Development and evaluation of a clinical simulation-based educational innovation on sexual orientation and gender identity in emergency medicine.

INTRODUCTION: Sexual orientation and gender identity (SOGI)-diverse patients are marginalized and poorly cared for in the emergency department, yet well-designed educational interventions to meet this gap are lacking. We developed, implemented, and assessed a novel multi-modal SOGI curriculum on health and cultural humility for emergency medicine physician trainees. METHODS: We conducted a prospective, single-arm evaluation of our educational intervention. A convenience sample of emergency medicine resident physicians (n = 21) participated in the facilitated curriculum including didactic and clinical simulation components. Participants completed a pre- and post-curriculum evaluation that assessed clinical skills, preparedness, attitudinal awareness, and basic knowledge in caring for SOGI-diverse patients. The content of the module was based on a scoping literature review and national needs assessment of Canadian emergency physicians, educators, and trainees along with expert collaborator and input from patient/community partners. The curriculum included a facilitated pre-brief, didactic presentation, clinical simulation modules, and a structured de-brief. Participant clinical skills were evaluated before and after the educational intervention. Our primary outcome was change in clinical preparedness, attitudinal awareness, and basic knowledge in caring for SOGI-diverse patients pre- and post-intervention. RESULTS: Our patient-centered, targeted emergency medicine SOGI health and cultural humility training resulted in a significant improvement in resident self-rated clinical preparedness, attitudes, and knowledge in caring for SOGI-diverse patients. This training was valued by participants. CONCLUSION: We have designed an effective, patient-centered curriculum in health and cultural humility for SOGI-diverse patients in EM. Other programs can consider using this model and developed resources in their jurisdictions to enhance provider capacities to care for this marginalized group.

RéSUMé: INTRODUCTION: L'orientation sexuelle et l'identité de genre (OSIG) - des patients de diverses natures sont marginalisés et mal soignés dans les services d'urgence, mais des interventions éducatives bien conçues pour combler cette lacune font défaut. Nous avons élaboré, mis en œuvre et évalué un nouveau programme multimodal de l'OSIG sur la santé et l'humilité culturelle pour les médecins d'urgence stagiaires. MéTHODES: Nous avons effectué une évaluation prospective de notre intervention éducative à un seul bras. Un échantillon pratique de médecins résidents en médecine d'urgence (n = 21) a participé au programme facilité, y compris les composantes didactiques et de simulation clinique. Les participants ont effectué une évaluation avant et après le programme d'études qui évaluait les compétences cliniques, la préparation, la sensibilisation aux attitudes et les connaissances de base en matière de soins aux patients atteints de diverses OSIG. Le contenu du module était fondé sur une analyse documentaire de portée et une évaluation des besoins nationaux des médecins d'urgence, des éducateurs et des stagiaires canadiens, ainsi que sur un collaborateur expert et les commentaires des patients et des partenaires communautaires. Le programme comprenait un pré-briefing animé, une présentation didactique, des modules de simulation clinique et un débriefing structuré. Les compétences cliniques des participants ont été évaluées avant et après l'intervention éducative. Notre résultat principal était un changement dans la préparation clinique, la sensibilisation aux attitudes et les connaissances de base dans les soins aux patients atteints de diverses OSIG avant et après l'intervention. RéSULTATS: Notre formation sur la santé et l'humilité culturelle axée sur le patient et ciblée en médecine d'urgence SOGI a permis d'améliorer considérablement la préparation clinique, les attitudes et les connaissances auto-évaluées des résidents en matière de soins aux patients SOGI-divers. Cette formation a été appréciée par les participants. CONCLUSIONS: Nous avons conçu un programme efficace et centré sur le patient en matière de santé et d'humilité culturelle pour les patients SOGI-divers en EM. D'autres programmes peuvent envisager d'utiliser ce modèle et d'élaborer des ressources dans leur administration pour améliorer les capacités des fournisseurs de soins à ce groupe marginalisé.

A novel online training program for sexual and gender minority health increases allyship in cisgender, heterosexual paramedics.

Introduction: Sexual and gender minorities (SGM) make up 4% of the Canadian population. Due to existing barriers to care in the community, SGM patients may seek more help and be sicker at presentation to hospital. Paramedics occupy a unique role and can remove or decrease these barriers. There are no existing evaluations of training programs in SGM health for prehospital providers. A training program to develop better allyship in paramedics toward SGM populations was developed and assessed. Methods: A 70- to 90-min mandatory, asynchronous, online training module in SGM health in the prehospital environment was developed and delivered via the emergency medical service (EMS) system's learning management system. A before-and-after study of cisgender, heterosexual, frontline paramedics was performed to measure the impact of the training module on the care of SGM patients. The validated Ally Identity Measure (AIM) tool was used to identify success of training and includes subscales of knowledge and skills, openness and support, and oppression awareness. Demographics and satisfaction scores were collected in the posttraining survey. Matched and unmatched pairs of surveys and demographic associations were analyzed using nonparametric statistics. Results: Of 609 paramedics, 571 completed the training, and 239 surveys were completed before and 105 (n = 344) surveys after the training; 60 surveys were paired. Overall AIM scores of matched pairs (n = 60) improved by 12% (p < 0.001), with knowledge and skills accounting for most of the increase (21%, p < 0.001). Unmatched pairs (n = 344) were similar in demographics and scores. Rural paramedics also had significantly lower pretraining oppression awareness scores and had lower posttraining AIM scores compared to suburban paramedics (6% difference). Satisfaction scores rated the training as relevant and applicable (87% and 82%, respectively). Conclusions: A novel prehospital training program in the care of SGM patients resulted in a statistically significant increase in allyship in cisgender, heterosexual-identified frontline paramedics.

Systematic Review, Quality Assessment, and Synthesis of Guidelines for Emergency Department Care of Transgender and Gender-diverse People: Recommendations for Immediate Action to Improve Care.

Introduction: We conducted this systematic review to identify emergency department (ED) relevant recommendations in current guidelines for care of transgender and gender-diverse (TGD) people internationally. Methods: Using PRISMA criteria, we did a systematic search of Ovid Medline, EMBASE, and CINAHL and a hand search of gray literature for clinical practice guidelines (CPG) or best practice statements (BPS) published until June 31, 2021. Articles were included if they were in English, included medical or paramedical care of TGD populations of any age, in any setting, region or nation, and were national or international in scope. Exclusion criteria included primary research studies, review articles, narrative reviews or otherwise non-CPG or BPS, editorials, or letters to the editor, articles of regional or individual hospital scope, non-medical articles, articles not in English, or if a more recent version of the guideline existed. Recommendations relevant to ED care were identified, recorded, and assessed for quality using the AGREE-II and AGREE-REX criteria. We performed interclass correlation coefficient for interrater reliability. Recommendations were coded for the relevant point of care while in the ED (triage, registration, rooming, investigations, etc.). Results: We screened 1,658 unique articles, and 1,555 were excluded. Of the remaining 103 articles included, seven had recommendations relevant to care in the ED, comprising a total of 10 recommendations. Four guidelines and eight recommendations were of high quality. They included recommendations for testing, prevention, referral, and provision of post-exposure prophylaxis for HIV, and culturally competent care of TGD people. Conclusions: This is the most comprehensive review to date of guidelines and best practices statements offering recommendations for care of ED TGD patients, and several are immediately actionable. There are also many opportunities to build community-led research programs to synthesize and inform a comprehensive dedicated guideline for care of TGD people in emergency settings.

Exploring a case for education about sexual and gender minorities in postgraduate emergency medicine training: forming recommendations for change.

Social medicine and health advocacy curricula are known to be uncommon in postgraduate medical education. As justice movements work to unveil the systemic barriers experienced by sexual and gender minority (SGM) populations, it is imperative that the emergency medicine (EM) community progress in its efforts to provide equitable, accessible, and competent care for these vulnerable groups. Given the paucity of literature on this subject in the context of EM in Canada, this commentary borrows evidence from other specialties across North America. Trainees across specialties and of all stages are caring for an increasing number of SGM patients. Lack of education at all levels of training is identified as a significant barrier to adequately caring for these populations, thereby precipitating significant health disparities. Cultural competency is often mistakenly attributed to a willingness to treat rather than the provision of quality care. However, positive attitudes do not necessarily correlate with trainee knowledge. Barriers to creating and implementing culturally competent curricula are plentiful, yet facilitating policies and resources are rare. While international bodies continuously publish position statements and calls to action, concrete change is seldom made. The scarcity of SGM curricula can be attributed to the universal absence of formal acknowledgment of SGM health as a required competency by accreditation boards and professional membership associations. This commentary synthesizes hand-picked literature in an attempt to inform healthcare professionals on their journey toward developing culturally competent postgraduate medical education. By thematically organizing evidence into a stepwise approach, the goal of this article is to borrow ideas across medical and surgical specialties to inform the creation of recommendations and make a case for an SGM curriculum for EM programs in Canada.

An Isocaloric High-Fat Diet Regulates Partially Genetically Determined Fatty Acid and Carbohydrate Uptake and Metabolism in Subcutaneous Adipose Tissue of Lean Adult Twins.

BACKGROUND: The dysfunction of energy metabolism in white adipose tissue (WAT) induces adiposity. Obesogenic diets that are high in saturated fat disturb nutrient metabolism in adipocytes. This study investigated the effect of an isocaloric high-fat diet without the confounding effects of weight gain on the gene expression of fatty acid and carbohydrate transport and metabolism and its genetic inheritance in subcutaneous (s.c.) WAT of healthy human twins. METHODS: Forty-six healthy pairs of twins (34 monozygotic, 12 dizygotic) received an isocaloric carbohydrate-rich diet (55% carbohydrates, 30% fat, 15% protein; LF) for 6 weeks followed by an isocaloric diet rich in saturated fat (40% carbohydrates, 45% fat, 15% protein; HF) for another 6 weeks. RESULTS: Gene expression analysis of s.c. WAT revealed that fatty acid transport was reduced after one week of the HF diet, which persisted throughout the study and was not inherited, whereas intracellular metabolism was decreased after six weeks and inherited. An increased inherited gene expression of fructose transport was observed after one and six weeks, potentially leading to increased de novo lipogenesis. CONCLUSION: An isocaloric dietary increase of fat induced a tightly orchestrated, partially inherited network of genes responsible for fatty acid and carbohydrate transport and metabolism in human s.c. WAT.

Education about sexual and gender minorities within Canadian emergency medicine residency programs.

OBJECTIVES: The CAEP 2021 2SLGBTQIA +i panel sought whether a gap exists within Canadian emergency medicine training pertaining to sexual and gender minority communities. This panel aimed to generate practical recommendations on improving emergency medicine education about sexual and gender minorities, thereby improving access to equitable healthcare. METHODS: From August 2020 to June 2021, a panel of emergency medicine practitioners, residents, students, and community representatives met monthly via videoconference. A literature review was undertaken, and three mixed methods surveys were distributed to the CAEP member list, CAEP Resident Section, College of Family Physicians of Canada (CFPC)iii Emergency Medicine Members Interest Group, and to emergency medicine residency program directors and their residents. Informed by the review and surveys, recommendations were drafted and refined by panel members before presentation at the 2021 CAEP Academic Symposium. A plenary was presented to symposium attendees composed of national emergency medicine community members, which reported the survey results and literature review. All attendees were divided into small groups to develop an action plan for each recommendation. CONCLUSIONS: The panel outlines eight recommendations for closing the curricular gap. It identifies three perceived or real barriers to the inclusion of sexual and gender minority content in emergency medicine residency curricula. It acknowledges three enabling recommendations that are beyond the scope of individual emergency medicine programs or emergency departments (EDs), that if enacted would enable the implementation of the recommendations. Each recommendation is accompanied by two action items as a guide to implementation. Each of the three barriers is accompanied by two action items that offer specific solutions to overcome these obstacles. Each enabling recommendation suggests an action that would shift emergency medicine towards sociocultural competence nationally. These recommendations set the primary steps towards closing the educational gap.

RéSUMé: OBJECTIFS: Le panel ACMU 2021 2SLGBTQIA+ i a cherché à savoir s'il existe une lacune dans la formation en médecine d'urgence au Canada en ce qui concerne les communautés de minorités sexuelles et de genre. Ce panel visait à générer des recommandations pratiques sur l'amélioration de l'éducation en médecine d'urgence sur les minorités sexuelles et de genre, améliorant ainsi l'accès à des soins de santé équitables. MéTHODES: D'août 2020 à juin 2021, un groupe de praticiens en médecine d'urgence, de résidents, d'étudiants et de représentants communautaires se sont réunis chaque mois par vidéoconférence. Une revue de la littérature a été entreprise et trois enquêtes à méthodes mixtes ont été distribuées à la liste des membres de l'ACMU, à la Section des résidents de l'ACMU, au Groupe d'intérêt des membres en médecine d'urgence du Collège des médecins de famille du Canada (CMFC) iii, ainsi qu'aux directeurs des programmes de résidence en médecine d'urgence et à leurs résidents. À la lumière de l'examen et des sondages, les recommandations ont été rédigées et peaufinées par les membres du comité avant d'être présentées au Symposium universitaire de l'ACMU de 2021. Une séance plénière a été présentée aux participants du symposium, composés de membres de la communauté nationale de la médecine d'urgence, qui ont fait état des résultats du sondage et de la revue de la littérature. Tous les participants ont été répartis en petits groupes afin d'élaborer un plan d'action pour chaque recommandation. CONCLUSIONS: Le groupe d'experts formule huit recommandations pour combler le fossé entre les programmes d'enseignement. Il identifie trois obstacles perçus ou réels à l'inclusion du contenu sur les minorités sexuelles et de genre dans les programmes de résidence en médecine d'urgence. Il reconnaît trois recommandations habilitantes qui dépassent la portée des programmes de médecine d'urgence individuels ou des services d'urgence (SU) et qui, si elles étaient adoptées, permettraient la mise en œuvre des recommandations. Chaque recommandation est accompagnée de deux mesures de suivi comme guide de mise en œuvre. Chacun des trois obstacles est accompagné de deux éléments d'action qui offrent des solutions spécifiques pour surmonter ces obstacles. Chaque recommandation habilitante suggère une action qui ferait évoluer la médecine d'urgence vers une compétence socioculturelle au niveau national. Ces recommandations établissent les principales étapes pour combler l'écart en matière d'éducation.

Care of Sexual and Gender Minorities in the Emergency Department: A Scoping Review.

STUDY OBJECTIVE: This scoping review was conducted to collate and summarize the published research literature addressing sexual and gender minority care in the emergency department (ED). METHODS: Using PRISMA-ScR criteria, an electronic search was conducted of CINAHL, Embase, Ovid Medline, and Web of Science for all studies that were published after 1995 involving sexual and gender minorities, throughout all life stages, presenting to an ED. We excluded non-US and Canadian studies and editorials. Titles and abstracts were screened, and full-text review was performed independently with 4 reviewers. Abstraction focused on study design, demographics, and outcomes, and the resulting data were analyzed using an ad hoc iterative thematic analysis. RESULTS: We found 972 unique articles and excluded 743 after title and abstract screening. The remaining 229 articles underwent full-text review, and 160 articles were included. Themes identified were HIV in sexual and gender minorities (n=61), population health (n=46), provider training (n=29), ED avoidance or barriers (n=23), ED use (n=21), and sexual orientation/gender identity information collection (n=9). CONCLUSION: The current literature encompassing ED sexual and gender minority care cluster into 6 themes. There are considerable gaps to be addressed in optimizing culturally competent and equitable care in the ED for this population. Future research to address these gaps should include substantial patient stakeholder engagement in all aspects of the research process to ensure patient-focused outcomes congruent with sexual and gender minority values and preferences.

Insulin Directly Regulates the Circadian Clock in Adipose Tissue.

Adipose tissue (AT) is a key metabolic organ which functions are rhythmically regulated by an endogenous circadian clock. Feeding is a "zeitgeber" aligning the clock in AT with the external time, but mechanisms of this regulation remain largely unclear. We tested the hypothesis that postprandial changes of the hormone insulin directly entrain circadian clocks in AT and investigated a transcriptional-dependent mechanism of this regulation. We analyzed gene expression in subcutaneous AT (SAT) of obese subjects collected before and after the hyperinsulinemic-euglycemic clamp or control saline infusion (SC). The expressions of core clock genes PER2, PER3, and NR1D1 in SAT were differentially changed upon insulin and saline infusion, suggesting insulin-dependent clock regulation. In human stem cell-derived adipocytes, mouse 3T3-L1 cells, and AT explants from mPer2Luc knockin mice, insulin induced a transient increase of the Per2 mRNA and protein expression, leading to the phase shift of circadian oscillations, with similar effects for Per1 Insulin effects were dependent on the region between -64 and -43 in the Per2 promoter but not on CRE and E-box elements. Our results demonstrate that insulin directly regulates circadian clocks in AT and isolated adipocytes, thus representing a primary mechanism of feeding-induced AT clock entrainment.

Orphan GPR116 mediates the insulin sensitizing effects of the hepatokine FNDC4 in adipose tissue.

The proper functional interaction between different tissues represents a key component in systemic metabolic control. Indeed, disruption of endocrine inter-tissue communication is a hallmark of severe metabolic dysfunction in obesity and diabetes. Here, we show that the FNDC4-GPR116, liver-white adipose tissue endocrine axis controls glucose homeostasis. We found that the liver primarily controlled the circulating levels of soluble FNDC4 (sFNDC4) and lowering of the hepatokine FNDC4 led to prediabetes in mice. Further, we identified the orphan adhesion GPCR GPR116 as a receptor of sFNDC4 in the white adipose tissue. Upon direct and high affinity binding of sFNDC4 to GPR116, sFNDC4 promoted insulin signaling and insulin-mediated glucose uptake in white adipocytes. Indeed, supplementation with FcsFNDC4 in prediabetic mice improved glucose tolerance and inflammatory markers in a white-adipocyte selective and GPR116-dependent manner. Of note, the sFNDC4-GPR116, liver-adipose tissue axis was dampened in (pre) diabetic human patients. Thus our findings will now allow for harnessing this endocrine circuit for alternative therapeutic strategies in obesity-related pre-diabetes.

Dietary Rapeseed Oil Supplementation Reduces Hepatic Steatosis in Obese Men-A Randomized Controlled Trial.

SCOPE: Effective treatment for obesity associated non-alcoholic fatty liver disease (NAFLD) is limited. Dietary supplementation of n-3 polyunsaturated fatty acids, specifically alpha linolenic acid (ALA), can resolve intrahepatic lipid content (IHL). This study investigates the effect of daily supplementation of either refined rapeseed (RA), containing high amounts of ALA, or refined olive (OL) oil on IHL and glucose metabolism in NAFLD patients. METHODS AND RESULTS: 27 obese men consumed an isocaloric diet including either 50 g of RA or OL daily for 8 weeks. Hepatic proton magnetic resonance spectroscopy, hyperinsulinemic-euglycemic clamp studies and blood tests are performed before and at the end of the study. At 8 weeks a significant reduction in IHL is observed for RA (13.1 ± 1.6 before versus 11.1 ± 1.6% after intervention) versus OL (13.3 ± 2.5 before versus 15.7 ± 2.7% after intervention). For RA, a 21% reduction (P < 0.02) in serum free fatty acids (FFA) and a 1.68-fold increase (P = 0.03) of serum interleukin-6 (IL-6) is observed after 8 weeks. CONCLUSION: RA has a beneficial effect on hepatic lipid metabolism as shown by reduced IHL and serum FFA. RA induced IL-6 production seems to be liver protective confirming previous results.

Sexually dimorphic metabolic responses to exposure of a high fat diet during pregnancy, lactation and early adulthood in Gipr-/- mice.

Obesity has a multifactorial origin. It is known that alterations of the intra uterine milieu induce developmental programming effects leading to metabolic diseases in offspring. Obesity is diminished in mice lacking the glucose-dependent insulinotropic polypeptide receptor (Gipr-/-) when exposed to a high fat diet (HFD). We investigated whether Gipr-/- mice are still protected from obesity when additionally exposure to a HFD during pregnancy and lactation occurs. Male and female wild type (WT) and Gipr-/- offspring received either a control/ low fat diet or HFD during pregnancy and lactation and were then either left on this diet or placed on the opposite diet after weaning until 24 weeks of life. Female WT mice showed increased body weight and adiposity when exposed to a HFD during pregnancy and lactation and post-weaning compared to female WT that received the HFD after weaning only. This exacerbated effect of a HFD during pregnancy and lactation was abolished in female Gipr-/- mice. Male Gipr-/- mice were protected from obesity to a much lesser extent. Male Gipr-/- mice exposed to a HFD during pregnancy and lactation and after weaning exhibited significantly increased fed serum glucose compared to Gipr-/- mice exposed to a HFD after weaning only. In female Gipr-/- mice no differences in fed blood glucose were observed between these groups. Our data indicate that female Gipr-/- mice are more protected from obesity. This protection is preserved in female Gipr-/- mice when additional deleterious effects of a HFD occur during fetal development.

Transforming our relationship with the social determinants of health: a scoping review of social justice interventions in Canadian Medical Schools.

This article was migrated. The article was marked as recommended. Background/Purpose: Physicians are in a powerful position to improve the health status of communities through mitigating disparities rooted in social inequities. However, it is uncertain whether medical schools are preparing future physicians with the skills needed to care for diverse populations. The current scoping review aimed to describe how Canadian medical schools teach social justice, comparing pedagogical strategies. Methods: A search was performed using OVID to identify published studies of implemented and evaluated social justice-based interventions within Canadian medical school curricula. Results: Six studies were included. Common themes included increased content knowledge, greater understanding of SDoH, acknowledgement of power and privilege imbalances, identification of physicians' roles as advocates, emphasis on the importance of interdisciplinary care, and increased capacity for self-reflection and personal growth. Experiential interventions were associated with greater personal transformation, but had limited accessibility. Conclusion: Despite the widespread recognition of physicians' roles as health advocates, there is a lack of consensus about an effective strategy for teaching social justice in medical education in Canada. While additional research focusing on the relative merits of didactic versus experiential learning is needed, these preliminary results suggest that experiential learning emphasizing self-reflection and personal growth may be optimal when approaching transformative learning.

VEGF and GLUT1 are highly heritable, inversely correlated and affected by dietary fat intake: Consequences for cognitive function in humans.

OBJECTIVE: Reduction of brain glucose transporter GLUT1 results in severe neurological dysfunction. VEGF is required to restore and maintain brain glucose uptake across the blood brain barrier via GLUT1, which was shown to be acutely diminished in response to a high fat diet (HFD) in mice. The genetic and HFD-related regulation and association of VEGF and GLUT1 (SLC2A1) in humans was investigated in the NUtriGenomic Analysis in Twins (NUGAT) study. METHODS: 92 healthy and non-obese twins were standardized to a high-carbohydrate low-fat diet for 6 weeks before switched to a 6-week HFD under isocaloric conditions. Three clinical investigation days were conducted: after 6 weeks of low-fat diet and after 1 and 6 weeks of HFD. Serum VEGF and other cytokine levels were measured using ELISA. Gene expression in subcutaneous adipose tissue was assessed by quantitative Real-Time PCR. Genotyping was performed using microarray. The Auditory Verbal Learning Task was conducted to measure cognitive performance. RESULTS: In this human study, we showed that the environmental regulation of SLC2A1 expression and serum VEGF by HFD was inversely correlated and both factors showed strong heritability (>90%). In response to the HFD containing 45% fat, serum VEGF levels increased (P = 0.002) while SLC2A1 mRNA expression in adipose tissue decreased (P = 0.001). Higher BMI was additionally associated with lower SLC2A1 expression. AA-genotypes of the rs9472159 polymorphism, which explained ∼39% of the variation in circulating VEGF concentrations, showed significantly reduced serum VEGF levels (P = 6.4 × 10-11) but higher SLC2A1 expression (P = 0.009) in adipose tissue compared to CC/CA-genotypes after 6 weeks of HFD. Memory performance in AA-genotypes declined in response to the HFD compared to CC- and CA-genotypes. CONCLUSIONS: The results provide evidence to suggest the translatability of the dietary regulation of VEGF and GLUT1 from mouse models to humans. Our data demonstrate that HFD induces a genetically determined and correlated decrease of GLUT1 and increase of VEGF which may affect memory performance. CLINICAL TRIAL REGISTRATION NUMBER: NCT01631123.

Dietary Fat Intake Modulates Effects of a Frequent ACE Gene Variant on Glucose Tolerance with association to Type 2 Diabetes.

The frequent ACE insertion/deletion polymorphism (I/D) is, albeit inconsistently, associated with impaired glucose tolerance and insulin resistance. We recently observed an enhanced upregulation of ACE by elevated fat intake in GG-carriers of the I/D-surrogate rs4343 variant and therefore investigated its potential nutrigenetic role in glucose metabolism. In this nutritional intervention study 46 healthy and non-obese twin pairs consumed recommended low fat diets for 6 weeks before they received a 6-week high fat (HF) diet under isocaloric conditions. Intravenous glucose tolerance tests were performed before and after 1 and 6 weeks of HF diet. While glucose tolerance did not differ between genotypes at baseline it significantly declined in GG-carriers after 6 weeks HF diet (p = 0.001) with higher 2 h glucose and insulin concentrations compared to AA/AG-carriers (p = 0.003 and p = 0.042). Furthermore, the gene-diet interaction was confirmed in the cross-sectional Metabolic Syndrome Berlin Potsdam study (p = 0.012), with the GG-genotypes being significantly associated with prevalent type 2 diabetes for participants with high dietary fat intake ≥37% (GG vs. AA/AG, OR 2.36 [1.02-5.49], p = 0.045). In conclusion, the association between the rs4343 variant and glucose tolerance is modulated by dietary fat intake. The ACE rs4343 variant is a novel nutrient-sensitive type 2 diabetes risk marker potentially applicable for nutrigenetic dietary counseling.

A High Fat Diet During Pregnancy and Lactation Induces Cardiac and Renal Abnormalities in GLUT4 +/- Male Mice.

BACKGROUND/AIMS: Altered nutrients during the in utero (IU) and/or lactation (L) period predispose offspring to cardio-renal diseases in adulthood. This study investigates the effect of a high fat diet (HFD) fed to female mice during IU/L on gene expression patterns associated with heart and kidney failure and hypertension in male offspring. METHODS: Female wild type (WT) mice were fed either a HFD or control chow (C) prior to mating with males with a genetic heterozygous deletion of GLUT4 (G4+/-, a model of peripheral insulin resistance and hypertension) and throughout IU/L. After weaning male offspring were placed on a standard rodent chow until 24 weeks of age. RESULTS: All offspring exposed to a maternal HFD showed increased heart and kidney weight and reduced cardiac insulin responsiveness. G4+/- offspring on a HFD displayed early hypertension associated with increased renal gene expression of renin and the AT1- receptors compared to G4+/- on a C diet. This group showed decreased cardiac expression of key genes involved in fatty acid oxidation compared to WT on a C diet. CONCLUSIONS: These results indicate an interaction between a HFD diet and genotype during early life development that can enhance susceptibility to cardio-renal diseases later in life.

Plasminogen Activator Inhibitor-1 is Regulated Through Dietary Fat Intake and Heritability: Studies in Twins.

In different pathophysiological conditions plasminogen activator inhibitor-1 (PAI-1) plasma concentrations are elevated. As dietary patterns are considered to influence PAI-1 concentration, we aimed to determine active PAI-1 plasma concentrations and mRNA expression in adipose tissue before and after consumption of a high-fat diet (HFD) and the impact of additive genetic effects herein in humans. For 6 weeks, 46 healthy, non-obese pairs of twins (aged 18-70) received a normal nutritionally balanced diet (ND) followed by an isocaloric HFD for 6 weeks. Active PAI-1 plasma levels and PAI-1 mRNA expression in subcutaneous adipose tissue were assessed after the ND and after 1 and 6 weeks of HFD. Active PAI-1 plasma concentrations and PAI-1 mRNA expression in adipose tissue were significantly increased after both 1 and 6 weeks of HFD when compared to concentrations determined after ND (p < .05), with increases of active PAI-1 being independent of gender, age, or changes of BMI and intrahepatic fat content, respectively. However, analysis of covariance suggests that serum insulin concentration significantly affected the increase of active PAI-1 plasma concentrations. Furthermore, the increase of active PAI-1 plasma concentrations after 6 weeks of HFD was highly heritable (47%). In contrast, changes in PAI-1 mRNA expression in fatty tissue in response to HFD showed no heritability and were independent of all tested covariates. In summary, our data suggest that even an isocaloric exchange of macronutrients - for example, a switch to a fat-rich diet - affects PAI-1 concentrations in humans and that this is highly heritable.

Heritability and responses to high fat diet of plasma lipidomics in a twin study.

Lipidomics have a great potential as clinical tool for monitoring metabolic changes in health and disease. Nevertheless hardly anything is known about the heritability of lipids. Therefore, it is necessary to clarify how and how much we can affect these progresses in individuals. In our interventional twin study (46 healthy, non-obese twin pairs) we investigated the lipid profile in plasma samples after switching from a low fat diet to an isocaloric high fat diet (HFD) to characterize the metabolic adaptation. Additionally we used the ACE model for Additive genetics, Common and unique Environment as well as linear mixed modelling to analyse the heritability of lipids. The heritability of lipids varied between 0-62% and applied to lipid species rather than to lipid classes. Phospholipids showed the highest inheritance. In addition, sex, body mass index (BMI) and age were important modifiers. The lipid profile changed already after one week of HFD and diverged further after 5 weeks of additional HFD. Basal concentrations of specific lipids within phospholipids are strongly inherited and are likely to be associated with heritable disease risks. BMI, sex and age were major modifiers. Nutrition strongly alters specific lipid classes, and has to be controlled in clinical association studies.

High-Saturated-Fat Diet Increases Circulating Angiotensin-Converting Enzyme, Which Is Enhanced by the rs4343 Polymorphism Defining Persons at Risk of Nutrient-Dependent Increases of Blood Pressure.

BACKGROUND: Angiotensin-converting enzyme (ACE) plays a major role in blood pressure regulation and cardiovascular homeostasis. Contrary to the assumption that ACE levels are stable, circulating ACE has been shown to be altered in obesity and weight loss. We sought to examine effects of a high-saturated-fat (HF) diet on ACE within the NUtriGenomic Analysis in Twins (NUGAT) study. METHODS AND RESULTS: Forty-six healthy and nonobese twin pairs initially consumed a carbohydrate-rich, low-fat diet over a period of 6 weeks to standardize for nutritional behavior prior to the study, followed by 6 weeks of HF diet under isocaloric conditions. After 6 weeks of HF diet, circulating ACE concentrations increased by 15% (P=1.6×10-30), accompanied by an increased ACE gene expression in adipose tissue (P=3.8×10-6). Stratification by ACE rs4343, a proxy for the ACE insertion/deletion polymorphism (I/D), revealed that homozygous carriers (GG) of the variant had higher baseline ACE concentrations (P=7.5×10-8) and additionally showed a 2-fold increase in ACE concentrations in response to the HF diet as compared to non- or heterozygous carriers (AA/AG, P=2×10-6). GG carriers also responded with higher systolic blood pressure as compared to AA/AG carriers (P=0.008). The strong gene-diet interaction was confirmed in a second independent, cross-sectional cohort, the Metabolic Syndrome Berlin Potsdam (MeSyBePo) study. CONCLUSIONS: The HF-diet-induced increase of ACE serum concentrations reveals ACE to be a potential molecular link between dietary fat intake and hypertension and cardiovascular disease (CVD). The GG genotype of the ACE rs4343 polymorphism represents a robust nutrigenetic marker for an unfavorable response to high-saturated-fat diets. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01631123.

High-Fat Diet During Mouse Pregnancy and Lactation Targets GIP-Regulated Metabolic Pathways in Adult Male Offspring.

Maternal obesity is a worldwide problem associated with increased risk of metabolic diseases in the offspring. Genetic deletion of the gastric inhibitory polypeptide (GIP) receptor (GIPR) prevents high-fat diet (HFD)-induced obesity in mice due to specific changes in energy and fat cell metabolism. We investigated whether GIP-associated pathways may be targeted by fetal programming and mimicked the situation by exposing pregnant mice to control or HFD during pregnancy (intrauterine [IU]) and lactation (L). Male wild-type (WT) and Gipr(-/-) offspring received control chow until 25 weeks of age followed by 20 weeks of HFD. Gipr(-/-) offspring of mice exposed to HFD during IU/L became insulin resistant and obese and exhibited increased adipose tissue inflammation and decreased peripheral tissue substrate utilization after being reintroduced to HFD, similar to WT mice on regular chow during IU/L. They showed decreased hypothalamic insulin sensitivity compared with Gipr(-/-) mice on control diet during IU/L. DNA methylation analysis revealed increased methylation of CpG dinucleotides and differential transcription factor binding of promoter regions of genes involved in lipid oxidation in the muscle of Gipr(-/-) offspring on HFD during IU/L, which were inversely correlated with gene expression levels. Our data identify GIP-regulated metabolic pathways that are targeted by fetal programming.