Poor Metabolic Profile Research Articles

Prevalence and predictive risk factors of hypertensive disorders in pregnant women at high risk for gestational diabetes. The PREeclampsia in DIabetiC gestaTION (PREDICTION) study.

Women with gestational diabetes (GDM) have increased risk of hypertensive disorders in pregnancy (HDP). However, knowledge remains limited for women with high-risk metabolic profiles, regardless of GDM diagnosis. This study aimed to evaluate the prevalence of HDP among women at high risk for GDM, while simultaneously identifying potential predictive clinical risk factors of HDP. Pregnant women who performed a 75-gr Oral Glucose Tolerance Test for the selective screening (based on pre-pregnancy risk factors) of GDM were prospectively enrolled (October 2019-June 2022). The development of HDPwas assessed. Logistic regression and ROC-curve analysis were used to identify predictive risk factors for HDP. Of the 398 women enrolled (53.5% with GDM), 30 (8%) developed HDP. Women developing HDP had more frequently a family history of type 2 diabetes, a personal history of GDM or preeclampsia, and showed higher pregestational BMI and first-trimester fasting plasma glucose. Moreover, at GDM screening, they had higher fasting and 1-hour glucose levels, and higher systolic and diastolic blood pressure. At logistic regression, systolic and diastolic blood pressure were the strongest risk factors for HDP. The risk increased for systolic blood pressure ≥ 127 mmHg (61% sensitivity, 86% specificity, PPV:27%, NPV:86%) and diastolic blood pressure ≥ 82 mmHg (57% sensitivity, 92% specificity, PPV:38%, NPV:96%). Women at high risk for GDM with poor metabolic profile have higher prevalence of HDP. Systolic and diastolic blood pressure at the time of GDM screening may identify women with higher risk of developing HDP, regardless of GDM diagnosis.

Effects of Genetic Risk and Lifestyle Habits on Gout: A Korean Cohort Study.

Gout is a type of inflammatory arthritis caused by monosodium urate crystal deposits, and the prevalence of this condition has been increasing. This study aimed to determine the combined effects of genetic risk factors and lifestyle habits on gout, using data from a Korean cohort study. Identifying high-risk individuals in advance can help prevent gout and its associated disorders. We analyzed data from the Korean Genome and Epidemiology Study-Urban Health Examinees cohort (KoGES-HEXA). Genetic information of the participants was collected at baseline, and gout cases were identified based on patient statements. The polygenic risk score (PRS) was calculated using nine independent genome-wide association study datasets, and lifestyle factors and metabolic syndrome status were measured for each participant using the KoGES. Logistic regression models were used to estimate the odds ratios (ORs) for gout in relation to genetic risk, lifestyle habits, and metabolic health status, after adjusting for age and sex. Among 44,605 participants, 617 were diagnosed with gout. Gout was associated with older age, higher body mass index, and higher prevalence of hypertension, diabetes, and hypertriglyceridemia. High PRS, unfavorable lifestyle habits, and poor metabolic profiles were significantly associated with an increased risk of gout. Compared with that in the low-genetic-risk and healthy lifestyle group or ideal metabolic profile group, the risk of gout was increased in the high-genetic-risk plus unfavorable lifestyle (OR, 3.64; 95% confidence interval [CI], 2.32-6.03) or poor metabolic profile (OR, 7.78; 95% CI, 4.61-13.40) group. Conversely, adherence to favorable lifestyle habits significantly reduced gout risk, especially in high-genetic-risk groups. Genetic predisposition and unhealthy lifestyle habits significantly increase the risk of gout. Promoting healthy lifestyle habits is crucial to prevent the development of gout, particularly in individuals with high genetic susceptibility.

Association of hemoglobin levels with metabolic traits in women with PCOS.

Within normal variation, higher hemoglobin (Hb) levels are associated with poorer metabolic profile in population cohorts, underlying the link between oxygen delivery and cell metabolism. Polycystic ovary syndrome (PCOS) is the most common endocrine disorder among women and is commonly accompanied by metabolic derangements. In this study we sought to investigate Hb levels, and their metabolic associations, in women with PCOS. We used data from Northern Finland Birth Cohort 1966 to evaluate Hb levels in women with or without PCOS at the ages of 31 and 46 years. Linear regression models were used to investigate associations between Hb levels and essential metabolic parameters in both groups. Women with PCOS had higher Hb levels than controls at the age of 31 years but not at the age of 46 years. Hb levels were associated positively with most of the metabolic parameters tested (body mass index, waist circumference, fasting insulin, homeostatic model assessment-insulin resistance (HOMA-IR), blood pressure, inflammatory markers, and blood lipids), with stronger associations in women with PCOS than in non-PCOS controls. There were fewer associations at the age of 46 than at 31 years, and body mass index seemed to explain many, though not all, differences between the PCOS and non-PCOS groups. Women with PCOS have higher Hb levels at the age of 31 years. In both women with and without PCOS, Hb levels associate with poorer metabolic profile.

Major depletion of insulin sensitivity-associated taxa in the gut microbiome of persons living with HIV controlled by antiretroviral drugs

BackgroundPersons living with HIV (PWH) harbor an altered gut microbiome (higher abundance of Prevotella and lower abundance of Bacillota and Ruminococcus lineages) compared to non-infected individuals. Some of these alterations are linked to sexual preference and others to the HIV infection. The relationship between these lineages and metabolic alterations, often present in aging PWH, has been poorly investigated.MethodsIn this study, we compared fecal metagenomes of 25 antiretroviral-treatment (ART)-controlled PWH to three independent control groups of 25 non-infected matched individuals by means of univariate analyses and machine learning methods. Moreover, we used two external datasets to validate predictive models of PWH classification. Next, we searched for associations between clinical and biological metabolic parameters with taxonomic and functional microbiome profiles. Finally, we compare the gut microbiome in 7 PWH after a 17-week ART switch to raltegravir/maraviroc.ResultsThree major enterotypes (Prevotella, Bacteroides and Ruminococcaceae) were present in all groups. The first Prevotella enterotype was enriched in PWH, with several of characteristic lineages associated with poor metabolic profiles (low HDL and adiponectin, high insulin resistance (HOMA-IR)). Conversely butyrate-producing lineages were markedly depleted in PWH independently of sexual preference and were associated with a better metabolic profile (higher HDL and adiponectin and lower HOMA-IR). Accordingly with the worst metabolic status of PWH, butyrate production and amino-acid degradation modules were associated with high HDL and adiponectin and low HOMA-IR. Random Forest models trained to classify PWH vs. control on taxonomic abundances displayed high generalization performance on two external holdout datasets (ROC AUC of 80–82%). Finally, no significant alterations in microbiome composition were observed after switching to raltegravir/maraviroc.ConclusionHigh resolution metagenomic analyses revealed major differences in the gut microbiome of ART-controlled PWH when compared with three independent matched cohorts of controls. The observed marked insulin resistance could result both from enrichment in Prevotella lineages, and from the depletion in species producing butyrate and involved into amino-acid degradation, which depletion is linked with the HIV infection.

IVF and risk of Type 1 diabetes mellitus: a population-based nested case-control study.

Is the mode of conception (natural, subfertility and non-IVF, and IVF) associated with the risk of Type 1 diabetes mellitus among offspring? The risk of Type 1 diabetes in offspring does not differ among natural, subfertility and non-IVF, and IVF conceptions. Evidence has shown that children born through IVF have an increased risk of impaired metabolic function. A population-based, nested case-control study was carried out, including 769 children with and 3110 children without Type 1 diabetes mellitus within the prospective cohort of 2228073 eligible parent-child triads between 1 January 2004 and 31 December 2017. Using registry data from Taiwan, the mode of conception was divided into three categories: natural conception, subfertility, and non-IVF (indicating infertility diagnosis but no IVF-facilitated conception), and IVF conception. The diagnosis of Type 1 diabetes mellitus was determined according to the International Classification of Diseases, 9th or 10th Revision, Clinical Modification. Each case was matched to four controls randomly selected after matching for child age and sex, residential township, and calendar date of Type 1 diabetes mellitus occurrence. Based on 14.3 million person-years of follow-up (median, 10 years), the incidence rates of Type 1 diabetes were 5.33, 5.61, and 4.74 per 100000 person-years for natural, subfertility and non-IVF, and IVF conceptions, respectively. Compared with natural conception, no significant differences in the risk of Type 1 diabetes were observed for subfertility and non-IVF conception (adjusted odds ratio, 1.04 [95% CI, 0.85-1.27]) and IVF conception (adjusted odds ratio, 1.00 [95% CI, 0.50-2.03]). In addition, there were no significant differences in the risk of Type 1 diabetes according to infertility source (male/female/both) and embryo type (fresh/frozen). Although the population-level data from Taiwanese registries was used, a limited number of exposed cases was included. We showed risk of Type 1 diabetes was not associated with infertility source or embryo type; however, caution with interpretation is required owing to the limited number of exposed events after the stratification. The exclusion criterion regarding parents' history of diabetes mellitus was only applicable after 1997, and this might have caused residual confounding. It has been reported that children born to parents who conceived through IVF had worse metabolic profiles than those who conceived naturally. Considering the findings of the present and previous studies, poor metabolic profiles may not be sufficient to develop Type 1 diabetes mellitus during childhood. This study was supported by grants from Shin Kong Wu Ho-Su Memorial Hospital (No. 109GB006-1). The funders had no role in considering the study design or in the collection, analysis, interpretation of data, writing of the report, or decision to submit the article for publication. The authors have no competing interests to disclose. N/A.

The effect of a low-calorie diet on depressive symptoms in individuals with overweight or obesity: a systematic review and meta-analysis of interventional studies.

Individuals with overweight or obesity are at a high risk for so-called 'atypical' or immunometabolic depression, with associated neurovegetative symptoms including overeating, fatigue, weight gain, and a poor metabolic profile evidenced e.g. by dyslipidemia or hyperglycemia. Research has generated preliminary evidence for a low-calorie diet (LCD) in reducing depressive symptoms. The aim of the current systematic review and meta-analysis is to examine this evidence to determine whether a LCD reduces depressive symptoms in people with overweight or obesity. Eligible studies were identified through PubMed, ISI Web of Science, and PsycINFO until August 2023. Standardized mean differences (SMDs) were derived using random-effects meta-analyses for (1) pre-post LCD comparisons of depression outcomes, and (2) LCD v. no-diet-control group comparisons of depression outcomes. A total of 25 studies were included in the pre-post meta-analysis, finding that depression scores were significantly lower following a LCD (SMD = -0.47), which was not significantly moderated by the addition of exercise or behavioral therapy as a non-diet adjunct. Meta-regressions indicated that a higher baseline BMI and greater weight reduction were associated with a greater reduction in depression scores. The intervention-control meta-analysis (n = 4) found that overweight or obese participants adhering to a LCD showed a nominally lower depression score compared with those given no intervention (SMD = -0.29). There is evidence that LCDs may reduce depressive symptoms in people with overweight or obesity in the short term. Future well-controlled intervention studies, including a non-active control group, and longer-term follow-ups, are warranted in order to make more definitive conclusions.

Posterior-only approach in patients with poor general condition and spinal metastatic vertebral fracture

PurposeThe surgical treatment of spinal metastases is mostly palliative in nature and focuses on improving the quality of life of patients. The posterior transpedicular surgical approach provides circumferential 360° decompression, allows reconstruction and stabilisation to be achieved in a single session and can be performed using an open, mini-open or minimally invasive approach. We present and discuss the surgical techniques and outcomes for patients with single-level metastatic spinal disease and in poor general condition who underwent surgery via the posterior-only transpedicular corpectomy approach and reconstruction with expandable corpectomy cages. MethodsPatients with a single level thoracolumbar metastatic disease (T3-L5) and a Karnofsky score of ≤70, who underwent a complete posterior transpedicular corpectomy with expandable cage reconstruction of the anterior spinal column were retrospectively reviewed. Patients’ demographics, SINS, modified Tokuhashi scores as well as preoperative and postoperative ASIA scale, Karnofsky scores, VAS scores and vertebral height/Cobb angle values were analysed. ResultsA total of 44 patients (24 M/20 F) (mean age 53.25±21.26 years) met the inclusion criteria. The modified Tokuhashi scores were as follows: score 0–8, 5 (11.4%) patients; score 9–11, 14 (31.8%) patients; and score 12–15, 25 (56.8%) patients. There were significant improvements in the postoperative VAS scores (mean 7.7–2.9), Karnofsky scores (mean 63.3–79.6) as well as the Cobb angles (18.6–12.8°) and vertebral height. Thirtyfive patients showed improved neurological function by at least one ASIA grade, whereas 9 showed no improvement during the postoperative period. ConclusionsThis technique, which has a low complication rate and a short recovery time, can help achieve satisfactory results even in patients with poor metabolic profiles and Karnofsky scores in the preoperative period. Further clinical studies with large patient groups are warranted to confirm the results of this study.

Posterior-only approach in patients with poor general condition and spinal metastatic vertebral fracture

PurposeThe surgical treatment of spinal metastases is mostly palliative in nature and focuses on improving the quality of life of patients. The posterior transpedicular surgical approach provides circumferential 360° decompression, allows reconstruction and stabilisation to be achieved in a single session and can be performed using an open, mini-open or minimally invasive approach. We present and discuss the surgical techniques and outcomes for patients with single-level metastatic spinal disease and in poor general condition who underwent surgery via the posterior-only transpedicular corpectomy approach and reconstruction with expandable corpectomy cages. MethodsPatients with a single level thoracolumbar metastatic disease (T3-L5) and a Karnofsky score of ≤70, who underwent a complete posterior transpedicular corpectomy with expandable cage reconstruction of the anterior spinal column were retrospectively reviewed. Patients’ demographics, SINS, modified Tokuhashi scores as well as preoperative and postoperative ASIA scale, Karnofsky scores, VAS scores and vertebral height/Cobb angle values were analysed. ResultsA total of 44 patients (24 M/20 F) (mean age 53.25±21.26 years) met the inclusion criteria. The modified Tokuhashi scores were as follows: score 0–8, 5 (11.4%) patients; score 9–11, 14 (31.8%) patients; and score 12–15, 25 (56.8%) patients. There were significant improvements in the postoperative VAS scores (mean 7.7–2.9), Karnofsky scores (mean 63.3–79.6) as well as the Cobb angles (18.6–12.8°) and vertebral height. Thirtyfive patients showed improved neurological function by at least one ASIA grade, whereas 9 showed no improvement during the postoperative period. ConclusionsThis technique, which has a low complication rate and a short recovery time, can help achieve satisfactory results even in patients with poor metabolic profiles and Karnofsky scores in the preoperative period. Further clinical studies with large patient groups are warranted to confirm the results of this study.

Efficacy and Safety of Doravirine-Based Regimens in Real Life: A Prospective Monocentric French Study.

Doravirine (DOR) efficacy and safety have been evaluated in adult naive or treated patients starting a DOR-based regimen between September 15, 2019, and December 31, 2020. Medical history and examination, laboratory results, and tolerance were assessed during the 48 weeks of follow-up. Among the 77 patients included, virological control (VC) was noticed for 66 patients at baseline. Median age was 51 years, and 62% were men. The most common reason for initiating a DOR-based therapy was toxicity (44; 67%) and, especially, weight gain. A virological suppression (VS) was maintained in 55 (83%) patients of the VC group and noticed in 9 (82%) of the non-VC patients at week 48, by intention-to-treat analysis. On treatment analysis, 98% and 100% patients achieved VS in the VC and non-VC groups, respectively. The renal and metabolic tolerance were good. DOR-based regimens appear to be a safe and relevant strategy to circumvent drug interactions and drugs with a poor metabolic tolerance profile.

Poor Metabolic Profile Is an Independent Risk Factor for Recurrence After Hiatal Hernia Repair When Using Tension-Free Mesh.

Purpose: The effect of metabolic risk factors on the recurrence rate of hiatal hernia (HH) after the initial repair is still controversial. In this study, we evaluated whether a poor preoperative metabolic profile is a risk factor for the recurrence of a HH after surgery. Methods: Perioperative patient data were obtained from hospital records. A poor metabolic profile was defined as having two or more metabolic conditions such as diabetes, hypertension, hyperlipidemia, or being overweight. The recurrence rates of HH were measured at 6 months, and again at 12 months after surgery. Results: Data were collected from a total of 221 patients. While 87 (39.4%) patients underwent tension-free mesh (TFM) repair, 137 (60.6%) were treated with suture repair. The poor metabolic profile has no effect on the recurrence rates in the suture-repair group. However, patients who underwent TFM repair displayed a significantly higher recurrence rate at the 12-month time point if they had poor metabolic profile, compared to the healthy group (respectively, 20.7% and 3.4%, P < .01). The logistic regression analysis showed that having a poor metabolic profile was an independent risk factor for recurrence after 12 months in the same group (odds ratio: 8.04 confidence interval [CI: 1.2-53.5] P = .03). Conclusion: The poor metabolic profile was found to be responsible for high recurrence rates only in patients who underwent TFM HH repair.

Assessing the mechanisms contributing to self-care behaviours in young and usual-onset diabetes.

Context: Young-onset diabetes (YOD) (age of onset 21-39 years) is associated with a poorer metabolic profile and a higher risk of complications, and poor self-care behaviours play a significant role. However, few studies have comprehensively examined the mechanisms (self-efficacy, dietary barriers, illness perceptions, knowledge, diabetes-related distress) that may contribute to poor self-care behaviours in YOD. Objectives: Our study aims to compare these mechanisms and self-care behaviours between participants with YOD and usualonset diabetes (age of onset 40-59 years). Study design: A cross-sectional survey was conducted in primary care clinics in participants with YOD or UOD, and type 2 diabetes for 10 years or less. Survey tools included the Diabetes Empowerment Scale short-form (DES-SF), dietary barriers of the Personal Diabetes Questionnaire (PDQ-DB), Brief Illness Perceptions Questionnaire (BIPQ), revised Michigan Diabetes Knowledge Test (DKT), diabetes distress scale (DDS), Summary of Diabetes Self-care Activities (SDSCA), International Physical Activity Questionnaire (IPAQ-SF) and medication adherence report scale (MARS-5), and means of both groups were compared using independent T-tests and effect sizes were analysed (Cohen's d). Results: 97 participants with YOD and 312 with UOD completed the survey. Compared with UOD, participants with YOD reported a lower adherence to a specific diet (d=0.45), with no significant differences in levels of physical activity or medication adherence. Participants with YOD experienced greater diabetes-related distress (d=0.35), especially with emotional (d=0.37), regimen-related (d=0.43) and interpersonal (d=0.39) distress. At the same time, perception of self-efficacy was significantly lower (d=0.27) and more dietary barriers were perceived (d=0.76). Participants with YOD also perceived that diabetes affected their lives more severely (consequence) (d=0.26), had a larger effect on their emotions (emotional representation) (d=0.28), will last longer (timeline) (d=0.37), and perceived that treatment was less likely help their diabetes (treatment control) (d=0.26). Conclusions: Participants with YOD experienced greater diabetes-related distress, lower self-efficacy and reported lower dietary adherence with more dietary barriers than those with UOD. Patients with YOD have distinctly different issues from UOD, and in providing care for YOD, clinicians should actively seek to identify and address these issues.

Relationships between fasting glucose levels, lifestyle factors, and metabolic parameters in Korean adults without diagnosis of diabetes mellitus.

BackgroundWe investigated the associations between fasting glucose level ranges with lifestyle factors and metabolic profiles among adults without previous diagnosis of diabetes.MethodsWe analyzed 13 625 adults without previous diagnosis of diabetes from the Korea National Health and Nutrition Examination Survey during 2016 to 2018. We categorized fasting glucose levels (mg/dl) as follows: <90, 90 to 99, 100 to 109, 110 to 124, and ≥125. We evaluated trends in the proportions of individuals with obesity, abdominal, obesity, current smoking, heavy drinking, and low physical activity according to these categories, and the odds for uncontrolled blood pressure (BP), low‐density lipoprotein cholesterol (LDL‐C), triglycerides (TG), and high‐density lipoprotein cholesterol (HDL‐C) for each fasting glucose level compared to a fasting glucose level of <90 mg/dl.ResultsThe proportions of individuals with obesity, abdominal obesity, and heavy drinking increased according to fasting glucose level (P for trend <.05). The odds for BP ≥140/90 mm Hg, TG ≥150 mg/dl, HDL‐C < 40 mg/dl in men, and HDL‐C < 50 mg/dl in women increased with increasing fasting glucose levels; however, the odds for LDL‐C ≥ 130 mg/dl increased with increasing fasting glucose levels only in women. The increases in odds for uncontrolled BP and lipid profiles were mostly observed for fasting glucose levels ≥90 mg/dl.ConclusionsEfforts are needed to prevent increased fasting glucose levels, as higher levels, even within normal range, were associated with poor metabolic profiles.

The Effects of Oxytocin on Appetite Regulation, Food Intake and Metabolism in Humans.

The hypothalamic peptide oxytocin and its receptor are involved in a range of physiological processes, including parturition, lactation, cell growth, wound healing, and social behavior. More recently, increasing evidence has established the effects of oxytocin on food intake, energy expenditure, and peripheral metabolism. In this review, we provide a comprehensive description of the central oxytocinergic system in which oxytocin acts to shape eating behavior and metabolism. Next, we discuss the peripheral beneficial effects oxytocin exerts on key metabolic organs, including suppression of visceral adipose tissue inflammation, skeletal muscle regeneration, and bone tissue mineralization. A brief summary of oxytocin actions learned from animal models is presented, showing that weight loss induced by chronic oxytocin treatment is related not only to its anorexigenic effects, but also to the resulting increase in energy expenditure and lipolysis. Following an in-depth discussion on the technical challenges related to endogenous oxytocin measurements in humans, we synthesize data related to the association between endogenous oxytocin levels, weight status, metabolic syndrome, and bone health. We then review clinical trials showing that in humans, acute oxytocin administration reduces food intake, attenuates fMRI activation of food motivation brain areas, and increases activation of self-control brain regions. Further strengthening the role of oxytocin in appetite regulation, we review conditions of hypothalamic insult and certain genetic pathologies associated with oxytocin depletion that present with hyperphagia, extreme weight gain, and poor metabolic profile. Intranasal oxytocin is currently being evaluated in human clinical trials to learn whether oxytocin-based therapeutics can be used to treat obesity and its associated sequela. At the end of this review, we address the fundamental challenges that remain in translating this line of research to clinical care.

Abstract 415: Effect of aerobic and resistance exercise on the mitochondrial peptide MOTSc in Hispanic and non-Hispanic breast cancer survivors

Abstract Background MOTS-c is a mitochondrial derived peptide with exercise mimetic activity that elicits beneficial effects on metabolism and exercise capacity. MOTS-c stimulates glucose utilization, fat-oxidization, reduces inflammation, and protects against experimental models of metabolic disease. Furthermore, MOTS-c effects in humans are affected by race, potentially via ethnic-specific mtDNA variations. Women treated for breast cancer are at an increased risk for risk for cardiovascular disease, diabetes and obesity, due to side effects of cancer-treatments. Exercise mitigates many of these side effects, but the role of MOTS-c regulation by exercise among breast cancer survivors (BCS) of varying ethnicities is unknown. We examined the effects of a 16-week aerobic and resistance exercise intervention on MOTS-c in Hispanic and Non-Hispanic BCS. Methods BCS (Stage I-III) were randomized to exercise (n=50) or standard care (n=50). The intervention promoted supervised, progressive moderate-vigorous aerobic and resistance exercise thrice weekly for 16 weeks. Aerobic exercise was performed at 65-85% maximum heart rate. Resistance exercise was performed in circuit-fashion with 3 sets of 10-15 repetitions including upper and lower body exercises at 65-70% 1-repetition maximum. Fasting blood draws were obtained at baseline and post-intervention (4 months). Body composition was assessed by dual energy x-ray absorptiometry. MOTS-c was analyzed in plasma using an in-house ELISA. Within and between group differences were assessed by paired t-test and repeated measures ANOVA. Pearson's correlation was computed to assess the association between MOTS-c and metabolic biomarkers. ResultsTwenty-five Hispanic BCS and 24 non-Hispanic BCS (age 53.5±10.4 years) and BMI of 33.5±5.5 kg/m2 were included. Hispanic BCS were younger, of greater adiposity, had higher stage cancers, and had worse metabolic profiles at baseline compared to non-Hispanic BCS (p&amp;lt;0.001). Post-exercise, MOTS-c levels significantly increased when compared to baseline and the usual care group among NHBCS (p&amp;lt;0.01). Post-exercise levels of MOTS-c among non-Hispanic BCS were significantly associated with reductions in fat mass, body weight, HOMA-IR, CRP, and an increase in lean mass (p&amp;lt;0.01). MOTS-c did not significantly change following exercise among Hispanic BCS (p&amp;gt;0.05). Conclusions A 16-week aerobic and resistance intervention increased MOTS-c levels among non-Hispanic BCS but not Hispanic BCS. Non-Hispanic BCS who experience exercise-induced improvements in MOTS-c may also experience improved insulin sensitivity thereby reducing the risk for comorbid conditions. Despite poorer metabolic profiles, Hispanic BCS may not experience exercise-induced benefits on MOTS-c. Future trials should aim for reducing potential ethnic differences in cardiometabolic health. Citation Format: Christina M. Dieli-Conwright, Nathalie Sami, Mary K. Norris, Junxiang Wan, Hiroshi Kumagai, Pinchas Cohen. Effect of aerobic and resistance exercise on the mitochondrial peptide MOTSc in Hispanic and non-Hispanic breast cancer survivors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 415.

Amphiphilic peptide-based MMP3 inhibitors for intra-articular treatment of knee OA

Since 2007, Metalloproteases (MMPs) have been considered potential targets for treating osteoarthritis (OA), for which the primary pathogenic event is the extensive degeneration of articular cartilage. MMP3 is an enzyme critical for these degenerative changes. However, problems of selectivity, low bioavailability and poor metabolic profile during clinical trials of MMPs inhibitors (MMPIs) led to limited beneficial effect and thus did not justify further pursuit of the clinical studies. In a previous work, a new alkyl derivative of hyaluronic acid (HA), HYADD4®, previously approved as intra-articular treatment for knee OA, was studied in vitro and in vivo as MMP3I. Molecular simulation studies confirmed the interaction between the alkyl side chain of this HA derivative and the additional S1′ pocket of MMP3. However, the high MW and the polar HA backbone of HYADD4® imply a high desolvation energy cost, which can potentially decrease its inhibitory potency. In this study, a new class of MMP3Is based on a small peptide backbone (CGV) chemically derivatized with an alkyl chain was developed through interactive cycles of design, synthesis and screening, accompanied by computational evaluation and optimization. Two MMP3Is, e(I) and l(II), were selected because of their effective inhibitory activity (3.2 and 10.2 µM, respectively) and water solubility. Both MMPIs showed a broad range of inhibitory effects against almost all the MMPs tested. In an in vitro model of inflammatory OA, e(I) was the most effective MMPI: at the concentration of 93 µM, it reversed inflammatory outcomes. Moreover, because of its amphiphilic structure, the e(I) MMPI promoted stable micellar formulation at concentrations higher than 0.2 mg/mL in water. The findings were confirmed by TEM and Nile red staining analysis. Based on these results, the e(I) MMPI can be considered a good candidate for the intra-articular treatment of OA, and the micellar formulation of this peptide in an aqueous buffer can potentially increase the bioavailability and, thus, the efficacy of the MMPIs.

Body composition and metabolic parameters in men with chronic traumatic paraplegia – A pilot study from India

Objective To study body composition, measures of insulin resistance and dyslipidemia in Indian men with paraplegia as compared to age and body mass index (BMI) matched able-bodied men. Design Cross sectional study Setting Departments of Physical Medicine and Rehabilitation and Endocrinology Participants Males aged 18–45 years with chronic traumatic paraplegia versus age and BMI-matched able-bodied men Interventions None Main outcome measures Measures of body composition such as total body fat, lean mass, regional adiposity using dual energy x-ray absorptiometry (DXA), metabolic profile and insulin resistance Results Subjects with paraplegia (n = 43), compared to controls (n = 36), had higher %Fat mass (FM) (25.5 (21.2–28.9) vs 20.2 (15.9–22.2); P < 0.01), lower trunk to leg ratio (0.66 (0.51–0.73) vs 0.87 (0.72–0.94); P < 0.01), lower lean mass index (14.38 (2.57) vs 17.80 (2.34); P < 0.01) and lower appendicular lean mass index (5.81 ± 1.26 vs 8.17 ± 1.12; P < 0.01). Fasting blood glucose (mg/dl) was higher (89.0(81.5–96.5) vs 80.0 (74.5–88.2); P < 0.01), Homeostasis model assessment of insulin resistance was higher (1.33 (1.03–2.12) vs 0.94 (0.52–1.78); P = 0.02), Quantitative insulin sensitivity check index (QUICKI) was lower (0.36 ± 0.04 vs 0.38 ± 0.05; P = 0.02) and HDL-C was lower (33.00 (30.00–42.75) vs 38.50 (33.00–43.25); P < 0.02) in cases compared to controls. QUICKI correlated positively with HDL-C and negatively with %FM, estimated VAT volume and TG. Trunk to leg ratio correlated positively with TG even after controlling for %FM. Conclusion Men with chronic paraplegia had lower lean mass, higher total and regional fat mass, increased insulin resistance and low HDL-C when compared with BMI-matched able-bodied controls. Both total and regional adiposity correlated with poor metabolic profile.

Molecular Modeling Studies on Cytochrome P450-mediated Drug Metabolism.

Drug metabolism studies play a critical role in the optimization of the therapeutic efficacy of newer drug candidates. Many drug candidates and drugs were withdrawn from the pre-clinical/clinical stage or market due to the poor metabolic profiles. The poor metabolic profiles may make the clinical candidates/drugs inactive or toxic. Therefore, it is necessary to optimize the metabolic profiles at the initial phase of drug discovery and development processes. Recently, molecular modeling approaches were found to be useful in the optimization of metabolic profiles of clinical candidates. The molecular modeling approaches were employed in the identification of various metabolic profiles. In the present study, the current status of the research work on drug metabolism based on molecular modeling methodologies has been reviewed. The basics of drug metabolism and its importance in the physiological process of the human body have been described. Moreover, the involvement of molecular modeling approaches like pharmacophore- based modeling, QSAR, molecular docking, virtual screening, quantum chemical analysis, molecular dynamics, etc., in predicting metabolic profiles of therapeutic agents is analyzed. The present review provides computational insights in the prediction of substrate specificity, metabolic activity, SOM, metabolites, toxicity, etc., on cytochrome P450-mediated drug metabolism. The study may help the researchers to design novel drug candidates for the various classes of therapeutic targets with efficient metabolic profiles.

Low Soluble Receptor for Advanced Glycation End Products Precedes and Predicts Cardiometabolic Events in Women With Rheumatoid Arthritis.

Background: Cardiovascular disease (CVD) causes premature mortality in rheumatoid arthritis (RA). Levels of soluble (s)RAGE change with aging, hypertension and hypercholesterolemia. We assessed whether sRAGE was associated with increased risk of CVD in RA patients.Methods: Serum sRAGE was measured in 184 female RA patients and analyzed with respect to CVD risk estimated by the Framingham algorithm (eCVR), metabolic profile and inflammation. Levels of sRAGE in 13 patients with known cardio-metabolic morbidity defined the cut-off for low sRAGE. Prospective 5-year follow-up of new CV and metabolic events was completed.Results: Low sRAGE was significantly associated with previous history and with new imminent cardiometabolic events in the prospective follow-up of RA patients. In both cases, low sRAGE reflected higher estimation of CVR in those patients. Low sRAGE was attributed to adverse metabolic parameters including high fasting plasma glucose and body fat content rather than inflammation. The association of sRAGE and poor metabolic profile was prominent in patients younger than 50 years.Conclusions: This study points at low sRAGE as a marker of metabolic failure developed during chronic inflammation. It highlights the importance for monitoring metabolic health in female RA patients for timely prevention of CVD.Trial registration: ClinicalTrials.gov with ID NCT03449589. Registered 28, February 2018.

The effect of succinic acid on the metabolic profile in high-fat diet-induced obesity and insulin resistance.

Obesity, insulin resistance, and poor metabolic profile are hallmarks of a high‐fat diet (HFD), highlighting the need to understand underlying mechanisms. Therefore, we sought to determine the effect of succinic acid (SA) on metabolism in high‐fat diet (HFD)‐induced obesity. Animals were randomly assigned to either low‐fat diet (LFD) or a high‐fat diet (HFD). Mice consumed their respective diets for 4.5 months and then assigned to the following groups: (LFD)+vehicle, LFD + SA (0.75 mg/ml), HFD + vehicle, or HFD + SA. Body weight (BW), food, and water intake, were tracked weekly. After 6 weeks, insulin, glucose, and pyruvate tolerance tests were completed, and spontaneous physical activity was assessed. Epididymal white adipose tissue (EWAT) mass and in vitro measurements of oxidative skeletal muscle (soleus) respiration were obtained. Expectedly, the HFD increased BW and EWAT mass, and reduced glucose and insulin tolerance. SA significantly reduced EWAT mass, more so in HFD (p < .05), but had no effect on any in vivo measurements (BW, insulin, glucose, or pyruvate tolerance, nor physical activity, all p > .05). A significant (p < .05) interaction was observed between mitochondrial respiration and treatment, where SA increased respiration, likely owed to greater mitochondrial content, as assessed by complex IV activity in both LFD and HFD. In HFD‐induced obesity, coupled with insulin desensitization, we found no favorable effect of succinic acid on glucose regulation, though adiposity was attenuated. In oxidative skeletal muscle, there was a tendency for increased respiratory capacity, likely owed to greater mitochondrial content, suggestive of a succinic acid‐induced mitochondrial biogenesis.

Role of diet and lifestyle modification in the management of nonalcoholic fatty liver disease and type 2 diabetes.

Nonalcoholic fatty liver disease (NAFLD) is considered as the hepatic evidence of insulin resistance which is the hallmark of type 2 diabetes. NAFLD is considered as the risk factor for developing type 2 diabetes and has a high frequency of occurrence in those with existing type 2 diabetes. Compared with patients with only NAFLD or type 2 diabetes, these patients show a poor metabolic profile and increase mortality. Hence, effective treatment strategies are necessary. Here, we review the role of diet and lifestyle modification in the management of NAFLD and type 2 diabetes. Based on the available studies, it has been shown that the addition of any kind of physical activity or exercise is beneficial for patients with both NAFLD and type 2 diabetes. Proper dietary management leads to weight loss are also effective in improving metabolic parameters in patients with both NAFLD and type 2 diabetes. In conclusion, it is clear that increasing physical activity or exercise is effective in improving metabolic parameters in patients who are suffering with both NAFLD and type 2 diabetes.