Diagnostic CT-Enabled Planning (DART): Results of a Randomized Trial in Palliative Radiation Therapy.

PURPOSE: Using diagnostic computed tomography (dCT) scans instead of CT simulation (CTsim) scans can increase departmental efficiency and reduce patient burden. The goal of the DART trial was to assess the efficacy and acceptability of dCT-based planning workflows with a focus on patient experiences, plan deliverability and adequacy of target coverage, and workflows. METHODS AND MATERIALS: Patients undergoing same-day CTsim and treatment for palliative radiation therapy to thoracic, abdominopelvic, or proximal limb targets with a recent dCT (within 28 days) in a reproducible position were eligible. After stratifying by target type (bone or soft tissue vs. visceral), participants were randomized (1:2 ratio) between CTsim-based (CTsim arm) vs. dCT-based planning (dCT arm). The primary endpoint was time in center (TIC), defined as total time spent in the cancer center on first day of treatment, from first radiation department appointment to first fraction completion. Secondary endpoints included plan deliverability, adequacy of target coverage, and stakeholder acceptability. RESULTS: Thirty-three patients (42 treatment sites) were enrolled between June 2022 and April 2023. The median age was 72 (interquartile range [IQR]: 67-78), 73% were male, and the most common primary cancers were lung (33%), prostate (24%), and breast (12%). The most common dose and fractionations were 8 Gy in 1 and 20 Gy in 5 fractions (50% and 43% of plans, respectively). TIC was 4.7 ± 1.1 hours (mean ± SD) in the CTsim arm vs. 0.41 ± 0.14 hours in the dCT arm (P < .001). All dCT plans were deliverable. All plans in both arms were rated as "acceptable" (80% CTsim; 81% dCT) or "acceptable with minor deviation" (20% CTsim; 19% dCT). Patient perception of acceptability was similar in both arms with the exception of time burden, which was rated as "acceptable" by 50% in the CTsim arm vs. 90% in the dCT arm (P = .025). CONCLUSION: dCT-based radiation planning substantially reduced TIC without detriment in plan deliverability or quality and had a tangible impact on patient experience with reduced patient-reported time burden.

ß Cell Stress and Endocrine Function During T1D: What Is Next to Discover?

Canonically, type 1 diabetes (T1D) is a disease characterized by autoreactive T cells as perpetrators of endocrine dysfunction and ß cell death in the spiral toward loss of ß cell mass, hyperglycemia, and insulin dependence. ß Cells have mostly been considered as bystanders in a flurry of autoimmune processes. More recently, our framework for understanding and investigating T1D has evolved. It appears increasingly likely that intracellular ß cell stress is an important component of T1D etiology/pathology that perpetuates autoimmunity during the progression to T1D. Here we discuss the emerging and complex role of ß cell stress in initiating, provoking, and catalyzing T1D. We outline the bridges between hyperglycemia, endoplasmic reticulum stress, oxidative stress, and autoimmunity from the viewpoint of intrinsic ß cell (dys)function, and we extend this discussion to the potential role for a therapeutic ß cell stress-metabolism axis in T1D. Lastly, we mention research angles that may be pursued to improve ß cell endocrine function during T1D. Biology gleaned from studying T1D will certainly overlap to innovate therapeutic strategies for T2D, and also enhance the pursuit of creating optimized stem cell-derived ß cells as endocrine therapy.

Protective Renalase Deficiency in ß-Cells Shapes Immune Metabolism and Function in Autoimmune Diabetes.

Type 1 diabetes (T1D) is caused by the immune-mediated loss of pancreatic ß-cells that produce insulin. The latest advances in stem cell (SC) ß-cell differentiation methods have made a cell replacement therapy for T1D feasible. However, recurring autoimmunity would rapidly destroy transplanted SC ß-cells. A promising strategy to overcome immune rejection is to genetically engineer SC ß-cells. We previously identified Renalase (Rnls) as a novel target for ß-cell protection. Here we show that Rnls deletion endows ß-cells with the capacity to modulate the metabolism and function of immune cells within the local graft microenvironment. We used flow cytometry and single-cell RNA sequencing to characterize ß-cell graft-infiltrating immune cells in a mouse model for T1D. Loss of Rnls within transplanted ß-cells affected both the composition and the transcriptional profile of infiltrating immune cells in favor of an anti-inflammatory profile with decreased antigen-presenting capacity. We propose that changes in ß-cell metabolism mediate local immune regulation and that this feature could be exploited for therapeutic goals. ARTICLE HIGHLIGHTS: Protective Renalase (Rnls) deficiency impacts ß-cell metabolism. Rnls-deficient ß-cell grafts do not exclude immune infiltration. Rnls deficiency in transplanted ß-cells broadly modifies local immune function. Immune cell in Rnls mutant ß-cell grafts adopt a noninflammatory phenotype.

Social Verification Theory: A New Way to Conceptualize Validation, Dissonance, and Belonging.

ACADEMIC ABSTRACT: In the present review, we propose a theory that seeks to recontextualize various existing theories as functions of people's perceptions of their consistency with those around them. This theory posits that people seek social consistency for both epistemic and relational needs and that social inconsistency is both negative and aversive, similar to the experience of cognitive dissonance. We further posit that the aversive nature of perceiving social inconsistency leads people to engage in various behaviors to mitigate or avoid these inconsistencies. When these behaviors fail, however, people experience chronic social inconsistency, which, much like chronic rejection, is associated with physical and mental health and well-being outcomes. Finally, we describe how mitigation and avoidance of social inconsistency underlie many seemingly unrelated theories, and we provide directions for how future research may expand on this theory. PUBLIC ABSTRACT: In the present review, we propose that people find inconsistency with those around them to be an unpleasant experience, as it threatens people's core need to belong. Because the threat of reduced belongingness evokes negative feelings, people are motivated to avoid inconsistency with others and to mitigate the negative feelings that are produced when it inevitably does arise. We outline several types of behaviors that can be implemented to avoid or mitigate these inconsistencies (e.g., validation, affirmation, distancing, etc.). When these behaviors cannot be implemented successfully, people experience chronic invalidation, which is associated with reduced physical and mental health and well-being outcomes. We discuss how invalidation may disproportionately affect individuals with minoritized identities. Furthermore, we discuss how belongingness could play a key role in radicalization into extremist groups.

Canagliflozin Prevents Hyperglycemia-Associated Muscle Extracellular Matrix Accumulation and Improves the Adaptive Response to Aerobic Exercise.

Chronic hyperglycemia is associated with low response to aerobic exercise training in rodent models and humans, including reduced aerobic exercise capacity and impaired oxidative remodeling in skeletal muscle. Here, we investigated whether glucose lowering with the sodium-glucose cotransporter 2 inhibitor (SGLT2i), canagliflozin (Cana; 30 mg/kg/day), could restore exercise training response in a model of hyperglycemia (low-dose streptozotocin [STZ]). Cana effectively prevented increased blood glucose in STZ-treated mice. After 6 weeks of voluntary wheel running, Cana-treated mice displayed improvements in aerobic exercise capacity, higher capillary density in striated muscle, and a more oxidative fiber-type in skeletal muscle. In contrast, these responses were blunted or absent in STZ-treated mice. Recent work implicates glucose-induced accumulation of skeletal muscle extracellular matrix (ECM) and hyperactivation of c-Jun N-terminal kinase (JNK)/SMAD2 mechanical signaling as potential mechanisms underlying poor exercise response. In line with this, muscle ECM accretion was prevented by Cana in STZ-treated mice. JNK/SMAD2 signaling with acute exercise was twofold higher in STZ compared with control but was normalized by Cana. In human participants, ECM accumulation was associated with increased JNK signaling, low VO2peak, and impaired metabolic health (oral glucose tolerance test-derived insulin sensitivity). These data demonstrate that hyperglycemia-associated impairments in exercise adaptation can be ameliorated by cotherapy with SGLT2i.

Learning About the Current State of Digital Mental Health Interventions for Canadian Youth to Inform Future Decision-Making: Mixed Methods Study.

BACKGROUND: The COVID-19 pandemic has increased the demand for youth mental health services in Canada as disruptions to clinical care continue to persist due to the risk of transmission and exposure to the virus. Digital mental health interventions, including web-based resources and mobile apps, have provided opportunities to support youth mental health remotely across Canada. There is a need to better understand how these digital interventions are being selected, recommended, and used in various regions across Canada. OBJECTIVE: A national jurisdictional scan was completed to (1) determine what web-based programs, apps, and websites are promoted and licensed in Canada for youth mental health; (2) identify criteria and decision-making processes that Canadian jurisdictions use to select web-based programs, apps, and websites for youth mental health; and (3) identify upcoming trends, innovations, and digital mental health possibilities that are emerging in the youth sector. METHODS: The aims of the jurisdictional scan were addressed through a review of related academic and grey literature; stakeholder interviews, including individuals involved in various areas of the youth mental health sector; and a social media review of pertinent Twitter content. RESULTS: A total of 66 web-based resources and apps were identified for use by youth in Canada. 16 stakeholder interviews were completed and included discussions with researchers, clinicians, youth organizations, and others involved in digital interventions for youth mental health. These discussions identified a limited use of frameworks used to guide decision-making processes when selecting digital interventions. Many clinicians agreed on a similar set of eligibility requirements for youth mental health apps and digital resources, such as the evidence base and cultural relevance of the intervention. Stakeholders also identified upcoming trends and innovations in the youth digital mental health space, including artificial intelligence, digital phenotyping, and personalized therapy. Over 4 weeks, 2184 tweets were reviewed to identify and compare global and national trends and innovations involving digital mental health and youth. Key trends included the promotion of regional chat services as well as the effects of the COVID-19 pandemic on youth mental health and access to care. CONCLUSIONS: As organizations begin to plan for the delivery of mental health care following the pandemic, there are concerns about the sustainability of these digital mental health interventions as well as a need for services to be more informed by the experiences and preferences of youth.

Being in the Moment So You Can Keep Moving Forward: Mindfulness and Rumination Mediate the Relationship between Attachment Orientations and Negative Conflict Styles.

Attachment insecurity has been associated with negative behaviors during conflict and decreased relationship satisfaction. We theorize that individuals high in attachment anxiety and/or avoidance are less mindful during conflict with their romantic partners, and thus more likely to ruminate. Decreased mindfulness and higher levels of rumination may be important mechanisms in the relationship between attachment insecurity and conflict behavior, as it may be more difficult to engage in constructive problem-solving skills when one is distracted from the present moment. We conducted an online survey assessing 360 participants' attachment orientations, levels of mindfulness and rumination, behavior during conflict, and experience with mindfulness activities. Using a serial mediation model, we found that mindfulness and rumination mediated the relationship between attachment insecurity and negative conflict behaviors. We further discovered that individuals high in attachment insecurity were more likely to report negative experiences with mindfulness activities (i.e., meditation and yoga), and that this relationship was mediated by higher levels of experiential avoidance, or a fear of engaging with one's own thoughts and feelings. We discuss the importance of increasing mindfulness and decreasing both rumination and experiential avoidance to assist individuals high in attachment insecurity in navigating relationship conflict using more constructive and relationship-promoting strategies.

Hyperglycaemia is associated with impaired muscle signalling and aerobic adaptation to exercise.

Increased aerobic exercise capacity, as a result of exercise training, has important health benefits. However, some individuals are resistant to improvements in exercise capacity, probably due to undetermined genetic and environmental factors. Here, we show that exercise-induced improvements in aerobic capacity are blunted and aerobic remodelling of skeletal muscle is impaired in several animal models associated with chronic hyperglycaemia. Our data point to chronic hyperglycaemia as a potential negative regulator of aerobic adaptation, in part, via glucose-mediated modifications of the extracellular matrix, impaired vascularization and aberrant mechanical signalling in muscle. We also observe low exercise capacity and enhanced c-Jun N-terminal kinase activation in response to exercise in humans with impaired glucose tolerance. Our work indicates that current shifts in dietary and metabolic health, associated with increasing incidence of hyperglycaemia, might impair muscular and organismal adaptations to exercise training, including aerobic capacity as one of its key health outcomes.

Perceived Knowledge Moderates the Relation Between Subjective Ambivalence and the "Impact" of Attitudes: An Attitude Strength Perspective.

Previous work has reliably demonstrated that when people experience more subjective ambivalence about an attitude object, their attitudes have less impact on strength-related outcomes such as attitude-related thinking, judging, or behaving. However, previous research has not considered whether the amount of perceived knowledge a person has about the topic might moderate these effects. Across eight studies on different topics using a variety of outcome measures, the current research demonstrates that perceived knowledge can moderate the relation between ambivalence and the impact of attitudes on related thinking, judging, and behaving. Although the typical Attitude × Ambivalence effect emerged when participants had relatively high perceived knowledge, this interaction did not emerge when participants were lower in perceived knowledge. This work provides a more nuanced view of the effects of subjective ambivalence on attitude impact and highlights the importance of understanding the combined impact of attitude strength antecedents.

Reduced sucrose nonfermenting AMPK-related kinase (SNARK) activity aggravates cancer-induced skeletal muscle wasting.

Sucrose nonfermenting AMPK-related kinase (SNARK) is a member of the AMPK family of kinases and has been implicated in the regulation of critical metabolic processes. Recent findings demonstrate that SNARK has an important role in the maintenance of muscle mass with age. Loss of skeletal muscle mass (cachexia) is a key problem for cancer patients. Thus, based on our previous findings with aging, we hypothesized that SNARK would play a role in regulating muscle mass under conditions of cancer cachexia. To test this hypothesis, Lewis Lung Carcinoma tumor cells or vehicle were injected subcutaneously in the right flank of wild type mice, muscle-specific transgenic mice expressing inactive SNARK mutant (SDN) or muscle-specific transgenic mice overexpressing wild-type SNARK (SWT). All tumor-bearing mice presented muscle wasting compared to vehicle-injected mice. However, SDN tumor-bearing mice had more pronounced atrophy compared to wild-type and SWT tumor-bearing mice. Histological analysis confirmed muscle atrophy in tumor-bearing mice, and SDN tumor-bearing mice exhibited a significantly smaller skeletal muscle cross-sectional area than wild-type and SWT tumor-bearing mice. Moreover, SDN tumor-bearing mice had increased skeletal muscle BAX protein expression, a marker of apoptosis, compared to other groups.Thus, lack of SNARK in skeletal muscle aggravates cancer-induced skeletal muscle wasting. These findings uncover a role for SNARK in the maintenance of skeletal muscle mass under cachexia conditions.

Exploring Stereotypes of Athletes With a Disability: A Behaviors From Intergroup Affect and Stereotypes Map Comparison.

Identifying as a regular exerciser has been found to effectively alter stereotypes related to warmth and competence for adults with a physical disability; however, it remains unclear how sport participation can influence this trend. Therefore, this study aimed to examine warmth and competence perceptions of adults with a physical disability portrayed as elite and nonelite athletes relative to other athletic and nonathletic subgroups of adults with and without a physical disability in the context of the stereotype content model. Using survey data from able-bodied participants (N = 302), cluster analyses were applied to a behaviors from intergroup affect and stereotypes map for displaying the intersection of warmth and competence perceptions. The results demonstrated that adults with a physical disability who are described as elite athletes (i.e., Paralympians) are clustered with high warmth and high competence, similar to their able-bodied athletic counterparts (i.e., Olympians). The findings suggest that perceiving athletic and elite sport statuses for adults with a physical disability may counter the stereotypes commonly applied to this group.

Meta-omics analysis of elite athletes identifies a performance-enhancing microbe that functions via lactate metabolism.

The human gut microbiome is linked to many states of human health and disease1. The metabolic repertoire of the gut microbiome is vast, but the health implications of these bacterial pathways are poorly understood. In this study, we identify a link between members of the genus Veillonella and exercise performance. We observed an increase in Veillonella relative abundance in marathon runners postmarathon and isolated a strain of Veillonella atypica from stool samples. Inoculation of this strain into mice significantly increased exhaustive treadmill run time. Veillonella utilize lactate as their sole carbon source, which prompted us to perform a shotgun metagenomic analysis in a cohort of elite athletes, finding that every gene in a major pathway metabolizing lactate to propionate is at higher relative abundance postexercise. Using 13C3-labeled lactate in mice, we demonstrate that serum lactate crosses the epithelial barrier into the lumen of the gut. We also show that intrarectal instillation of propionate is sufficient to reproduce the increased treadmill run time performance observed with V. atypica gavage. Taken together, these studies reveal that V. atypica improves run time via its metabolic conversion of exercise-induced lactate into propionate, thereby identifying a natural, microbiome-encoded enzymatic process that enhances athletic performance.

JNK regulates muscle remodeling via myostatin/SMAD inhibition.

Skeletal muscle has a remarkable plasticity to adapt and remodel in response to environmental cues, such as physical exercise. Endurance exercise stimulates improvements in muscle oxidative capacity, while resistance exercise induces muscle growth. Here we show that the c-Jun N-terminal kinase (JNK) is a molecular switch that when active, stimulates muscle fibers to grow, resulting in increased muscle mass. Conversely, when muscle JNK activation is suppressed, an alternative remodeling program is initiated, resulting in smaller, more oxidative muscle fibers, and enhanced aerobic fitness. When muscle is exposed to mechanical stress, JNK initiates muscle growth via phosphorylation of the transcription factor, SMAD2, at specific linker region residues leading to inhibition of the growth suppressor, myostatin. In human skeletal muscle, this JNK/SMAD signaling axis is activated by resistance exercise, but not endurance exercise. We conclude that JNK acts as a key mediator of muscle remodeling during exercise via regulation of myostatin/SMAD signaling.

Subcutaneous and Visceral Adipose Tissue Secretions from Extremely Obese Men and Women both Acutely Suppress Muscle Insulin Signaling.

Adipose tissue plays a key role in the development of type-2 diabetes via the secretion of adipokines. The current study investigated if secretion media derived from intact visceral (VAT) and subcutaneous (SAT) adipose tissues from extremely obese men and women differently suppressed insulin signaling in human skeletal myotubes derived from a healthy, non-diabetic male and female donor, respectively. Adipose tissue samples were collected from men and women during laparoscopic bariatric surgery. In general, secretion media collected from both SAT and VAT depots caused impaired insulin signaling in myotubes, independent of sex. In females, this was true regardless of the protein kinase B (Akt) phosphorylation site (Akt Thr308 and Akt Ser473) assessed (p < 0.01). In males, both SAT and VAT secretion media reduced Akt Thr308 activation in insulin-stimulated myotubes compared to controls (p < 0.001); however, only the VAT secretion media impaired Akt Ser473 phosphorylation. Independent of sex, 13 out of 18 detected cytokines, chemokines, and growth factors were more abundant in VAT versus SAT secretion media (p < 0.01). Both SAT and VAT secretion media from obese men and women acutely suppress insulin signaling in myotubes, despite different secretion profiles. We propose that this crosstalk model will help to extend our understanding of the interplay between adipose and muscle, as well as the pathogenesis of type-2 diabetes.

Estradiol does not directly regulate adipose lipolysis.

The mechanisms by which estradiol modulates adipose lipolysis are poorly understood. We sought to measure basal and ß3-stimulated indices of lipoysis (FFAs, glycerol) in vivo in E2 deficient or supplemented rats, and ex vivo with direct acute E2 exposure. For 2 weeks, ovariectomized (OVX) and OVX rats treated with a daily oral dose of E2 (OVX E2) were pairfed to SHAM controls (n = 12 per group). Adipocyte size was modestly (∼40%) increased in OVX rats, but did not reach significance (p = 0.2). After 2 weeks, half of the animals in each group received an in vivo injection of saline or 1 mg/kg of the ß3 agonist CL 316, 243. Serum FFA concentrations, but not glycerol, were lower in OVX and OVX E2 rats compared with SHAM controls (p = 0.02). A significant CL response was present in all groups (p<0.001) and HSL activation was unaffected by OVX or OVX E2 in retroperitoneal (r.p.) or inguinal (iWAT) adipose depots in vivo. Ex vivo, CL increased FFA and glycerol accumulation in the media as well as HSL phosphorylation by several fold in r.p. and iWAT explants, but responses from OVX and OVX E2 rats were comparable to SHAMs. To assess whether E2 can directly affect lipolysis, r.p. and iWAT tissue was treated with E2, CL or E2 + CL for 2, 4 or 8 hours using adipose tissue organ culture. CL stimulated FFA release (p<0.001), but was unaffected by E2. Overall, our results indicate that E2 does not directly regulate adipose tissue lipolysis.

Using behavior change frameworks to improve healthcare worker influenza vaccination rates: A systematic review.

BACKGROUND: Influenza vaccination of healthcare workers (HCW) is important for protecting staff and patients, yet vaccine coverage among HCW remains below recommended targets. Psychological theories of behavior change may help guide interventions to improve vaccine uptake. Our objectives were to: (1) review the effectiveness of interventions based on psychological theories of behavior change to improve HCW influenza vaccination rates, and (2) determine which psychological theories have been used to predict HCW influenza vaccination uptake. METHODS: MEDLINE, EMBASE, CINAHL, PsycINFO, The Joanna Briggs Institute, SocINDEX, and Cochrane Database of Systematic Reviews were searched for studies that applied psychological theories of behavior change to improve and/or predict influenza vaccination uptake among HCW. RESULTS: The literature search yielded a total of 1810 publications; 10 articles met eligibility criteria. All studies used behavior change theories to predict HCW vaccination behavior; none evaluated interventions based on these theories. The Health Belief Model was the most frequently employed theory to predict influenza vaccination uptake among HCW. The remaining predictive studies employed the Theory of Planned Behavior, the Risk Perception Attitude, and the Triandis Model of Interpersonal Behavior. The behavior change framework constructs were successful in differentiating between vaccinated and non-vaccinated HCW. Key constructs identified included: attitudes regarding the efficacy and safety of influenza vaccination, perceptions of risk and benefit to self and others, self-efficacy, cues to action, and social-professional norms. The behavior change frameworks, along with sociodemographic variables, successfully predicted 85-95% of HCW influenza vaccination uptake. CONCLUSION: Vaccination is a complex behavior. Our results suggest that psychological theories of behavior change are promising tools to increase HCW influenza vaccination uptake. Future studies are needed to develop and evaluate novel interventions based on behavior change theories, which may help achieve recommended HCW vaccination targets.

The Person and the Partner: Individual Differences Moderate the Relationship Between Partner Feedback and Condom Use.

Attachment anxiety is negatively associated with condom use; however, little research has assessed mechanisms underlying this relationship. In two studies we assessed the relationships among attachment orientations, perceived partner rejection, and condom use. In Study 1 we used a survey methodology and found that a measure of perceived partner rejection mediated the relationship between attachment anxiety and reported condom use behavior. In Study 2, women responded to condom use scenarios in which rejection was manipulated. We found a three-way interaction among attachment anxiety, attachment avoidance, and condom use intentions, such that perceived rejection from a potential sexual partner was associated with greater intentions to engage in unprotected sexual intercourse among women high in attachment anxiety and low in attachment avoidance, and among those high in attachment avoidance and low in attachment anxiety.

Exercise training is an effective alternative to estrogen supplementation for improving glucose homeostasis in ovariectomized rats.

The irreversible loss of estrogen (specifically 17-ß-estradiol; E2) compromises whole-body glucose tolerance in women. Hormone replacement therapy (HRT) is frequently prescribed to treat estrogen deficiency, but has several deleterious side effects. Exercise has been proposed as an HRT substitute, however, their relative abilities to treat glucose intolerance are unknown. Thirty ovariectomized (OVX) and 20 SHAM (control) rats underwent glucose tolerance tests (GTT) 10 weeks post surgery. Area under the curve (AUC) for OVX rats was 60% greater than SHAM controls (P = 0.0005). Rats were then randomly assigned to the following treatment groups: SHAM sedentary (sed) or exercise (ex; 60 min, 5×/weeks), OVX sed, ex, or E2 (28 µg/kg bw/day) for 4 weeks. OVX ex rats experienced a ~45% improvement in AUC relative to OVX sed rats, whereas OVX E2 underwent a partial reduction (17%; P = 0.08). Maximal insulin-stimulated glucose uptake in soleus and EDL was not impaired in OVX rats, or augmented with exercise or E2. Akt phosphorylation did not differ in soleus, EDL, or liver of any group. However, OVX ex and OVX E2 experienced greater increases in p-Akt Ser473 in VAT and SQ tissues compared with SHAM and OVX sed groups. Mitochondrial markers CS, COXIV, and core1 were increased in soleus posttraining in OVX ex rats. The content of COXIV was reduced by 52% and 61% in SQ of OVX sed and E2 rats, compared to SHAM controls, but fully restored in OVX ex rats. In summary, exercise restores glucose tolerance in OVX rats more effectively than E2. This is not reflected by alterations in muscle maximal insulin response, but increased insulin signaling in adipose depots may underlie whole-body improvements.

Feeding butter with elevated content of trans-10, cis-12 conjugated linoleic acid to obese-prone rats impairs glucose and insulin tolerance.

BACKGROUND: We recently demonstrated that feeding a natural CLAt10,c12-enriched butter to lean female rats resulted in small, but significant increases in fasting glucose and insulin concentrations, and impaired insulin tolerance. Our goal was to extend these findings by utilizing the diabetes-prone female fatty Zucker rat. Rats were fed custom diets containing 45 % kcal of fat derived from control and CLAt10,c12-enriched butter for 8 weeks. METHODS: CLA t10,c12-enriched butter was prepared from milk collected from cows fed a high fermentable carbohydrate diet to create subacute rumen acidosis (SARA); control (non-SARA) butter was collected from cows fed a low grain diet. Female fatty Zucker rats (10 weeks old) were randomly assigned to one of four diet treatments: i) low fat (10 % kcal), ii) 45 % kcal lard, iii) 45 % kcal SARA butter, or iv) 45 % kcal non-SARA butter. A low fat fed lean Zucker group was used as a control group. After 8 weeks, i) glucose and insulin tolerance tests, ii) insulin signaling in muscle, adipose and liver, and iii) metabolic caging measurements were performed. RESULTS: Glucose and insulin tolerance were significantly impaired in all fatty Zucker groups, but to the greatest extent in the LARD and SARA conditions. Insulin signaling (AKT phosphorylation) was impaired in muscle, visceral (perigonadal) adipose tissue and liver in fatty Zucker rats, but was generally similar across dietary groups. Physical activity, oxygen consumption, food intake and weight gain were also similar amongst the various fatty Zucker groups. CONCLUSIONS: Increasing the consumption of a food naturally enriched with CLAt10,c12 significantly worsens glucose and insulin tolerance in a diabetes-prone rodent model. This outcome is not explained by changes in tissue insulin signaling, physical activity, energy expenditure, food intake or body mass.

Feeding butter with elevated content of trans-10, cis-12 conjugated linoleic acid to lean rats does not impair glucose tolerance or muscle insulin response.

BACKGROUND: Numerous studies have investigated the effects of isolated CLA supplementation on glucose homeostasis in humans and rodents. However, both the amount and relative abundance of CLA isomers in supplemental form are not representative of what is consumed from natural sources. No study to date has examined the effects of altered CLA isomer content within a natural food source. Our goal was to increase the content of the insulin desensitizing CLAt10,c12 isomer relative to the CLAc9,t11 isomer in cow's milk by inducing subacute rumenal acidosis (SARA), and subsequently investigate the effects of this milk fat on parameters related to glucose and insulin tolerance in rats. METHODS: We fed female rats (~2.5 to 3 months of age) CLA t10,c12 -enriched (SARA) butter or non-SARA butter based diets for 4 weeks in either low (10% of kcal from fat; 0.18% total CLA by weight) or high (60% of kcal from fat; 0.55% total CLA by weight) amounts. In an effort to extend these findings, we then fed rats high (60% kcal) amounts of SARA or non-SARA butter for a longer duration (8 weeks) and assessed changes in whole body glucose, insulin and pyruvate tolerance in comparison to low fat and 60% lard conditions. RESULTS: There was a main effect for increased fasting blood glucose and insulin in SARA vs. non-SARA butter groups after 4 weeks of feeding (p < 0.05). However, blood glucose and insulin concentration, and maximal insulin-stimulated glucose uptake in skeletal muscle were similar in all groups. Following 8 weeks of feeding, insulin tolerance was impaired by the SARA butter, but not glucose or pyruvate tolerance. The non-SARA butter did not impair tolerance to glucose, insulin or pyruvate. CONCLUSIONS: This study suggests that increasing the consumption of a naturally enriched CLAt10,c12 source, at least in rats, has minimal impact on whole body glucose tolerance or muscle specific insulin response.