Janet Pritchard

Adiponectin resistance precedes the accumulation of skeletal muscle lipids and insulin resistance in high-fat-fed rats

High-fat (HF) diets can induce insulin resistance (IR) by altering skeletal muscle lipid metabolism. An imbalance between fatty acid (FA) uptake and oxidation results in intramuscular lipid accumulation, which can impair the insulin-signaling cascade. Adiponectin (Ad) is an insulin-sensitizing adipokine known to stimulate skeletal muscle FA oxidation and reduce lipid accumulation. Evidence of Ad resistance has been shown in obesity and following chronic HF feeding and may contribute to lipid accumulation observed in these conditions. Whether Ad resistance precedes and is associated with the development of IR is unknown. We conducted a time course HF feeding trial for 3 days, 2 wk, or 4 wk to determine the onset of Ad resistance and identify the ensuing changes in lipid metabolism and insulin signaling leading to IR in skeletal muscle. Ad stimulated FA oxidation (+28%, P < or = 0.05) and acetyl-CoA carboxylase phosphorylation (+34%, P < or = 0.05) in control animals but failed to do so in any HF-fed group (i.e., as early as 3 days). By 2 wk, plasma membrane FA transporters and intramuscular diacylglycerol (DAG) and ceramide were increased, and insulin-stimulated phosphorylation of both protein kinase B and protein kinase B substrate 160 was blunted compared with control animals. After 4 wk of HF feeding, maximal insulin-stimulated glucose transport was impaired compared with control. Taken together, our results demonstrate that an early loss of Ads stimulatory effect on FA oxidation precedes an increase in plasmalemmal FA transporters and the accumulation of intramuscular DAG and ceramide, blunted insulin signaling, and ultimately impaired maximal insulin-stimulated glucose transport in skeletal muscle induced by HF diets.

A Food Frequency Questionnaire for the Assessment of Calcium, Vitamin D and Vitamin K: A Pilot Validation Study

The study objective was to validate a food frequency questionnaire (FFQ) to assess calcium, vitamin D and vitamin K intakes in overweight and obese postmenopausal community-dwelling women. The FFQ was validated against intakes derived from a 5-day diet record (5DDR) that also included assessment of supplement intake. Strong correlations between methods were observed for all nutrients (r = 0.63, 0.89, 0.54 for calcium, vitamin D and vitamin K, respectively) and cross-classification analyses demonstrated no major misclassification of participants into intake quartiles. Bland-Altman analysis showed that the FFQ overestimated intakes for calcium, by 576 mg/day (95% CI, −668 to 1,821 mg/day), for vitamin D by 75 IU/day (95% CI, −359 to 510 IU/day), and forvitamin K by 167 mcg/day (95% CI, −233 to 568 mcg/day). This pilot study showed promising validation evidence for the use of this FFQ, which focuses on calcium, vitamin D and vitamin K intakes in postmenopausal women, as a screening tool in clinicaland research settings.

Association of larger holes in the trabecular bone at the distal radius in postmenopausal women with type 2 diabetes mellitus compared to controls.

Adults with type 2 diabetes mellitus (DM) have an elevated fracture risk despite normal areal bone mineral density (aBMD). The study objective was to compare trabecular bone microarchitecture of postmenopausal women with type 2 DM and women without type 2 DM.

Prevalence of Osteoporosis in Osteoarthritic Patients Undergoing Total Hip or Total Knee Arthroplasty

OBJECTIVE To determine the prevalence of osteoporosis in osteoarthritic patients undergoing total hip or total knee arthroplasty. DESIGN Cross-sectional study. SETTING The Specialized Outpatient Rehabilitation Services (SORS) Pre-surgical Arthroplasty Service located at the Chedoke Hospital, Hamilton Health Sciences, Hamilton, ON, Canada. PARTICIPANTS SORS outpatients (N=364), from the period of March 2006 to March 2007. INTERVENTIONS Not applicable. MAIN OUTCOME MEASURES Prevalence of osteoporosis was determined by review of a self-reported survey, and defined by (1) self-reported diagnosis of osteoporosis, (2) history of fragility fracture (defined by a bone fracture occurring as a result of a fall from standing height or less after the age of 50), or (3) current treatment for osteoporosis using bisphosphonates. RESULTS Of the study cohort, 26% were classified as having osteoporosis, according to our criteria. Of the patients with self-reported osteoporosis or a history of fragility fractures, only 37% and 17% reported current treatment with bisphosphonates, respectively. CONCLUSIONS Osteoporosis is common in the osteoarthritic arthroplasty population, with a prevalence at least equal to that in the general population. Due to the self-reported nature of the study, the prevalence of osteoporosis in this population is likely significantly higher. Results from this study indicate need for further research, specifically in formal assessment for osteoporosis in patients undergoing a joint replacement.

A randomized controlled trial of vitamin D dosing strategies after acute hip fracture: No advantage of loading doses over daily supplementation

BackgroundThere remains uncertainty regarding the appropriate therapeutic management of hip fracture patients. The primary aim of our study was to examine whether large loading doses in addition to daily vitamin D offered any advantage over a simple daily low-dose vitamin D regimen for increasing vitamin D levels.MethodsIn this randomized controlled study, patients over age 50 with an acute fragility hip fracture were enrolled from two hospital sites in Ontario, Canada. Participants were randomized to one of three loading dose groups: placebo; 50,000 IU vitamin D2; or 100,000 IU D2. Following a placebo/loading dose, all patients received a daily tablet of 1,000 IU vitamin D3 for 90 days. Serum 25-hydroxy vitamin D (25-OHD) was measured at baseline, discharge from acute care (approximately 4-weeks), and 3-months.ResultsSixty-five patients were enrolled in the study (44% male). An immediate rise in 25-OHD occurred in the 100,000 group, however there were no significant differences in 25-OHD between the placebo, 50,000 and 100,000 loading dose groups after 4-weeks (69.3, 84.5, 75.6 nmol/L, p = 0.15) and 3-months (86.7, 84.2, 73.3 nmol/L, p = 0.09), respectively. At the end of the study, approximately 75% of the placebo and 50,000 groups had reached the target therapeutic range (75 nmol/L), and 44% of the 100,000 group.ConclusionsIn correcting vitamin D insufficiency/deficiency in elderly patients with hip fracture, our findings suggest that starting with a lower daily dose of Vitamin D3 achieved similar results as providing an additional large loading dose of Vitamin D2. At the end of the study, all three groups were equally effective in attaining improvement in 25-OHD levels. Given that a daily dose of 1,000 IU vitamin D3 (with or without a loading dose) resulted in at least 25% of patients having suboptimal vitamin D status, patients with acute hip fracture may benefit from a higher daily dose of vitamin D.Trial registrationClinical Trials # NCT00424619

Changes in trabecular bone microarchitecture in postmenopausal women with and without type 2 diabetes: a two year longitudinal study

BackgroundThe risk of experiencing an osteoporotic fracture is greater for adults with type 2 diabetes despite higher than normal bone mineral density (BMD). In addition to BMD, trabecular bone microarchitecture contributes to bone strength, but is not assessed using conventional BMD measurement by dual x-ray absorptiometry (DXA). The aim of this study was to compare two year changes in trabecular bone microarchitecture in women with and without type 2 diabetes.MethodsWe used a 1 Tesla magnetic resonance imaging (MRI) scanner to acquire axial images (resolution 195 μm × 195 μm × 1000 μm) of the distal radius. We report the change in the number and size of trabecular bone holes, bone volume fraction (BVTV), trabecular thickness (Tb.Th), number (Tb.N) and separation (Tb.Sp), endosteal area, nodal and branch density for each group. Lumbar spine and proximal femur BMD were measured with DXA (Hologic, Discovery QDR4500A) at baseline and follow-up. Using a multivariable linear regression model, we evaluated whether the percent change in the trabecular bone microarchitecture variables differed between women with and without type 2 diabetes.ResultsOf the 54 participants at baseline with valid MRI image sets, 37 participants (baseline mean [SD] age, 70.8 [4.4] years) returned for follow-up assessment after 25.4 [1.9] months. Lumbar spine BMD was greater for women with diabetes compared to without diabetes at both baseline and follow-up. After adjustment for ethnicity, women with diabetes had a higher percent increase in number of trabecular bone holes compared to controls (10[1] % versus −7 [2]%, p=0.010), however results were no longer significant after adjustment for multiple comparisons (p=0.090). There were no differences in the change in other trabecular bone microarchitecture variables between groups.ConclusionThere were no differences in percent change in trabecular bone microarchitecture variables over two years in women with type 2 diabetes compared to women without diabetes. This study provides feasibility data, which will inform future trials assessing change in trabecular bone microarchitecture in women with type 2 diabetes. Larger studies using higher resolution imaging modalities that can assess change in trabecular and cortical bone compartments in women with type 2 diabetes are needed.

Clinical risk factors for fracture in diabetes: a matched cohort analysis.

The objective was to determine which individuals with diabetes are at increased risk for fracture. It is unknown whether traditional clinical risk factors (CRFs) can be used in this population to identify individuals at higher risk of fracture. Using the Manitoba Bone Density Program database, we identified 3054 diabetic women and 9151 matched nondiabetic controls. The independent association of specific CRFs with incident osteoporotic fracture risk was assessed separately in those with diabetes and in controls, with subsequent examination of the interaction between diagnosed diabetes and each CRF. Prior major fractures were more prevalent in the diabetic group compared with the nondiabetic group (16.2% vs 14.3%, p<0.001). During mean 4 yr of observation, 259 (8.5%) of diabetic women and 559 (6.5%) of nondiabetic women experienced an incident major osteoporotic fracture (unadjusted hazard ratio [HR] for diabetes 1.49 [95% confidence interval (CI): 1.28-1.72], p<0.001; adjusted HR 1.14 [95% CI: 1.10-1.18], p<0.001). There were no significant differences between the 2 groups in the HRs for incident fracture associated with any of the CRFs studied (all p-for-interaction >0.1). Diabetes is a risk factor for major fracture. The ability of traditional CRFs to predict osteoporotic fractures is not influenced by the diagnosis of diabetes.

Bone mineralization is elevated and less heterogeneous in adults with type 2 diabetes and osteoarthritis compared to controls with osteoarthritis alone

PURPOSE The purpose of this study was to determine whether trabecular bone mineralization differed in adults with type 2 diabetes compared to adults without type 2 diabetes. METHODS Proximal femur specimens were obtained following a total hip replacement procedure from men and women ≥65 years of age with and without type 2 diabetes. A scanning electron microscope was used for quantitative backscattered electron imaging (qBEI) analysis of trabecular bone samples from the femoral neck. Gray scale images (pixel size=5.6 μm(2)) were uploaded to ImageJ software and gray level (GL) values were converted to calcium concentrations (weight [wt] % calcium [Ca]) using data obtained with energy dispersive X-ray spectrometry. The following bone mineralization density distribution (BMDD) outcomes were collected: the weighted mean bone calcium concentration (CaMEAN), the most frequently occurring bone calcium concentration (CaPEAK) and mineralization heterogeneity (CaWIDTH). Differences between groups were assessed using the Students t-test for normally distributed data and Mann-Whitney U-test for non-normally distributed data. An alpha value of <0.05 was considered significant. RESULTS Thirty-five Caucasian participants were recruited (mean [standard deviation, SD] age, 75.5 [6.5]years): 14 adults with type 2 diabetes (years since type 2 diabetes diagnosis, 13.5 [7.4]years) and 21 adults without type 2 diabetes. In the adults with type 2 diabetes, bone CaMEAN was 4.9% greater (20.36 [0.98]wt.% Ca versus 19.40 [1.07]wt.% Ca, p=0.015) and CaWIDTH was 9.4% lower (median [interquartile range] 3.55 [2.99-4.12]wt.% Ca versus 3.95 [0.71]wt.% Ca, p<0.001) compared to controls. There was no between-group difference in CaPEAK (21.12 [0.97]wt.% Ca for type 2 diabetes versus 20.44 [1.30]wt.% Ca for controls, p=0.121). CONCLUSION The combination of elevated mean calcium concentration in bone and lower mineralization heterogeneity in adults with type 2 diabetes may have deleterious effects on the biomechanical properties of bone. These microscopic alterations in bone mineralization, which may be mediated by suppressed bone remodeling, further elucidate higher fracture risk in adults with type 2 diabetes.

The Relationship between Intramuscular Adipose Tissue, Functional Mobility, and Strength in Postmenopausal Women with and without Type 2 Diabetes.

Objectives. To determine (1) whether intramuscular adipose tissue (IntraMAT) differs between women with and without type 2 diabetes and (2) the association between IntraMAT and mobility and strength. Methods. 59 women ≥ 65 years with and without type 2 diabetes were included. A 1-Tesla MRI was used to acquire images of the leg. Timed-up-and-go (TUG) and grip strength were measured. Regression was used to determine associations between the following: (1) type 2 diabetes and IntraMAT (covariates: age, ethnicity, BMI, waist : hip ratio, and energy expenditure), (2) IntraMAT and TUG (covariates: diabetes, age, BMI, and energy expenditure), and (3) IntraMAT and grip strength (covariates: diabetes, age, height, and lean mass). Results. Women with diabetes had more IntraMAT. After adjustment, IntraMAT was similar between groups (diabetes mean [SD] = 13.2 [1.4]%, controls 11.8 [1.3]%, P = 0.515). IntraMAT was related to TUG and grip strength, but the relationships became nonsignificant after adjustment for covariates (difference/percent IntraMAT [95% CI]: TUG = 0.041 seconds [−0.079–0.161], P = 0.498, grip strength = −0.144 kg [−0.335–0.066], P = 0.175). Conclusions. IntraMAT alone may not be a clinically important predictor of functional mobility and strength; however, whether losses in functional mobility and strength are promoted by IntraMAT accumulation should be explored.