fat oxidation. CONCLUSION. These data support a key pathogenic role of adipose tissue IR to increase glycerol and FFA availability to the liver in both receptor and postreceptor IR. However, the fate of FFA diverges in these populations. In receptor-level IR, FFA oxidation drives gluconeogenesis rather than being reesterified to triglyceride. In contrast, in postreceptor IR, FFA contributes to both gluconeogenesis and hepatic steatosis. TRIAL REGISTRATION. ClinicalTrials.gov NCT01778556, NCT00001987, and NCT02457897. FUNDING. National Institute of Diabetes and Digestive and Kidney Diseases, US Department of Agriculture/Agricultural Research Service 58-3092-5-001., Introduction Insulin is a hormone that signals the fed state, promoting a switch from net glucose production to net glucose uptake and shifting lipids from lipid metabolism to lipid storage. [...]

BACKGROUND. Mirabegron is a [beta]3-adrenergic receptor ([beta]3-AR) agonist approved only for the treatment of overactive bladder. Encouraging preclinical results suggest that [beta]3-AR agonists could also improve obesity-related metabolic disease by increasing brown adipose tissue (BAT) thermogenesis, white adipose tissue (WAT) lipolysis, and insulin sensitivity. METHODS. We treated 14 healthy women of diverse ethnicities (27.5 [+ or -] 1.1 years of age, BMI of 25.4 [+ or -] 1.2 kg/[m.sup.2]) with 100 mg mirabegron (Myrbetriq extended-release tablet, Astellas Pharma) for 4 weeks in an open-label study. The primary endpoint was the change in BAT metabolic activity as measured by [[sup.18]F]-2-fluoro -D-2-deoxy-D-glucose ([sup.18]F-FDG) PET/CT. Secondary endpoints included resting energy expenditure (REE), plasma metabolites, and glucose and insulin metabolism as assessed by a frequently sampled intravenous glucose tolerance test. RESULTS. Chronic mirabegron therapy increased BAT metabolic activity. Whole-body REE was higher, without changes in body weight or composition. Additionally, there were elevations in plasma levels of the beneficial lipoprotein biomarkers HDL and ApoA1, as well as total bile acids. Adiponectin, a WAT-derived hormone that has antidiabetic and antiinflammatory capabilities, increased with acute treatment and was 35% higher upon completion of the study. Finally, an intravenous glucose tolerance test revealed higher insulin sensitivity, glucose effectiveness, and insulin secretion. CONCLUSION. These findings indicate that human BAT metabolic activity can be increased after chronic pharmacological stimulation with mirabegron and support the investigation of [beta]3-AR agonists as a treatment for metabolic disease. TRIAL REGISTRATION. Clinicaltrials.gov NCT03049462. FUNDING. This work was supported by grants from the Intramural Research Program of the NIDDK, NIH (DK075112, DK075116, DK071013, and DK071014)., Introduction The rising rates of obesity are a global health epidemic. In the US alone, by 2030 it is predicted that 86% of adults will be overweight or obese (1). [...]

Direct evidence in humans for the impact of the microbiome on nutrient absorption is lacking. We conducted an extended inpatient study using two interventions that we hypothesized would alter the gut microbiome and nutrient absorption. In each, stool calorie loss, a direct proxy of nutrient absorption, was measured. The first phase was a randomized cross-over dietary intervention in which all participants underwent in random order 3 d of over- and underfeeding. The second was a randomized, double-blind, placebo-controlled pharmacologic intervention using oral vancomycin or matching placebo ((https://clinicaltrials.gov/ct2/show/NCT02037295)). Twenty-seven volunteers (17 men and 10 women, age 35.1 [plus or minus] 7.3, BMI 32.3 [plus or minus] 8.0), who were healthy other than having impaired glucose tolerance and obesity, were enrolled and 25 completed the entire trial. The primary endpoints were the effects of dietary and pharmacological intervention on stool calorie loss. We hypothesized that stool calories expressed as percentage of caloric intake would increase with underfeeding compared with overfeeding and increase during oral vancomycin treatment. Both primary endpoints were met. Greater stool calorie loss was observed during underfeeding relative to overfeeding and during vancomycin treatment compared with placebo. Key secondary endpoints were to evaluate the changes in gut microbial community structure as evidenced by amplicon sequencing and metagenomics. We observed only a modest perturbation of gut microbial community structure with under- versus overfeeding but a more widespread change in community structure with reduced diversity with oral vancomycin. Increase in Akkermansia muciniphila was common to both interventions that resulted in greater stool calorie loss. These results indicate that nutrient absorption is sensitive to environmental perturbations and support the translational relevance of preclinical models demonstrating a possible causal role for the gut microbiome in dietary energy harvest. A proof-of-concept clinical study shows that perturbations to the gut microbiome affect nutrient absorption in humans., Author(s): Alessio Basolo [sup.1] , Maximilian Hohenadel [sup.1] , Qi Yan Ang [sup.2] , Paolo Piaggi [sup.1] , Sascha Heinitz [sup.1] [sup.3] [sup.4] , Mary Walter [sup.5] , Peter Walter [...]

Context Childhood overnutrition is associated with increased growth and bone mineral density (BMD) vs the opposite for undernutrition. The role of insulin receptor (InsR) signaling in these phenotypes is unclear. Rare disease patients with hyperinsulinemia and impaired InsR function (homozygous [−/−] or heterozygous [+/−] INSR pathogenic variants, type B insulin resistance [TBIR]) model increased InsR signaling, while patients with intact InsR function (congenital generalized lipodystrophy, CGL) model decreased InsR signaling. Objective This work aimed to understand mechanisms whereby InsR signaling influences growth. Methods A cross-sectional comparison was conducted of CGL (N = 23), INSR −/− (N = 13), INSR +/− (N = 17), and TBIR (N = 8) at the National Institutes of Health. Main outcome measures included SD scores (SDS) for height, body mass index, insulin-like growth factor (IGF)-1, and BMD, and IGF binding proteins (IGFBP)-1 and -3. Results INSR -/− vs CGL had higher insulin (median 266 [222-457] vs 33 [15-55] mcU/mL), higher IGFBP-1 (72 350 [55 571-103 107] vs 6453 [1634-26 674] pg/mL), lower BMI SDS (−0.7 ± 1.1 vs 0.5 ± 0.9), lower height SDS (−1.9[−4.3 to −1.3] vs 1.1 [0.5-2.5]), lower BMD SDS (−1.9 ± 1.4 vs 1.9 ± 0.7), and lower IGFBP-3 (0.37 [0.19-1.05] vs 2.00 [1.45-2.67] μg/mL) (P <.05 for all). INSR +/− were variable. Remission of TBIR lowered insulin and IGFBP-1, and increased IGF-1 and IGFBP-3 (P <.05). Conclusion Patients with hyperinsulinemia and impaired InsR function exhibit impaired growth and lower BMD, whereas elevated InsR signaling (CGL) causes accelerated growth and higher BMD. These patients demonstrate that insulin action through the InsR stimulates direct anabolic effects in bone and indirect actions through the growth hormone (GH)–IGF-1 axis. TBIR patients exhibit abnormalities in the GH axis that resolve when InsR signaling is restored, supporting a causal relationship between InsR and GH axis signaling. [ABSTRACT FROM AUTHOR]

Purpose: Patients with multiple endocrine neoplasia type 1 (MEN1) are predisposed to develop duodenopancreatic neuroendocrine tumors (dpNETs), and metastatic dpNET is the primary cause of disease-related mortality. Presently, there is a paucity of prognostic factors that can reliably identify patients with MEN1-related dpNETS who are at high risk of distant metastasis. In the current study, we aimed to establish novel circulating molecular protein signatures associated with disease progression. Experimental Design: Mass spectrometry-based proteomic profiling was conducted on plasmas procured through an international collaboration between MD Anderson Cancer Center, the National Institutes of Health, and the University Medical Center Utrecht from a cohort of 56 patients with MEN1 [14 with distant metastasis dpNETs (cases) and 42 with either indolent dpNETs or no dpNETs (controls)]. Findings were compared to proteomic profiles generated from serially collected plasmas from a mouse model of Men1-pancreatic neuroendocrine tumors (Men1fl/flPdx1-CreTg) and control mice (Men1fl/fl). Results: A total of 187 proteins were found to be elevated in MEN1 patients with distant metastasis compared to controls, including 9 proteins previously associated with pancreatic cancer and other neuronal proteins. Analyses of mouse plasmas revealed 196 proteins enriched for transcriptional targets of oncogenic MYCN, YAP1, POU5F1, and SMAD that were associated with disease progression in Men1fl/flPdx1-CreTg mice. Cross-species intersection revealed 19 proteins positively associated with disease progression in both human patients and in Men1fl/flPdx1-CreTg mice. Conclusions: Our integrated analyses identified novel circulating protein markers associated with disease progression in MEN1-related dpNET. [ABSTRACT FROM AUTHOR]

BACKGROUND. Recombinant leptin (metreleptin) ameliorates hyperphagia and metabolic abnormalities in leptin-deficient humans with lipodystrophy. We aimed to determine whether metreleptin improves glucose and lipid metabolism in humans when food intake is held constant. METHODS. Patients with lipodystrophy were hospitalized for 19 days, with food intake held constant by a controlled diet in an inpatient metabolic ward. In a nonrandomized, crossover design, patients previously treated with metreleptin (n = 8) were continued on metreleptin for 5 days and then taken off metreleptin for the next 14 days (withdrawal cohort). This order was reversed in metreleptin-naive patients (n = 14), who were reevaluated after 6 months of metreleptin treatment on an ad libitum diet (initiation cohort). Outcome measurements included insulin sensitivity by hyperinsulinemic-euglycemic clamp, fasting glucose and triglyceride levels, lipolysis measured using isotopic tracers, and liver fat by magnetic resonance spectroscopy. RESULTS. With food intake constant, peripheral insulin sensitivity decreased by 41% after stopping metreleptin for 14 days (withdrawal cohort) and increased by 32% after treatment with metreleptin for 14 days (initiation cohort). In the initiation cohort only, metreleptin decreased fasting glucose by 11% and triglycerides by 41% and increased hepatic insulin sensitivity. Liver fat decreased from 21.8% to 18.7%. In the initiation cohort, changes in lipolysis were not independent of food intake, but after 6 months of metreleptin treatment on an ad libitum diet, lipolysis decreased by 30% (palmitate turnover) to 35% (glycerol turnover). CONCLUSION. Using lipodystrophy as a human model of leptin deficiency and replacement, we show that metreleptin improves insulin sensitivity and decreases hepatic and circulating triglycerides and that these improvements are independent of its effects on food intake. TRIAL REGISTRATION. ClinicalTrials.gov NCT01778556 FUNDING. This research was supported by the intramural research program of the NIDDK., Introduction Leptin is an adipocyte-derived hormone that signals overall body energy sufficiency (1) and acute energy balance (2). Leptin-deficient states, such as starvation or mutations in the leptin gene, lead [...]

Objective This study aimed to investigate human fetal exposure to non-nutritive sweeteners (NNS) by analyzing amniotic fluid and umbilical cord blood. Study Design Concentrations of four NNS (acesulfame-potassium [ace-K], saccharin, steviol glucuronide, and sucralose) were measured in amniotic fluid (n = 13) and cord blood samples (n = 15) using liquid chromatography-mass spectrometry. Amniotic fluid samples were obtained for research purposes at the time of term elective cesarean birth or clinically indicated third trimester amnioreduction at Mercy Hospital for Women (Melbourne, Australia). All except four women were in the fasting state. Cord blood samples were obtained from an independent cohort of newborns whose mothers were enrolled in a separate clinical trial at the National Institutes of Health. Results Ten of 13 amniotic fluid samples contained at least one NNS (ace-K, saccharin, steviol glucuronide, and/or sucralose). Maximum amniotic fluid NNS concentrations of ace-K, saccharin, steviol glucuronide, and sucralose were 78.9, 55.9, 93.5, and 30.6 ng/mL, respectively. Ace-K and saccharin were present in 100% and 80% of the cord blood samples, with maximal concentrations of 6.5 and 2.7 ng/mL, respectively. Sucralose was not detected and steviol glucuronide was not measurable in any of the cord blood samples. Conclusion Our results provide evidence of human transplacental transmission of NNS. Based on results predominantly obtained from rodent models, we speculate that NNS exposure may adversely influence the offsprings' metabolic health. Well-designed, prospective clinical trials are necessary to understand the impact of NNS intake during pregnancy on human development and long-term health. Key Points NNS consumption during pregnancy has increased in recent years. Maternal NNS intake during pregnancy is associated with preterm birth and higher infant weight gain in epidemiologic studies. In rodents, in utero NNS exposure induces metabolic abnormalities in mothers and their offspring, alters offspring gut microbiota composition, and promotes sweet taste preference in adulthood. It is presently unknown whether and to what degree maternal NNS ingestion in humans leads to direct in utero exposure. This study provides the first evidence of in utero NNS exposure in humans and highlights the urgent need to investigate clinical consequences of early life NNS exposure on metabolism, weight, taste preference, and general health. [ABSTRACT FROM AUTHOR]

The purpose of this study was to examine the executive function of 4th- to 6th-grade students in three distinctively different private school environments: a Montessori school, a classical school, and a Catholic school. Using the Behavior Rating Inventory of Executive Function, parent-teacher dyads rated the executive function of 112 students. Results indicated differences in executive function ratings according to school environment, as well as by the source of the rating, with parents tending to rate their children higher as compared to the teacher ratings. (Contains 1 table.)

Production studies have shown that speakers of languages with larger phoneme inventories expand their acoustic space relative to languages with smaller inventories [Bradlow, A. (1995). A comparative acoustic study of English and Spanish vowels. "Journal of the Acoustical Society of America," 97(3), 1916-1924; Jongman, A., Fourakis, M., & Sereno, J. (1989). The acoustic vowel space of Modern Greek and German. "Language Speech," 32, 221-248]. In this study, we investigated whether this acoustic expansion in production has a perceptual correlate, that is, whether the "perceived" distance between pairs of sounds separated by equal "acoustic" distances varies as a function of inventory size or organization. We used magnetoencephalography, specifically the mismatch field response (MMF), and compared two language groups, French and Spanish, whose vowel inventories differ in size and organization. Our results show that the MMF is sensitive to inventory size but not organization, suggesting that speakers of languages with larger inventories perceive the same sounds as less similar than speakers with smaller inventories.