A Randomized Prospective Survey Targeting Knowledge, Barriers, Facilitators and Readiness to Participation in Dementia Research.

BACKGROUND: While the U.S. National Institute on Aging has developed a strategy for recruitment of minority populations in dementia research, including increasing awareness and engagement, minority populations remain under-represented, and the evidence-base is limited. We tested a conceptually driven communication approach targeting barriers and facilitators to research participation vs. standard education. METHODS: In this 2-phase project, input from the minority advisory board of the Cleveland Alzheimer's Disease Research Center informed development of 2 brief health communication videos which differentially focused on research barriers and facilitators (POWER) versus an education control (Phase 1). In Phase 2, a randomized prospective survey compared POWER vs. an active comparator control on pre/post video change in dementia knowledge, cumulative barriers, and facilitators to dementia research, and change in research readiness measured by the Transtheoretical behavior change model. Changes in outcomes were evaluated using two group by two time points repeated measure analysis of variance (RMANOVA) controlling for age, gender, race, and education. RESULTS: The pre-video sample (n=242) had mean age of 57.6 (SD17.2) years, mostly female (n=181, 74.8%), 42.6% non-white. The analyzable sample who completed both pre and post assessments comprised n=102 in the POWER and n=105 in the control group. Non-white participants made up 41.1% of the analyzable POWER (n=51) and 44.1% (n= 52) of controls. Adjusted for age, gender, race and education, controls had a greater increase in dementia knowledge (p=0.004). There was a significant reduction in barriers for POWER (p=.044) vs. control. There were no differences in research facilitators and research readiness between POWER vs. control. Among African Americans (n=59, 28.5% of the analyzable sample) there was a trend for improved dementia knowledge (p=.059) favoring control and in research readiness (p=.051), favoring POWER. CONCLUSIONS: Targeting barriers and attitudes towards research could inform development of approaches with potential to improve dementia research participation across diverse communities.

Feasibility of Actigraphy for Evaluating Sleep and Daytime Physical Activity in Children with Autism Spectrum Disorder.

This research evaluated the feasibility of actigraphy to measure sleep and physical activity in children (ages 2-8 years) with autism spectrum disorder (ASD). We also explored associations between sleep and physical activity. Validated screening measures established eligibility. Questionnaires, diaries, and 5 days and 5 nights of actigraphy monitoring were used to collect data. Of the 32 children enrolled, 27 (84.4%) completed actigraphy monitoring. Based on the median steps per day, children with high physical activity had lower total sleep time and more disruptive behaviors than children with low physical activity. Findings support the feasibility of using actigraphy to measure sleep and physical activity in children with ASD. Larger studies are needed to evaluate interactions of physical activity on sleep in this population.

Erratum to: Frailty has a stronger association with inflammation than age in older veterans.

[This corrects the article DOI: 10.1186/s12979-016-0082-z.].

Frailty has a stronger association with inflammation than age in older veterans.

BACKGROUND: Upregulation of pro-inflammatory cytokines has not only been associated with increased morbidity and mortality in older adults but also has been linked to frailty. In the current study we aimed to compare the relative relationship of age and frailty on inflammation and thrombosis in older veterans. RESULTS: We analyzed 117 subjects (age range 62-95 years; median 81) divided into 3 cohorts: non-frail, pre-frail and frail based on the Fried phenotype of frailty. Serum inflammatory markers were determined using commercially available ELISA kits. Frail and pre-frail (PF) subjects had higher levels than non-frail (NF) subjects of IL-6 (NF vs. PF: p = 0.002; NF vs. F: p < 0.001), TNFR1 (NF vs. F: p = 0.012), TNFRII (NF vs. F: 0.002; NF vs. PF: p = 0.005) and inflammatory index: = 0.333*log(IL-6) + 0.666*log(sTNFR1) (NF vs. F: p = 0.009; NF vs. PF: p < 0.001). Frailty status explained a greater percent of variability in markers of inflammation than age: IL-6 (12 % vs. 0.3 %), TNFR1 (5 % vs. 4 %), TNFR2 (11 % vs. 6 %), inflammatory index (16 % vs. 8 %). Aging was significantly associated with higher fibrinogen (p = 0.04) and D-dimer levels (p = 0.01) but only among NF subjects. CONCLUSION: In conclusion, these data suggest that among older veterans, frailty status has a stronger association with inflammation and the inflammatory index than age does. Larger studies, in more diverse populations are needed to confirm these findings.

Preliminary Evidence for Effectiveness of Resourcefulness Training in Women Dementia Caregivers.

Nearly 10 million women in the U.S. are caregivers for an elder with dementia, which often produces overwhelming stress and adversely affects their health. Resourcefulness training (RT) may promote the caregiver's optimal health and continue in their caregiving role. This pilot trial of 138 women dementia caregivers examined the effectiveness of RT on perceived stress, depressive cognitions, and negative emotions over time. Caregivers were first randomized to RT or no RT and then further randomized into random versus choice conditions followed by assignment to the journal or recorder methods, thus creating eight groups. We examined differences on perceived stress, depressive cognitions, and negative emotions between groups: 1) RT versus no-RT, 2) choice versus random condition; and 3) journaling versus recording. Significant time by group interactions were found on stress (F=4.36, p<.05), depressive cognitions (F=10.93, p<.001), and negative emotions (F=20.48, p<.001) in the RT versus no RT group. No differences were found between the random versus choice conditions or the journaling versus recording methods for practicing the RT skills. The results provide evidence for the effectiveness of RT for decreasing stress, depressive cognitions, and negative emotions in women caregivers of elders with dementia. The findings also suggest the need for further examination of the effects of allowing caregivers to choose a method for practicing RT in larger samples if caregivers of elders with dementia.

CD4 T-cell cytokine correlates of diagnostic tests for latent tuberculous infection in HIV-1-infected subjects.

SETTING: Public human immunodeficiency virus (HIV) clinic and tuberculosis (TB) clinics in Kampala, Uganda. OBJECTIVE: To examine TB-specific CD4 T-cell single and polyfunctional cytokine correlates of clinical diagnostic tests for latent tuberculous infection (LTBI) in HIV-1-infected subjects. DESIGN: Thirty antiretroviral therapy-naïve HIV-1-infected adults without active TB disease underwent clinical tuberculin skin test (TST), interferon-gamma release assay (IGRA), and in vitro flow cytometry analysis on cells stimulated with purified protein derivative (PPD) and TB antigens early secreted antigenic target 6 + culture filtrate protein 10 (EC) for frequencies of interleukin (IL) 2, IL-17, interferon-gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α) expressing cells. RESULTS: PPD-specific CD4 T-cell expression of TNF-α and IFN-γ was higher in the TST-positive than in the TST-negative group. EC-specific CD4 T-cell expression of TNF-α and IL-2 was higher in the TST+ group than in the TST- group. Expression of both PPD and EC-specific expression of IL-2, IFN-γ and TNF-α were greater in IGRA-positive than in IGRA-negative subjects. The TST+ group exhibited greater polyfunctionality than the TST- group. All cytokine combinations that contained TNF-α correlated strongly with TST size. CONCLUSION: While IL-2, IFN-γ and TNF-α correlate with clinical tests of LTBI, TNF-α is the dominant cytokine correlating with both TST size and magnitude of IGRA response.

Developmental programming: exposure to testosterone excess disrupts steroidal and metabolic environment in pregnant sheep.

Gestational exposure to excess T leads to intrauterine growth restriction, low birth weight, and adult metabolic/reproductive disorders in female sheep. We hypothesized that as early mediators of such disruptions, gestational T disrupts steroidal and metabolic homeostasis in both the mother and fetus by both androgenic and metabolic pathways. Maternal blood samples were measured weekly for levels of insulin, glucose, and progesterone from four groups of animals: control; gestational T (twice weekly im injections of 100 mg of T propionate from d 30 to d 90 of gestation); T plus an androgen antagonist, flutamide (15 mg/kg·d oral; T-Flutamide); and T plus the insulin sensitizer, rosiglitazone (0.11 mg/kg·d oral; T-Rosi) (n = 10-12/group). On day 90 of gestation, maternal and umbilical cord samples were collected after a 48-hour fast from a subset (n = 6/group) for the measurement of steroids, free fatty acids, amino acids, and acylcarnitines. Gestational T decreased maternal progesterone levels by 36.5% (P < .05), which was prevented by flutamide showing direct androgenic mediation. Gestational T also augmented maternal insulin levels and decreased medium chained acylcarnitines, suggesting increased mitochondrial fatty acid oxidation. These changes were prevented by rosiglitazone, suggesting alterations in maternal fuel use. Gestational T-induced increases in fetal estradiol were not prevented by either cotreatment. Gestational T disrupted associations of steroids with metabolites and progesterone with acylcarnitines, which was prevented either by androgen antagonist or insulin sensitizer cotreatment. These findings suggest a future combination of these treatments might be required to prevent alteration in maternal/fetal steroidal and metabolic milieu(s).

One or two types of death? Attitudes of health professionals towards brain death and donation after circulatory death in three countries.

This study examined health professionals' (HPs) experience, beliefs and attitudes towards brain death (BD) and two types of donation after circulatory death (DCD)--controlled and uncontrolled DCD. Five hundred and eighty-seven HPs likely to be involved in the process of organ procurement were interviewed in 14 hospitals with transplant programs in France, Spain and the US. Three potential donation scenarios--BD, uncontrolled DCD and controlled DCD--were presented to study subjects during individual face-to-face interviews. Our study has two main findings: (1) In the context of organ procurement, HPs believe that BD is a more reliable standard for determining death than circulatory death, and (2) While the vast majority of HPs consider it morally acceptable to retrieve organs from brain-dead donors, retrieving organs from DCD patients is much more controversial. We offer the following possible explanations. DCD introduces new conditions that deviate from standard medical practice, allow procurement of organs when donors' loss of circulatory function could be reversed, and raises questions about "death" as a unified concept. Our results suggest that, for many HPs, these concerns seem related in part to the fact that a rigorous brain examination is neither clinically performed nor legally required in DCD. Their discomfort could also come from a belief that irreversible loss of circulatory function has not been adequately demonstrated. If DCD protocols are to achieve their full potential for increasing organ supply, the sources of HPs' discomfort must be further identified and addressed.

Characterization of MHC-II antigen presentation by B cells and monocytes from older individuals.

In this study we examine the effects of aging on antigen presentation of B cells and monocytes. We compared the antigen presentation function of peripheral blood B cells from young and old subjects using a system that specifically measures the B cell receptor (BCR)-mediated MHC-II antigen presentation. Monocytes were studied as well. Overall the mean magnitude of antigen presentation of soluble antigen and peptide was not different in older and younger subjects for both B cells and monocytes. Older subjects, however, showed increased heterogeneity of BCR-mediated antigen presentation by their B cells. The magnitude and variability of peptide presentation, which do not require uptake and processing, were the same between groups. Presentation by monocytes had similar variability between the older and younger subjects. These data suggest that poor B cell antigen processing, which results in diminished presentation in some older individuals may contribute to poor vaccine responses.

Efficacy and tolerability of the DPP-4 inhibitor alogliptin combined with pioglitazone, in metformin-treated patients with type 2 diabetes.

CONTEXT: Optimal management of type 2 diabetes remains an elusive goal. Combination therapy addressing the core defects of impaired insulin secretion and insulin resistance shows promise in maintaining glycemic control. OBJECTIVE: The aim of the study was to assess the efficacy and tolerability of alogliptin combined with pioglitazone in metformin-treated type 2 diabetic patients. DESIGN, SETTING, AND PATIENTS: We conducted a multicenter, randomized, double-blind, placebo-controlled, parallel-arm study in patients with type 2 diabetes. INTERVENTIONS: The study consisted of 26-wk treatment with alogliptin (12.5 or 25 mg qd) alone or combined with pioglitazone (15, 30, or 45 mg qd) in 1554 patients on stable-dose metformin monotherapy (≥1500 mg) with inadequate glycemic control. MAIN OUTCOME MEASURE: The primary endpoint was change in glycosylated hemoglobin (HbA(1c)) from baseline to wk 26. Secondary endpoints included changes in fasting plasma glucose and ß-cell function. Primary analyses compared pioglitazone therapy [all doses pooled, pioglitazone alone (Pio alone); n = 387] with alogliptin 12.5 mg plus any dose of pioglitazone (A12.5+P; n = 390) or alogliptin 25 mg plus any dose of pioglitazone (A25+P; n = 390). RESULTS: When added to metformin, the least squares mean change (LSMΔ) from baseline HbA(1c) was -0.9 ± 0.05% in the Pio-alone group and -1.4 ± 0.05% in both the A12.5+P and A25+P groups (P < 0.001 for both comparisons). A12.5+P and A25+P produced greater reductions in fasting plasma glucose (LSMΔ = -2.5 ± 0.1 mmol/liter for both) than Pio alone (LSMΔ = -1.6 ± 0.1 mmol/liter; P < 0.001). A12.5+P and A25+P significantly improved measures of ß-cell function (proinsulin:insulin and homeostasis model assessment of ß-cell function) compared to Pio alone, but had no effect on homeostasis model assessment of insulin resistance. The LSMΔ body weight was 1.8 ± 0.2, 1.9 ± 0.2, and 1.5 ± 0.2 kg in A12.5+P, A25+P, and Pio-alone groups, respectively. Hypoglycemia was reported by 1.0, 1.5, and 2.1% of patients in the A12.5+P, A25+P, and Pio-alone groups, respectively. CONCLUSIONS: In type 2 diabetic patients inadequately controlled by metformin, the reduction in HbA(1c) by alogliptin and pioglitazone was additive. The decreases in HbA(1c) with A12.5+P and A25+P were similar. All treatments were well tolerated.

Preserved MHC-II antigen processing and presentation function in chronic HCV infection.

Individuals with chronic HCV infection have impaired response to vaccine, though the etiology remains to be elucidated. Dendritic cells (DC) and monocytes (MN) provide antigen uptake, processing, presentation, and costimulatory functions necessary to achieve optimal immune responses. The integrity of antigen processing and presentation function within these antigen presenting cells (APC) in the setting of HCV infection has been unclear. We used a novel T cell hybridoma system that specifically measures MHC-II antigen processing and presentation function of human APC. Results demonstrate MHC-II antigen processing and presentation function is preserved in both myeloid DC (mDC) and MN in the peripheral blood of chronically HCV-infected individuals, and indicates that an alteration in this function does not likely underlie the defective HCV-infected host response to vaccination.

Satisfaction of early breast cancer patients with discussions during initial oncology consultations with a medical oncologist.

OBJECTIVE: The purpose of this report is to extend the current understanding of patient satisfaction by examining expectations of a sample of breast cancer patients and concordance with their medical oncologists about the content of consultations and the importance of consultation items. METHODS: Three hundred and ninety-five female early stage breast cancer patients of 56 oncologists participated. Patients and oncologists completed a matched questionnaire measuring (a) met expectations, (b) concordance over content and item importance, and (c) satisfaction. RESULTS: Overall patient satisfaction was extremely high (x=91/100%) although expectations were not met at the stated level desired. Patients and physicians disagreed over what was conveyed and received. Higher overall satisfaction was predicted by levels of met expectations (unstandardized beta=0.69, p=0.008, SE=0.26) and concordance over (a) content (unstandardized beta=1.09, p=0.002, SE=0.34) and (b) importance (unstandardized beta=-0.78, p=0.006, SE 0.28). CONCLUSION: Although patient expectations were not well met and physician-patient discord was high about the content of consultations and the importance of consultation items, patients reported high levels of satisfaction. Expectation fulfillment and levels of concordance predicted satisfaction.

Measurement and correlates of family caregiver self-efficacy for managing dementia.

Researchers in the aging field are paying increasing attention to the importance of perceived self-efficacy in understanding experiences and health-related outcomes of family caregivers. This paper details the strategy we used to measure family caregiver self-efficacy for managing dementia, and reports on observed associations between the resulting self-efficacy measures, caregiver depressive symptoms, and caregiver physical health symptoms. Family caregivers (n = 197) were interviewed after calling a local Alzheimer's Association chapter in the mid-western USA. Nine items inquiring about caregivers' certainty that they could carry out specific behaviors related to dementia care clustered into two distinct self-efficacy factors: symptom management self-efficacy (4 items) and community support service use self-efficacy (5 items). Internal consistency reliability for both factors was high (Cronbach's alpha = 0.77 and 0.78, respectively). Symptom management self-efficacy demonstrated a much stronger correlation with a published global caregiver competence measure than did service use self-efficacy (r = 0.49 and 0.27, respectively). In a multivariate regression model predicting caregiver depression symptoms, higher symptom management self-efficacy scores were associated with fewer depressive symptoms (beta = -0.17, p < 0.05). In a separate model, higher service use self-efficacy scores (beta = -0.20, p < 0.01) and higher symptom management self-efficacy scores (beta = -0.16, p < 0.05) were associated with fewer physical health symptoms. These new measures of dementia management self-efficacy hold promise for use in future studies.

Bidirectional child-family influences on outcomes of traumatic brain injury in children.

Child behavior problems, injury-related family burden, and parent psychological distress were assessed longitudinally over the first year post injury in 40 children with severe traumatic brain injury (TBI), 52 with moderate TBI, and 55 with orthopedic injuries not involving brain insult. Parents rated children's preinjury behavior soon after injury. Postinjury child behavior and family outcomes were assessed at 6- and 12-month follow-ups. Findings from path analysis revealed both direct and indirect effects of TBI on child behavior and family outcomes, as well as cross-lagged child-family associations. Higher parent distress at 6 months predicted more child behavior problems at 12 months, controlling for earlier behavior problems; and more behavior problems at 6 months predicted poorer family outcomes at 12 months, controlling for earlier family outcomes. Support for bidirectional influences is tentative given that limited sample size precluded use of structural equation modeling. The findings nevertheless provide impetus for considering the influences of person-environment interactions on outcomes of TBI.

Disruption of Sur2-containing K(ATP) channels enhances insulin-stimulated glucose uptake in skeletal muscle.

ATP-sensitive potassium channels (K(ATP)) are involved in a diverse array of physiologic functions including protection of tissue against ischemic insult, regulation of vascular tone, and modulation of insulin secretion. To improve our understanding of the role of K(ATP) in these processes, we used a gene-targeting strategy to generate mice with a disruption in the muscle-specific K(ATP) regulatory subunit, SUR2. Insertional mutagenesis of the Sur2 locus generated homozygous null (Sur2(-/-)) mice and heterozygote (Sur2(+/-)) mice that are viable and phenotypically similar to their wild-type littermates to 6 weeks of age despite, respectively, half or no SUR2 mRNA expression or channel activity in skeletal muscle or heart. Sur2(-/-) animals had lower fasting and fed serum glucose, exhibited improved glucose tolerance during a glucose tolerance test, and demonstrated a more rapid and severe hypoglycemia after administration of insulin. Enhanced glucose use was also observed during in vivo hyperinsulinemic euglycemic clamp studies during which Sur2(-/-) mice required a greater glucose infusion rate to maintain a target blood glucose level. Enhanced insulin action was intrinsic to the skeletal muscle, as in vitro insulin-stimulated glucose transport was 1.5-fold greater in Sur2(-/-) muscle than in wild type. Thus, membrane excitability and K(ATP) activity, to our knowledge, seem to be new components of the insulin-stimulated glucose uptake mechanism, suggesting possible future therapeutic approaches for individuals suffering from diabetes mellitus.

Diabetes-related changes in cAMP response element-binding protein content enhance smooth muscle cell proliferation and migration.

We hypothesized that diabetes and glucose-induced reactive oxygen species lead to depletion of cAMP response element-binding protein (CREB) content in the vasculature. In primary cultures of smooth muscle cells (SMC) high medium glucose decreased CREB function but increased SMC chemokinesis and entry into the cell cycle. These effects were blocked by pretreatment with the antioxidants. High glucose increased intracellular reactive oxygen species detected by CM-H(2)DCFA. SMC exposed to oxidative stress (H(2)O(2)) demonstrated a 3.5-fold increase in chemokinesis (p < 0.05) and accelerated entry into cell cycle, accompanied by a significant decrease in CREB content. Chronic oxidative challenge similar to the microenvironment in diabetes (glucose oxidase treatment) decreases CREB content (40-50%). Adenoviral-mediated expression of constitutively active CREB abolished the increase in chemokinesis and cell cycle progression induced by either high glucose or oxidative stress. Analysis of vessels from insulin resistant or diabetic animals indicates that CREB content is decreased in the vascular stroma. Treatment of insulin-resistant animals with the insulin sensitizer rosiglitazone restores vessel wall CREB content toward that observed in normal animals. In summary, high glucose and oxidative stress decrease SMC CREB content increase chemokinesis and entry into the cell cycle, which is blocked by antioxidants or restoration of CREB content. Thus, decreased vascular CREB content could be one of the molecular mechanisms leading to increased atherosclerosis in diabetes.

Calpains play a role in insulin secretion and action.

Studies of the genetic basis of type 2 diabetes suggest that variation in the calpain-10 gene affects susceptibility to this common disorder, raising the possibility that calpain-sensitive pathways may play a role in regulating insulin secretion and/or action. Calpains are ubiquitously expressed cysteine proteases that are thought to regulate a variety of normal cellular functions. Here, we report that short-term (4-h) exposure to the cell-permeable calpain inhibitors calpain inhibitor II and E-64-d increases the insulin secretory response to glucose in mouse pancreatic islets. This dose-dependent effect is observed at glucose concentrations above 8 mmol/l. This effect was also seen with other calpain inhibitors with different mechanisms of action but not with cathepsin inhibitors or other protease inhibitors. Enhancement of insulin secretion with short-term exposure to calpain inhibitors is not mediated by increased responses in intracellular Ca2+ or increased glucose metabolism in islets but by accelerated exocytosis of insulin granules. In muscle strips and adipocytes, exposure to both calpain inhibitor II and E-64-d reduced insulin-mediated glucose transport. Incorporation of glucose into glycogen in muscle also was reduced. These results are consistent with a role for calpains in the regulation of insulin secretion and insulin action.

Variation in perceptions of treatment and self-care practices in elderly with osteoarthritis: a comparison between African American and white patients.

OBJECTIVE: To compare elderly African American and white patients with osteoarthritis of the knee or hip with respect to their perceptions of the efficacy of traditional and complementary treatments and their self-care practices. METHODS: An observational, cross-sectional study design using structured questionnaires was employed. RESULTS: The sample consisted of 593 patients (44% African American and 56% white). The 2 groups were comparable with respect to age, disease severity or functional status, and comorbidities. African Americans were more likely than whites to report lower educational level and household income. African Americans were also more likely than whites to perceive various traditional and complementary care modalities as efficacious. However, they were less likely than whites to perceive joint replacement therapy as efficacious (odds ratio 0.52, 95% confidence interval 0.28-0.98). African American patients were more likely than white patients to rely on self-care measures for their arthritis. CONCLUSION: African American and white patients with osteoarthritis of the knee or hip differ with respect to their perceptions of traditional and complementary treatments for arthritis and their self-care practices.

Effects of type-2 diabetes and troglitazone on the expression patterns of small intestinal sugar transporters and PPAR-gamma in the Zucker diabetic fatty rat.

BACKGROUND/AIMS: We have used the Zucker diabetic fatty (ZDF) rat to study the effects of type-2 diabetes and troglitazone on the small intestinal mucosal mass, sugar transporters and the peroxisomal proliferator-activated receptor, PPAR-gamma. METHODS: Age-matched ZDF and lean control (ZLC) rats were fed a standard chow or a troglitazone-enriched diet for 6 weeks. The mucosa of the small intestines were then extracted, weighed, and SGLT1, GLUT2, GLUT5 and PPAR-gamma mRNA expression levels assessed by Northern blotting. In the same animal groups, Western blotting and immunohistochemistry were used to study SGLT1, GLUT2 and GLUT5 protein expression levels and targeting. RESULTS: The ZDF rat small intestinal mucosal mass was 60% greater than the ZLC rat. However, the expression levels of SGLT1, GLUT2, GLUT5 mRNA and protein, and PPAR-gamma mRNA in the ZDF and ZLC rats were the same. In addition, the targeting of brush-border GLUT5 and basolateral GLUT2 protein in the ZDF and ZLC rats were the same. Troglitazone treatment reduced SGLT1 mRNA and protein expression levels by 50% in ZDF and ZLC rats, but had no effect on mucosal mass or the expression levels of GLUT2 mRNA and protein, GLUT5 mRNA, and PPAR-gamma mRNA. The expression levels of GLUT5 protein in troglitazone-treated ZLC rats were unchanged when compared to untreated ZLC rats. However, GLUT5 protein expression levels in the troglitazone-treated ZDF rats were 50% below the untreated ZDF rats. CONCLUSIONS: Hyperphagia and insulin are the chronic regulators of small intestinal mucosal mass and sugar transporter expression patterns, respectively. Furthermore, troglitazone suppresses SGLT1 expression at the transcriptional level and GLUT5 at the post-translational level, independent of changes in glycemia or PPAR-gamma gene expression.

Effects of troglitazone on substrate storage and utilization in insulin-resistant rats.

Elevated serum and tissue lipid stores are associated with skeletal muscle insulin resistance and diminished glucose-stimulated insulin secretion, the hallmarks of type 2 diabetes. We studied the effects of 6-wk treatment with the insulin sensitizer troglitazone on substrate storage and utilization in lean control and Zucker diabetic fatty (ZDF) rats. Troglitazone prevented development of diabetes and lowered serum triglycerides (TG) in ZDF rats. Soleus muscle glycogen and TG content were elevated twofold in untreated ZDF rats, and both were normalized by troglitazone to lean control levels (P < 0.05). Troglitazone also normalized insulin-stimulated glucose uptake as well as basal and insulin-stimulated glycogen synthesis, implying increased skeletal muscle glycogen turnover. The proportion of active pyruvate dehydrogenase (PDH) in soleus muscle was reduced in ZDF relative to lean control rat muscle (16 +/- 2 vs. 21 +/- 2%) but was restored by troglitazone treatment (30 +/- 3%). Increased PDH activation was associated with a 70% increase in glucose oxidation. Muscle lipoprotein lipase activity was decreased by 35% in ZDF compared with lean control rats and was increased twofold by troglitazone. Palmitate oxidation and incorporation into TG were higher in ZDF relative to lean control rats but were unaffected by troglitazone treatment. Troglitazone decreased the incorporation of glucose into the acyl group of TG by 60% in ZDF rats. In summary, ZDF rats demonstrate increased skeletal muscle glycogen and TG stores, both of which were reduced by troglitazone treatment. Troglitazone appears to increase both glycogen and TG turnover in skeletal muscle. Normalization of PDH activity and decreased glucose incorporation into acyl TG may underlie the improvements in intracellular substrate utilization and energy stores, which lead to decreased serum TG and glucose.