Diets Varying in Carbohydrate Content Differentially Alter Brain Activity in Homeostatic and Reward Regions in Adults.

BACKGROUND: Obesity has one of the highest refractory rates of all chronic diseases, in part because weight loss induced by calorie restriction, the first-line treatment for obesity, elicits biological adaptations that promote weight regain. Although acute feeding trials suggest a role for macronutrient composition in modifying brain activity related to hunger and satiety, relevance of these findings to weight-loss maintenance has not been studied. OBJECTIVES: We investigated effects of weight-loss maintenance diets varying in macronutrient content on regional cerebral blood flow (rCBF) in brain regions involved in hunger and reward. METHODS: In conjunction with a randomized controlled feeding trial, we investigated the effects of weight-loss maintenance diets varying in carbohydrate content [high, 60% of total energy: n = 20; 6 men/14 women; mean age: 32.5 y; mean BMI (in kg/m 2): 27.4; moderate, 40% of total energy: n = 22; 10 men/12 women; mean age: 32.5 y; mean BMI: 29.0; low, 20% of total energy: n = 28; 12 men/16 women; mean age: 33.2 y; mean BMI: 27.7] on rCBF in brain regions involved in hunger and reward preprandial and 4 h postprandial after 14-20 wk on the diets. The primary outcome was rCBF in the nucleus accumbens (NAcc) at 4 h postprandial; the secondary outcome was preprandial rCBF in the hypothalamus. RESULTS: Consistent with a priori hypothesis, at 4 h postprandial, NAcc rCBF was 43% higher in adults assigned to the high- compared with low-carbohydrate diet {P[family-wise error (FWE)-corrected] < 0.05}. Preprandial hypothalamus rCBF was 41% higher on high-carbohydrate diet [P(FWE-corrected) < 0.001]. Exploratory analyses revealed that elevated rCBF on high-carbohydrate diet was not specific to prandial state: preprandial NAcc rCBF [P(FWE-corrected) < 0.001] and 4 h postprandial rCBF in hypothalamus [P(FWE-corrected) < 0.001]. Insulin secretion predicted differential postprandial activation of the NAcc by diet. CONCLUSIONS: We report significant differences in rCBF in adults assigned to diets varying in carbohydrate content for several months, which appear to be partially associated with insulin secretion. These findings suggest that chronic intake of a high-carbohydrate diet may affect brain reward and homeostatic activity in ways that could impede weight-loss maintenance. This trial was registered at clinicaltrials.gov as NCT02300857.

Do adolescents with extreme obesity differ according to previous treatment seeking behavior? The Youth with Extreme obesity Study (YES) cohort.

OBJECTIVES: Adolescent extreme obesity is associated with somatic and psychiatric comorbidity, low quality of life, and social dysfunction. Nevertheless, few adolescents seek obesity treatment, thus many may elope appropriate care. We examine whether previous treatment seeking relates to disease burden, and whether previously non-treatment seeking adolescents accept diagnostic and therapeutic offers. This information is important to inform intervention strategies. METHODS: The Youth with Extreme obesity Study (YES) is a prospective, multicenter cohort study. We developed a novel recruitment strategy to span medical and vocational ascertainment settings and directly compare previously treatment seeking and non-treatment seeking youth. Participants aged 14-24 years; BMI ≥ 30 kg/m2 were enrolled at four medical- and one job centers. We present comorbidity and psycho-social baseline data by sex, obesity WHO grade I-III, and treatment-seeking status, defined as self-reported previous participation in a weight-loss program. RESULTS: Of 431 participants, 47% were male; mean age 16.6 (standard deviation 2.3) years, BMI 39.2 (7.5) kg/m2. Somatic comorbidity increased with obesity grade, p < 0.05: hypertension (42, 55, 64%), dyslipidemia (28, 24, 37%,), dysglycemia (9, 19, 20%,), elevated transaminases (15, 26, 30%). Quality of life (EQ5 D) decreased (74, 71, 70). Rates of psychiatric disorders were stable: depression 11%, attention deficit disorder 6%, substance use disorder 2%, self-injurious behavior 5%, suicide attempt 3%. Only 63% (56, 64, 69%) reported previous treatment seeking. Acceptance of the diagnostic (89%) or therapeutic (28%) program, medical or psychosocial situation did not differ by treatment seeking status. Acceptance of the therapeutic program was generally low, but high at the job center (92%). CONCLUSION: Irrespective of previous treatment seeking, adolescent extreme obesity was associated with high comorbidity and psychosocial burden. Acceptance of the diagnostic program overall and the therapeutic program at the job center were high. This underscores the need of innovative, accessible programs beyond the currently offered care.

Effects of sodium benzoate, a widely used food preservative, on glucose homeostasis and metabolic profiles in humans.

Sodium benzoate is a widely used preservative found in many foods and soft drinks. It is metabolized within mitochondria to produce hippurate, which is then cleared by the kidneys. We previously reported that ingestion of sodium benzoate at the generally regarded as safe (GRAS) dose leads to a robust excursion in the plasma hippurate level [1]. Since previous reports demonstrated adverse effects of benzoate and hippurate on glucose homeostasis in cells and in animal models, we hypothesized that benzoate might represent a widespread and underappreciated diabetogenic dietary exposure in humans. Here, we evaluated whether acute exposure to GRAS levels of sodium benzoate alters insulin and glucose homeostasis through a randomized, controlled, cross-over study of 14 overweight subjects. Serial blood samples were collected following an oral glucose challenge, in the presence or absence of sodium benzoate. Outcome measurements included glucose, insulin, glucagon, as well as temporal mass spectrometry-based metabolic profiles. We did not find a statistically significant effect of an acute oral exposure to sodium benzoate on glucose homeostasis. Of the 146 metabolites targeted, four changed significantly in response to benzoate, including the expected rise in benzoate and hippurate. In addition, anthranilic acid, a tryptophan metabolite, exhibited a robust rise, while acetylglycine dropped. Although our study shows that GRAS doses of benzoate do not have an acute, adverse effect on glucose homeostasis, future studies will be necessary to explore the metabolic impact of chronic benzoate exposure.

Twelve-Month Outcomes after Metabolic and Bariatric Surgery among Youths Participating in a Structured Preparation and Follow-Up Program: Results of the Youth with Extreme Obesity Study.

INTRODUCTION: While invasive and associated with risks, metabolic and bariatric surgery (MBS) can promote sustained weight loss and substantial health benefits in youths with extreme obesity. The path toward informed decision making for or against MBS is poorly characterized and postoperative follow-up to assess risks and benefits is inconsistent. In youths with extreme obesity, we aimed to evaluate decision making toward MBS, as well as MBS outcomes and adherence with follow-up and recommendations in the setting of a structured pre- and post-MBS program. METHODS: Participants were recruited in the setting of the multicenter "Youth with Extreme Obesity Study" (YES). YES is a cohort study in adolescents and young adults aged 14-24 years with obesity (BMI ≥30.0 kg/m2) who were recruited at four medical centers and one job center in Germany between 2012 and 2018. Participants at two medical centers with BMI ≥35 kg/m2, aged 14-24 years, and interested in pursuing MBS were included in the subproject 3 "Safety and effectiveness of weight loss surgery in adolescents with severe obesity within a structured pre- and post-surgery treatment program - an observational study" that comprised a 2-months pre- and 12-months post-MBS program. RESULTS: Twenty-eight of 169 youths (17%) with BMI ≥35 kg/m2 were interested in MBS. Twenty-six fulfilled published eligibility criteria for MBS and participated in the structured pre-MBS preparation program. Of these, 9 participants (2 females) decided against, and 17 (n = 11 females) decided for MBS (sleeve gastrectomy). The 12-month follow-up rate was high (16/17 [94%]) and all participants achieved significant weight reduction (ΔBMI: -16.1 ± 5.6 kg/m2). Eleven of 16 participants (69%) reported taking the prescribed dietary supplements in the first year after MBS, but only five of them (31%) did so daily. In contrast to the high 12-month retention rate, follow-up after completion of the structured program was low at 24-months (9/16 [56%]) and at 36-months (5/15 [36%]), respectively. CONCLUSION: Participants demonstrated active decision making for or against MBS and high adherence with the structured pre- and 12 months post-MBS program, but participation was low thereafter. These findings endorse the need for longer term structured post-MBS programs to capture long-term outcomes and provide adequate care in this vulnerable group at the transition to adulthood.

Carbohydrate restriction for diabetes: rediscovering centuries-old wisdom.

Carbohydrate restriction, used since the 1700s to prolong survival in people with diabetes, fell out of favor after the discovery of insulin. Despite costly pharmacological and technological developments in the last few decades, current therapies do not achieve optimal outcomes, and most people with diabetes remain at high risk for micro- and macrovascular complications. Recently, low-carbohydrate diets have regained popularity, with preliminary evidence of benefit for body weight, postprandial hyperglycemia, hyperinsulinemia, and other cardiometabolic risk factors in type 2 diabetes and, with more limited data, in type 1 diabetes. High-quality, long-term trials are needed to assess safety concerns and determine whether this old dietary approach might help people with diabetes attain clinical targets more effectively, and at a lower cost, than conventional treatment.

Behavioral Characteristics and Self-Reported Health Status among 2029 Adults Consuming a "Carnivore Diet".

BACKGROUND: The "carnivore diet," based on animal foods and excluding most or all plant foods, has attracted recent popular attention. However, little is known about the health effects and tolerability of this diet, and concerns for nutrient deficiencies and cardiovascular disease risk have been raised. OBJECTIVES: We obtained descriptive data on the nutritional practices and health status of a large group of carnivore diet consumers. METHODS: A social media survey was conducted 30 March-24 June, 2020 among adults self-identifying as consuming a carnivore diet for ≥6 mo. Survey questions interrogated motivation, dietary intake patterns, symptoms suggestive of nutritional deficiencies or other adverse effects, satisfaction, prior and current health conditions, anthropometrics, and laboratory data. RESULTS: A total of 2029 respondents (median age: 44 y, 67% male) reported consuming a carnivore diet for 14 mo (IQR: 9-20 mo), motivated primarily by health reasons (93%). Red meat consumption was reported as daily or more often by 85%. Under 10% reported consuming vegetables, fruits, or grains more often than monthly, and 37% denied vitamin supplement use. Prevalence of adverse symptoms was low (<1% to 5.5%). Symptoms included gastrointestinal (3.1%-5.5%), muscular (0.3%-4.0%), and dermatologic (0.1%-1.9%). Participants reported high levels of satisfaction and improvements in overall health (95%), well-being (66%-91%), various medical conditions (48%-98%), and median [IQR] BMI (in kg/m2) (from 27.2 [23.5-31.9] to 24.3 [22.1-27.0]). Among a subset reporting current lipids, LDL-cholesterol was markedly elevated (172 mg/dL), whereas HDL-cholesterol (68 mg/dL) and triglycerides (68 mg/dL) were optimal. Participants with diabetes reported benefits including reductions in median [IQR] BMI (4.3 [1.4-7.2]), glycated hemoglobin (0.4% [0%-1.7%]), and diabetes medication use (84%-100%). CONCLUSIONS: Contrary to common expectations, adults consuming a carnivore diet experienced few adverse effects and instead reported health benefits and high satisfaction. Cardiovascular disease risk factors were variably affected. The generalizability of these findings and the long-term effects of this dietary pattern require further study.

Treatment of Hypothalamic Obesity with Dextroamphetamine: A Case Series.

BACKGROUND: A limited number of published case reports suggest a positive effect of dextroamphetamine, an adrenergic agonist affecting both the central nervous system (CNS) and peripheral nervous system, on physical activity and weight in patients with hypothalamic obesity (intractable obesity following CNS insult). Here, we present our clinical experience with dextroamphetamine treatment for hypothalamic obesity. METHODS: The clinical course of all patients started on dextroamphetamine treatment for severe hypothalamic obesity at our institution between 2010 and 2013 is reported. Dextroamphetamine administration was initiated at a single dose of 5 mg per day and titrated to effect up to a dose of 20 mg/day. BMI z-score velocity was calculated as change in BMI z-score over standardized intervals of 12 months. Parameters of treatment success and adverse events were assessed in a standardized fashion. RESULTS: Seven patients (2 males; mean age 17.6 years [range 12.9-24.5]) underwent individual treatment attempts with dextroamphetamine between 2010 and 2013. The primary diagnoses were craniopharyngioma (n = 4), ganglioglioma WHO I (n = 1), astrocytoma (n = 1), and neonatal meningitis (n = 1). Time from initial CNS insult to initiation of dextroamphetamine treatment averaged 5.2 years (range 2.4 months to 16.5 years). All patients demonstrated a steady increase in BMI z-score from the time of initial diagnosis until initiation of dextroamphetamine treatment. Mean baseline BMI z-score was +3.17 ± 0.93 (+1.9 to +4.4). Mean BMI z-score velocity decelerated to -0.18 ± 0.12 per year during the first year of treatment and stabilized at +0.05 ± 0.32 per year during the second year of treatment. No significant adverse events were reported. CONCLUSION: Dextroamphetamine treatment led to stabilization or reduction of BMI z-score in a cohort of 7 patients with hypothalamic obesity, with no adverse effects. Considering the projected increase in BMI z-score according to the natural course of the disease, these findings are promising and warrant further study.

Management of Type 1 Diabetes With a Very Low-Carbohydrate Diet.

OBJECTIVES: To evaluate glycemic control among children and adults with type 1 diabetes mellitus (T1DM) who consume a very low-carbohydrate diet (VLCD). METHODS: We conducted an online survey of an international social media group for people with T1DM who follow a VLCD. Respondents included adults and parents of children with T1DM. We assessed current hemoglobin A1c (HbA1c) (primary measure), change in HbA1c after the self-reported beginning of the VLCD, total daily insulin dose, and adverse events. We obtained confirmatory data from diabetes care providers and medical records. RESULTS: Of 316 respondents, 131 (42%) were parents of children with T1DM, and 57% were of female sex. Suggestive evidence of T1DM (based on a 3-tier scoring system in which researchers took into consideration age and weight at diagnosis, pancreatic autoimmunity, insulin requirement, and clinical presentation) was obtained for 273 (86%) respondents. The mean age at diagnosis was 16 ± 14 years, the duration of diabetes was 11 ± 13 years, and the time following a VLCD was 2.2 ± 3.9 years. Participants had a mean daily carbohydrate intake of 36 ± 15 g. Reported mean HbA1c was 5.67% ± 0.66%. Only 7 (2%) respondents reported diabetes-related hospitalizations in the past year, including 4 (1%) for ketoacidosis and 2 (1%) for hypoglycemia. CONCLUSIONS: Exceptional glycemic control of T1DM with low rates of adverse events was reported by a community of children and adults who consume a VLCD. The generalizability of these findings requires further studies, including high-quality randomized controlled trials.

Effects of dietary glycemic index on brain regions related to reward and craving in men.

BACKGROUND: Qualitative aspects of diet influence eating behavior, but the physiologic mechanisms for these calorie-independent effects remain speculative. OBJECTIVE: We examined effects of the glycemic index (GI) on brain activity in the late postprandial period after a typical intermeal interval. DESIGN: With the use of a randomized, blinded, crossover design, 12 overweight or obese men aged 18-35 y consumed high- and low-GI meals controlled for calories, macronutrients, and palatability on 2 occasions. The primary outcome was cerebral blood flow as a measure of resting brain activity, which was assessed by using arterial spin-labeling functional magnetic resonance imaging 4 h after test meals. We hypothesized that brain activity would be greater after the high-GI meal in prespecified regions involved in eating behavior, reward, and craving. RESULTS: Incremental venous plasma glucose (2-h area under the curve) was 2.4-fold greater after the high- than the low-GI meal (P = 0.0001). Plasma glucose was lower (mean ± SE: 4.7 ± 0.14 compared with 5.3 ± 0.16 mmol/L; P = 0.005) and reported hunger was greater (P = 0.04) 4 h after the high- than the low-GI meal. At this time, the high-GI meal elicited greater brain activity centered in the right nucleus accumbens (a prespecified area; P = 0.0006 with adjustment for multiple comparisons) that spread to other areas of the right striatum and to the olfactory area. CONCLUSIONS: Compared with an isocaloric low-GI meal, a high-GI meal decreased plasma glucose, increased hunger, and selectively stimulated brain regions associated with reward and craving in the late postprandial period, which is a time with special significance to eating behavior at the next meal. This trial was registered at clinicaltrials.gov as NCT01064778.

A case of phace syndrome and acquired hypopituitarism?

BACKGROUND: PHACE is a neurocutaneous syndrome associated with: Posterior fossa brain malformations, large "segmental" facial hemangiomas, arterial cerebrovascular-, cardiovascular-, and eye anomalies. CASE VIGNETTE: We are reporting a girl with PHACE syndrome. The patient had a congenital right-sided facial hemangioma with plaque-morphology. At age 11 years and 2 months she presented with short stature, markedly decreased growth velocity and signs and symptoms suggestive of hypothyroidism. Magnetic Resonance Imaging (MRI) of the brain revealed complex structural and cerebrovascular arterial anomalies, including an empty sella. Testing of pituitary function revealed multiple pituitary dysfunctions, including absolute growth hormone deficiency, hypogonadotropic hypogonadism, central hypothyroidism, and secondary adrenal insufficiency. CONCLUSIONS: This case suggests the necessity to screen all patients with PHACE syndrome and intracranial malformations for pituitary dysfunction at regular intervals.