Search

In November 2019, the NIH held the “Sensory Nutrition and Disease” workshop to challenge multidisciplinary researchers working at the interface of sensory science, food science, psychology, neuroscience, nutrition, and health sciences to explore how chemosensation influences dietary choice and health. This report summarizes deliberations of the workshop, as well as follow-up discussion in the wake of the current pandemic. Three topics were addressed: A) the need to optimize human chemosensory testing and assessment, B) the plasticity of chemosensory systems, and C) the interplay of chemosensory signals, cognitive signals, dietary intake, and metabolism. Several ways to advance sensory nutrition research emerged from the workshop: 1) refining methods to measure chemosensation in large cohort studies and validating measures that reflect perception of complex chemosensations relevant to dietary choice; 2) characterizing interindividual differences in chemosensory function and how they affect ingestive behaviors, health, and disease risk; 3) defining circuit-level organization and function that link and interact with gustatory, olfactory, homeostatic, visceral, and cognitive systems; and 4) discovering new ligands for chemosensory receptors (e.g., those produced by the microbiome) and cataloging cell types expressing these receptors. Several of these priorities were made more urgent by the current pandemic because infection with sudden acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the ensuing coronavirus disease of 2019 has direct short- and perhaps long-term effects on flavor perception. There is increasing evidence of functional interactions between the chemosensory and nutritional sciences. Better characterization of this interface is expected to yield insights to promote health, mitigate disease risk, and guide nutrition policy.

Background We do not fully understand how hypercortisolism causes central hypothyroidism or what factors influence recovery of the hypothalamic-pituitary-thyroid axis. We evaluated thyroid function during and after cure of Cushing syndrome (CS). Methods We performed a retrospective cohort study of adult patients with CS seen from 2005 to 2018 (cohort 1, c1, n = 68) or 1985 to 1994 (cohort 2, c2, n = 55) at a clinical research center. Urine (UFC) and diurnal serum cortisol (F: ~8 am and ~midnight [pm]), morning 3,5,3′-triiodothyronine (T3), free thyroxine (FT4), and thyrotropin (TSH) (c1) or hourly TSH from 1500 to 1900 h (day) and 2400 to 04000 h (night) (c2), were measured before and after curative surgery. Results While hypercortisolemic, 53% of c1 had central hypothyroidism (low/low normal FT4 + unelevated TSH). Of those followed long term, 31% and 44% had initially subnormal FT4 and T3, respectively, which normalized 6 to 12 months after cure. Hypogonadism was more frequent in hypothyroid (69%) compared to euthyroid (13%) patients. Duration of symptoms, morning and midnight F, adrenocorticotropin, and UFC were inversely related to TSH, FT4, and/or T3 levels (r = –0.24 to –0.52, P < .001 to 0.02). In c2, the nocturnal surge of TSH (mIU/L) was subnormal before (day 1.00 ± 0.04 vs night 1.08 ± 0.05, P = .3) and normal at a mean of 8 months after cure (day 1.30 ± 0.14 vs night 2.17 ± 0.27, P = .01). UFC greater than or equal to 1000 μg/day was an independent adverse prognostic marker of time to thyroid hormone recovery. Conclusions Abnormal thyroid function, likely mediated by subnormal nocturnal TSH, is prevalent in Cushing syndrome and is reversible after cure.

To determine whether sex, age, and body mass index are correlated with active glucagon-like-peptide 1 concentrations and to investigate glucagon-like-peptide 1 reproducibility during repeated oral glucose tolerance tests.Sixty-one healthy volunteers underwent four 2-hour repeated oral glucose tolerance tests approximately 1 week apart. Because this randomized same-subject crossover trial was designed to investigate effects of non-nutritive sweeteners, participants received 355 mL (12 ounces) of water or a beverage containing non-nutritive sweeteners 10 minutes prior to each oral glucose tolerance test. Blood samples were collected 10 minutes before, and 0, 10, 20, 30, 60, 90, and 120 minutes following ingestion of 75 grams of glucose.Basal active glucagon-like-peptide 1, peak glucagon-like-peptide 1, and glucagon-like-peptide 1 area-under-the-curve were higher in men than women (all p ≤0.04), adjusting for body mass index and age. Fasting and stimulated active glucagon-like-peptide 1 results were highly reproducible with little within-subject variability (between-subjects to within-subject variability ratio 4.2 and 3.5 for fasting glucagon-like-peptide 1 and glucagon-like-peptide 1 area-under-the-curve).Men had higher active glucagon-like-peptide 1 concentrations than women. In contrast to considerable inter-individual variability of basal and stimulated active glucagon-like-peptide 1 concentrations, intra-individual variability was low, consistent with tight physiological regulation.

Summary Sodium-glucose co-transporter-2 (SGLT2) inhibitors have several beneficial effects in patients with type 2 diabetes, including glucose lowering, weight loss, blood pressure lowering, and a reduced risk of major adverse cardiovascular events. To address high unmet medical need via improved glycaemic control, several clinical trials have been done to assess the efficacy and safety of SGLT2 inhibitors in combination with insulin therapy in patients with type 1 diabetes. In this Personal View, we summarise data from eight clinical trials of canagliflozin, dapagliflozin, empagliflozin, and sotagliflozin in patients with type 1 diabetes. HbA1c-lowering efficacy was greatest at 8–12 weeks of therapy, but the magnitude of HbA1c lowering waned with longer duration of treatment (up to 52 weeks). Data are not yet available to establish for how long glycaemic efficacy could be sustained during long-term therapy in patients with type 1 diabetes. Moreover, SGLT2 inhibitor therapy induces serious adverse events, including a roughly six-times increased risk of diabetic ketoacidosis. The US Food and Drug Administration estimated that one additional case of ketoacidosis will occur for every 26 patient-years of exposure of patients with type 1 diabetes to sotagliflozin therapy. Assuming a case mortality of 0·4%, this estimate translates into 16 additional deaths per year per 100 000 patients with type 1 diabetes undergoing treatment. These considerations raise important questions about the risk-to-benefit profile of SGLT2 inhibitors when used as adjunctive therapy in patients with type 1 diabetes.

This study aimed to investigate human fetal exposure to non-nutritive sweeteners (NNS) by analyzing amniotic fluid and umbilical cord blood. Concentrations of four NNS (acesulfame-potassium [ace-K], saccharin, steviol glucuronide, and sucralose) were measured in amniotic fluid ( 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. 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.· 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..

Context Lipodystrophy syndromes cause hypertriglyceridemia that improves with leptin treatment using metreleptin. Mechanisms causing hypertriglyceridemia and improvements after metreleptin are incompletely understood. Objective Determine relationship of circulating lipoprotein lipase (LPL) modulators with hypertriglyceridemia in healthy controls and in patients with lipodystrophy before and after metreleptin. Methods Cross-sectional comparison of patients with lipodystrophy (generalized lipodystrophy n = 3; partial lipodystrophy n = 11) vs age/sex-matched healthy controls (n = 28), and longitudinal analyses in patients before and after 2 weeks and 6 months of metreleptin. The study was carried out at the National Institutes of Health, Bethesda, Maryland. Outcomes were LPL stimulators apolipoprotein (apo) C-II and apoA-V and inhibitors apoC-III and angiopoietin-like proteins (ANGPTLs) 3, 4, and 8; ex vivo activation of LPL by plasma. Results Patients with lipodystrophy were hypertriglyceridemic and had higher levels of all LPL stimulators and inhibitors vs controls except for ANGPTL4, with >300-fold higher ANGPTL8, 4-fold higher apoC-III, 3.5-fold higher apoC-II, 1.9-fold higher apoA-V, 1.6-fold higher ANGPTL3 (P < .05 for all). At baseline, all LPL modulators except ANGPLT4 positively correlated with triglycerides. Metreleptin decreased apoC-II and apoC-III after 2 weeks and 6 months, and decreased ANGPTL8 after 6 months (P < 0.05 for all). Plasma from patients with lipodystrophy caused higher ex vivo LPL activation vs hypertriglyceridemic control plasma (P < .0001), which did not change after metreleptin. Conclusion Elevations in LPL inhibitors apoC-III and ANGPTL8 may contribute to hypertriglyceridemia in lipodystrophy, and may mediate reductions in circulating and hepatic triglycerides after metreleptin. These therefore are strong candidates for therapies to lower triglycerides in these patients.

OBJECTIVES: Stevia rebaudiana (Bertoni) is a perennial herb native to South America. Its sweetness (∼200–400 times sweeter than sucrose) results from steviol glycosides, particularly stevioside and rebaudioside A. Steviol glycosides are hydrolyzed in the gastrointestinal tract resulting in steviol, which is incompletely absorbed in the colon. In the liver, steviol is converted into its glucuronide derivative and renally excreted. While the use of stevia leaves and crude extracts is still prohibited in the US, steviol glycosides have been ‘generally recognized as safe’ (GRAS) by the Food and Drug Administration (FDA) in 2008. We aimed to determine whether steviol glycosides and glucuronidation products can be found in biosamples collected as early as 2004. METHODS: In 38 adults, steviol glycosides and glucuronide were analyzed in plasma and in corresponding cerebrospinal fluid samples (CSF); additional 2 persons had only CSF tested. Prenatal exposure was determined in biosamples from 28 individuals (13 amniotic fluid, 15 cord blood). We used ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) utilizing a Thermo Scientific Vanquish UPLC and a Thermo Scientific Altis triple quadruple mass spectrometer with heated electrospray ionization (HESI-II, Thermo Scientific) in negative ion mode (2500 V). RESULTS: Seven of 38 adults (18%) had detectable steviol glucuronide concentrations (5 in plasma only, 2 in both plasma and CSF). Maximal concentrations in plasma were 805.4 ng/mL and in CSF 3.3 ng/mL. Two of 13 amniotic fluid samples were positive for steviol glucuronide (max. conc. 93.5 ng/mL) and 1 of 15 cord blood samples contained a trace. In contrast to steviol glucuronide, steviol glycoside could not be measured. CONCLUSIONS: Steviol glucuronide was found in all types of biosamples (plasma, CSF, amniotic fluid and cord blood), most commonly in plasma (18%). This indicates that exposure to steviol metabolites starts in prenatal life and that these metabolites cross various barriers (e.g., blood-CSF, blood-amniotic fluid). Only samples obtained in and after 2008 were positive for steviol glucuronide, which coincides with the FDA approval. Potential health consequences of exposure to stevia metabolites require further study. FUNDING SOURCES: N/A.

Introduction: In adults, epidemiologic studies consistently show negative health outcomes (e.g. insulin resistance, stroke) related to artificial (or non-nutritive) sweetener (NNS) intake. In children, NNS sweetened beverage consumption is associated with higher total energy and sugar intake. In infants, we documented the immediate appearance of NNS in breast milk after mothers consume diet soda. A positive association between prenatal NNS exposure and higher BMI at 1 year of life has been observed in infants whose mothers routinely consumed NNS during pregnancy. In mice, we recently reported marked changes in intestinal microbiome and hepatic detoxification pathways of pups that had been exposed to NNS via their mothers’ intake during pregnancy and lactation. Thus, we conducted a pilot project to determine whether there is direct evidence for prenatal NNS exposure in humans. In future studies, we will investigate effects on health outcomes. Methods: Concentrations of 3 NNS (acesulfame-potassium (ace-K), sucralose and saccharin) were measured with liquid chromatography-mass spectrometry in cord blood samples (n=15) and amniotic fluid samples (n=13). Aspartame cannot be measured because of its prompt metabolism into aspartic acid and phenylalanine. The cord blood samples were obtained from offspring of women enrolled in a sickle cell clinical trial at the NIH, while the amniotic fluid samples had been obtained for clinical purposes during the 3rd trimester. No dietary information was available other than 2 of 13 women were not in the fasting state when undergoing amniocentesis. Results: In the cord blood samples, ace-K and saccharin were present in 12/15 (80%) samples. None of the samples contained sucralose. In the 13 amniotic fluid samples, 10 (77%) samples contained at least one sweetener. One sample was positive for all 3 sweeteners. Maximum concentrations in cord blood were 6.5 ng/mL for ace-K and 2.7 ng/mL for saccharin, while maximum concentrations in amniotic fluid were 78.9 ng/mL for ace-K, 55.9 ng/mL for saccharin, and 30.6 ng/mL for sucralose (non-fasting sample). Most women were in the fasting state before undergoing amniocentesis or giving birth, thus NNS peak concentrations could not be determined in this pilot study. Discussion and Conclusion: 80% of cord blood samples (babies’ blood) and 77% of amniotic fluid samples (reflecting babies’ direct gastrointestinal/lung exposure) contained ace-K, saccharin and/or sucralose. We speculate that NNS exposure may influence in utero growth and development, e.g. sweet taste preference and metabolic pathways. Prospective studies are necessary to test these hypotheses. Results will determine whether current recommendations (or lack thereof) regarding NNS intake during pregnancy and lactation need to be revised.

Objective: The aim of this study was to determine sucralose and acesulfame-potassium (ace-K) pharmacokinetics in breast milk following maternal ingestion of a diet soda. Methods: Thirty-four exclusively breast-feeding women (14 normal-weight, 20 obese) consumed 12 ounces of Diet Rite Cola, sweetened with 68-mg sucralose and 41-mg ace-K, before a standardized breakfast meal. Habitual non-nutritional sweeteners intake was assessed via a diet questionnaire. Breast milk was collected from the same breast before beverage ingestion and hourly for 6 hours. Results: Owing to one mother having extremely high concentrations, peak sucralose and acesulfame-potassium concentrations following ingestion of diet soda ranged from 4.0 to 7387.9 ng/mL (median peak 8.1 ng/mL) and 299.0 to 4764.2 ng/mL (median peak 945.3 ng/mL), respectively. Conclusions: Ace-K and sucralose transfer into breast milk following ingestion of a diet soda. Future research should measure concentrations after repeated exposure and determine whether chronic ingestion of sucralose and acesulfame-potassium via the breast milk has clinically relevant health consequences.

Objective The objective of this review was to critically review findings from recent studies evaluating the effects of nonnutritive sweeteners (NNSs) on metabolism, weight, and obesity-related chronic diseases. Biologic mechanisms that may explain NNS effects will also be addressed. Methods A comprehensive review of the relevant scientific literature was conducted. Results Most cross-sectional and prospective cohort studies report positive associations between NNS consumption, body weight, and health conditions, including type 2 diabetes, cardiovascular disease, and nonalcoholic fatty liver disease. Although findings in cellular and rodent models suggest that NNSs have harmful effects on metabolic health, most randomized controlled trials in humans demonstrate marginal benefits of NNS use on body weight, with little data available on other metabolic outcomes. Conclusions NNS consumption is associated with higher body weight and metabolic disease in observational studies. In contrast, randomized controlled trials demonstrate that NNSs may support weight loss, particularly when used alongside behavioral weight loss support. Additional long-term, well-controlled intervention studies in humans are needed to determine the effects of NNSs on weight, adiposity, and chronic disease under free-living conditions.

Objective The aim of this study was to investigate the relationship between low-calorie sweeteners (LCSs), energy intake, and weight in US youth. Methods Data were collected from individuals aged 2 to 19 years who participated in the National Health and Nutrition Examination Survey (NHANES) 2009-2010 (n = 3,296), 2011-2012 (n = 3,139), and 2013-2014 (n = 3,034). Logistic regression, unadjusted and adjusted for age, sex, race/ethnicity, income, energy intake, and physical activity, was used to estimate the odds of obesity in LCS consumers versus nonconsumers, both overall and across product categories (foods vs. beverages) and sociodemographic subgroups. Results Among adolescents, the odds of obesity were 55% and 70% higher in LCS beverage consumers than in nonconsumers in unadjusted and adjusted models, respectively. Energy intakes did not differ based on LCS consumption. In contrast, associations between LCS consumption and obesity risk were not statistically significant among children (2-11 y old), except in boys and those who self-identified as Hispanic. Conclusions LCS consumption is associated with increased odds of obesity among adolescents. This relationship is strikingly independent of total energy intake. Although findings should be interpreted cautiously because of the limitations of self-reported dietary intake and the cross-sectional nature of this analysis, the observational analysis in this study supports the need to investigate the mechanisms by which LCS may influence body weight, independently of changes in energy intake.

Here, we tested the hypothesis that sucralose differentially affects metabolic responses to labeled oral glucose tolerance tests (OGTTs) in participants with normal weight and obesity. Participants (10 with normal weight and 11 with obesity) without diabetes underwent three dual-tracer OGTTs preceded, in a randomized order, by consuming sucralose or water, or by tasting and expectorating sucralose (e.g., sham-fed, sweetness control). Indices of &beta, cell function and insulin sensitivity (SI) were estimated using oral minimal models of glucose, insulin, and C-peptide kinetics. Compared with water, sucralose ingested (but not sham-fed) resulted in a 30 &plusmn, 10% increased glucose area under the curve in both weight groups. In contrast, the insulin response to sucralose ingestion differed depending on the presence of obesity: decreased within 20&ndash, 40 min of the OGTT in normal-weight participants but increased within 90&ndash, 120 min in participants with obesity. Sham-fed sucralose similarly decreased insulin concentrations within 60 min of the OGTT in both weight groups. Sucralose ingested (but not sham-fed) increased SI in normal-weight participants by 52 &plusmn, 20% but did not affect SI in participants with obesity. Sucralose did not affect glucose rates of appearance or &beta, cell function in either weight group. Our data underscore a physiological role for taste perception in postprandial glucose responses, suggesting sweeteners should be consumed in moderation.

Low-calorie sweetener (LCS) consumption is associated with metabolic disease in observational studies. However, physiologic mechanisms underlying LCS-induced metabolic impairments in humans are unclear. This study is aimed at identifying molecular pathways in adipose impacted by LCSs.Seven females with overweight or obesity, who did not report LCS use, consumed 12 ounces of diet soda containing sucralose and acesulfame-potassium (Ace-K) three times daily for 8 weeks. A subcutaneous adipose biopsy from the left abdomen and a fasting blood sample were collected at baseline and post-intervention. Global gene expression were assessed using RNA-sequencing followed by functional pathway analysis. No differences in circulating metabolic or inflammatory biomarkers were observed. However, ANOVA detected 828 differentially expressed annotated genes after diet soda consumption (p 0.05), including transcripts for inflammatory cytokines. Fifty-eight of 140 canonical pathways represented in pathway analyses regulated inflammation, and several key upstream regulators of inflammation (e.g., TNF-alpha) were also represented.Consumption of diet soda with sucralose and Ace-K alters inflammatory transcriptomic pathways (e.g., NF-κB signaling) in subcutaneous adipose tissue but does not significantly alter circulating biomarkers. Findings highlight the need to examine molecular and metabolic effects of LCS exposure in a larger randomized control trial for a longer duration.

AIMS: Increased adiposity is a risk factor for suboptimal diabetes control and cardiovascular disease (CVD) complications. Our goal was to identify modifiable behavioral characteristics of overweight and obese pediatric patients with type 1 diabetes mellitus (T1DM) who achieve optimal glycemic control and to evaluate their CVD risk compared to lean patients. Our hypothesis was that optimally controlled obese and overweight participants require more total daily insulin and are at higher CVD risk compared to optimally controlled lean participants. METHODS: We analyzed a cohort of 9,263 participants with T1DM aged

Non-nutritive sweeteners (NNS) are marketed as sugar alternatives providing sweet taste with few or no calories. Yet their consumption has been linked to metabolic dysfunction and changes in the gut microbiome. NNS exposure mostly originates from diet beverages and sweetener packages in adults or breastmilk in infants. Consequences of early life exposure remain largely unknown. We exposed pregnant and lactating mice to NNS (sucralose, acesulfame-K) at doses relevant for human consumption. While the pups’ exposure was low, metabolic changes were drastic, indicating extensive downregulation of hepatic detoxification mechanisms and changes in bacterial metabolites. Microbiome profiling confirmed a significant increase in firmicutes and a striking decrease of Akkermansia muciniphila. Similar microbiome alterations in humans have been linked to metabolic disease and obesity. While our findings need to be reproduced in humans, they suggest that NNS consumption during pregnancy and lactation may have adverse effects on infant metabolism.

Lipodystrophy syndromes (LD) result from selective deficiency of adipose tissue, leading to low leptin. Low leptin leads to hyperphagia and ectopic lipid storage, causing severe insulin resistance and metabolic complications including high triglycerides (TG) and subsequent pancreatitis. Replacement of leptin using metreleptin (ML) in LD decreases TG. TG are broken down to non-esterified fatty acids (NEFA) by lipoprotein lipase (LPL). We previously demonstrated that patients with LD had high apoCIII and ANGPLT8 (inhibitors of LPL) that decreased with ML, suggesting that ML may lower TG by reducing inhibition of LPL activity. We hypothesized that plasma from patients with LD would cause greater inhibition of LPL compared to controls, and that ML would ameliorate this. We further hypothesized that net inhibition of LPL in LD would be reflected by a decreased ratio of apoCII (an LPL stimulator) to apoCIII (an LPL inhibitor) vs. controls. METHODS: Plasma from ML-naive patients with LD (n=14) and a pooled high-TG control group (651 mg/dL, n=10) were diluted to the same concentration of TG. Samples were incubated with bovine LPL, and NEFA produced was measured enzymatically over 1hr at 37⁰C. Because the concentrations of added LPL and TG were equal in each patient sample, NEFA generation (nmole) reflected the net effect of LPL stimulators and inhibitors in plasma. To test the effects of ML, the same method was applied to samples from patients with LD after ML 5 mg Q12h for 2 weeks and 6 months. ApoCII and apoCIII were compared in patients with LD (n=14) versus healthy controls (TG = 74 [54, 97] mg/dL, n=28). RESULTS: Patients with LD had baseline TG 492 [208, 1016] mg/dL which decreased to 279 [171, 648] after 2 weeks of ML (n=14, p=.0023) and to 223 [118, 335] after 6 months of ML (n=11, p=0.15). Prior to ML, patients with LD had higher NEFA generation vs. controls (patients 0.79 ± 0.08; controls 0.59 ± 0.1; p0.05). ApoCII:apoCIII ratio did not differ in LD vs controls (0.63±0.31 vs 0.54±0.17, p=0.6), and did not change after ML. CONCLUSIONS: Counter to our hypothesis, patients with LD had higher NEFA generation compared to high TG controls, consistent with less net inhibition of LPL, while the ratio of LPL activator (apoCII) to inhibitor (apoCIII) did not differ in LD vs normal TG controls. Furthermore, NEFA generation and apoCII:apoCIII ratio did not change after ML therapy, suggesting no net change in inhibition of LPL with ML. These findings suggest that changes in circulating activators and inhibitors of LPL are not a major mechanism by which ML lowers TG in LD. Studies including direct measurement of LPL activity after heparin stimulation are needed to further explore the role of LPL in regulating TG in LD.

Lipodystrophy syndromes are rare disorders of deficient adipose tissue. Metreleptin, a human analog of leptin, improved metabolic abnormalities in mixed cohorts of children and adults with lipodystrophy and low leptin.Determine effects of metreleptin on diabetes, hyperlipidemia, nonalcoholic fatty liver disease (NAFLD), growth, and puberty in pediatric patients with lipodystrophy and low leptin.Prospective, single-arm, open-label studies with continuous enrollment since 2000.National Institutes of Health, Bethesda, Maryland.Fifty-three patients aged 6 months to18 years with lipodystrophy, leptin level8 ng/mL (male patients) or12 ng/mL (female patients), and ≥1 metabolic abnormality (diabetes, insulin resistance, or hypertriglyceridemia).Subcutaneous metreleptin injections (0.04 to 0.19 mg/kg/d).Change in A1c, lipid, and transaminase levels after a mean ± standard deviation (SD) of 12 ± 0.2 months and 61 ± 39 months. Changes in liver histology, growth, and pubertal development throughout treatment.After 12 months, the A1c level (mean ± SD) decreased from 8.3% ± 2.4% to 6.5% ± 1.8%, and median triglyceride level decreased from 374 mg/dL [geometric mean (25th,75th percentile), 190, 1065] to 189 mg/dL (112, 334; P0.0001), despite decreased glucose- and lipid-lowering medications. The median [geometric mean (25th,75th percentile)] alanine aminotransferase level decreased from 73 U/L (45, 126) to 41 U/L (25, 59; P = 0.001), and that of aspartate aminotransferase decreased from 51 U/L (29, 90) to 26 U/L (18, 42; P = 0.0002). These improvements were maintained over long-term treatment. In 17 patients who underwent paired biopsies, the NAFLD activity score (mean ± SD) decreased from 4.5 ± 2.0 to 3.4 ± 2.0 after 3.3 ± 3.2 years of metreleptin therapy (P = 0.03). There were no clinically significant changes in growth or puberty.Metreleptin lowered A1c and triglyceride levels, and improved biomarkers of NAFLD in pediatric patients with lipodystrophy. These improvements are likely to reduce the lifetime burden of disease.

Objective: Lipodystrophy syndromes are extremely rare disorders of deficient body fat associated with potentially serious metabolic complications, including diabetes, hypertriglyceridemia, and steatohepatitis. Due to their rarity, most clinicians are not familiar with their diagnosis and management. This practice guideline summarizes the diagnosis and management of lipodystrophy syndromes not associated with HIV or injectable drugs. Participants: Seventeen participants were nominated by worldwide endocrine societies or selected by the committee as content experts. Funding was via an unrestricted educational grant from Astra Zeneca to the Pediatric Endocrine Society. Meetings were not open to the general public. Evidence: A literature review was conducted by the committee. Recommendations of the committee were graded using the system of the American Heart Association. Expert opinion was used when published data were unavailable or scarce. Consensus Process: The guideline was drafted by committee members and reviewed, revised, and approved by the entire committee during group meetings. Contributing societies reviewed the document and provided approval. Conclusions: Lipodystrophy syndromes are heterogeneous and are diagnosed by clinical phenotype, supplemented by genetic testing in certain forms. Patients with most lipodystrophy syndromes should be screened for diabetes, dyslipidemia, and liver, kidney, and heart disease annually. Diet is essential for the management of metabolic complications of lipodystrophy. Metreleptin therapy is effective for metabolic complications in hypoleptinemic patients with generalized lipodystrophy and selected patients with partial lipodystrophy. Other treatments not specific for lipodystrophy may be helpful as well (eg, metformin for diabetes, and statins or fibrates for hyperlipidemia). Oral estrogens are contraindicated., Multiple worldwide endocrine societies developed practice guidelines for diagnosis and management of lipodystrophy syndromes based on current evidence.

A reduction in the consumption of added sugars and sugar-sweetened beverages (SSBs) is a key focus of public health recommendations for a healthy diet among children. One approach to lower added sugar intake is to instead use low-calorie sweeteners (LCSs), which contain no or few calories. Consumption of LCSs is increasing worldwide, with the most marked rise observed among children and adolescents. However, the extent to which LCS consumption is helpful or harmful for weight management is controversial, particularly when LCS consumption begins in childhood. Herein, we summarize the limited existing literature examining effects of paediatric LCS consumption on appetite, energy intake, and body weight. While positive associations between LCS consumption and weight gain are reported in observational analyses, the majority of intervention studies, some of which blinded children to the contents of the drinks, report benefits of LCSs for reducing excessive child weight gain. Several potential mechanisms have been proposed to explain LCS effects on body weight, including LCS-induced promotion of appetite and energy intake. Yet studies assessing effects of beverages with LCSs (LCSBs) compared with SSBs on child appetite report mixed findings. Some demonstrate that children completely compensate for the diluted energy content of LCSBs by eating more solid food calories at subsequent meals compared with children administered SSBs, while others report a reduction in total energy intake with LCSB ingestion. Given the limited studies and resulting uncertainty as to whether LCSs benefit or worsen weight and metabolic health in children is integral that effects of LCS use during childhood continue to be investigated in future prospective studies.

We report on two patients with type 1 diabetes (T1D) after solitary islet transplantation in 2001. They received steroid-sparing immunosuppression (daclizumab, sirolimus, and tacrolimus according to the Edmonton protocol). Both patients became insulin independent for 2 years: Patient A, a 42-year-old female with a 12-year history of T1D, received two islet infusions; patient B, a 53-year-old female with a 40-year T1D history, received one islet infusion. Pretransplant, both had undetectable C-peptide concentrations and frequent and severe hypoglycemia. Pretransplant, hemoglobin A1c (HbA1c) was 7.8% and 8.8% and insulin requirements were 0.47 and 0.33 units/kg/day, respectively. Posttransplant, C-peptide levels remained detectable while immunosuppression was continued, but decreased over time. Insulin was re-started 2 years posttransplant in both patients. Since patient A’s glycemia and insulin requirements trended toward pretransplant levels, immunosuppression was discontinued after 13 years. This resulted in a sudden cessation of C-peptide secretion. Patient B continues on immunosuppression, has better HbA1c, and half the insulin requirement compared to pretransplant. Both patients no longer experience severe hypoglycemia. Herein, we document blood glucose concentrations over time (>30 000 measurements per patient) and β cell function based on C-peptide secretion. Despite renewed insulin dependence, both patients express satisfaction with having undergone the procedure.

Journal Article; Research Support, N.I.H., Intramural; Research Support, Non-U.S. Gov't;Erratium en J Clin Invest. 2016 Feb 1;126(2):795. doi: 10.1172/JCI86020: https://www.jci.org/articles/view/86020 Autosomal recessive mutations in proteasome subunit β 8 (PSMB8), which encodes the inducible proteasome subunit β5i, cause the immune-dysregulatory disease chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE), which is classified as a proteasome-associated autoinflammatory syndrome (PRAAS). Here, we identified 8 mutations in 4 proteasome genes, PSMA3 (encodes α7), PSMB4 (encodes β7), PSMB9 (encodes β1i), and proteasome maturation protein (POMP), that have not been previously associated with disease and 1 mutation in PSMB8 that has not been previously reported. One patient was compound heterozygous for PSMB4 mutations, 6 patients from 4 families were heterozygous for a missense mutation in 1 inducible proteasome subunit and a mutation in a constitutive proteasome subunit, and 1 patient was heterozygous for a POMP mutation, thus establishing a digenic and autosomal dominant inheritance pattern of PRAAS. Function evaluation revealed that these mutations variably affect transcription, protein expression, protein folding, proteasome assembly, and, ultimately, proteasome activity. Moreover, defects in proteasome formation and function were recapitulated by siRNA-mediated knockdown of the respective subunits in primary fibroblasts from healthy individuals. Patient-isolated hematopoietic and nonhematopoietic cells exhibited a strong IFN gene-expression signature, irrespective of genotype. Additionally, chemical proteasome inhibition or progressive depletion of proteasome subunit gene transcription with siRNA induced transcription of type I IFN genes in healthy control cells. Our results provide further insight into CANDLE genetics and link global proteasome dysfunction to increased type I IFN production. Yes

Next-generation sequencing provides the opportunity to practice predictive medicine based on identified variants. Putative loss-of-function (pLOF) variants are common in genomes and understanding their contribution to disease is critical for predictive medicine. To this end, we characterized the consequences of pLOF variants in an exome cohort by iterative phenotyping. Exome data were generated on 951 participants from the ClinSeq cohort and filtered for pLOF variants in genes likely to cause a phenotype in heterozygotes. 103 of 951 exomes had such a pLOF variant and 79 participants were evaluated. Of those 79, 34 had findings or family histories that could be attributed to the variant (28 variants in 18 genes), 2 had indeterminate findings (2 variants in 2 genes), and 43 had no findings or a negative family history for the trait (34 variants in 28 genes). The presence of a phenotype was correlated with two mutation attributes: prior report of pathogenicity for the variant (p = 0.0001) and prior report of other mutations in the same exon (p = 0.0001). We conclude that 1/30 unselected individuals harbor a pLOF mutation associated with a phenotype either in themselves or their family. This is more common than has been assumed and has implications for the setting of prior probabilities of affection status for predictive medicine.

Non-nutritive sweeteners (NNSs) elicit a multitude of endocrine effects in vitro, in animal models, and in humans. The best-characterized consequences of NNS exposure are metabolic changes, which may be mediated by activation of sweet taste receptors in oral and extraoral tissues (e.g., intestine, pancreatic β cells, and brain), and alterations of the gut microbiome. These mechanisms are likely synergistic and may differ across species and chemically distinct NNSs. However, the extent to which these hormonal effects are clinically relevant in the context of human consumption is unclear. Further investigation following prolonged exposure is required to better understand the role of NNSs in human health, with careful consideration of genetic, dietary, anthropometric, and other interindividual differences.

BACKGROUND. Monogenic IFN–mediated autoinflammatory diseases present in infancy with systemic inflammation, an IFN response gene signature, inflammatory organ damage, and high mortality. We used the JAK inhibitor baricitinib, with IFN-blocking activity in vitro, to ameliorate disease. METHODS. Between October 2011 and February 2017, 10 patients with CANDLE (chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperatures), 4 patients with SAVI (stimulator of IFN genes–associated [STING-associated] vasculopathy with onset in infancy), and 4 patients with other interferonopathies were enrolled in an expanded access program. The patients underwent dose escalation, and the benefit was assessed by reductions in daily disease symptoms and corticosteroid requirement. Quality of life, organ inflammation, changes in IFN-induced biomarkers, and safety were longitudinally assessed. RESULTS. Eighteen patients were treated for a mean duration of 3.0 years (1.5–4.9 years). The median daily symptom score decreased from 1.3 (interquartile range [IQR], 0.93–1.78) to 0.25 (IQR, 0.1–0.63) (P < 0.0001). In 14 patients receiving corticosteroids at baseline, daily prednisone doses decreased from 0.44 mg/kg/day (IQR, 0.31–1.09) to 0.11 mg/kg/day (IQR, 0.02–0.24) (P < 0.01), and 5 of 10 patients with CANDLE achieved lasting clinical remission. The patients’ quality of life and height and bone mineral density Z-scores significantly improved, and their IFN biomarkers decreased. Three patients, two of whom had genetically undefined conditions, discontinued treatment because of lack of efficacy, and one CANDLE patient discontinued treatment because of BK viremia and azotemia. The most common adverse events were upper respiratory infections, gastroenteritis, and BK viruria and viremia. CONCLUSION. Upon baricitinib treatment, clinical manifestations and inflammatory and IFN biomarkers improved in patients with the monogenic interferonopathies CANDLE, SAVI, and other interferonopathies. Monitoring safety and efficacy is important in benefit-risk assessment. TRIAL REGISTRATION. ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01724580","term_id":"NCT01724580"}}NCT01724580 and {"type":"clinical-trial","attrs":{"text":"NCT02974595","term_id":"NCT02974595"}}NCT02974595. FUNDING. This research was supported by the Intramural Research Program of the NIH, NIAID, and NIAMS. Baricitinib was provided by Eli Lilly and Company, which is the sponsor of the expanded access program for this drug.

Sucralose is partially absorbed after oral ingestion, with the majority excreted in the feces. We aimed to measure plasma sucralose concentrations following ingestion of doses reflecting a range of consumption (from one can of diet soda up to multiple sodas over the course of a day) and to compare concentrations in children and adults. Eleven adults (7 females, 4 males) consumed 355 mL water containing 0 mg sucralose (control) or 68, 170, or 250 mg sucralose (equivalent to 1–4 diet sodas). A second group of adults (n=11, 6 females and 5 males) consumed 355 mL Diet Rite Cola™ (68 mg sucralose and 41 mg acesulfame-potassium (ace-K)) or 68 mg sucralose and 41 mg ace-K in seltzer. Beverages were provided at separate visits in randomized order, prior to an oral glucose tolerance test. Eleven children (7 females and 4 males) consumed 0 or 68 mg sucralose in 240 mL water, in an identical study design. Blood was collected before beverage ingestion and serially for 120 min. Sucralose doses (corrected for weight) resulted in similar plasma concentrations in children and adults. Children reached peak concentrations of 145–400 ng/mL after 68 mg (mean 262.3 ± 24.6 ng/mL). Most adults reached similar peak concentrations (200–400 ng/mL after 250 mg (365.6 ± 69.9 ng/mL)) with the exception of two adults (1520 ng/mL and 1557 ng/mL, respectively). Concentrations were comparable whether sucralose was administered in water, combined with ace-K, or in diet soda. Due to their lower body weight and blood volume, children have markedly higher plasma sucralose concentrations after consumption of a typical diet soda, emphasizing the need to determine the clinical implications of sucralose use in children.

Purpose of Review Patients with type 1 diabetes have increased risk for cardiovascular disease. The purpose of this review is to examine the following:i)current evidence for subclinical cardiovascular disease (CVD) in children with type 1 diabetes (T1DM)ii)known modifiable risk factors for CVD and their relationship to subclinical CVD in this populationiii)studies that have addressed these risk factors in order to improve CVD outcomes in children with T1DM Recent Findings Subclinical CVD presents in children as increased carotid intima-media thickness, increased arterial stiffness, and endothelial and myocardial dysfunction. Modifiable risk factors for CVD include hyperglycemia, hyperlipidemia, obesity, hypertension, depression, and autonomic dysfunction. Very few randomized controlled studies have been done in children with T1DM to examine how modification of these risk factors can affect their CVD. Summary Children with T1DM have subclinical CVD and multiple modifiable risk factors for CVD. More research is needed to define how modification of these factors affects the progression of CVD.

Background Factitious hypoglycemia is a condition of self-induced hypoglycemia due to surreptitious administration of insulin or oral hypoglycemic agents. In adults, it is an uncommon, but well known clinical entity observed in individuals with and without diabetes. Objectives To report a case of factitious hypoglycemia highlighting diagnostic pitfalls, to identify common characteristics of children and adolescents with factitious hypoglycemia, and to examine whether the information on long-term outcome exists. Methods We present a case of an adolescent with type 1 diabetes who had self-induced hypoglycemia of several years' duration; and we conducted a systematic literature review on factitious hypoglycemia in pediatric patients with diabetes. Results We identified a total of 83 articles of which 14 met the inclusion criteria (describing 39 cases). All but 1 individual had type 1 diabetes and the majority was female (63%). Average age was 13.5 ± 2.0 years with the youngest patient presenting at the age 9.5 years. Blood glucose control was poor (hemoglobin A1c: 12.1 ± 4.0%). In 35%, psychiatric disorders were mentioned as contributing factors. Only 3 reports provided follow-up beyond 6 months. Conclusions Factitious hypoglycemia typically occurs in adolescents with type 1 diabetes who use insulin to induce hypoglycemia. Awareness of this differential diagnosis and knowledge of potentially misleading laboratory results may facilitate earlier recognition and intervention. Little information exists on effective treatments and long-term outcome.

Humans have an innate liking for sweetness, which may have an evolutionary basis. Sweetness typically signals the presence of calories and nutrients and thus, universal liking for sweet taste once served to support survival. In the modern food supply, however, sweetness is often delivered via added sugars and sweeteners devoid of other beneficial nutrients. Nonnutritive sweeteners (NNS) provide sweetness with no or few calories, and therefore may offer a potential strategy to maintain food and beverage palatability, while reducing the caloric content. Despite marked increases in NNS use, their metabolic and health effects are not well-characterized, and particularly little is known about their effects when exposure starts early in life. Herein, we critically review existing data on NNS exposure in utero, during lactation, and throughout childhood and adolescence with respect to taste preferences, weight trajectory, and development of chronic disease. We specifically focus on potential mechanisms through which sweetness exposure during early development may affect key metabolic outcomes.

The aim of this study was to investigate the relationship between low-calorie sweeteners (LCSs), energy intake, and weight in US youth.Data were collected from individuals aged 2 to 19 years who participated in the National Health and Nutrition Examination Survey (NHANES) 2009-2010 (n = 3,296), 2011-2012 (n = 3,139), and 2013-2014 (n = 3,034). Logistic regression, unadjusted and adjusted for age, sex, race/ethnicity, income, energy intake, and physical activity, was used to estimate the odds of obesity in LCS consumers versus nonconsumers, both overall and across product categories (foods vs. beverages) and sociodemographic subgroups.Among adolescents, the odds of obesity were 55% and 70% higher in LCS beverage consumers than in nonconsumers in unadjusted and adjusted models, respectively. Energy intakes did not differ based on LCS consumption. In contrast, associations between LCS consumption and obesity risk were not statistically significant among children (2-11 y old), except in boys and those who self-identified as Hispanic.LCS consumption is associated with increased odds of obesity among adolescents. This relationship is strikingly independent of total energy intake. Although findings should be interpreted cautiously because of the limitations of self-reported dietary intake and the cross-sectional nature of this analysis, the observational analysis in this study supports the need to investigate the mechanisms by which LCS may influence body weight, independently of changes in energy intake.

Background: Weight loss is a key factor in reducing diabetes risk. The Diabetes Prevention Program (DPP) is a completed clinical trial that randomly assigned individuals at high risk of diabetes to a placebo (PLBO), metformin (MET), or intensive lifestyle intervention (ILS) group, which included physical activity (PA) and reduced dietary fat intake.Objective: We aimed to evaluate the associations between diet and weight at baseline and to identify specific dietary factors that predicted weight loss among DPP participants.Methods: Diet was assessed by a food frequency questionnaire. The associations between intakes of macronutrients and various food groups and body weight among DPP participants at baseline were assessed by linear regression, adjusted for race/ethnicity, age, sex, calorie intake, and PA. Models that predicted weight loss at year 1 were adjusted for baseline weight, change in calorie intake, and change in PA and stratified by treatment allocation (MET, ILS, and PLBO). All results are presented as estimates ± SEs.Results: A total of 3234 participants were enrolled in the DPP; 2924 had completed dietary data (67.5% women; mean age: 50.6 ± 10.7 y). Adjusted for calorie intake, baseline weight was negatively associated with carbohydrate intake (-1.14 ± 0.18 kg body weight/100 kcal carbohydrate, P < 0.0001) and, specifically, dietary fiber (-1.26 ± 0.28 kg/5 g fiber, P < 0.0001). Baseline weight was positively associated with total fat (1.25 ± 0.21 kg/100 kcal, P < 0.0001), saturated fat (1.96 ± 0.46 kg/100 kcal, P < 0.0001), and protein (0.21 ± 0.05 kg/100 kcal, P < 0.0001). For all groups, weight loss after 1 y was associated with increases in carbohydrate intake, specifically dietary fiber, and decreases in total fat and saturated fat intake.Conclusions: Higher carbohydrate consumption among DPP participants, specifically high-fiber carbohydrates, and lower total and saturated fat intake best predicted weight loss when adjusted for changes in calorie intake. Our results support the benefits of a high-carbohydrate, high-fiber, low-fat diet in the context of overall calorie reduction leading to weight loss, which may prevent diabetes in high-risk individuals. This trial was registered at clinicaltrials.gov as NCT00004992.

Background Minimizing consumption of added sugars is recommended to prevent excessive weight gain among pregnant women. A common approach to lowering sugar intake is the use of low-calorie sweeteners (LCSs), yet little is known about LCS use during pregnancy or its effects on infant weight and health. Objective The aim of the study was to investigate temporal trends in LCS consumption by source (foods, beverages, or packets) among pregnant women in the United States from 1999 to 2014 and to compare recent LCS consumption patterns across sociodemographic subgroups and product categories. Methods Data were collected from pregnant women aged 20–39 y (n = 1,265) who participated in the NHANES from 1999–2000 through 2013–2014. Prevalence of LCS consumption was assessed using two 24-h dietary recalls. Analytical procedures for complex survey design were used, and sampling weights were applied to estimate national prevalence of LCS use. Rao–Scott modified chi-square tests were used to compare consumption prevalence across sociodemographic subgroups, and logistic regression was used to examine trends in LCS use over time. Results The prevalence of LCS consumption among pregnant women increased by approximately 50% rising from 16.2% in 1999–2004 to 24.0% in 2007–2014, P = 0.04, with the highest prevalence observed in 2005–2006 (38.4%). This trend was driven predominantly by increases in LCS beverage use (9.9% in 1999–2004 compared with 18.3% in 2007–2014, P = 0.02). Prevalence of LCS consumption was highest among non-Hispanic white women and increased with education and income. No differences were observed based on prepregnancy weight status or trimester of pregnancy. Conclusions Approximately one-quarter of pregnant women in the United States reported consumption of LCS during at least 1 of 2 dietary recalls. Given the widespread LCS consumption during pregnancy, research to elucidate potential effects of early life LCS exposure on taste preferences, weight trajectory, and risk of later metabolic disease is needed.

We recently determined that nonnutritive (NNS) sweeteners ingested by lactating mothers are passed to their infants in breast milk (Sylvetsky et al., 2015). Three NNS including sucralose, acesulfame-K (ace-K), and saccharin were found in the breast milk of 65% of twenty lactating women who had been enrolled in the study, irrespective of their history of NNS usage. While most of the mothers reported NNS intake during the day prior to collection of the breast milk sample, NNS were also found in samples from women who were not aware of consuming NNS. The findings that NNS are present in breast milk raises several issues regarding infant exposure to these nonnutritive compounds and highlights the need for future research studying the potential short- and long-term effects of exposure to NNS early in life.

PurposeTo better understand and overcome difficulties with recruitment of adolescents with type 2 diabetes into clinical trials at three United States institutions, we reviewed recruitment and retention strategies in clinical trials of youth with various chronic conditions. We explored whether similar strategies might be applicable to pediatric patients with type 2 diabetes.MethodsWe compiled data on recruitment and retention of adolescents with type 2 diabetes at three centers (National Institutes of Health, Bethesda, Maryland; Baylor College of Medicine, Houston, Texas; and Children's National Medical Center, Washington, DC) from January 2009 to December 2011. We also conducted a thorough literature review on recruitment and retention in adolescents with chronic health conditions.ResultsThe number of recruited patients was inadequate for timely completion of ongoing trials. Our review of recruitment strategies in adolescents included monetary and material incentives, technology-based advertising, word-of-mouth referral, and continuous patient–research team contact. Cellular or Internet technology appeared promising in improving participation among youths in studies of various chronic conditions and social behaviors.ConclusionsAdolescents with type 2 diabetes are particularly difficult to engage in clinical trials. Monetary incentives and use of technology do not represent “magic bullets,” but may presently be the most effective tools. Future studies should be conducted to explore motivation in this population. We speculate that (1) recruitment into interventional trials that address the main concerns of the affected youth (e.g., weight loss, body image, and stress management) combined with less tangible outcomes (e.g., blood glucose control) may be more successful; and (2) study participation and retention may be improved by accommodating patients' and caregivers' schedules, by scheduling study visits before and after working hours, and in more convenient locations than in medical facilities.

OBJECTIVE Exenatide treatment improves glycemia in adults with type 2 diabetes and has been shown to reduce postprandial hyperglycemia in adolescents with type 1 diabetes. We studied the effects of exenatide on glucose homeostasis in adults with long-standing type 1 diabetes. RESEARCH DESIGN AND METHODS Fourteen patients with type 1 diabetes participated in a crossover study of 6 months' duration on exenatide (10 μg four times a day) and 6 months off exenatide. We assessed changes in fasting and postprandial blood glucose and changes in insulin sensitivity before and after each study period. RESULTS High-dose exenatide therapy reduced postprandial blood glucose but was associated with higher fasting glucose concentrations without net changes in hemoglobin A1c. Exenatide increased insulin sensitivity beyond the effects expected as a result of weight reduction. CONCLUSIONS Exenatide is a promising adjunctive agent to insulin therapy because of its beneficial effects on postprandial blood glucose and insulin sensitivity in patients with type 1 diabetes.

In der vorliegenden, multizentrischen, randomisierten cross-over Studie wurde die Wirkung von Ganzkorpervibration (WBV) auf Biomarker der Knochenresorption, das Sturzrisiko und die Schmerzen im unteren Rucken untersucht. Die Studie erstreckte sich uber einen Zeitraum von 12 Wochen. Es wurden 58 Patientinnen mit postmenopausaler Osteoporose eingeschlossen, die mit Alendronat (n=41) oder Raloxifen (n=17) behandelt werden. Die Patientinnen wurden in 2 Gruppen randomisiert. Die erste Gruppe erhielt wahrend des ersten 6-wochigen Zeitraums der Studie (Periode I) WBV mit 3 Behandlungen pro Woche und mindestens 15 Behandlungen innerhalb von 6 Wochen. In den folgenden 6 Wochen (Periode II) erhielten die Patientinnen, die in Periode I nicht mit WBV behandelt wurden die Therapie und die andere Gruppe nicht mehr. Nach 3, 6, 9 und 12 Wochen wurden die Biomarker Ostase und DXP erfasst, das Sturzrisiko anhand des Tinetti-Tests „Tinetti Mobility Test“ (TMT) beurteilt und die Schmerzstarke im unteren Ruckenbereich anhand der numerischen 11-Punkte-Skala ermittelt. Der statistischen Auswertung diente der Wilcoxon-Test (2-Perioden-Crossover-Analyse). Im Ergebnis stellte sich heraus, dass bezuglich der Biomarker des Knochenumbaus keine signifikante Wirkung der Vibrationstherapie (p=0,857 und 0,778) zu verzeichnen war. Im Gegensatz dazu war die Wirkung sowohl auf die Schmerzen im unteren Rucken (p=0,0049) und wie auch auf das Sturzrisiko (p=0,0023) hoch signifikant. WBV scheint eine wertvolle Erganzung fur die symptomatische Behandlung von Schmerzen im unteren Rucken und erhohtem Sturzrisiko bei postmenopausalen Frauen mit Osteoporose zu sein.

Summary Sitagliptin, a dipeptidyl-peptidase 4 (DPP-4) inhibitor, improves blood glucose control in patients with type 2 diabetes by blocking cleavage of glucagon-like peptide 1 (GLP-1). In type 2 diabetes patients sitagliptin use is associated with an increase in minor infections, and in new-onset type 1 diabetes patients the ability of sitagliptin to dampen autoimmunity is currently being tested. DPP-4, also known as CD26, is expressed on leucocytes and can inactivate many chemokines important for leucocyte migration, as well as act as a co-stimulatory molecule on T cells. Therefore, this study was conducted to test whether sitagliptin is immunomodulatory. In this randomized, placebo-controlled trial, healthy volunteers were given sitagliptin or placebo daily for 28 days, and blood was drawn for immune assays. No significant differences were observed in the percentage of leucocyte subsets within peripheral blood mononuclear cells (PBMCs), plasma chemokine/cytokine levels or cytokines released by stimulation of PBMCs with either lipopolysaccharide (LPS) or anti-CD3. Individuals taking sitagliptin displayed increases in the percentage of cells expressing higher levels of CD26 at early time-points compared to placebo controls, but these differences resolved by day 28 of treatment. Therefore, in healthy volunteers, treatment with sitagliptin daily for 28 days does not overtly alter systemic immune function.

Lipodystrophies are a heterogeneous group of conditions in which individuals never develop or progressively lose adipose tissue in parts or all of their bodies (1,2) (Table 1). In this commentary, we will make the case that 1 ) defining lipodystrophy is a work in progress; 2 ) not all forms of lipodystrophy are very rare; 3 ) lipodystrophy and obesity can occur simultaneously and their metabolic consequences are similar and possibly synergistic; 4 ) leptin treatment can have impressive therapeutic effects; and 5 ) these conditions provide useful paradigms to explore the role of the adipose tissue on metabolic homeostasis and to investigate pathways leading from distinct genetic mutations to very different clinical phenotypes. View this table: Table 1 Phenotypic characterization of lipodystrophy subtypes with inclusion of genotype (if available) What is lipodystrophy? A recent consensus statement by the American Association of Clinical Endocrinologists acknowledges the difficulty in determining quantitative criteria and concludes that “lipodystrophy is a condition characterized by regional or total loss or absence of subcutaneous fat. This can occur either in the presence or absence of metabolic abnormalities, and with diverse clinical presentations. While generalized forms of lipodystrophy are often diagnosed during childhood or adolescence, some forms of lipodystrophy, particularly familial partial lipodystrophy, may bear some resemblance to common metabolic disorders managed by adult endocrinologists” (3). There are no specific cutoff levels for percent body fat or leptin concentrations, and it often requires time and long-term follow-up to confirm the diagnosis. Much progress has been made in identifying the genetic etiologies of many lipodystrophy forms (1). How missing or abnormal gene products prevent adipocyte development or cause disappearance of adipose tissue in distinct regions of the human body, however, remains mostly unknown. An excellent example is familial partial lipodystrophy or Dunnigan syndrome, in which numerous mutations of the LMNA gene have been found. LMNA is …

Humans have an innate liking for sweetness, which may have an evolutionary basis. Sweetness typically signals the presence of calories and nutrients and thus, universal liking for sweet taste once served to support survival. In the modern food supply, however, sweetness is often delivered via added sugars and sweeteners devoid of other beneficial nutrients. Nonnutritive sweeteners (NNS) provide sweetness with no or few calories, and therefore may offer a potential strategy to maintain food and beverage palatability, while reducing the caloric content. Despite marked increases in NNS use, their metabolic and health effects are not well-characterized, and particularly little is known about their effects when exposure starts early in life. Herein, we critically review existing data on NNS exposure in utero, during lactation, and throughout childhood and adolescence with respect to taste preferences, weight trajectory, and development of chronic disease. We specifically focus on potential mechanisms through which sweetness exposure during early development may affect key metabolic outcomes.

Glucagon-like peptide 1 agonists such as exenatide have been reported to improve fasting and postprandial lipid profiles and cardiovascular outcomes in patients with type 2 diabetes but to have minimal effects on fasting profiles in patients with type 1 diabetes based on standard lipid measurements. In this study, we used nuclear magnetic resonance (NMR) to determine the effects of exenatide on lipoprotein particle characteristics, which might be indicative of a change in cardiovascular risk in patients with type 1 diabetes. This is an ancillary study of a previously published clinical trial (ClinicalTrials.gov identifier NCT00064714) (1). Briefly, 14 patients were randomized to receive exenatide (10 µg four times daily) either in the first or the second 6-month study period in addition to insulin (1). The patients were also randomized to treatment with or without the immunomodulatory drug daclizumab for 12 months (1). Patients underwent repeated mixed-meal tests after an overnight fast. Tests were conducted at the beginning and end of each 6-month period. To estimate the mean differences between treatment groups, linear mixed models were used to control for sequence and period effects and to allow for correlation within the same group using Stata's pkcross command for the analysis of crossover experiments. Results are …

Background: Pigment epithelium-derived factor (PEDF) is associated with obesity and diabetes complications in adults, yet little is known about PEDF in younger individuals. We investigated the relationship between PEDF and various metabolic biomarkers in young healthy volunteers (HV) and similar-aged patients with diabetes (type 1 and type 2). Methods: A fasting blood sample was collected in 48 HV, 11 patients with type 1 diabetes (T1D), and 11 patients with type 2 diabetes (T2D) 12–25 years of age. In 9 healthy subjects, PEDF was also serially measured during a frequently sampled oral glucose tolerance test (OGTT). Results: PEDF was positively correlated with BMI and systolic blood pressure and negatively correlated with vitamin D. Upon multivariable analysis, BMI and vitamin D were independent predictors of PEDF. Prior to adjustment, PEDF was highest in T2D patients (7,168.9 ± 4417.4 ng/mL) and lowest in individuals with T1D (2,967.7 ± 947.1 ng/mL) but did not differ by diagnosis when adjusted for BMI and vitamin D. Among volunteers who underwent an OGTT, PEDF declined by ∼20% in response to an oral glucose load. Conclusion: PEDF was acutely regulated by a glucose load and was correlated with BMI but not with diabetes. The negative correlation with vitamin D, independent of BMI, raises the question whether PEDF plays a compensatory role in bone matrix mineralization.