Context: Strength training induces muscle remodeling and may improve insulin responsiveness. Objective: This study will quantify the impact of resistance training on insulin sensitivity in subjects with the metabolic syndrome and correlate this with activation of intramuscular pathways mediating mitochondrial biogenesis and muscle fiber hypertrophy. Design: Tens ubjects with the metabolic syndrome(MS) and nine sedentary controls underwent 8 wk of supervised resistance exercise training with pre-and post-training anthropometric and muscle biochemical assessments. Setting: Resistance exercise training took place in a sports laboratory on a college campus. Main Outcome Measures: Pre- and posttraining insulin responsiveness was quantified using a euglycemic clamp. Changes in expression of muscle 5-AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) pathways were quantified using immunoblots. Results: Strength and stamina increased in both groups. Insulin sensitivity increased in controls (steady-state glucose infusion rate 7.0 2.0 mg/kg min pretraining training vs. 8.7 3.1 mg/kg min posttraining; P 0.01) but did not improve in MS subjects (3.3 1.3 pre vs. 3.1 1.0 post).Muscleglucosetransporter4increased67%incontrolsand36%intheMSsubjects.Control subjects increased muscle phospho-AMPK (43%), peroxisome proliferator-activated receptor coactivator1 (57%),andATPsynthase(60%),morethanMSsubjects(8,28,and21%,respectively). In contrast, muscle phospho-mTOR increased most in the MS group (57 vs. 32%). Conclusion: Failure of resistance training to improve insulin responsiveness in MS subjects was coincident with diminished phosphorylation of muscle AMPK, but increased phosphorylation of mTOR, suggesting activation of the mTOR pathway could be involved in inhibition of exercise training-related increases in AMPK and its activation and downstream events

BACKGROUND: Polycystic Ovary Syndrome (PCOS) is the most common endocrine disorder affecting women of reproductive age. It is characterized by oligomenorrhea/menstrual irregularity, androgen excess, and polycystic ovary morphology. Currently there are three distinct diagnostic criteria used to ascertain PCOS in the population: The National Institutes of Health (NIH) criteria created in 1990 and later reviewed in 2012, the Rotterdam criteria established in 2003, and the most recent criteria by the Androgen Excess & PCOS Society (AE-PCOS) criteria developed in 2006. Some prevalence studies suggest that PCOS affects 6.5-8% of the population while others state 10-20% qualify for a PCOS diagnosis. Recent literature shows patients with PCOS have a 43% prevalence rate or 2-fold higher rate than the age-adjusted sample of all ages in the general US population of developing Metabolic Syndrome (Met-S ) (Apridonidze et al. 2005; Essah, Wickham, and Nestler 2007). This is important because it can alert physicians to refer their PCOS patients to a nutritionist or endocrinologist as a preventive measurement. OBJECTIVES: This thesis based on The Ovulation and Menstruation Health (OM) Pilot Study, sets out to accomplish the following: ascertain the prevalence of PCOS in different racial/ethnic groups, determine Body-Mass Index (BMI) distribution patterns in PCOS participants based on how they were diagnosed (by a physician/self-diagnosed), and most importantly to determine the prevalence of Met-S risk factors in PCOS vs. Non-PCOS groups. METHODS: The (OM) Pilot Study is an online survey with clinical, community, and online recruitment. After a consent and screening process, the survey asks questions related to demographics, anthropometrics, menstrual cycles, contraceptive history, medications and supplement use, PCOS, reproductive health, general health, diet and lifestyle and lastly, pregnancy and birth history. The questions in this online survey, were designed for an 8th-grade reading level to improve comprehension by a diverse cohort of women. This was done to help address the lack of diversity and PCOS ascertainment in pre-existing cohorts. RESULTS: Following recruitment for The OM Pilot Study, 388 participants completed the consent form and 4 declined consent. 384 completed screener and 34 were deemed not eligible because: 18 were no longer menstruating and 16 were unable/unwilling to provide an email address to the receive survey; thus 350 were eligible. Of those 350 participants that were deemed eligible, only 283 started survey. 283 individuals determined to be eligible based on their gender, capacity to menstruate, and age started the survey. Age eligibility was ≥18 years old. 249 completed the survey through its last section (XIII. Pregnancy & Birth History). Of the 283 participants who enrolled and were eligible to partake in the study, 177 (64.1%) identified as White, 22 (7.97%) as Hispanic/Latina/Spanish Origin, 34 (12.3%) as Black/African American, 4 (1.4%) as East Asian, 5 (1.8%) as Southeast Asian, 7 (2.5%) as South Asian, 27 (9.8%) selected more than 1 race/ethnicity, and 7 (2.5%) chose not to answer (Table 5). Participants from the PCOS group had higher prevalence for all the risk factors for Met-S when compared to Non-PCOS group: abdominal fat determined as those who tend to gain weight around stomach/waist (73% versus 60%), abdominal fat ascertained by body figure (33% versus 17%), hypertension (6.9% versus 3.1%), high cholesterol (20.7% versus 8.8%), diabetes (5.3% versus 1.0%), non-alcoholic fatty liver disease (NAFLD) (5.2% versus 0.5%), and lastly sleep apnea (SA) (5.2% versus 2.1%). More noticeably is the absolute difference in prevalence in abdominal fat as determined by the body figure image in which the PCOS group (33%) had a 16% higher prevalence than the Non-PCOS group (17%). Participants that reported having PCOS diagnosed by a physician (37) had a higher prevalence of overweight/obese women (73%) than those that self-diagnosed (23) with PCOS (56.5%). CONCLUSIONS: The OM Pilot Study has demonstrated that it is possible to launch and recruit a diverse sample group representative of the actual population. With this new tool, future studies can better assess risk factors associated with Met-S in PCOS patients taking into consideration their racial/ethnic background.

Objetivo: Evaluar la asociación entre síndrome metabólico (SM) y carga glicémica (CG) de la ingesta alimentaria en niños y adolescentes obesos atendidos en consulta endocrinológica de un hospital de referencia pediátrica en Lima, Perú. Pacientes y método: Estudio transversal en niños y adolescentes obesos (IMC ≥ percentil 95) de 10 a 15 años. Se utilizó los criterios de la International Diabetes Federation (IDF) para la clasificación de SM. Se aplicó recordatorio de 24 horas y se calculó la CG total y por tiempos de comida. Se evaluó la asociación entre los terciles de CG (comparación contra el inferior) y SM usando razones de prevalencia ajustadas (RPa) por variables demográficas, familiares, actividad física y consumo total de carbohidratos en modelos de regresión de Poisson con varianza robusta. Resultados: De 273 niños y adolescentes obesos, 52,4% fueron varones, 94,9% fueron físicamente inactivos y el IMC promedio fue 27,2 kg/m2. La mediana de carga glicémica fue de 213,3 (p25-p75:164,8 – 287,35) y de 2275 kcal (p25-p75: 1851,05 – 3024) de ingesta calórica diaria, dado principalmente por carbohidratos (62%).La prevalencia de SM fue de 22,3%, los componentes más prevalentes fueron la obesidad abdominal (81,7%) y el HDL bajo (63,7%). Se encontró asociación entre el consumo elevado de CG y el riesgo a presentar SM (RPa: 4,5; IC95%:1,3-15,31). Conclusiones: Existe asociación entre el alto consumo de CG y la presencia de SM en niños y adolescentes con obesidad. / Objective: Evaluate the association between metabolic syndrome (MS) and glycemic load (GL) of the food intake in obese children and adolescents attended in endocrinology consultation of a pediatric referral hospital in Lima, Peru. Patients and methods: Cross-sectional study in obese (BMI ≥ 95 percentile) children and adolescents between 10 to 15 years old. MS was classified according to the International Diabetes Federation (IDF). 24- hours recall was applied and calculated the GL total and by meal. The association between the tertiles of GL (comparison against the lower) and MS was found using adjusted prevalence ratios (RPa) for demographic variables, family, physical activity and total carbohydrates intake by Poisson regression models with robust variance. Results: 273 obese children and adolescents were recruited, 52.4% were male and 94.9% were physically inactive and IMC average was 27, 2 kg/m2. The median of GL was 213, 3 (164, 8 – 287, 35: 122, 6) and 2275 kcal (1851, 05 – 3024: 1172, 9) for daily caloric intake, mainly due of carbohydrates (62%). The prevalence of MS was 22, 3%, the components more relevant were abdominal obesity (81,7%) and low HDL (63,7%). The association between a high consumption of CG and the risk having MS (Rpa: 4,5; IC95%: 1,3-15,31) Conclusions: There is an association between the high intake of GL and the presence of MS. / Tesis

INTRODUCTION: Polycystic Ovary Syndrome (PCOS) is the most common endocrinopathy causing infertility in women of reproductive age. According to the Rotterdam criteria, a PCOS diagnosis should be given if at least two of the following are met: 1) hyperandrogenism; 2) oligo-anovulation; and 3) polycystic ovarian morphology. Previous studies analyzing the prevalence of PCOS have done so in unselected and clinical populations but few studies have attempted to characterize the syndrome and its long-term outcomes within Electronic Health Records using International Classification of Disease (ICD) codes. OBJECTIVES: With a hospital-based electronic health record dataset, this thesis seeks to: (1) characterize PCOS in reproductively aged women (18-34) using the diagnostic codes (ICD-9 and ICD-10) versus the Rotterdam criteria, (2) determine the prevalence of metabolic syndrome (MetS), Type 2 Diabetes, and cardiac events in women above age 35, (3) determine age of diagnosis for MetS and time to diagnosis of MetS. METHODS: The following 3 cohorts were queried on the Research Patient Data Registry (RPDR): 1) patients aged 18-34 with classic PCOS (phenotype A and B) but without an ICD diagnosis for PCOS, 2) patients aged 18-34 with a PCOS ICD-9/10 diagnosis and 3) patients above age 35 with a history or current diagnosis of PCOS. Their electronic health records (between January 1 , 2003 and December 31 , 2020) were ascertained from 9 Mass General Brigham institutions after IRB approval and analyzed on Software for Statistics and Data Science (STATA). RESULTS: Overall, RPDR identified 12,669 patients aged 18-34 who fit the Rotterdam criteria (under multiple phenotypes), 4646 of which had classic PCOS but lacked an ICD- 9/10 code for PCOS. RPDR also identified 9341 women aged 35 and above with a past or current diagnosis of PCOS. Hispanics/Latinas (18-34) were two times more likely to be undiagnosed when compared to Non-Hispanic Whites (OR: 2.25, 95% CI: 1.98-2.56). The prevalence of MetS, specified by a diagnostic code (277.7 or E88.81), and other cardiac conditions in women above age 35 were considerably lower than those found in the current literature. CONCLUSION: Databases such as RPDR allow for a detailed analysis of patient demographics, labs, procedures and diagnoses. Additionally, it allows for larger cohorts of patients matching more specific criteria to be ascertained. Future studies should compare the prevalence of individual features of MetS by ICD codes and analyze the cardiology reports to determine if the events are being reported but not codified. / 2023-11-30

Vaspin is an adipokine which improves glucose metabolism and insulin sensitivity in obesity. Kallikrein 7 (KLK7) is the first known protease target inhibited by vaspin and a potential target for the treatment of metabolic disorders. Here, we tested the hypothesis that inhibition of KLK7 in adipose tissue may beneficially affect glucose metabolism and adipose tissue function. Therefore, we have inactivated the Klk7 gene in adipose tissue using conditional gene-targeting strategies in mice. Klk7-deficient mice (ATKlk7 −/−) exhibited less weight gain, predominant expansion of subcutaneous adipose tissue and improved whole body insulin sensitivity under a high fat diet (HFD). ATKlk7 −/− mice displayed higher energy expenditure and food intake, most likely due to altered adipokine secretion including lower circulating leptin. Pro-inflammatory cytokine expression was significantly reduced in combination with an increased percentage of alternatively activated (anti-inflammatory) M2 macrophages in epigonadal adipose tissue of ATKlk7 −/−. Taken together, by attenuating adipose tissue inflammation, altering adipokine secretion and epigonadal adipose tissue expansion, Klk7 deficiency in adipose tissue partially ameliorates the adverse effects of HFD-induced obesity. In summary, we provide first evidence for a previously unrecognized role of KLK7 in adipose tissue with effects on whole body energy expenditure and insulin sensitivity.

Orientador: Eliana Aguiar Petri Nahas / Resumo: Objetivo: Avaliar a associação entre a síndrome metabólica (SM) e o perfil imuno-histoquímico (IHQ) do câncer de mama em mulheres na pós-menopausa. Métodos: Realizou-se estudo clínico de corte transversal com 189 mulheres, idade entre 45-75 anos, atendidas em Hospital Universitário. Foram incluídas mulheres em amenorreia >12 meses e idade ≥ 45 anos, com diagnóstico recente de câncer de mama, sem tratamento oncológico prévio. Por meio de entrevista foram coletados dados clínicos, antropométricos (peso, altura e circunferência da cintura) e bioquímicos (colesterol total, HDL-c, LDL-c, triglicerídeos (TG) e glicose). A partir do anatomopatológico e da imuno-histoquímica foram coletados dados sobre o câncer de mama (histopatológico, grau, estádio do tumor, linfonodos) e o status hormonal (receptor de estrogênio, RE; receptor de progesterona, RP; receptor do fator de crescimento epidérmico humano-2, HER-2) e a atividade proliferativa epitelial (Ki67). Por convenção da IHQ, os tumores foram agrupados em cinco subtipos: Luminal A (RE +, RP +, HER-2 - e Ki-67 <14%); Luminal B HER-2 - (RE+, RP+ ou -, HER-2 - e Ki-67 ≥14%); Luminal B HER-2 + (RE+, RP+ ou -, HER-2 + e qualquer Ki-67); Não-luminal HER-2 (RE -, RP -, HER2 + e qualquer Ki-67) e Triplo-negativo (RE-, RP-, HER2- e qualquer Ki-67). Foram consideradas com SM as mulheres que apresentaram três ou mais critérios diagnósticos: circunferência da cintura (CC) > 88 cm; TG  150 mg/dL; HDL colesterol < 50 mg/dL; pressão arterial 130/... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Objective: To evaluate the association between metabolic syndrome (MetS) and the breast cancer immunohistochemical profile in postmenopausal women. Methods: An analytical cross sectional study was conducted with 189 women, aged 45-75 years, attended at University Hospital. Women with newly diagnosed breast cancer, no previous cancer treatment, in amenorrhea> 12 months and age ≥ 45 years, were included. Clinical, anthropometric and biochemical (total cholesterol, HDL, LDL, triglycerides (TG) and glucose) data were collected. Data on breast cancer (histopathology, grade, tumor stage, lymph nodes), hormone status (estrogen receptor, ER, progesterone receptor, PR, human epidermal growth factor receptor-2, HER2) and epithelial proliferative activity (Ki67) were collected. Tumors were grouped into five subtypes: Luminal A (ER +, PR +, HER-2 -, Ki-67 <14%); Luminal B HER-2 negative (ER+, PP+ or -, HER-2 -, Ki-67 ≥14%); Luminal B HER-2 positive (ER+, PR+ or -, HER-2 +, any Ki-67); Non-luminal HER-2 (ER -, PR -, HER-2 +, any Ki-67) and Triple-negative (ER-, PR-, HER-2-, any Ki-67). Women with three or more of the following criteria were diagnosed with metabolic syndrome (MetS): waist circumference ≥ 88 cm; triglycerides ≥ 150 mg/dL; HDL cholesterol < 50 mg/dL; blood pressure≥ 130/85 mmHg; glucose≥ 100 mg/dL. For statistical analysis, the t-student test, the Gamma Distribution (asymmetric variables), the chi-square test and the logistic regression (OR-odds ratio) were used. Results: Am... (Complete abstract click electronic access below) / Mestre

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We seek to observe the association between childhood obesity by different measures and adult obesity, metabolic syndrome (MetS), and diabetes. Thousand two hundred and nine subjects from “Beijing Blood Pressure Cohort Study” were followed 22.9 ± 0.5 years in average from childhood to adulthood. We defined childhood obesity using body mass index (BMI) or left subscapular skinfold (LSSF), and adult obesity as BMI ≥28 kg/m2. MetS was defined according to the joint statement of International Diabetes Federation and American Heart Association with modified waist circumference (≥90/85 cm for men/women). Diabetes was defined as fasting plasma glucose ≥7.0 mmol/L or blood glucose 2 h after oral glucose tolerance test ≥11.1 mmol/L or currently using blood glucose-lowering agents. Multiple linear and logistic regression models were used to assess the association. The incidence of adult obesity was 13.4, 60.0, 48.3, and 65.1 % for children without obesity, having obesity by BMI only, by LSSF only, and by both, respectively. Compared to children without obesity, children obese by LSSF only or by both had higher risk of diabetes. After controlling for adult obesity, childhood obesity predicted independently long-term risks of diabetes (odds ratio 2.8, 95 % confidence interval 1.2–6.3) or abdominal obesity (2.7, 1.6–4.7) other than MetS as a whole (1.2, 0.6–2.4). Childhood obesity predicts long-term risk of adult diabetes, and the effect is independent of adult obesity. LSSF is better than BMI in predicting adult diabetes.

Recently, the body mass of college football lineman has increased markedly and places them at higher risk for a number of post competitive pathogenic chronic health consequences. Recognition of problems associated with oversized athletes is easily accepted intellectually-however, the practicalities of solving the problem have not been fully realized.

Bone-derived osteocalcin has been suggested to be a metabolic regulator, potentially improving insulin sensitivity. To scrutinize the relation between osteocalcin and peripheral insulin sensitivity, I analyzed changes of serum osteocalcin relative to changes in insulin sensitivity, low-grade inflammation and bone mineral density following lifestyle-induced weight loss in individuals with metabolic syndrome (MetS). 74 nonsmoking men (45–55 yr) with MetS were randomized to a lifestyle-induced weight loss program (supervision via telemonitoring) or to a control group. Before and after the 6 months intervention period clinical and laboratory parameters and serum osteocalcin levels were determined in fasting blood samples. Lifestyle-induced changes of body composition were analyzed by Dual Energy X Ray-Absorptiometry (DXA). 30 participants in the control and 33 participants in the intervention group completed the study and were included in the data analysis. In participants of the intervention group, weight loss resulted in markedly improved insulin sensitivity and amelioration of low-grade inflammation. Increased serum levels of osteocalcin correlated inversely with BMI (r= -0.63; p< 0.001), total fat mass (r= -0.58, p< 0.001), total lean mass (r= -0.45, p< 0.001), C-reactive protein (CRP) (r= -0.37; p< 0.01), insulin (r= -0.4; p< 0.001), leptin (r= -0.53; p< 0.001), triglycerides (r= -0.42; p< 0.001) and alanine aminotransferase (ALAT) (r=-0.52; p< 0.001). Regression analysis revealed that osteocalcin was associated with changes in CRP but not with changes in insulin concentration, adipose tissue mass or bone mineral density. These results illustrate that the weight loss-induced higher serum osteocalcin is primarily associated with reduced inflammation.:List of abbreviations ................................................................................................................................ 4 Short summary ........................................................................................................................................ 5 Graphical abstract ................................................................................................................................... 6 2 Introduction ......................................................................................................................................... 7 2a The metabolic syndrome ............................................................................................................... 8 2b C-reactive protein (CRP) and its role in MetS .............................................................................. 12 2c Bone-derived osteocalcin and inflammation ............................................................................... 14 2d Study design ................................................................................................................................. 17 3 Original peer-reviewed publication: “Osteocalcin Is Independently Associated with C-Reactive Protein during Lifestyle-Induced Weight Loss in Metabolic Syndrome” .............................................. 19 4 Summary ............................................................................................................................................ 32 5 References ......................................................................................................................................... 36 6 Supplementary data ........................................................................................................................... 45 7 Declaration about the independent preparation of the work ........................................................... 48 8 Presentation of own contribution ..................................................................................................... 49 9 Curriculum vitae ................................................................................................................................. 51 10 Publications ...................................................................................................................................... 57 11 Acknowledgments ............................................................................................................................ 58