Insulin resistance before type 2 diabetes onset is associated with increased risk of albuminuria after diabetes onset: A prospective cohort study.

AIM: Reduced renal insulin signalling is implicated in the pathogenesis of albuminuria. We sought to investigate whether insulin action and secretion, measured before diabetes onset, are associated with the development of albuminuria after diabetes onset. MATERIALS AND METHODS: Baseline body composition, insulin sensitivity by hyperinsulinaemic-euglycaemic clamp at submaximal and maximal insulin stimulation (240 and 2400 pmol/m2/min; M-low and M-high), and insulin secretion by intravenous glucose tolerance test [acute insulin response (AIR)] were measured in 170 Southwestern Indigenous American adults who subsequently developed diabetes. After diabetes onset and during the median follow-up of 13.6 years, 81 participants (48%) developed albuminuria (urine albumin-to-creatinine ratio ≥30 mg/g). Separate associations of M-low, M-high and AIR (per 1-SD change) with the risk of albuminuria were assessed by Cox regression models adjusted for age, sex and body fat (%). RESULTS: Participants who developed albuminuria were of similar age (26.4 ± 5.4 vs. 27.5 ± 6.1 years), sex (46% vs. 48% male), body fat (36.4 ± 7.5 vs. 35.7 ± 7.9%) and AIR [2.3 ± 0.3 vs. 2.3 ± 0.3, pmol/L (log)] as those who did not develop albuminuria but had lower insulin sensitivity [M-low: 0.33 ± 0.08 vs. 0.36 ± 0.12, p = .03; M-high: 0.87 ± 0.11 vs. 0.91 ± 0.12, p = .02; mg/kg-metabolic body size/min (log)]. In separate adjusted models, lower M-low and M-high were both associated with an increased risk for albuminuria [hazard ratio (HR) 1.51, 95% confidence interval (CI) 1.14, 2.00, p = .004; HR 1.31, 95% CI 1.06, 1.63, p = .01), whereas AIR was not (HR 1.15, 95% CI 0.87, 1.56, p = .3). CONCLUSIONS: Lower insulin sensitivity is associated with the development of albuminuria, suggesting a role for insulin signalling in the pathogenesis of proteinuria.

Dietary metabolic signatures and cardiometabolic risk.

AIMS: Observational studies of diet in cardiometabolic-cardiovascular disease (CM-CVD) focus on self-reported consumption of food or dietary pattern, with limited information on individual metabolic responses to dietary intake linked to CM-CVD. Here, machine learning approaches were used to identify individual metabolic patterns related to diet and relation to long-term CM-CVD in early adulthood. METHODS AND RESULTS: In 2259 White and Black adults (age 32.1 ± 3.6 years, 45% women, 44% Black) in the Coronary Artery Risk Development in Young Adults (CARDIA) study, multivariate models were employed to identify metabolite signatures of food group and composite dietary intake across 17 food groups, 2 nutrient groups, and healthy eating index-2015 (HEI2015) diet quality score. A broad array of metabolites associated with diet were uncovered, reflecting food-related components/catabolites (e.g. fish and long-chain unsaturated triacylglycerols), interactions with host features (microbiome), or pathways broadly implicated in CM-CVD (e.g. ceramide/sphingomyelin lipid metabolism). To integrate diet with metabolism, penalized machine learning models were used to define a metabolite signature linked to a putative CM-CVD-adverse diet (e.g. high in red/processed meat, refined grains), which was subsequently associated with long-term diabetes and CVD risk numerically more strongly than HEI2015 in CARDIA [e.g. diabetes: standardized hazard ratio (HR): 1.62, 95% confidence interval (CI): 1.32-1.97, P < 0.0001; CVD: HR: 1.55, 95% CI: 1.12-2.14, P = 0.008], with associations replicated for diabetes (P < 0.0001) in the Framingham Heart Study. CONCLUSION: Metabolic signatures of diet are associated with long-term CM-CVD independent of lifestyle and traditional risk factors. Metabolomics improves precision to identify adverse consequences and pathways of diet-related CM-CVD.

Identification and characterization of the long non-coding RNA NFIA-AS2 as a novel locus for body mass index in American Indians.

BACKGROUND: Genome-wide association studies have shown that body mass index (BMI), an estimate of obesity, is highly polygenic. Individual variants typically have small effect sizes, making it challenging to identify unique loci in under-represented ethnic groups which lack statistical power due to their small sample size. Yet obesity is a major health disparity and is particularly prevalent in southwestern American Indians. Here, we identify and characterize a new locus for BMI that was detected by analyzing moderate associations with BMI obtained in a population-based sample of southwestern American Indians together with the well-powered GIANT dataset. METHODS: Genotypes for 10.5 million variants were tested for association with BMI in 5870 American Indians and 2600 variants that showed an association P < 10-3 in the American Indian sample were combined in a meta-analysis with the BMI data reported in GIANT (N = 240,608). The newly identified gene, NFIA-AS2 was functionally characterized, and the impact of its lead associated variant rs1777538 was studied both in-silico and in-vitro. RESULTS: Rs1777538 (T/C; C allele frequency = 0.16 in American Indians and 0.04 in GIANT, meta-analysis P = 5.0 × 10-7) exhibited a large effect in American Indians (1 kg/m2 decrease in BMI per copy of C allele). NFIA-AS2 was found to be a nuclear localized long non-coding RNA expressed in tissues pertinent to human obesity. Analysis of this variant in human brown preadipocytes showed that NFIA-AS2 transcripts carrying the C allele had increased RNA degradation compared to the T allele transcripts (half-lives = 9 h, 13 h respectively). During brown adipogenesis, NFIA-AS2 featured a stage-specific regulation of nearby gene expression where rs1777538 demonstrated an allelic difference in regulation in the mature adipocytes (the strongest difference was observed for L1TD1, P = 0.007). CONCLUSION: Our findings support a role for NFIA-AS2 in regulating pathways that impact BMI.

How can we assess "thrifty" and "spendthrift" phenotypes?

PURPOSE OF REVIEW: There is a large inter-individual variability in the magnitude of body weight change that cannot be fully explained by differences in daily energy intake and physical activity levels and that can be attributed to differences in energy metabolism. Measuring the short-term metabolic response to acute changes in energy intake can better uncover this inter-individual variability and quantify the degree of metabolic thriftiness that characterizes an individual's susceptibility to weight gain and resistance to weight loss. This review summarizes the methods used to identify the individual-specific metabolic phenotype (thrifty vs. spendthrift) in research and clinical settings. RECENT FINDINGS: The metabolic responses to short-term fasting, protein-imbalanced overfeeding, and mild cold exposure constitute quantitative factors that characterize metabolic thriftiness. SUMMARY: The energy expenditure response to prolonged fasting is considered the most accurate and reproducible measure of metabolic thriftiness, likely because the largest energy deficit best captures interindividual differences in the extent of metabolic slowing. However, all the other dietary/environmental challenges can be used to quantify the degree of thriftiness using whole-room indirect calorimetry. Efforts are underway to identify alternative methods to assess metabolic phenotypes in clinical and outpatient settings such as the hormonal response to low-protein meals.

Disinhibition augments thirst perception from two dehydrating stimuli in men.

Physiological systems controlling water and energy ingestion are coordinated. Whether maladaptive eating behavior and appetite for water are linked is unknown. Thus, we sought to investigate the association between maladaptive eating and both thirst and water drinking behavior with two dehydrating conditions. Twenty-two lean men and 20 men with obesity (mean age 32.3 ± 8.4 years and 30.0 ± 11.1 years, respectively) completed the Three-Factor Eating Questionnaire (TFEQ) and Gormally Binge Eating Scale. On separate days, volunteers were dehydrated by a 2-h hypertonic saline infusion and a 24-h water deprivation, and thirst was measured on a 100-mm visual analogue scale (VAS) during each procedure. After each dehydrating condition, ad libitum water intake was measured. In the saline infusion, higher Disinhibition on the TFEQ was associated with thirst in the lean group (ß = 4.2 mm VAS, p = 0.03) but not in the group with obesity (p = 0.51). In the water-deprivation condition, higher Disinhibition was also associated with thirst in the lean group (ß = 5.6 mm VAS, p = 0.01) with the strength of relationship being 3.5-fold stronger than that observed in the group with obesity (ß = 1.6 mm VAS, p = 0.0003). Hunger, Restraint, and binge-eating scores were not associated with thirst in either dehydrating condition (all p > 0.05). Maladaptive eating behaviors were not associated with ad libitum water intake (all p > 0.05). Disinhibition is associated with higher thirst perception in healthy weight individuals and may be attenuated in obesity. The characteristics of disinhibition which typically includes a heightened readiness to eat, may reflect a more general phenotype that also reflects a readiness to drink.

Circulating metabolite profile in young adulthood identifies long-term diabetes susceptibility: the Coronary Artery Risk Development in Young Adults (CARDIA) study.

AIMS/HYPOTHESIS: The aim of this work was to define metabolic correlates and pathways of diabetes pathogenesis in young adults during a subclinical latent phase of diabetes development. METHODS: We studied 2083 young adults of Black and White ethnicity in the prospective observational cohort Coronary Artery Risk Development in Young Adults (CARDIA) study (mean ± SD age 32.1 ± 3.6 years; 43.9% women; 42.7% Black; mean ± SD BMI 25.6 ± 4.9 kg/m2) and 1797 Framingham Heart Study (FHS) participants (mean ± SD age 54.7 ± 9.7 years; 52.1% women; mean ± SD BMI 27.4 ± 4.8 kg/m2), examining the association of comprehensive metabolite profiles with endophenotypes of diabetes susceptibility (adipose and muscle tissue phenotypes and systemic inflammation). Statistical learning techniques and Cox regression were used to identify metabolite signatures of incident diabetes over a median of nearly two decades of follow-up across both cohorts. RESULTS: We identified known and novel metabolites associated with endophenotypes that delineate the complex pathophysiological architecture of diabetes, spanning mechanisms of muscle insulin resistance, inflammatory lipid signalling and beta cell metabolism (e.g. bioactive lipids, amino acids and microbe- and diet-derived metabolites). Integrating endophenotypes of diabetes susceptibility with the metabolome generated two multi-parametric metabolite scores, one of which (a proinflammatory adiposity score) was associated with incident diabetes across the life course in participants from both the CARDIA study (young adults; HR in a fully adjusted model 2.10 [95% CI 1.72, 2.55], p<0.0001) and FHS (middle-aged and older adults; HR 1.33 [95% CI 1.14, 1.56], p=0.0004). A metabolite score based on the outcome of diabetes was strongly related to diabetes in CARDIA study participants (fully adjusted HR 3.41 [95% CI 2.85, 4.07], p<0.0001) but not in the older FHS population (HR 1.15 [95% CI 0.99, 1.33], p=0.07). CONCLUSIONS/INTERPRETATION: Selected metabolic abnormalities in young adulthood identify individuals with heightened diabetes risk independent of race, sex and traditional diabetes risk factors. These signatures replicate across the life course.

Meal-to-meal and day-to-day macronutrient variation in an ad libitum vending food paradigm.

BACKGROUND: Theory posits that macronutrient intake is regulated by protein consumption and adequate intake of protein results in consumption of less carbohydrates and fat. The current study investigates the effect of protein intake on calorie and macronutrient content using an ad libitum vending machine paradigm. METHODS: Healthy volunteers (n = 287; 177 m; Age = 36 ± 11; BMI = 32 ± 8) were admitted to our clinical research unit. Macronutrient meal content (grams) and energy intake (Kcal) were quantified by specialized food processing software and collected on an hourly basis over a three-day period using a validated ad libitum vending machine paradigm. Body composition was assessed by DXA. Lagged multi-level models accounting for age, sex, race/ethnicity, fat and fat free mass indices were fitted to examine the impact of prior macronutrient content on subsequent meals. RESULTS: Protein intake was associated with decreased energy intake (Kcal; B = -1.67 kcal, p = 0.0048), lower protein and carbohydrate intake (B = -0.08 g, p = 0.0006; B = -0.21 g, p = 0.0003, respectively) at subsequent meals. Daily Macronutrient intake and subsequent intake were positively associated. CONCLUSIONS: Dietary protein exhibits a negative regulatory effect on a short-term meal-to-meal rather than day-to-day basis. In the setting of readily available food, protein intake impacts energy intake only over very short time courses.

Teaching geriatric medicine through gamification: a tool for enhancing postgraduate education in geriatric medicine.

BACKGROUND: Polypharmacy is becoming increasingly common and all doctors must be prepared to manage it competently. AIMS: The aim of this project is to evaluate the feasibility and use of a novel gamification-based teaching intervention on polypharmacy among doctors undergoing advanced geriatric training. Among others, one of the learning goals for the students was to be able to describe the adherence to medication. METHODS: Electronic questionnaire sent to students of the third session "evidence-based medicine in geriatrics" of advanced postgraduate course in geriatrics of the European Academy for Medicine of Ageing. RESULTS: Most students reported issues with forgetting doses and remembering sufficiently to establish a medication routine due to busy schedules as well as social influences around medication taking. Reflecting on the challenges of the game, most students reported that their own prescribing practice was likely to change. DISCUSSION AND CONCLUSION: The current model of learning appears to be a feasible approach for postgraduate medical education or in other areas of healthcare such as nursing or physiotherapy. Learning through action and reflection promotes deeper thinking and can lead to behavioral change, in this case thus enhancing the attitudes and understanding regarding pharmacological issues associated with ageing. Recommendations for future research in medical education about medication adherence are outlined.

Lower insulin clearance is associated with increased risk of type 2 diabetes in Native Americans.

AIMS/HYPOTHESIS: Impaired insulin clearance is implicated in the pathogenesis of type 2 diabetes, but prospective evidence remains limited. Therefore, we sought to identify factors associated with the metabolic clearance rate of insulin (MCRI) and to investigate whether lower MCRI is associated with increased risk of incident type 2 diabetes. METHODS: From a longitudinal cohort, 570 adult Native Americans without diabetes living in the Southwestern United States were characterised at baseline and 448 participants were monitored over a median follow-up period of 7.9 years with 146 (32%) incident cases of diabetes identified (fasting plasma glucose ≥7.0 mmol/l, 2 h plasma glucose [2-h PG] ≥11.1 mmol/l, or clinical diagnosis). At baseline, participants underwent dual-energy x-ray absorptiometry or hydrodensitometry to assess body composition, a 75 g OGTT, an IVGTT to assess acute insulin response (AIR), and a hyperinsulinaemic-euglycaemic clamp to assess MCRI and insulin action (M). RESULTS: In adjusted linear models, MCRI was inversely associated with body fat percentage (r = -0.35), fasting plasma insulin (r = -0.55) and AIR (r = -0.22), and positively associated with M (r = 0.17; all p < 0.0001). In multivariable Cox proportional hazard models, lower MCRI was associated with an increased risk of diabetes after adjustment for age, sex, heritage, body fat percentage, AIR, M, fasting plasma glucose, 2-h PG, and fasting plasma insulin (HR per one-SD difference in MCRI: 0.77; 95% CI 0.61, 0.98; p = 0.03). CONCLUSIONS/INTERPRETATION: Lower MCRI is associated with an unfavourable metabolic phenotype and is associated with incident type 2 diabetes independent of established risk factors. CLINICAL TRIAL REGISTRATION NUMBERS: ClinicalTrials.gov NCT00339482; NCT00340132.

Reduced metabolic efficiency in sedentary eucaloric conditions predicts greater weight regain in adults with obesity following sustained weight loss.

BACKGROUND: Successful long-term weight loss maintenance after caloric restriction (CR) is rarely achieved. Besides known metabolic, behavioural, and cognitive factors, 24-hour energy expenditure (24hEE) relative to body size (i.e., metabolic efficiency) might influence subsequent weight loss maintenance. METHODS: Eleven participants with obesity (BMI = 39.0 ± 8.7 kg/m2, body fat = 36.1 ± 6.4%) had 24hEE measured in a whole-room indirect calorimeter during eucaloric conditions and weight stability prior to starting a 6-week inpatient CR study (50% of daily energy needs). Twenty-four-hour energy expenditure was adjusted via regression analysis for fat free mass (FFM) and fat mass (FM) by DXA. Body composition was reassessed at the end of CR and after 1-year follow-up. Free-living weight was assessed by monthly weight measurements during 12 months. RESULTS: After 6-week CR, participants lost 8.5 ± 2.7% weight (FFM: -6.3 ± 3.6 kg, FM: -3.4 ± 1.2 kg) but regained 5.1 ± 8.0% 1 year following CR, which was mostly due to FFM regain (+5.7 ± 5.5 kg) and unchanged FM. A relatively higher 24hEE by 100 kcal/day prior to CR was associated with an average greater rate of weight regain by +0.3 kg/month during follow-up and a greater final weight regain by +5.1 kg after 1 year of follow-up. CONCLUSION: These results suggest that reduced metabolic efficiency in 24hEE during eucaloric, sedentary conditions may predict greater weight regain after CR-induced weight loss.

Non-transmural myocardial infarction associated with regional contractile function is an independent predictor of positive outcome: an integrated approach to myocardial viability.

BACKGROUND: Cardiovascular magnetic resonance permits assessment of irreversible myocardial fibrosis and contractile function in patients with previous myocardial infarction. We aimed to assess the prognostic value of myocardial fibrotic tissue with preserved/restored contractile activity. METHODS: In 730 consecutive myocardial infarction patients (64 ± 11 years), we quantified left ventricular (LV) end-diastolic (EDV) and end-systolic (ESV) volumes, ejection fraction (EF), regional wall motion (WM) (1 normal, 2 hypokinetic, 3 akinetic, 4 dyskinetic), and WM score index (WMSI), and measured the transmural (1-50 and 51-100) and global extent of the infarct scar by late gadolinium enhancement (LGE). Contractile fibrotic (CT-F) segments were identified as those showing WM-1 and WM-2 with LGE ≤ or ≥ 50%. RESULTS: During follow-up (median 2.5, range 1-4.7 years), cardiac events (cardiac death or appropriate implantable defibrillator shocks) occurred in 123 patients (17%). At univariate analysis, age, LVEDV, LVESV, LVEF, WMSI, extent of LGE, segments with transmural extent > 50%, and CT-F segments were associated with cardiac events. At multivariate analysis, age > 65 years, LVEF < 30%, WMSI > 1.7, and dilated LVEDV independently predicted cardiac events, while CT-F tissue was the only independent predictor of better outcome. After adjustment for LVEF < 30% and LVEDV dilatation, the presence of CT-F tissue was associated with good prognosis. CONCLUSIONS: In addition to CMR imaging parameters associated with adverse outcome (severe LV dysfunction, poor WM, and dilated EDV), the presence of fibrotic myocardium showing contractile activity in patients with previous myocardial infarction yields a beneficial effect on patient survival.

Nonthyroidal second primary malignancies in differentiated thyroid cancer patients: Is the incidence increased comparing to the general population and could it be a radioiodine therapy consequence?

The long-term survival of differentiated thyroid cancer (DTC) patients and the need to perform several treatments with radioiodine (131-I) lead to the question if the lifetime risk of developing a nonthyroidal second primary cancer (NTSPC) is increased in these patients. In our study, we assessed the prevalence of NTSPCs in thyroid cancer population and evaluated the possible causative role of 131-I treatment. We analyzed 1096 consecutive patients followed at our institution from 1964 to 1998. A total of 101 NTSPCs were observed in 92/1096 patients (8.4%) among which 17/101 (16.8%) diagnosed before DTC and 84/101 (83.2%) diagnosed after. The most frequent tumor sites observed were breast and bladder/urinary tract in the post-DTC group and breast and hematological system in the pre-DTC group. Regarding 131-I treatment, we did not observe any significant differences regarding either the number of treatments or the cumulative activity. The only significant parameter associated with an increased incidence of NTSPC was follow-up (P = .02): a longer follow-up period was associated with a higher number of NTSPCs. The mean latency between 131-I and NTSPC was 10.52 ± 7.69 years. Comparing with the general Italian population, independent of radioiodine treatment, the standard incidence ratio in our cohort was similar to that of the general population (SIR 1.07) and this result was confirmed by analyzing only the treated group. In conclusion, these results show that the risk of NTSPCs in the DTC patients' population is similar to that in the general population and 131-I treatment was not associated with an increased risk.

The impact of menarche on health-related quality of life in a sample of Italian adolescents: evidence from school-based AVATAR project.

Adolescence is a period characterized by rapid physical maturation, involving bodily changes that often necessitate a reorganization of self-perception. The current study investigated the impact of menarche on the determinants of quality of life in healthy female adolescents. Data were collected from 361 healthy female adolescents divided into two groups: pre- and post-menarcheal event. Participants, according the AVATAR project, completed Italian version of KIDSCREEN-52 questionnaires on health-related quality of life. Pre-menarcheal females had the higher score in psychological well-being and mood than post-menarcheal females. As concerns self-perception, post-menarcheal females exhibited lower score compared to pre-menarcheal females. In social context, pre-menarcheal females perceived a better school environment, also when we considered it in terms of social acceptance.Conclusion: Menarche event affects all the components of quality of life, from mood, self-esteem to social relationships, underlining how this hormonal variation is responsible of psychological and emotional changes, opening up the opportunity for preventive approaches aimed not only at traditional risk factors but according a more integrated perspective.What is Known:• Adolescence is a time of increasing behavioural divergence between males and females, probably due to the different hormonal development.• There is a possible link between menarche and the health-related quality of life variables.What is New:• Menarche condition affects all the components of quality of life, from mood to social relationships.• Post-menarcheal condition is associated to psychosocial and emotional changes, with possible multiple pathways to post-pubertal depressive symptoms.

DELAYED 131-I FIRST TREATMENT AFTER SURGERY HAS NO IMPACT ON THE MEDIAN TERM OUTCOME OF PATIENTS WITH INTERMEDIATE RISK DIFFERENTIATED THYROID CANCER.

Objective: In intermediate risk (IR) differentiated thyroid cancer (DTC) patients, selective use of radioiodine (131-I) for remnant ablation and/or as adjuvant therapy (RRA) is advocated. The recently suggested postoperative evaluation could delay the use of RRA. The aim of this study was to evaluate if a delayed RRA can worsen the clinical outcome of IR-DTC patients. Methods: Four hundred and fourteen consecutive IR-DTC patients were divided according to the time elapsed from surgery to RRA, <6 months (group A, 186/414 [44.9%]), or ≥6 months (group B, 228/414 [55.1%]). Clinical and biochemical data were collected, and clinical outcome was analyzed at the first evaluation (EV) after RRA (first-EV) and after a median of 6 years of follow-up (last-EV). Results: No difference in the clinical outcome of group A and B was found. Since a different activity of 131-I could have an impact on the outcome, we separately analyzed the groups according to the 131-I activity (low-activity group: 1,110 MBq/30 mCi [n = 320], and high-activity group: 3,700 MBq/100 mCi [n = 94]), further subdivided according to the time elapsed from surgery to RRA. No major differences were found in both the low- and high-activity groups when comparing the features of their subgroups A and B, as far as in their clinical outcome. Conclusion: The time elapsed between surgery and the first 131-I treatment does not influence the clinical outcome of IR-DTC patients. This finding allows a more relaxed attitude in the decision making process whether to perform the RRA in IR-DTC cases in which a selective use of 131-I is recommended. Abbreviations: ATA = American Thyroid Association; DTC = differentiated thyroid cancer; EV = evaluation; HR = high risk; 131-I = radioiodine; IR = intermediate risk; LR = low risk; rhTSH = recombinant human thyroid-stimulating hormone; RRA = radioiodine for remnant ablation; Tg = thyroglobulin; TgAb = thyroglobulin autoantibody; US = ultrasound.

Role of Prophylactic Central Compartment Lymph Node Dissection on the Outcome Of Patients With Papillary Thyroid Carcinoma and Synchronous Ipsilateral Cervical Lymph Node Metastases.

OBJECTIVE: Prophylactic central compartment lymph node dissection (pCCND) results in a higher percentage of surgical-related complications. To date, no evidence of the impact of pCCND on the clinical outcome of papillary thyroid carcinoma (PTC) patients with synchronous ipsilateral cervical lymph node metastases has been reported. METHODS: We evaluated all consecutive patients affected by PTC and synchronous ipsilateral cervical, but without evidence of central compartment, lymph node metastases. We selected 54 consecutive patients (group A) treated by total thyroidectomy, ipsilateral cervical lymph node dissection, and pCCND and 115 patients (group B) matched for sex, age at diagnosis, number and dimension of the metastatic lateral cervical lymph nodes, without pCCND. Clinical outcome after a median of 5 years and surgical-related complications were assessed. RESULTS: The two groups were completely similar in terms of clinical features. Clinical outcomes showed a higher percentage of biochemical and indeterminate but not structural response in group B. Group B required significantly more radioiodine treatments, but no difference was shown in the need to repeat surgery for recurrences. Conversely, the prevalence of permanent hypoparathyroidism was significantly higher in group A (14.8%) than in group B (4.3%). CONCLUSION: In PTC patients with synchronous ipsilateral cervical lymph node metastases, in absence of clinically evident lymph node metastases of the central compartment, performing pCCND does not improve the 5-year outcome in terms of structural disease, despite a greater number of 131I treatments. However, pCCND is severely affected by a higher percentage of permanent hypoparathyroidism, even in the hands of expert surgeons. ABBREVIATIONS: IQR = interquartile range; pCCND = prophylactic central compartment lymph node dissection; PTC = papillary thyroid carcinoma; Tg = thyroglobulin; US = ultrasound.

Psychopathological and psychiatric evaluation of patients affected by lipodystrophy.

PURPOSE: Lipodystrophy is a collection of rare disorders defined by complete or partial loss of adipose tissue, due to abnormal adipocyte production, function, or distribution; it shares the main metabolic complications with obesity. Aims of the present study were to investigate the psychopathological characteristics of non-HIV lipodystrophic patients in comparison with a group of obese patients, a group of patients affected by oncologic chronic illness, and a control group of healthy subjects. METHODS: All participants were female: 16 non-HIV lipodystrophic women (mean age 42 ± 12 years), 20 women with breast cancer (adenocarcinoma with a positive sentinel lymph node in outpatients awaiting chemotherapy, mean age 44 ± 5 years), 20 obese women (mean age 40 ± 3 years), and 20 healthy women (mean age 40 ± 2 years). Each lipodystrophic patient received a psychiatric assessment, following the diagnostic criteria for DSM-5. Patients and controls received a battery of self-report instruments measuring general psychopathology, body image concerns, eating habits and food craving, and pain concerns. The following psychopathological rating scales were used: SCL-90-R (Symptom Check List) for general psychopathology, BUT (Body Uneasiness Test) for body image, FCQ-T (Food Cravings Questionnaire Trait) for food craving, and WHYMPI (West Haven Yale Multidimensional Pain Inventory) for multidimensional pain inventory. RESULTS: The psychiatric assessment of the 16 lipodystrophic patients revealed: three lifetime mood disorder, six current mood disorder, six lifetime anxiety disorder, five current anxiety disorder, four current somatic symptom disorder with predominant pain, six current binge eating disorder, 11 eating disorder not otherwise specified, two borderline personality disorder, one obsessive-compulsive personality disorder, one avoidant personality disorder, and five personality disorder not otherwise specified. In SCL-90-R scale, the subscale sensitivity showed a significantly higher score in the lipodystrophic and oncologic groups compared to healthy subjects. The subscale paranoid ideation showed a significantly higher score in the lipodystrophic group vs all the other groups. The total score of BUT scale was significantly higher in the lipodystrophic compared to healthy subjects. In WHYMPI scale, the scores of pain interference and family support were significantly higher in the lipodystrophic group. The scores of negative responses were significantly higher in the lipodystrophic group vs healthy subjects. In FCQ-T scale, the score of Cues dimension in lipodystrophic patients was significantly lower as compared with all the other groups. CONCLUSIONS: Our findings suggest that lipodystrophic patients have an increased prevalence of mood, anxiety, pain, and eating disorders. LEVEL OF EVIDENCE: Level III. Evidence obtained from case-control analytic study.

Cognitive dietary restraint, disinhibition, and hunger are associated with 24-h energy expenditure.

BACKGROUND: Higher energy expenditure (EE) is associated with greater food intake, possibly because the human body senses EE and modifies eating behaviors to regulate food intake and ultimately achieve energy balance. As eating behaviors are also influenced by social and cultural factors, any association between EE and eating behavior may differ between ethnicities and sexes. OBJECTIVE: To assess relationships between EE and eating behavior constructs of the Three-Factor Eating Questionnaire (TFEQ). SUBJECTS/METHODS: In all, 307 healthy adults (201 M/106 F, 160 Native Americans) completed the TFEQ and had measures of 24-h EE in a whole-room calorimeter during energy balance. Body composition was assessed by DXA. RESULTS: On average, adjusted 24-h EE was lower (ß = -229 kcal/day, CI: -309 to -148, p < 0.001) but cognitive restraint (Δ = + 1.5; CI: 0.5 to 2.5, p = 0.003) and disinhibition (Δ = + 2.1, CI: 1.3 to 2.8, p < 0.001) scores were higher in women compared with men. In Native Americans, adjusted 24-h EE (ß = + 94 kcal/day, CI: 48 to 139, p < 0.001) and disinhibition scores (Δ = + 1.0, CI: 0.1 to 2.0, p = 0.003) were higher compared with other ethnicities. Higher 24-h EE associated with lower cognitive restraint in women (ρ = -0.20, p = 0.04), but not men (p = 0.71; interaction term p = 0.01) with no ethnic differences. Greater 24-h EE associated with higher disinhibition (ρ = 0.20, p = 0.001) and hunger cues (ρ = 0.16, p = 0.004) with no gender differences. These associations were primarily present in non-Native Americans (ρ = 0.23, p = 0.006 and ρ = 0.25, p = 0.003) but not observed in Native Americans (both p > 0.40). CONCLUSIONS: Higher EE is associated with psychological constructs of eating behaviors that favors overeating including lower cognitive restraint, higher dietary disinhibition, and greater susceptibility to hungers cues, supporting the existence of energy-sensing mechanisms influencing human eating behavior. These associations were observed in ethnicities other than Native Americans, possibly explaining the contradictory relationships reported between EE and weight change in different ethnic groups. We propose that increased EE may alter eating behaviors, potentially leading to uncontrolled overeating and weight gain.

Response of skeletal muscle UCP2-expression during metabolic adaptation to caloric restriction.

BACKGROUND/OBJECTIVES: Spendthrift vs. thrifty individuals expend more energy and experience greater weight loss during caloric restriction (CR). Adaptive mechanisms in skeletal muscle, adipose tissue, and on hormone level modulate energy expenditure (EE) during weight loss. Metabolic mechanisms underlying the variability in EE during CR are unclear. The present study explored whether during long-term CR (i) gene expression changes in skeletal muscle and adipose tissue relate with the individual EE response and weight loss, and (ii) altered catecholamine and FGF21-concentrations are associated with measures of metabolic adaptation. SUBJECTS/METHODS: In a 10-week inpatient study, 24-h EE was measured before and after 6 weeks of 50% CR in 12 subjects using whole-room indirect calorimetry. Weight loss was assessed and repeated hormone measurements performed. Muscle and adipose tissue biopsies were taken before and after CR, and gene expression was assessed (RNA-Seq). Genes showing the most significant changes after CR were tested for association with EE and followed-up for further association with metabolic measures in a separate phenotyping study (n = 103). RESULTS: Muscle UCP2 showed the strongest change after CR (log2-fold change = -1.57, false discovery rate = 0.10) and was considered the best gene for exploration of metabolic adaptive processes. A greater decrease in UCP2-expression was associated with less weight loss (P = 0.03, r = 0.77) and relatively lower 24-h EE after CR (P = 0.001, r = -0.96). Post-CR changes in FGF21-plasma concentrations correlated with UCP2-expression change (P = 0.02, r = -0.89) and weight loss (P = 0.003, r = -0.83). In a separate metabolic phenotyping study, muscle UCP2-expression correlated with respiratory quotient and macronutrient oxidation. In adipose tissue, no candidate genes for metabolic exploration were found. CONCLUSIONS: Changes in muscle UCP2-expression reflect an inter-individual metabolic response to long-term CR and may influence EE and weight loss via modulation of substrate oxidation.

Decline in the acute insulin response in relationship to plasma glucose concentrations.

BACKGROUND: To investigate (1) whether the decline in acute insulin response (AIR) precedes or coincides with defined glucose regulation categories and whether acute insulin response decline varies by race and adiposity, (2) linearity of the relationship between acute insulin response and increasing plasma glucose concentrations, (3) longitudinal changes in acute insulin response accounting for changes in insulin action across categories of glucose tolerance. METHODS: Clinical cross-sectional and longitudinal study of nondiabetic subjects. Inpatient assessment of oral glucose tolerance (2-h PG, fasting PG), and acute insulin response (intravenous glucose tolerance test) in 326 and 84 Native Americans of full and ≤6/8th Southwestern heritage, respectively, and 115 Whites. Linearity of acute insulin response vs plasma glucose concentrations investigated using spline analyses. Follow-up (average = 2.07 years) glucose tolerance, acute insulin response, and insulin action (hyperinsulinemic-euglycemic clamp) assessed in 230 full Native Americans. RESULTS: In certain groups, the relationship between acute insulin response and increasing plasma glucose levels was non-linear. In all groups, acute insulin response decline preceded the cut-offs for traditional glucose regulation categories, although the timing with respect to increasing plasma glucose varied by race and adiposity. Longitudinal data indicated that improvement in insulin action is the key factor to preserve insulin secretion, underlying the reversion of glucose tolerance in prediabetic individuals. CONCLUSIONS: With worsening insulin action, the decline in insulin secretion occurred prior to current diagnostic guidelines for impaired glucose regulation. However, the relationship between acute insulin response and increasing plasma glucose varies and was not always non-linear. Understanding the dynamics of this relationship may determine when to initiate preventive pharmacotherapy directed at the preservation of ß-cell failure.