A review of the carbohydrate-insulin model of obesity.

This corrects the article DOI: 10.1038/ejcn.2017.21.

A quantitative analysis of statistical power identifies obesity end points for improved in vivo preclinical study design.

The design of well-powered in vivo preclinical studies is a key element in building the knowledge of disease physiology for the purpose of identifying and effectively testing potential antiobesity drug targets. However, as a result of the complexity of the obese phenotype, there is limited understanding of the variability within and between study animals of macroscopic end points such as food intake and body composition. This, combined with limitations inherent in the measurement of certain end points, presents challenges to study design that can have significant consequences for an antiobesity program. Here, we analyze a large, longitudinal study of mouse food intake and body composition during diet perturbation to quantify the variability and interaction of the key metabolic end points. To demonstrate how conclusions can change as a function of study size, we show that a simulated preclinical study properly powered for one end point may lead to false conclusions based on secondary end points. We then propose the guidelines for end point selection and study size estimation under different conditions to facilitate proper power calculation for a more successful in vivo study design.

A review of the carbohydrate-insulin model of obesity.

The carbohydrate-insulin model of obesity theorizes that diets high in carbohydrate are particularly fattening due to their propensity to elevate insulin secretion. Insulin directs the partitioning of energy toward storage as fat in adipose tissue and away from oxidation by metabolically active tissues and purportedly results in a perceived state of cellular internal starvation. In response, hunger and appetite increases and metabolism is suppressed, thereby promoting the positive energy balance associated with the development of obesity. Several logical consequences of this carbohydrate-insulin model of obesity were recently investigated in a pair of carefully controlled inpatient feeding studies whose results failed to support key model predictions. Therefore, important aspects of carbohydrate-insulin model have been experimentally falsified suggesting that the model is too simplistic. This review describes the current state of the carbohydrate-insulin model and the implications of its recent experimental tests.

Striatal dopamine D2-like receptor correlation patterns with human obesity and opportunistic eating behavior.

The obesity epidemic is believed to be driven by a food environment that promotes consumption of inexpensive, convenient, high-calorie, palatable foods. Individual differences in obesity susceptibility or resistance to weight loss may arise because of alterations in the neurocircuitry supporting food reward and eating habits. In particular, dopamine signaling in the ventromedial striatum is thought to encode food reward and motivation, whereas dopamine in the dorsal and lateral striatum orchestrates the development of eating habits. We measured striatal dopamine D2-like receptor binding potential (D2BP) using positron emission tomography with [(18)F]fallypride in 43 human subjects with body mass indices (BMI) ranging from 18 to 45 kg m(-)(2). Opportunistic eating behavior and BMI were both positively associated with D2BP in the dorsal and lateral striatum, whereas BMI was negatively associated with D2BP in the ventromedial striatum. These results suggest that obese people have alterations in dopamine neurocircuitry that may increase their susceptibility to opportunistic overeating while at the same time making food intake less rewarding, less goal directed and more habitual. Whether or not the observed neurocircuitry alterations pre-existed or occurred as a result of obesity development, they may perpetuate obesity given the omnipresence of palatable foods and their associated cues.

Functional body composition and related aspects in research on obesity and cachexia: report on the 12th Stock Conference held on 6 and 7 September 2013 in Hamburg, Germany.

The 12th Stock Conference addressed body composition and related functions in two extreme situations, obesity and cancer cachexia. The concept of 'functional body composition' integrates body components into regulatory systems relating the mass of organs and tissues to corresponding in vivo functions and metabolic processes. This concept adds to an understanding of organ/tissue mass and function in the context of metabolic adaptations to weight change and disease. During weight gain and loss, there are associated changes in individual body components while the relationships between organ and tissue mass are fixed. Thus an understanding of body weight regulation involves an examination of the relationships between organs and tissues rather than individual organ and tissue masses only. The between organ/tissue mass relationships are associated with and explained by crosstalks between organs and tissues mediated by cytokines, hormones and metabolites that are coupled with changes in body weight, composition and function as observed in obesity and cancer cachexia. In addition to established roles in intermediary metabolism, cell function and inflammation, organ-tissue crosstalk mediators are determinants of body composition and its change with weight gain and loss. The 12th Stock Conference supported Michael Stocks' concept of gaining new insights by integrating research ideas from obesity and cancer cachexia. The conference presentations provide an in-depth understanding of body composition and metabolism.

Allometric relationship between changes of visceral fat and total fat mass.

OBJECTIVE: To elucidate the mathematical relationship between changes of visceral adipose tissue (VAT) and total body fat mass (FM) during weight loss. DESIGN: We hypothesized that changes of VAT mass are allometrically related to changes of FM, regardless of the type of weight-loss intervention, as defined by the differential equation dVAT/dFM=k x VAT/FM, where k is a dimensionless constant. We performed a systematic search of the published literature for studies that included measurements of VAT changes via magnetic resonance imaging (MRI) or computed tomography (CT) imaging along with measurements of FM changes by dual-energy X-ray absorptiometry, hydrodensitometry, air-displacement plethysmography or whole-body MRI or CT imaging. We then examined whether or not the data could be explained by the allometric model. RESULT: We found 37 published studies satisfying our search criteria, representing 1407 men and women of various ethnicities, degrees of adiposity and weight-loss interventions. The hypothesized allometric equation relating changes of VAT and FM accurately modeled the data for both men and women and for all methods of weight loss studied. The best-fit value for the dimensionless constant was k=1.3+/-0.1 and the resulting model had an R(2)=0.73. CONCLUSION: This is the first report to reveal an allometric relationship between changes of VAT and FM that holds for both genders as well as a wide variety of weight-loss interventions including bariatric surgery, caloric restriction with or without exercise and exercise alone. We conclude that changes of VAT are primarily determined by FM changes as well as the initial VAT to FM ratio.

What is the required energy deficit per unit weight loss?

One of the most pervasive weight loss rules is that a cumulative energy deficit of 3500 kcal is required per pound of body weight loss, or equivalently 32.2 MJ kg(-1). Under what conditions is it appropriate to use this rule of thumb and what are the factors that determine the cumulative energy deficit required per unit weight loss? Here, I examine this question using a modification of the classic Forbes equation that predicts the composition of weight loss as a function of the initial body fat and magnitude of weight loss. The resulting model predicts that a larger cumulative energy deficit is required per unit weight loss for people with greater initial body fat-a prediction supported by published weight loss data from obese and lean subjects. This may also explain why men can lose more weight than women for a given energy deficit since women typically have more body fat than men of similar body weight. Furthermore, additional weight loss is predicted to be associated with a lower average cumulative energy deficit since a greater proportion of the weight loss is predicted to result from loss of lean body mass, which has a relatively low energy density in comparison with body fat. The rule of thumb approximately matches the predicted energy density of lost weight in obese subjects with an initial body fat above 30 kg but overestimates the cumulative energy deficit required per unit weight loss for people with lower initial body fat. International Journal of Obesity (2008) 32, 573-576; doi:10.1038/sj.ijo.0803720; published online 11 September 2007.

How adaptations of substrate utilization regulate body composition.

OBJECTIVE: To elucidate the mathematical relationship between longitudinal changes of body composition and the adaptations of substrate utilization required to produce those changes. DESIGN: We developed a simple mathematical model of macronutrient balance. By using an empirical relationship describing lean body mass as a function of fat mass, we derived a mathematical expression for how substrate utilization adapts to changes of diet, energy expenditure and body fat such that energy imbalances produced the required changes of body composition. RESULTS: The general properties of our model implied that short-term changes of dietary fat alone had little impact on either fat or non-fat oxidation rates, in agreement with indirect calorimetry data. In contrast, changes of non-fat intake caused robust adaptations of both fat and non-fat oxidation rates. Without fitting any model parameters, the predicted body composition changes and oxidation rates agreed with experimental studies of overfeeding and underfeeding when the measured food intake, energy expenditure and initial body composition were used as model inputs. CONCLUSION: This is the first report to define the quantitative connection between longitudinal changes of body composition and the required relationship between substrate utilization, diet, energy expenditure and body fat mass. The mathematical model predictions are in good agreement with experimental data and provide the basis for future study of how changes of substrate utilization impact body composition regulation.

A longitudinal investigation of speaking rate in preschool children who stutter.

Both clinical and theoretical interest in stuttering as a disorder of speech motor control has led to numerous investigations of speaking rate in people who stutter. The majority of these studies, however, has been conducted with adult and school-age groups. Most studies of preschoolers have included older children. Despite the ongoing theoretical and clinical focus on speaking rate in young children who stutter and their parents, no longitudinal or cross-sectional studies have been conducted to answer questions about the possible developmental link between stuttering and the rate of speech, or about differences in rate development between preschool children who stutter and normally fluent children. This investigation compared changes in articulatory rate over a period of 2 years in subgroups of preschool-age children who stutter and normally fluent children. Within the group of stuttering children, comparisons also were made between those who exhibited persistent stuttering and those who eventually recovered without intervention. Furthermore, the study compared two metrics of articulatory rate. Spontaneous speech samples, collected longitudinally over a 2-year period, were analyzed acoustically to determine speaking rate measured in number of syllables and phones per second. Results indicated no differences among the 3 groups when articulation rate was measured in syllables per second. Using the phones per second measure, however, significant group differences were found when comparing the control group to the recovered and persistent groups.

Reversion to a previously learned foreign accent after stroke.

Foreign accent syndrome occurs rarely after stroke. Most patients with this syndrome develop an aphasia characterized by a new accent. This report presents a 48-year-old man who sustained a left parietal hemorrhagic stroke resulting in right hemiparesis and the inability to speak. As spontaneous speech emerged several weeks later, he was noted to have a Broca's aphasia and a Dutch accent. Analysis of his speech demonstrated final consonant deletion, substitution of "d" for "th" sounds, vowel distortions, additional "uh" syllables added at the end of words, and errors in voicing. This speech pattern has persisted for more than 5 years after the stroke. Elicitation of additional history found that the patient was born in Holland and lived there until the age of 5 years, when he moved to the United States with his family. Before his stroke, he had no foreign accent. This report illustrates the importance of considering foreign accent syndrome during aphasia recovery and suggests several pathogenetic mechanisms that may contribute to the development of this syndrome.

Comparison of fundamental frequency and perturbation measurements among three analysis systems.

The need for standardization of procedures in approaches to voice measurement has been recently emphasized. The purpose of this study was to determine the extent to which the acoustic perturbation measurements from three different analysis systems agree when standardized recording and analysis procedures are used. High-quality acoustic voice recordings from 20 patients were analyzed. The results showed that, although fundamental frequency measurements were in strong agreement among the three systems tested, frequency and amplitude perturbation measurements were not in agreement. The underlying approaches to perturbation measurement appeared to be sufficiently different to produce different results. An argument is made for a standardized set of acoustic signals representing normal, dysphonic, and synthesized voices with known characteristics to facilitate testing of new acoustic analysis systems and confirm measurement accuracy and sensitivity.

Variations across time in acoustic and electroglottographic measures of phonatory function in women with and without vocal nodules.

The purpose of this investigation was to identify variations over time in phonatory function of women with and without vocal nodules using acoustic and electroglottographic measures. Subjects were 10 women with vocal nodules (mean age = 22.1, range = 19-25) and 10 women with healthy larynges (mean age = 25.0, range = 18-32). Electroglottographic and audio recordings of speech were obtained for each subject over 3 consecutive days at three target times: morning, afternoon, and evening. Estimates of fundamental frequency (Hz), jitter (msec), shimmer (dB), and signal-to-noise ratio (dB) were made from a 1000 msec midportion of the vowel /a/ produced in a carrier phrase. In addition, a closed-to-open ratio was derived from the EGG duty cycle of the same 1000 msec segment and used to estimate timing characteristics of vocal fold vibration. The results showed no significant differences between the groups regarding a pattern of change in the acoustic or the EGG measures across times throughout the day. Furthermore, the experimental group demonstrated significantly lower closed-to-open ratios than the control group. With this exception, no other statistically significant differences between the groups were found.

Temporal relations within repetitions of preschool children near the onset of stuttering: a preliminary report.

The purpose of this study was to compare duration characteristics of single repetitions of single-syllable words in the speech of preschool children who stutter (N = 15) recorded near the onset of their stuttering to those of control nonstuttering children (N = 18). Disfluent episodes were identified in audio tape recordings of the subjects' conversational speech. The digitized signals were analyzed by means of the CSpeech computer software (Milenkovic, 1987). Using visual displays of the sound-pressure waveforms, as well as spectrography, the durations of the first production of the word (1st Unit), the second production (2nd Unit), the silent interval, and the total disfluency were measured. There were no statistically significant differences between the two groups on any of these segments although there was a tendency for the stutters to exhibit shorter silent intervals between repeated units. Relative measures, however, indicated that the ratio of the 2nd Unit to the total disfluency was significantly larger for the stutterers than the controls. For both groups, the ratio of the 1st to the 2nd Unit was positive, that is, the first production of the word was longer than the second. There was also a tendency for the ratio of the silent interval to total disfluency to be smaller for the stutterers. Overall, there appears to be a tendency for repetitions of very early stutterers to be faster than repetitions of nonstuttering children.

Differential strength decline in patients with osteoarthritis of the knee: revision of a hypothesis.

A quadriceps-to-hamstring isometric peak torque ratio (Q/H ratio) of approximately 2.0 is considered necessary for appropriate knee biomechanics. Lower ratios may affect the function of persons with osteoarthritis (OA) and the progression of the disease. This study examined the isometric Q/H ratio in subjects with and without OA of the knee and explored the effect of age, pain, and joint enlargement on the ratio. Twenty-one pairs of subjects (OA, control) were matched on age (mean = 62.6 years; SD = 13.9), gender (F = 17, M = 4), and leg dominance (Dominant = 10, Nondominant = 11). Isometric quadriceps and hamstring peak torque, knee pain, and joint enlargement were measured. Paired t-tests demonstrated that the OA group had significantly lower quadriceps peak torque than the control group but did not have significantly lower hamstring peak torque or gravity-corrected isometric Q/H ratio. Age correlated with the ratio in subjects without OA (rho = -0.46; P = 0.03) but not in subjects with OA. Pain was not significantly correlated with the ratio in either group. Joint enlargement correlated with the ratio in the OA group (rho = -0.45; P = 0.03). The gravity-corrected isometric Q/H ratio appears to decrease with age in subjects without OA. In subjects with OA, the Q/H ratio appears not to change with disease, pain, or age. Joint enlargement may decrease the ratio and merits further study.

Fundamental frequency, jitter, and shimmer in preschoolers who stutter.

This investigation examined acoustic correlates of phonatory control in the speech of 10 preschool-aged boys who were stutterers (mean age = 45 months) recorded relatively close to the time of stuttering onset and in the speech of 10 boys who were nonstutterers (mean age = 46 months). For each subject, acoustic measurements of fundamental frequency, jitter, and shimmer were extracted from the 100 msec midportion of 30 vowels selected from fluent utterances in spontaneous speech. Significant differences between the two groups for shimmer measures are among the few positive findings in recent publications concerning the fluent speech of children who stutter.

[Brain function and level of consciousness in fentanyl anesthesia in heart surgery]. / Gehirnfunktion und Bewusstseinslage während der Fentanylnarkose in der Herzchirurgie.

The level of consciousness and the supply/demand ratio of oxygen in the brain was studied in anaesthetized patients undergoing open heart surgery. Anaesthesia was accomplished with intravenous fentanyl; 26 patients received 25 micrograms/kg and 24 patients received 50 micrograms/kg fentanyl. In addition only pancuronium bromide was administered for muscular relaxation; all patients were ventilated with 100% oxygen. The following measurements were made during induction and prior to cardiopulmonary bypass and in the first ten minutes of bypass: 1. EEG with the Klein EEG Analyzer. This instrument permits simultaneous analysis of frequency and amplitude while eliminating muscular artifacts. 2. Cerebral oxygen with the Niroscope. This instrument uses an infrared light beam through the brain to evaluate cerebral oxygen sufficiency. 3. Oxygen supply/demand ratio in the whole body, estimated from mixed venous oxygen saturation measured with a fiberoptic pulmonary artery catheter. Clinical unconsciousness occurred in all patients within about 30 s after the administration of fentanyl. Simultaneously the EEG showed a significant decrease in frequency and an increase in amplitude. With the Niroscope no change in oxygen supply and demand was seen in any patients. This is in contrast to previous studies with thiopental, where changes were seen. A slight increase in mixed venous oxygen saturation was observed. This indicates an increase in the total oxygen supply/demand ratio, probably due to decreased muscle metabolism induced by pancuronium bromide paralysis. From the end of induction until cardiopulmonary bypass a slight increase in cerebral electrical activity was observed; an additional increase occurred in the first ten minutes of bypass.(ABSTRACT TRUNCATED AT 250 WORDS)