Dropout risk and effectiveness of retention strategies in the Memory Advancement by Intranasal Insulin in Type 2 Diabetes (MemAID) Clinical Trial.

BACKGROUND: Effective recruitment and retention strategies are essential in clinical trials. METHODS: The MemAID trial consisted of 12 visits during 24 weeks of intranasal insulin or placebo treatment and 24 weeks of post-treatment follow-up in older people with and without diabetes. Enhanced retention strategies were implemented mid study to address high drop-out rate. Baseline variables used in Cox regression models to identify dropout risk factors were: demographics and social characteristics, functional measures, metabolic and cardiovascular parameters, and medications. RESULTS: 244 participants were randomized; 13 (5.3%) were discontinued due to adverse events. From the remaining 231 randomized participants, 65 (28.1%) dropped out, and 166 (71.9%) did not. The Non-retention group included 95 participants not exposed to retention strategies, of which 43 (45.2%) dropped out. The Retention group included 136 participants exposed to enhanced retention strategies, of which 22 (16.2%) dropped out. Dropout risk factors included being unmarried, a longer diabetes duration, using oral antidiabetics as compared to not using, worse executive function and chronic pain. After adjusting for exposure to retention strategies, worse baseline executive function composite score (p = 0.001) and chronic pain diagnosis (p = 0.032) were independently associated with a greater risk of dropping out. The probability of dropping out decreased with longer exposure to retention strategies and the dropout rate per month decreased from 4.1% to 1.8% (p = 0.04) on retention strategies. CONCLUSIONS: Baseline characteristics allow prediction of dropping out from a clinical trial in older participants. Retention strategies has been effective at minimizing the impact of dropout-related risk factors. TRIAL REGISTRATION: Clinical trials.gov NCT2415556 3/23/2015 (www. CLINICALTRIALS: gov).

Safety of Intranasal Insulin in Type 2 Diabetes on Systemic Insulin: A Double-Blinded Placebo-Controlled Sub-Study of Memaid Trial.

Aims: To determine safety of intranasal insulin (INI) in MemAID trial participants with diabetes treated with systemic insulins. Materials and Methods: This randomized, double-blinded trial consisted of 24-week INI or placebo treatment once daily and 24-week follow-up. Safety outcomes were: 1) Short-term effects on glycemic variability, hypoglycemic episodes on continuous glucose monitoring (CGM) at baseline and on-treatment. 2) Long-term effects on glucose metabolism and weight on INI/placebo treatment and post-treatment follow-up. Of 86 screened subjects, 14 were randomized, 9 (5 INI, 4 Placebo) completed CGM at baseline and on-treatment, and 5 (2 INI, 3 Placebo) completed treatment and follow-up. Results: INI was safe and was not associated with serious adverse events, hypoglycemic episodes or weight gain. INI administration did not acutely affect capillary glucose. Glycemic variability on CGM decreased with INI, compared to baseline. On INI treatment, there was a long-term trend toward lower HbA1c, plasma glucose and insulin. No interactions with subcutaneous insulins were observed. Conclusions: INI is safe in older people with diabetes treated with systemic insulins, and it is not associated with adverse events, hypoglycemia or weight gain. Future studies are needed to determine whether INI administration can reduce glycemic variability, improve insulin sensitivity and thus potentially lessen diabetes burden in this population.

Mediterranean diet is inversely associated with steatosis and fibrosis and decreases ten-year diabetes and cardiovascular risk in NAFLD subjects: Results from the ATTICA prospective cohort study.

BACKGROUND AND AIMS: We assessed the association of Mediterranean diet with NAFLD and their interaction in predicting ten-year diabetes onset and first fatal/non-fatal cardiovascular disease (CVD) incidence. METHODS: The ATTICA prospective observational study in Athens, Greece included 1,514 men and 1,528 women (>18 years old) free-of-CVD at baseline. Liver steatosis and fibrosis indices were calculated. Mediterranean diet adherence was assessed through MedDietScore. At the ten-year follow-up visit, CVD evaluation was performed in an a priori specified subgroup of n = 2,020 participants and diabetes onset in n = 1,485 free-of-diabetes participants. RESULTS: MedDietScore was inversely associated with steatosis and fibrosis; e.g. in the case of the TyG index the Odds Ratio (OR) of the 3rd vs. 1st MedDietScore tertile was = 0·53, [95% Confidence Interval (95% CI) (0·29, 0·95)] and the associations persisted in multi-adjusted models. NAFLD predicted incident diabetes prospectively over a ten year period [HR = 1·87, 95% CI (0·75, 4·61)] and the association remained significant only in subjects with low MedDietScore (below median) whereas diabetes onset among subjects with higher MedDietScore was not influenced by NAFLD. Similarly, NAFLD predicted CVD [Hazard Ratio (HR) = 3·01, 95%CI(2·28, 3·95)]; the effect remained significant only in subjects with MedDietScore below median [HR = 1·38, 95% CI (1·00, 1·93)] whereas it was essentially null [HR = 1·00,95% CI (0·38, 2·63)] among subjects with higher score. Mediation analysis revealed that adiponectin and adiponectin-to-leptin ratio were the strongest mediators. CONCLUSIONS: We report an inverse association between Mediterranean diet and NAFLD. Mediterranean diet protected against diabetes and CVD prospectively among subjects with NAFLD.

Memory advancement by intranasal insulin in type 2 diabetes (MemAID) randomized controlled clinical trial: Design, methods and rationale.

BACKGROUND: Type 2 diabetes mellitus (T2DM) accelerates brain aging and increases the risk for dementia. Insulin is a key neurotrophic factor in the brain, where it modulates energy metabolism, neurovascular coupling, and regeneration. Impaired insulin-mediated brain signaling and central insulin resistance may contribute to cognitive and functional decline in T2DM. Intranasal insulin (INI) has emerged as a potential therapy for treating T2DM-related cognitive impairment. METHODS/DESIGN: Ongoing from 2015, a prospective, two-center, randomized, double-blind, placebo-controlled trial of 210 subjects (120 T2DM and 90 non-diabetic older adults) randomized into four treatment arms (60 T2DM-INI, 60 T2DM-Placebo, 45 Control-INI, and 45 Control-Placebo) evaluating the long-term effects of daily intranasal administration of 40 International Units (IU) of human insulin, as compared to placebo (sterile saline) over 24 weeks and 24 weeks of post-treatment follow-up. Study outcomes are: 1) long-term INI effects on cognition, daily functionality, and gait speed; 2) identifying a clinically relevant phenotype that predicts response to INI therapy; 3) long-term safety. CONCLUSION: This study addresses an important knowledge gap about the long-term effects of intranasal insulin on memory and cognition in older people with T2DM and non-diabetic controls, and may provide a novel therapeutic target for prevention and treatment of cognitive and functional decline and dementia. Trial Registration NCT02415556.

Efficacy and safety of anti-hyperglycaemic drugs in patients with non-alcoholic fatty liver disease with or without diabetes: An updated systematic review of randomized controlled trials.

AIM: There are no approved drugs for the treatment of non-alcoholic fatty liver disease (NAFLD). However, many randomized controlled trials (RCT) have examined the effect of anti-hyperglycaemic agents on NAFLD in patients with and without type 2 diabetes mellitus (T2DM), since both T2DM and insulin resistance are closely linked to this burdensome liver disease. METHODS: We systematically searched publication databases using predefined keywords to identify head-to-head or placebo-controlled RCTs (published until September 30, 2019) of NAFLD individuals testing the efficacy of anti-hyperglycaemic drugs to specifically treat NAFLD or non-alcoholic steatohepatitis (NASH). Outcomes of interest included changes in serum liver enzyme levels, liver fat, liver fibrosis, or histologic resolution of NASH. RESULTS: We included 29 RCTs involving a total of 2,617 individuals (∼45% had T2DM) that have used metformin (n=6 studies), glitazones (n=8 studies), glucagon-like peptide-1 receptor agonists (n=6 studies), dipeptidyl peptidase-4 inhibitors (n=4 studies) or sodium-glucose cotransporter-2 inhibitors (n=7 studies) to treat NAFLD. Although most anti-hyperglycaemic drugs improved serum liver enzyme levels, only glitazones (especially pioglitazone) and liraglutide showed an improvement of histologic features of NAFLD, with a mild beneficial effect also on liver fibrosis for pioglitazone only. CONCLUSION: RCT evidence supports the efficacy of some anti-hyperglycaemic agents (especially pioglitazone) in patients with NAFLD or NASH, though weight gain with pioglitazone may warrant caution. Further well-designed RCTs are needed to better characterize the efficacy and safety of monotherapy and combination therapy with anti-hyperglycaemic agents in patients with NAFLD.

Obesity as a risk factor for Alzheimer's disease: weighing the evidence.

Alzheimer's disease (AD) is the sixth leading cause of death in the USA today; therefore, it is imperative that public health initiatives and clinical strategies are developed to prevent and effectively treat AD. Despite the enormous impact that AD has on individuals, families, society, and the health care system, there are no biomarkers to clearly identify those at risk for AD, public health prevention strategies in place, or treatments to address the underlying pathology or stop the progression of AD. There is ample scientific as well as empirical evidence that obesity and its metabolic and vascular comorbidities are related to AD and likely in the causative pathway. Obesity prevention and treatment could prove to be an efficacious and safe approach to preventing AD, a serious and daunting epidemic disease. In this review, we present the current pathophysiological and clinical evidence linking obesity and obesity-related comorbidities (eg, insulin resistance, hyperglycaemia, and type 2 diabetes) with AD. Additionally, we discuss which population to target and when to consider treatment for AD. Finally, we summarize the current evidence regarding the efficacy of anti-obesity and anti-diabetic pharmacotherapeutic agents for the treatment of AD.

Associations of maternal and cord blood adipokines with offspring adiposity in Project Viva: is there an interaction with child age?

OBJECTIVES: Higher leptin and lower adiponectin correlate with adult and childhood adiposity, but it is unclear how exposure to these adipokines during gestation relates to offspring growth. We aimed to investigate the relationships of maternal and cord adipokines with offspring adiposity across childhood to early adolescence, as well as interactions with child age. METHODS: In mother-child pairs in the Project Viva cohort, we measured adipokines in mothers at second trimester (n=1106) and in cord blood at birth (n=657). We measured offspring adiposity indices at early childhood (mean 3.3±s.d. 0.3 years), mid-childhood (7.9±0.8 years) and early adolescence (13.2±0.9 years). We analyzed associations of maternal and cord adipokines with offspring longitudinal adiposity using a linear mixed model adjusting for pre-pregnancy body mass index (BMI), gestational weight gain (GWG), and other confounders. RESULTS: Mothers with higher BMI and GWG had higher leptin. Offspring born to mothers with the highest vs lowest quartile of leptin had lower BMI z-score (-0.49 units, 95% confidence interval (CI):-0.72,-0.26), waist circumference (-2.6 cm, 95% CI: -3.7,-1.5) and sum of subscapular and triceps skinfolds (-2.8 mm, 95% CI: -4.1,-1.4) in early life. An interaction term between maternal leptin and child age was positive, suggesting that the associations between maternal leptin and child adiposity were not constant over time. Offspring born to mothers with lowest vs highest quartile of maternal adiponectin had lower early life adiposity (BMI z-score -0.27 units, 95% CI: -0.48,-0.05). Results were similar for cord leptin but not cord adiponectin. CONCLUSIONS: Our findings showed higher maternal and cord leptin, and lower maternal adiponectin are associated with lower offspring adiposity from childhood to early adolescence, independent of maternal BMI and GWG. However, the strength of these associations was not constant over time.

Adherence to the Mediterranean diet during pregnancy and offspring adiposity and cardiometabolic traits in childhood.

BACKGROUND: In adults, adherence to the Mediterranean diet has been inversely associated with cardiovascular risk, but the extent to which diet in pregnancy is associated with offspring adiposity is unclear. We aimed to investigate the association between adherence to Mediterranean diet in pregnancy and offspring cardiometabolic traits in two pregnancy cohorts. METHODS: We studied 997 mother-child pairs from Project Viva in Massachusetts, USA, and 569 pairs from the Rhea study in Crete, Greece. We estimated adherence to the Mediterranean diet with an a priori defined score (MDS) of nine foods and nutrients (0 to 9). We measured child weight, height, waist circumference, skin-fold thicknesses, blood pressure, and blood levels of lipids, c-reactive protein and adipokines in mid-childhood (median 7.7 years) in Viva, and in early childhood (median 4.2 years) in Rhea. We calculated cohort-specific effects and pooled effects estimates with random-effects models for cohort and child age. RESULTS: In Project Viva, the mean (SD, standard deviation) MDS was 2.7 (1.6); in Rhea it was 3.8 (1.7). In the pooled analysis, for each 3-point increment in the MDS, offspring BMI z-score was lower by 0.14 units (95% CI, -0.15 to -0.13), waist circumference by 0.39 cm (95% CI, -0.64 to -0.14), and the sum of skin-fold thicknesses by 0.63 mm (95% CI, -0.98 to -0.28). We also observed lower offspring systolic (-1.03 mmHg; 95% CI, -1.65 to -0.42) and diastolic blood pressure (-0.57 mmHg; 95% CI, -0.98 to -0.16). CONCLUSION: Greater adherence to Mediterranean diet during pregnancy may protect against excess offspring cardiometabolic risk.

Prenatal and early life exposure to traffic pollution and cardiometabolic health in childhood.

BACKGROUND: Prenatal exposure to traffic pollution has been associated with faster infant weight gain, but implications for cardiometabolic health in later childhood are unknown. METHODS: Among 1418 children in Project Viva, a Boston-area pre-birth cohort, we assessed anthropometric and biochemical parameters of cardiometabolic health in early (median age 3.3 years) and mid- (median age 7.7 years) childhood. We used spatiotemporal models to estimate prenatal and early life residential PM2.5 and black carbon exposure as well as traffic density and roadway proximity. We performed linear regression analyses adjusted for sociodemographics. RESULTS: Children whose mothers lived close to a major roadway at the time of delivery had higher markers of adverse cardiometabolic risk in early and mid-childhood. For example, total fat mass was 2.1 kg (95%CI: 0.8, 3.5) higher in mid-childhood for children of mothers who lived <50 m vs. ≥200 m from a major roadway. Black carbon exposure and traffic density were generally not associated with cardiometabolic parameters, and PM2.5 exposure during the year prior was paradoxically associated with improved cardiometabolic profile. CONCLUSIONS: Infants whose mothers lived close to a major roadway at the time of delivery may be at later risk for adverse cardiometabolic health.

Obese individuals with more components of the metabolic syndrome and/or prediabetes demonstrate decreased activation of reward-related brain centers in response to food cues in both the fed and fasting states: a preliminary fMRI study.

It remains unknown whether obese individuals with more components of the metabolic syndrome and/or prediabetes demonstrate altered activation of brain centers in response to food cues. We examined obese individuals with prediabetes (n=26) vs obese individuals without prediabetes (n=11) using fMRI. We also performed regression analyses on the basis of the number of MetS components per subject. Obese individuals with prediabetes have decreased activation of the reward-related putamen in the fasting state and decreased activation of the salience- and reward-related insula after eating. Obese individuals with more components of MetS demonstrate decreased activation of the putamen while fasting. All these activations remain significant when corrected for BMI, waist circumference (WC), HbA1c and gender. Decreased activation in the reward-related central nervous system areas among the obese is more pronounced in subjects with prediabetes and MetS. Prospective studies are needed to quantify their contributions to the development of prediabetes/MetS and to study whether they may predispose to the exacerbation of obesity and the development of comorbidities over time.

Leptin administration in physiological or pharmacological doses does not alter circulating irisin levels in humans.

Leptin is an adipokine causing browning of adipose tissue, and it thus increases energy expenditure. The same is true for irisin. We studied whether exogenously administered metreleptin affects serum irisin concentrations in humans, which would suggest a direct interplay between leptin and irisin. We performed two studies: a dose-escalating 1-day-long study and a randomized placebo-controlled study. Study 1: 15 healthy, normal-weight and/or obese male and female individuals participated in three 1-day-long trials of metreleptin administration in the fed state. Metreleptin was administered once at physiological and pharmacological (0.01, 0.1 and 0.3 mg per kg body weight) doses. Study 2: 18 apparently healthy hypoleptinemic young women with hypoleptinemia and secondary amenorrhea took part in this study. Subjects received either metreleptin in replacement doses (0.08 and/or 0.12 mg kg(-1)) or placebo for 16 weeks. Blood samples were analyzed for leptin and irisin. We found no effect of metreleptin administration on irisin levels of subjects studied at either the fasting or the fed state either in the short or the long term. We provide evidence that leptin is not altering circulating irisin levels in humans.

Lack of mature lymphocytes results in obese but metabolically healthy mice when fed a high-fat diet.

BACKGROUND/OBJECTIVES: Obesity is characterized by chronic inflammation and immune dysregulation, as well as insulin resistance, but the link between obesity and adaptive immunity remains to be fully studied. METHODS: To elucidate the role of adaptive immunity on body composition, glucose homeostasis and inflammation, recombination-activating gene 1 knockout (Rag1-/-) mice, without mature T-lymphocytes or B-lymphocytes, were maintained on a low- or high-fat diet (LFD and HFD, respectively) for 11 weeks. RESULTS: Rag1-/- mice fed HFD gained significantly more weight and had increased body fat compared with wild type. Downregulation of energy expenditure as well as brown fat uncoupling protein UCP-1 and UCP-3 gene expression were noticed in HFD-fed Rag1-/- mice compared with LFD. HFD mice had significantly decreased energy intake compared with LFD mice, consistent with decreased agouti-related protein and increased pro-opiomelanocortin gene expression levels in the hypothalamus. Moreover, compared with wild type, Rag1-/- mice had lower interleukin (IL)-4 levels, a cytokine recently found to induce browning in white adipocytes, and higher IL-12 levels in HFD-fed Rag1-/- mice. Despite that HFD Rag1-/- mice were more obese, they had similar glucose, insulin and adiponectin levels, while leptin was marginally increased. CONCLUSIONS: Mice with deficiency in adaptive immunity are obese, partly owing to decreased energy expenditure, but are metabolically normal, suggesting that mature lymphocytes have necessary roles in the development of obesity-related metabolic dysregulation.

Posttraumatic stress disorder, alone or additively with early life adversity, is associated with obesity and cardiometabolic risk.

BACKGROUND AND AIMS: There is some evidence that posttraumatic stress disorder (PTSD) and early life adversity may influence metabolic outcomes such as obesity, diabetes, and cardiovascular disease. However, whether and how these interact is not clear. METHODS: We analyzed data from a cross-sectional and longitudinal study to determine how PTSD severity influences obesity, insulin sensitivity, and key measures and biomarkers of cardiovascular risk. We then looked at how PTSD and early life adversity may interact to impact these same outcomes. RESULTS: PTSD severity is associated with increasing risk of obesity, diabetes, and cardiovascular disease, with higher symptoms correlating with higher values of BMI, leptin, fibrinogen, and blood pressure, and lower values of insulin sensitivity. PTSD and early life adversity have an additive effect on these metabolic outcomes. The longitudinal study confirmed findings from the cross sectional study and showed that fat mass, leptin, CRP, sICAM-1, and sTNFRII were significantly increased with higher PTSD severity during a 2.5 year follow-up period. CONCLUSIONS: Individuals with early life adversity and PTSD are at high risk and should be monitored carefully for obesity, insulin resistance, and cardiometabolic risk.

Lack of Day/Night variation in fibroblast growth factor 21 levels in young healthy men.

BACKGROUND: Fibroblast growth factor (FGF) 21 is an endocrine factor with an emerging role as a metabolic regulator. We previously reported the presence of a significant day/night variation of FGF-21 in energy-replete, healthy female subjects. However the day/night patterns of secretion in male subjects remain to be fully elucidated. To elucidate day/night pattern of FGF-21 levels in male subjects in the energy-replete state, its relationship to FFA and to investigate whether a sexual dimorphism exists in FGF-21 physiology. METHODS: Eight healthy lean male subjects were studied for up to 5 days while on an isocaloric diet. Blood samples were obtained for measurement of FGF-21 and free fatty acids (FFA) hourly from 0800 AM on day 4 till 0800AM on day 5. RESULTS: FGF-21 did not exhibit any statistically significant day/night variation pattern of circulating FGF-21 levels during the isocaloric fed state in male subjects. FGF-21 levels in male subjects are closely cross-correlated with FFA levels, similar to female subjects. CONCLUSIONS: A sexual dimorphism exists in FGF-21 physiology; that as opposed to female subjects, no significant day/night variation exists in FGF-21 rhythm in male subjects in the energy-replete state. Circulating pattern of FGF-21, similar to the female subjects, was highly cross-correlated to the FFA levels in the male subjects, signifying that the sexual dimorphism in FGF-21 physiology may be related to the differing lipid metabolism in both the genders.

Circulating irisin levels and coronary heart disease: association with future acute coronary syndrome and major adverse cardiovascular events.

INTRODUCTION: Irisin is a newly discovered myokine, associated with 'browning' of the white adipose tissue, obesity, insulin resistance and metabolic syndrome. The purpose of this study is to evaluate circulating irisin as a predictor of acute coronary syndromes (ACSs) and major adverse cardiovascular events (MACE). METHODS: Sub-study 1: a case-control study, nested within the Veteran's Affairs Normative Ageing Study, evaluating circulating irisin levels in 88 ACS cases and 158 age- and sampling year-matched controls, as a predictor of ACS. Sub-study 2: a prospective cohort study, where 103 participants with established coronary artery disease were stratified by circulating irisin levels at the time they received percutaneous coronary interventions (PCIs) and were followed for the development of MACE. RESULTS: Study 1: there was no association between irisin levels and ACS in otherwise healthy individuals (odds ratio: 1.00 95% confidence interval: (0.99-1.00)). Study 2: the incidence of MACE was significantly lower in the first irisin tertile compared with the second and third (incidence rate 0 vs 0.92 (0.51-1.61) vs 0.57 (0.28-1.14) events per 1000 person-days; P < 0.01). This was primarily driven by the lower incidence of unstable angina (incidence rate 0 vs 0.61 (0.31-1.22) vs 0.43 (0.19-0.96) per 1000 person-days; P = 0.01). CONCLUSION: This is the first study to date that demonstrates that, although circulating irisin levels do not predict the development of ACS in healthy individuals, increased irisin levels are associated with the development of MACE in patients with established coronary artery disease after PCI.

Irisin stimulates muscle growth-related genes and regulates adipocyte differentiation and metabolism in humans.

BACKGROUND: Irisin is a recently identified exercise-induced myokine suggested to induce browning of white adipocytes. Deficiency of myostatin, and thus stimulation of muscle growth, has also been reported to induce irisin and its precursor FNDC5 expression in muscle and drive the browning of white adipocytes in mice, implying that irisin may be related to muscle growth in addition to its beneficial effects in adipocytes. In humans, the effect of irisin in muscle hypertrophy as well as adipocyte metabolism has not been fully investigated. METHODS: Primary cultured human myocytes/adipocytes and 3T3-L1 cells were used to examine irisin-regulated gene/protein expression. Lipid accumulation, ATP content, glycolysis, lipolysis and metabolite profile were measured in control and irisin-treated (10 and 50 nM) adipocytes. RESULTS: In human myocytes, FNDC5 mRNA and irisin secretion were increased during myogenic differentiation, along with PGC1α and myogenin expression. Irisin treatment significantly increased insulin-like growth factor 1 and decreased myostatin gene expression through ERK pathway. PGC1α4, a newly discovered PGC1α isoform specifically related to muscle hypertrophy, was also upregulated. In human adipocytes, irisin induced uncoupling protein 1 and consequently increased adipocyte energy expenditure, expression of metabolic enzymes and metabolite intermediates, resulting in inhibition of lipid accumulation. Irisin and FNDC5 treatment also reduced preadipocyte differentiation, suggesting an additional mechanism in suppressing fat mass. CONCLUSIONS: These results suggest that irisin/FNDC5 has a pleiotropic role in muscle and improvement of adipocyte metabolism in humans.

Levels of circulating selenoprotein P, fibroblast growth factor (FGF) 21 and FGF23 in relation to the metabolic syndrome in young children.

BACKGROUND/OBJECTIVES: Circulating selenoprotein P (SeP), fibroblast growth factor (FGF) 21 and FGF23 have been associated with metabolic syndrome (MetS) in adults but not in children. We sought to evaluate the association among SeP, FGF21, FGF23 and MetS in young children. SUBJECTS/METHODS: A cross-sectional study conducted during a school health examination on 210 children aged 9 years. We measured serum SeP, FGF21 and FGF23 levels, and assessed anthropometric and cardiometabolic variables. MetS was defined as the presence of ⩾3 of the following five criteria: high blood pressure, low high-density lipoprotein cholesterol (HDL-C), high triglyceride, high fasting glucose and abdominal obesity. RESULTS: SeP was correlated positively with HDL-C and negatively with body mass index, waist circumference (WC), blood pressure, transaminases, triglyceride and homeostasis model assessment of insulin resistance (HOMA-IR). FGF21 was directly correlated with WC, triglyceride and HOMA-IR, and FGF23 was inversely correlated with fasting glucose and alanine aminotransferase. Children with MetS had lower SeP and FGF23 levels and higher HOMA-IR than children without MetS. The highest tertile of SeP had decreased odds for MetS (odds ratio 0.05, 95% confidence interval (CI) 0.00-0.96, P for trend=0.042), whereas FGF21 and FGF23 did not relate to the risk for MetS after controlling for confounders. CONCLUSIONS: Elevated SeP concentrations are independently associated with a reduced risk of MetS in children. The associations between FGF21, FGF23 and metabolic parameters are not of comparable significance.

Circulating irisin is associated with osteoporotic fractures in postmenopausal women with low bone mass but is not affected by either teriparatide or denosumab treatment for 3 months.

UNLABELLED: In vitro data suggest that myokine irisin may affect bone metabolism by promoting osteoblast differentiation while inhibiting osteoclast differentiation. In this study, circulating irisin levels were associated with previous osteoporotic fractures but not with bone mass and were not affected by denosumab or teriparatide treatment for 3 months. INTRODUCTION: This study aimed to evaluate predictors of circulating irisin in postmenopausal women with low bone mass and to assess a potential effect of denosumab or teriparatide treatment for 3 months. METHODS: Serum samples for irisin measurement were obtained from (a) postmenopausal women with low bone mass (lumbar spinal [LS] or femoral neck [FN] bone mineral density [BMD] T-score ≤-2.0) and their age-matched controls at baseline and 3 months after denosumab (Dmab) injection (Dmab group, n = 50; Dmab control group, n = 25) and (b) women with more severe disease (LS or FN BMD T-score ≤-2.8) and their age-matched controls at the above-mentioned time points after teriparatide (TPTD) initiation (TPTD group, n = 25; TPTD control group, n = 25). RESULTS: At baseline, irisin levels were inversely correlated with age (partial coefficient (r p ) = -0.24; p = 0.009), parathyroid hormone (PTH) (r p = -0.30; p = 0.001), and creatinine (r p = -0.23; p = 0.016) in univariate analysis, and were lower in women with (n = 26; 41.6 ± 2.7 ng/dL) than without previous osteoporotic fracture(s) (n = 99; 51.0 ± 1.6 ng/dL; p = 0.007). In multiple linear regression, previous osteoporotic fracture(s) and PTH were independently negatively associated with irisin [p = 0.04, CI -16.1 to -0.4 and p = 0.002, CI -0.3 to -0.07, respectively], but only the association with PTH remained after controlling for creatinine levels. Serum irisin levels were not different between women with or without low bone mass and were not affected by either Dmab or TPTD treatment for 3 months. CONCLUSIONS: Circulating irisin levels were associated with previous osteoporotic fracture(s); whether this association is independent or is due to confounding by lower muscle mass, potentially reflected by lower creatinine levels, remains to be fully clarified.

Obesity and thyroid cancer: epidemiologic associations and underlying mechanisms.

The incidence of thyroid cancer has been rising over the past few decades along with a parallel increase in obesity. Observational studies have provided evidence for a potential association between the two. By contrast, clinical data for a link between type 2 diabetes mellitus, a condition strongly associated with obesity, and thyroid cancer are limited and largely not supportive of such an association. Obesity leads to hypoadiponectinemia, a pro-inflammatory state, and insulin resistance, which, in turn, leads to high circulating insulin and insulin-like growth factor-1 levels, thereby possibly increasing the risk for thyroid cancer. Thus, insulin resistance possibly plays a pivotal role in underlying the observed association between obesity and thyroid cancer, potentially leading to the development and/or progression of thyroid cancer, through its interconnections with other factors including insulin-like growth factor-1, adipocytokines/cytokines and thyroid-stimulating hormone. In this review, epidemiological and clinical evidence and potential mechanisms underlying the proposed association between obesity and thyroid cancer risk are reviewed. If the association between obesity and thyroid cancer demonstrated in observational studies proves to be causal, targeting obesity (and/or downstream mediators of risk) could be of importance in the prevention and management of thyroid cancer.

Clinical and genetic predictors of weight gain in patients diagnosed with breast cancer.

BACKGROUND: Post-diagnosis weight gain in breast cancer patients has been associated with increased cancer recurrence and mortality. Our study was designed to identify risk factors for this weight gain and create a predictive model to identify a high-risk population for targeted interventions. METHODS: Chart review was conducted on 459 breast cancer patients from Northwestern Robert H. Lurie Cancer Centre to obtain weights and body mass indices (BMIs) over an 18-month period from diagnosis. We also recorded tumour characteristics, demographics, clinical factors, and treatment regimens. Blood samples were genotyped for 14 single-nucleotide polymorphisms (SNPs) in fat mass and obesity-associated protein (FTO) and adiponectin pathway genes (ADIPOQ and ADIPOR1). RESULTS: In all, 56% of patients had >0.5 kg m(-2) increase in BMI from diagnosis to 18 months, with average BMI and weight gain of 1.9 kg m(-2) and 5.1 kg, respectively. Our best predictive model was a primarily SNP-based model incorporating all 14 FTO and adiponectin pathway SNPs studied, their epistatic interactions, and age and BMI at diagnosis, with area under receiver operating characteristic curve of 0.85 for 18-month weight gain. CONCLUSION: We created a powerful risk prediction model that can identify breast cancer patients at high risk for weight gain.