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Inflammation is implicated in the etiology of obesity-related diseases. Thromboxane-prostanoid receptor (TPR) is known to play a role in mediating an inflammatory response in a variety of cells. Gut-derived lipopolysaccharide (LPS), a TLR4 agonist, is elevated in obesity. Moreover, free fatty acids (FFAs) are important mediators of obesity-related inflammation. However, the role and mechanisms by which TPR regulates the inflammatory response in human immune cells remain unclear. We sought to determine the link between TPR and obesity and the role/mechanisms by which TPR alters LPS- or stearic acid (SA)-induced inflammatory responses in PBMCs. Cells were pre-treated with agents blocking TPR signaling, followed by treatment with LPS or stearic acid (SA). Our findings showed that TPR mRNA levels are higher in PBMCs from individuals with obesity. Blockade of TPR as well as ROCK, which acts downstream of TPR, attenuated LPS- and/or SA-induced pro-inflammatory responses. On the other hand, TPR activation using its agonist enhanced the pro-inflammatory effects of LPS and/or SA. Of note, the TPR agonist by itself elicits an inflammatory response, which was attenuated by blocking TPR or ROCK. Our data suggest that TPR plays a key role in promoting an inflammatory response in human PBMCs, and this effect is mediated via TLR4 and/or ROCK signaling.

Objective: Circulating exosome-enriched extracellular vesicles (EVs) have drawn considerable importance in obesity-related insulin-resistance (IR). We sought to compare the proteomics profile of serum exosomes from normal individuals and those with obesity and IR., Methods: We isolated serum exosomes from male subjects with obesity and insulin resistance (Ob-IR, HOMA-IR > 2.0) and lean/overweight insulin-sensitive (Normal (N), HOMA-IR < 2.0) individuals. The differential protein expression between the two groups was detected by a label-free quantitative mass spectrometry analysis followed by GO annotation and ingenuity pathway analysis (IPA)., Results: We identified 23 upregulated and 46 downregulated proteins between Ob-IR and N groups. Some of these proteins are involved in altering insulin signaling (VPS13C, TBC1D32, TTR, and ADIPOQ), inflammation (NFκB and CRP), and B-cell proliferation/activation (IGLV4-69, IGKV1D-13, and IGHV4-28). GO analysis revealed that the differentially expressed proteins (DEPs) are mainly involved in regulating immune cell activation and are located in extracellular space. IPA analysis showed that top molecules mediating IR, inflammation and B-cell activation were upregulated in Ob-IR subjects compared to N subjects., Conclusions: Serum exosomal proteins can be used as biomarkers to identify the future risk of diabetes and a therapeutic target to prevent or slow down the progression of diabetes in high-risk individuals.

Introduction: Understanding how race may influence the association between A1c and glycemia can improve diabetes screening. We sought to determine whether, for a given A1c level, glucose levels during an oral glucose tolerance test (OGTT) differed by race., Research Design and Methods: From data collected at 22 US clinical sites, we conducted a cross-sectional study of concurrently measured A1c and OGTT and observational longitudinal follow-up of the subset with high-risk pre-diabetes. Numerical integration methods were used to calculate area under the glycemic curve (AUC glu ) during OGTT and least squares regression model to estimate A1c for a given AUC glu by race, controlling for potential confounders., Results: 1016 black, 2658 white, and 193 Asian persons at risk of diabetes were included in cross-sectional analysis. Of these, 2154 with high-risk pre-diabetes were followed for 2.5 years. For a given A1c level, AUC glu was lower in black versus white participants. After adjustment for potential confounders, A1c levels for a given AUC glu quintile were 0.15-0.20 and 0.02-0.19 percentage points higher in black and Asian compared with white participants, respectively (p<0.05). In longitudinal analyses, black participants were more likely to be diagnosed with diabetes by A1c than white participants (28% vs 10%, respectively; p<0.01). Black and Asian participants were less likely to be diagnosed by fasting glucose than white participants (16% vs 15% vs 37%, respectively; p<0.05). Black participants with A1c levels in the lower-level quintiles had greater increase in A1c over time compared with white participants., Conclusions: Use of additional testing beyond A1c to screen for diabetes may better stratify diabetes risk in the diverse US population., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Context: Intermediate-term glycemic control metrics may represent a viable alternative to continuous glucose monitoring (CGM) in patients without access to CGM., Objective: This work aimed to compare the relationship between CGM parameters and glycated albumin (GA), glycated hemoglobin A1c (HbA1c), and fructosamine for 24 weeks., Methods: We conducted exploratory comparative analyses of CGM subgroup data from a previously published 24-week prospective study of assay performance in 8 US clinics. Participants included 34 individuals with type 1 (n = 18) and type 2 diabetes (n = 16) undergoing changes to improve glycemic control (n = 22; group 1) or with stable diabetes therapy (n = 12; group 2). Main outcome measures included Pearson correlations between CGM and glycemic indices and receiver operating characteristic (ROC) analysis of glycemic index values predictive of time in range (TIR) greater than 70%., Results: At weeks 4 and 8, GA correlations with TIR were higher than HbA1c correlations in group 1. In group 2, GA correlations with TIR were statistically significant, whereas HbA1c correlations were not. In both groups over the first 12 weeks, GA correlations with TIR were higher than fructosamine-TIR correlations. In the ROC analysis, GA predicted a TIR greater than 70% during weeks 2 to 24 (area under the curve >0.80); HbA1c was predictive during weeks 12 to 24. Cutoff values for TIR greater than 70% were 17.5% (sensitivity and specificity, 0.88) for GA and 7.3% (0.86) for HbA1c., Conclusion: GA is the most accurate predictor of TIR over 8 weeks compared with other glycemic indices, which may assist in clinical evaluation of changes in treatment where CGM is not possible and it is too early to use HbA1c (NCT02489773)., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)

Poor glycemic control in type 2 diabetes has been associated with accentuated age-related cognitive decline, although the underlying neural mechanisms are not well understood. The current study sought to identify the impact of glycemic control on the neural dynamics serving working memory in adults with type 2 diabetes. Participants (n = 34, ages = 55-73) performed a working memory task while undergoing MEG. Significant neural responses were examined relative to poorer (A1c > 7.0%) or tighter glycemic control (A1c < 7.0%). Those with poorer glycemic control showed diminished responses within left temporal and prefrontal regions during encoding and showed diminished responses within right occipital cortex during maintenance but showed an enhanced activity in the left temporal, occipital, and cerebellar regions during maintenance. Notably, left temporal activity in encoding and left lateral occipital activity in maintenance significantly predicted performance on the task such that diminished temporal activity led to longer reaction times, which were driven by the poorer glycemic control group. Greater lateral occipital activity during maintenance was associated with both lower accuracy and longer reaction times across all participants. These findings suggest that glycemic control has a robust impact on the neural dynamics serving working memory, with distinct effects by subprocess (e.g. encoding vs. maintenance) and direct effects on behavior., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Type 2 diabetes is known to negatively affect higher order cognition and the brain, but the underlying mechanisms are not fully understood. In particular, glycemic control and common comorbidities are both thought to contribute to alterations in cortical neurophysiology in type 2 diabetes, but their specific impact remains unknown. The current study probed the dynamics underlying cognitive control in older participants with type 2 diabetes, with and without additional comorbid conditions (i.e., cardiovascular disease, nephropathy, peripheral neuropathy, retinopathy), using a task switching paradigm and a dynamic functional brain mapping method based on magnetoencephalography (MEG). We hypothesized that neural dynamics would be differentially impacted by the level of glycemic control (i.e., diabetes itself) and the burden of additional comorbid conditions. Supporting this hypothesis, our findings indicated separable, but widespread alterations across frontal, parietal, temporal and cerebellum regions in neural task-switch costs in type 2 diabetes that were differentially attributable to glycemic control and the presence of comorbid conditions. These effects were spatially non-overlapping and the effects were not statistically related to one another. Further, several of the effects that were related to the presence of comorbidities were associated with behavioral performance, indicating progressive deficits in brain function with extended disease. These findings provide insight on the underlying neuropathology and may inform future treatment plans to curtail the neural impact of type 2 diabetes.

Saturated fatty acids (SFAs) are considered to be detrimental to human health. One of the SFAs, myristic acid (MA), is known to exert a hypercholesterolemic effect in mice as well as humans. However, its effects on altering adipose tissue (AT) inflammation and systemic insulin resistance (IR) in obesity are still unclear. Here, we sought to determine the effects of a high fat (HF) diet supplemented with MA on obesity-associated metabolic disorders in mice. Wild-type C57BL/6 mice were fed a HF diet in the presence or absence of 3% MA for 12 weeks. Plasma lipids, plasma adipokines, AT inflammation, systemic IR, glucose homeostasis, and hepatic steatosis were assessed. The body weight and visceral adipose tissue (VAT) mass were significantly higher in mice receiving the HF+MA diet compared to HF diet-fed controls. Plasma total cholesterol levels were marginally increased in HF+MA-fed mice compared to controls. Fasting blood glucose was comparable between HF and HF+MA-fed mice. Interestingly, the plasma insulin and HOMA-IR index, a measure of insulin resistance, were significantly higher in HF+MA-fed mice compared to HF controls. Macrophage and inflammatory markers were significantly elevated in the AT and AT-derived stromal vascular cells upon MA feeding. Moreover, the level of circulating resistin, an adipokine promoting insulin resistance, was significantly higher in HF+MA-fed mice compared with HF controls. The insulin tolerance test revealed that the IR was higher in mice receiving the MA supplementation compared to HF controls. Moreover, the glucose tolerance test showed impairment in systemic glucose homeostasis in MA-fed mice. Analyses of liver samples showed a trend towards an increase in liver TG upon MA feeding. However, markers of oxidative stress and inflammation were reduced in the liver of mice fed an MA diet compared to controls. Taken together, our data suggest that chronic administration of MA in diet exacerbates obesity-associated insulin resistance and this effect is mediated in part, via increased AT inflammation and increased secretion of resistin.

Objective: In this secondary analysis of the Rural Engagement in Primary Care for Optimizing Weight Reduction (RE-POWER) randomized trial, the authors determined the effectiveness of weight-loss interventions in people with diabetes compared with those without diabetes living in rural areas., Methods: The RE-POWER study was a randomized trial designed to determine the effectiveness of nonpharmacological behavioral weight-loss interventions in rural participants with obesity, comparing the individual in-clinic visit model to in-person group sessions and phone group sessions over 24 months. In this secondary analysis, weight loss was compared in participants with and without diabetes. The effects of factors such as medications, insulin, and behavioral factors were compared., Results: Participants with diabetes were less likely to lose weight during the study compared with those without diabetes up to 18 months (4.12% vs. 5.31%; net difference = 1.46%; 95% CI: 0.63%-2.28%). Participants with diabetes on insulin lost less weight than patients with diabetes not on insulin at 6 months (4.52% vs. 6.88%; net difference = 2.35%; 95% CI: 0.55%-4.16%). The group with diabetes had significantly lower changes in blood pressure and lipid parameters versus the group without diabetes., Conclusions: Patients with diabetes in rural areas were less likely to lose weight, and metabolic parameters were less responsive to weight loss, compared with patients without diabetes., (© 2022 The Obesity Society (TOS). This article has been contributed to by US Government employees and their work is in the public domain in the USA.)

Objective: Fasting plasma glucose (FPG), 2-hour plasma glucose (2hPG) from a 75-g oral glucose tolerance test (OGTT) and glycated hemoglobin (HbA1c) can lead to different results when diagnosing prediabetes and diabetes. The Hemoglobin Glycation Index (HGI) quantifies the interindividual variation in glycation resulting in discrepancies between FPG and HbA1c. We used data from the Vitamin D and Type 2 Diabetes (D2d) study to calculate HGI, to identify HGI-associated variables, and to determine how HGI affects prediabetes and diabetes diagnosis., Measurements: A linear regression equation [HbA1c (%) = 0.0164 × FPG (mg/dL) + 4.2] was derived using the screening cohort (n = 6829) and applied to calculate predicted HbA1c. This was subtracted from the observed HbA1c to determine HGI in the baseline cohort with 2hPG data (n = 3945). Baseline variables plus prediabetes and diabetes diagnosis by FPG, HbA1c, and 2hPG were compared among low, moderate, and high HGI subgroups., Results: The proportion of women and Black/African American individuals increased from low to high HGI subgroups. Mean FPG decreased and mean HbA1c increased from low to high HGI subgroups, consistent with the HGI calculation; however, mean 2hPG was not significantly different among HGI subgroups., Conclusions: High HGI was associated with Black race and female sex as reported previously. The observation that 2hPG was not different across HGI subgroups suggests that variation in postprandial glucose is not a significant source of population variation in HGI. Exclusive use of HbA1c for diagnosis will classify more Black individuals and women as having prediabetes compared with using FPG or 2hPG., (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Context: Intermediate-term glycemic control metrics fulfill a need for measures beyond hemoglobin A1C., Objective: Compare glycated albumin (GA), a 14-day blood glucose measure, with other glycemic indices., Design: 24-week prospective study of assay performance., Setting: 8 US clinics., Participants: Subjects with type 1 (n = 73) and type 2 diabetes (n = 77) undergoing changes to improve glycemic control (n = 98) or with stable diabetes therapy (n = 52)., Interventions: GA, fructosamine, and A1C measured at prespecified intervals. Mean blood glucose (MBG) calculated using weekly self-monitored blood glucose profiles., Main Outcome Measures: Primary: Pearson correlation between GA and fructosamine. Secondary: magnitude (Spearman correlation) and direction (Kendall correlation) of change of glycemic indices in the first 3 months after a change in diabetes management., Results: GA was more concordant (60.8%) with changes in MBG than fructosamine (55.5%) or A1C (45.5%). Across all subjects and visits, the GA Pearson correlation with fructosamine was 0.920. Pearson correlations with A1C were 0.655 for GA and 0.515 for fructosamine (P < .001) and with MBG were 0.590 and 0.454, respectively (P < .001). At the individual subject level, Pearson correlations with both A1C and MBG were higher for GA than for fructosamine in 56% of subjects; only 4% of subjects had higher fructosamine correlations with A1C and MBG. GA had a higher Pearson correlation with A1C and MBG in 82% and 70% of subjects, respectively., Conclusions: Compared with fructosamine, GA correlates significantly better with both short-term MBG and long-term A1C and may be more useful than fructosamine in clinical situations requiring monitoring of intermediate-term glycemic control (NCT02489773)., (© Endocrine Society 2019.)

We previously reported that fish oil in combination with cyclooxygenase (COX) inhibitors exerts enhanced hypolipidemic and anti-inflammatory effects in mice. Here, we sought to determine the effects of omega-3 polyunsaturated fatty acids (ω-3 PUFAs) in combination with naproxen (NX), a COX inhibitor, on dyslipidemia and gene expression in adipose tissue (AT) in humans. Obese dyslipidemic patients were randomly assigned to one of these interventions for 12 wk: 1) Standard nutrition counseling (control), 2) ω-3 PUFAs (2 g twice daily), 3) NX (220 mg twice daily), and 4) ω-3 PUFAs (2 g twice daily) + NX (220 mg twice daily). The serum triglycerides showed a trend towards a reduction and a significant reduction (P<0.05) in ω-3 and ω3 + NX-treated subjects, respectively, compared to control. The mRNA expression of vascular cell adhesion molecule-1 (Vcam1), an inflammatory marker, increased significantly in AT of ω-3 PUFA-treated subjects but not in ω-3 PUFAs+NX-treated group. The plasma level of glycine-conjugated hyodeoxycholic acid, a secondary bile acid with hypolipidemic property, increased significantly in ω-3 PUFAs + NX-treated group. Our data suggest that combining NX with ω-3 PUFAs increases their effectiveness in reducing serum TG and favorably altering AT gene expression and plasma bile acid profile., (Published by Elsevier Inc.)

Type 1 diabetes has been associated with alterations in attentional processing and other cognitive functions, and previous studies have found alterations in both brain structure and function in affected patients. However, these previous neuroimaging studies have generally examined older patients, particularly those with major comorbidities known to affect functioning independent of diabetes. The primary aim of the current study was to examine the neural dynamics of selective attention processing in a young group of patients with type 1 diabetes who were otherwise healthy (i.e., without major comorbidities). Our hypothesis was that these patients would exhibit significant aberrations in attention circuitry relative to closely matched controls. The final sample included 69 participants age 19-35 years old, 35 with type 1 diabetes and 34 matched nondiabetic controls, who completed an Eriksen flanker task while undergoing magnetoencephalography. Significant group differences in flanker interference activity were found across a network of brain regions, including the anterior cingulate, inferior parietal cortices, paracentral lobule, and the left precentral gyrus. In addition, neural activity in the anterior cingulate and the paracentral lobule was correlated with disease duration in patients with type 1 diabetes. These findings suggest that alterations in the neural circuitry underlying selective attention emerge early in the disease process and are specifically related to type 1 diabetes and not common comorbidities. These findings highlight the need for longitudinal studies in large cohorts to clarify the clinical implications of type 1 diabetes on cognition and the brain., (© 2018 Wiley Periodicals, Inc.)

Type 1 diabetes (T1D) has been linked to alterations in both brain structure and function. However, the neural basis of the most commonly reported neuropsychological deficit in T1D, psychomotor speed, remains severely understudied. To begin to address this, the current study focuses on the neural dynamics underlying motor control using magnetoencephalographic (MEG) imaging. Briefly, 40 young adults with T1D who were clear of common comorbidities (e.g., vascular disease, retinopathy, etc.) and a demographically-matched group of 40 controls without T1D completed an arrow-based flanker movement task during MEG. The resulting signals were examined in the time-frequency domain and imaged using a beamforming approach, and then voxel time series were extracted from peak responses to evaluate the dynamics. The resulting time series were statistically examined for group and conditional effects using a rigorous permutation testing approach. Our primary hypothesis was that participants with T1D would have altered beta and gamma oscillatory dynamics within the primary motor cortex during movement, and that these alterations would reflect compensatory processing to maintain adequate performance. Our results indicated that the group with T1D had a significantly stronger post-movement beta rebound (PMBR) contralateral to movement compared to controls, and a smaller neural flanker effect (i.e., difference in neural activity between conditions). In addition, a significant group-by-condition interaction was observed in the ipsilateral beta event-related desynchronization (bERD) and the ipsilateral PMBR. We also examined the relationship between oscillatory motor response amplitude and reaction time, finding a differential effect of the driving oscillatory responses on behavioral performance by group. Overall, our findings suggest compensatory activity in the motor cortices is detectable early in the disease in a relatively healthy sample of adults with T1D. Future studies are needed to examine how these subtle effects on neural activity in young, otherwise healthy patients affect outcomes in aging., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To investigate the efficacy and safety of once-daily semaglutide in comparison with once-daily liraglutide and placebo in patients with type 2 diabetes., Research Design and Methods: This 26-week, multicenter, double-blind trial involved patients diagnosed with type 2 diabetes with HbA 1c 7.0-10.0% (53-86 mmol/mol) and treated with diet and exercise with or without metformin. Patients were randomized 2:2:1 to once-daily semaglutide, liraglutide, or placebo in one of four volume-matched doses (semaglutide 0.05, 0.1, 0.2, or 0.3 mg and liraglutide 0.3, 0.6, 1.2, or 1.8 mg, with both compared within each volume-matched dose group). Primary end point was change in HbA 1c from baseline to week 26., Results: In total, 705 randomized patients were exposed to trial products. At week 26, a dose-dependent change in HbA 1c was observed with semaglutide from -1.1% (0.05 mg) to -1.9% (0.3 mg) and with liraglutide from -0.5% (0.3 mg) to -1.3% (1.8 mg) (all P < 0.001 in favor of volume-matched semaglutide dose). Change with pooled placebo was -0.02% ( P < 0.0001 vs. semaglutide). Gastrointestinal (GI) disorders were the most common adverse events (AEs) with semaglutide and liraglutide, occurring in 32.8-54.0% and 21.9-41.5% of patients, respectively., Conclusions: Once-daily semaglutide at doses up to 0.3 mg/day resulted in greater reductions in HbA 1c compared with liraglutide or placebo but with a higher frequency of GI AEs., (© 2018 by the American Diabetes Association.)

Objective: To describe baseline characteristics of the Vitamin D and Type 2 Diabetes (D2d) study, the first large U.S. diabetes prevention clinical trial to apply current American Diabetes Association (ADA) criteria for prediabetes., Research Design and Methods: This is a multicenter ( n = 22 sites), randomized, double-blind, placebo-controlled, primary prevention clinical trial testing effects of oral daily 4,000 IU cholecalciferol (D 3 ) compared with placebo on incident diabetes in U.S. adults at risk for diabetes. Eligible participants were at risk for diabetes, defined as not meeting criteria for diabetes but meeting at least two 2010 ADA glycemic criteria for prediabetes: fasting plasma glucose (FPG) 100-125 mg/dL, 2-h postload glucose (2hPG) after a 75-g oral glucose load 140-199 mg/dL, and/or a hemoglobin A 1c (HbA 1c ) 5.7-6.4% (39-46 mmol/mol)., Results: A total of 2,423 participants (45% of whom were women and 33% nonwhite) were randomized to cholecalciferol or placebo. Mean (SD) age was 59 (9.9) years and BMI 32 (4.5) kg/m 2 . Thirty-five percent met all three prediabetes criteria, 49% met the FPG/HbA 1c criteria only, 9.5% met the 2hPG/FPG criteria only, and 6.3% met the 2hPG/HbA 1c criteria only. Black participants had the highest mean HbA 1c and lowest FPG concentration compared with white, Asian, and other races ( P < 0.01); 2hPG concentration did not differ among racial groups. When compared with previous prediabetes cohorts, the D2d cohort had lower mean 2hPG concentration but similar HbA 1c and FPG concentrations., Conclusions: D2d will establish whether vitamin D supplementation lowers risk of diabetes and will inform about the natural history of prediabetes per contemporary ADA criteria., (© 2018 by the American Diabetes Association.)

It is now generally accepted that diabetes increases the risk for cognitive impairment, but the precise mechanisms are poorly understood. A critical problem in linking diabetes to cognitive impairment is that patients often have multiple comorbidities (e.g., obesity, hypertension) that have been independently linked to cognitive deficits. In the study reported here we focused on young adults with and without type 1 diabetes who were virtually free of such comorbidities. The two groups were matched on major health and demographic factors, and all participants completed a verbal working memory task during magnetoencephalographic brain imaging. We hypothesized that patients would have altered neural dynamics in verbal working memory processing and that these differences would directly relate to clinical disease measures. Accordingly, we found that patients had significantly stronger neural responses in the superior parietal cortices during memory encoding and significantly weaker activity in parietal-occipital regions during maintenance compared with control subjects. Moreover, disease duration and glycemic control were both significantly correlated with neural responses in various brain regions. In conclusion, young healthy adults with type 1 diabetes already have aberrant neural processing relative to their peers without diabetes, using compensatory responses to perform the task, and glucose management and duration may play a central role., (© 2018 by the American Diabetes Association.)

Evidence suggests that superoxide dismutase 1 (SOD1) promotes glucose vs lipid metabolism depending on the diet type. We recently reported that nanoformulated SOD1 (Nano) improved lipid metabolism without altering glucose homeostasis in high-fat (HF) diet-fed mice. Here, we sought to determine the effects and potential mechanisms of Nano in modulating glucose and lipid homeostasis in mice fed a normal chow diet (CD) vs HF diet. Mice were fed a CD or a HF diet (45%) for 10 wk and injected with Nano once every 2 days for 15 days. The fasting glucose level was lower (P < 0.05) in CD + Nano-treated mice compared to control. Conversely, blood glucose was not altered but serum triglycerides were lower in HF + Nano-treated mice. Genes involved in fatty acid synthesis were reduced by Nano in the skeletal muscle of CD but not of HF diet-fed mice. Adenosine monophosphate-activated protein kinase (AMPK), which promotes both glucose and lipid metabolism depending on the fuel availability, is activated by Nano in CD-fed mice. Moreover, Nano increased phosphorylation of ACC, a downstream target of AMPK, in both CD and HF diet-fed mice. Nano increased mitochondrial respiration in C2C12 myocytes in the presence of glucose or fatty acid, and this effect is inhibited by Compound C, an AMPK inhibitor. Our data suggest that Nano promotes glucose and lipid metabolism in CD and HF diet-fed mice, respectively, and this effect is mediated partly via AMPK signaling., (Copyright © 2017 Elsevier Inc. All rights reserved.)

We sought to determine whether a combination of purified n-3 fatty acids (n-3) and SC-560 (SC), a cyclooxygenase-1-specific inhibitor, is effective in ameliorating nonalcoholic fatty liver disease in obesity. Female wild-type mice were fed a high-fat and high-cholesterol diet (HF) supplemented with n-3 in the presence or absence of SC. Mice treated with SC alone exhibited no change in liver lipids, whereas n-3-fed mice tended to have lower hepatic lipids. Mice given n-3+SC had significantly lower liver lipids compared with HF controls indicating enhanced lipid clearance. Total and sulfated bile acids were significantly higher only in n-3+SC-treated mice compared with chow diet (CD) controls. Regarding mechanisms, the level of pregnane X receptor (PXR), a nuclear receptor regulating drug/bile detoxification, was significantly higher in mice given n-3 or n-3+SC. Studies in precision-cut liver slices and in cultured hepatoma cells showed that n-3+SC enhanced not only the expression/activation of PXR and its target genes but also the expression of farnesoid X receptor (FXR), another regulator of bile synthesis/clearance, indicating that n-3+SC can induce both PXR and FXR. The mRNA level of FGFR4 which inhibits bile formation showed a significant reduction in Huh 7 cells upon n-3 and n-3+SC treatment. PXR overexpression in hepatoma cells confirmed that n-3 or SC each induced the expression of PXR target genes and in combination had an enhanced effect. Our findings suggest that combining SC with n-3 potentiates its lipid-lowering effect, in part, by enhanced PXR and/or altered FXR/FGFR4 signaling., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: Endothelial cell (EC) oxidative stress can lead to vascular dysfunction which is an underlying event in the development of cardiovascular disease (CVD). The lack of a potent and bioavailable anti-oxidant enzyme is a major challenge in studies on antioxidant therapy. The objective of this study is to determine whether copper/zinc superoxide dismutase (CuZnSOD or SOD1) after nanoformulation (nanoSOD) can effectively reduce EC oxidative stress and/or vascular inflammation in obesity., Methods: Human aortic endothelial cells (HAECs) were treated with native- or nanoSOD for 6 h followed by treatment with linoleic acid (LA), a free fatty acid, for 6-24 h. To determine the in vivo relevance, the effectiveness of nanoSOD in reducing vascular cell activation was studied in a mouse model of diet-induced obesity., Results: We noted that nanoSOD was more effectively taken up by ECs than native SOD. Western blot analysis further confirmed that the intracellular accumulation of SOD1 protein was greatly increased upon nanoSOD treatment. Importantly, nanoSOD pretreatment led to a significant decrease in LA-induced oxidative stress in ECs which was associated with a marked increase in SOD enzyme activity in ECs. In vivo studies showed a significant decrease in markers of EC/vascular cell activation and/or inflammation in visceral adipose tissue (VAT), thoracic aorta, and heart collected from nanoSOD-treated mice compared to obese control mice. Interestingly, the expression of metallothionein 2, an antioxidant gene was significantly increased in nanoSOD-treated mice., Conclusion: Our data show that nanoSOD is very effective in delivering active SOD to ECs and in reducing EC oxidative stress. Our data also demonstrate that nanoSOD will be a useful tool to reduce vascular cell activation in VAT and aorta in obesity which, in turn, can protect against obesity-associated CVD, in particular, hypertension., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: An intimate association exists between oxidative stress and inflammation. Because adipose tissue (AT) inflammation is intricately linked to metabolic disorders, it was hypothesized that reducing oxidative stress would be effective in ameliorating AT inflammation in obesity., Methods: Wild-type mice were fed a high-fat diet (HF) for 8 weeks followed by a 2-week treatment with nanoformulated copper/zinc superoxide dismutase (NanoSOD). The mice were divided into: 1) chow diet, 2) HF, and 3) HF + NanoSOD., Results: The HF + NanoSOD-treated mice showed a significant decrease in plasma and liver triglycerides when compared with HF-fed mice. Interestingly, NanoSOD reduced the expression of macrophage and inflammatory markers in visceral AT (VAT) and stromal cells derived from VAT. Moreover, the activation of proinflammatory signaling pathways, in particular, the extracellular signal-regulated kinases, was blunted in VAT on NanoSOD treatment. However, markers of oxidative stress were not altered significantly in the HF + NanoSOD group in the experimental conditions. Pretreatment of either macrophages or adipocytes significantly reduced the inflammatory response invoked in an in vitro coculture system, further supporting the role of NanoSOD in inhibiting obesity-linked inflammation., Conclusions: This data suggest that NanoSOD is effective not only in reducing AT macrophage accumulation and AT inflammation but also in promoting triglyceride metabolism in obesity., (© 2015 The Obesity Society.)

Objective: Evaluate the performance of glycated albumin (GA) monitoring by comparing it to other measures of glycemic control during intensification of antidiabetic therapy., Methods: This 12-week, prospective, multicenter study compared the diagnostic clinical performance of GA to glycated hemoglobin A1C (A1C), fructosamine corrected for albumin (FRA), fasting plasma glucose (FPG), and mean blood glucose (MBG) estimated from self-monitoring of blood glucose (SMBG) and continuous glucose monitoring (CGM) in 30 patients with suboptimally controlled type 1 or 2 diabetes., Results: Mean A1C decreased from 9.5% to 8.1%. Mean SMBG correlated closely with CGM (Pearson r = 0.783 for daily estimates and r = 0.746 for weekly estimates, P<.0001). Both GA and FRA levels significantly correlated with changes from baseline in A1C and mean weekly SMBG (P<.001). The lowest observed median GA occurred at 4 weeks, followed by a small increase and then a slight reduction, mirroring changes in overall mean SMBG values. The median A1C fell throughout the treatment period, failing to reflect short-term changes in SMBG. A ≥1% reduction in GA at 4 weeks was significantly associated with a ≥0.5% change in A1C at 12 weeks (odds ratio [OR] = 19.0, 95% confidence interval [CI]: 1.4, 944, P = .018)., Conclusion: In patients receiving glucose-lowering therapy, changes in GA at 4 weeks were concordant with changes in A1C at 12 weeks, and both GA and FRA more accurately reflected short-term blood glucose fluctuations than A1C.

Objective: Adipose tissue (AT) macrophages mediate AT inflammation in obesity, and cyclooxygenase-2 (COX-2) is a major inflammatory gene. It was hypothesized that deletion of hematopoietic COX-2 will inhibit AT inflammation in obesity., Methods: Lethally irradiated wild-type (WT) mice were injected with bone marrow (BM) cells collected from WT or COX-2 knock-out (COX-2-/-) donor mice and fed a high-fat diet for 16 weeks., Results: The mice that received BM cells from COX-2-/- mice (BM-COX-2-/-) gained increased body weight, fat mass, and visceral AT (VAT) mass. These mice exhibited reduced inflammatory markers in the VAT stromal vascular cells (SVC). However, the inflammatory markers were increased in adipocyte fraction and/or whole VAT. The activation of ERK1/2 MAPK, a pro-inflammatory signaling pathway, was increased in BM-COX-2-/- mice. The molecular markers of adipogenesis were increased in the VAT or adipocyte fraction. Wnt signaling markers which inhibit adipogenesis, including Wnt3A and DVL3, were reduced, and Wnt5a/b which promotes inflammation was increased in the VAT and/or adipocytes. Finally, an increase in hepatic triglyceride levels in BM-COX-2-/- mice was noted., Conclusions: The data suggest that COX-2 deletion in hematopoietic cells reduces SVC inflammation but increases VAT inflammation and promotes adiposity likely via altered Wnt signaling., (© 2015 The Obesity Society.)

Purpose: Within the past decade, many new classes of drugs have received approval from the US Food and Drug Administration for treatment of type 2 diabetes mellitus, including glucagon-like peptide-1agonists, dipeptidyl peptidase-4 inhibitors, and the sodium-glucose cotransporter-2 inhibitors. Many trials have been performed, and several more are currently ongoing to evaluate these drugs. This review addresses the broad therapeutic and pleiotropic effects of these drugs. The review also discusses the role of these drugs in the treatment paradigm for type 2 diabetes and identifies patients who would be suitable candidates for treatment with these drugs., Methods: In this comprehensive evidence-based review, the following databases were searched from 1990 to the present: PubMed/MEDLINE, Scopus, CINAHL, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Portal, and the American Diabetes Association and European Association for the Study of Diabetes abstract databases. Randomized clinical trials (RCTs) were only included for the main therapeutic and cardiovascular (CV) effects of these drug classes. For pleiotropic effects, RCTs were included unless no RCTs exist, in which case other studies as specified in the detailed Methods section were included., Findings: All 3 drug classes are effective in lowering hemoglobin A1c between 0.4% and 1.4%, depending on the drug class and population selected. These drug classes have beneficial effects on CV risk factors, such as weight, lipids, and blood pressure, in addition to lowering blood glucose levels. The CV tolerability of some drugs has been evaluated and found to be neutral; however, most trials are currently ongoing to assess CV tolerability. There are no concrete guidelines to determine where these drugs fit in the diabetes management paradigm, and there are ongoing trials to determine the best combination drug with metformin., Implications: These 3 drug classes will potentially increase the armamentarium against hyperglycemia. However, the specific combinations with other antidiabetic drugs and populations that will best benefit from these drugs are still being tested. Future research is also being conducted on the use of glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 inhibitors in patients with type 1 diabetes., (Published by Elsevier Inc.)

The objective of this study was to determine the effects of enrichment with n-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), on the differentiation of 3T3-L1 preadipocytes. Enrichment with DHA but not EPA significantly increased the differentiation markers compared to control differentiated cells. DHA compared to EPA treatment led to a greater increase in adiponectin secretion and, conditioned media collected from DHA treated cells inhibited monocyte migration. Moreover, DHA treatment resulted in inhibition of pro-inflammatory signaling pathways. DHA treated cells predominantly accumulated DHA in phospholipids whereas EPA treatment led to accumulation of both EPA and its elongation product docosapentaenoic acid (DPA), an n-3 fatty acid. Of note, adding DPA to DHA inhibited DHA-induced differentiation. The differential effects of EPA and DHA on preadipocyte differentiation may be due, in part, to differences in their intracellular modification which could impact the type of n-3 fatty acids incorporated into the cells., (© 2013 Published by Elsevier Ltd.)

Objective: Adipose tissue (AT)-specific inflammation is considered to mediate the pathological consequences of obesity and macrophages are known to activate inflammatory pathways in obese AT. Because cyclooxygenases play a central role in regulating the inflammatory processes, we sought to determine the role of hematopoietic cyclooxygenase-1 (COX-1) in modulating AT inflammation in obesity., Materials/methods: Bone marrow transplantation was performed to delete COX-1 in hematopoietic cells. Briefly, female wild type (wt) mice were lethally irradiated and injected with bone marrow (BM) cells collected from wild type (COX-1+/+) or COX-1 knock-out (COX-1-/-) donor mice. The mice were fed a high fat diet for 16 weeks., Results: The mice that received COX-1-/- bone marrow (BM-COX-1-/-) exhibited a significant increase in fasting glucose, total cholesterol and triglycerides in the circulation compared to control (BM-COX-1+/+) mice. Markers of AT-inflammation were increased and were associated with increased leptin and decreased adiponectin in plasma. Hepatic inflammation was reduced with a concomitant reduction in TXB2 levels. The hepatic mRNA expression of genes involved in lipogenesis and lipid transport was increased while expression of genes involved in regulating hepatic glucose output was reduced in BM-COX-1-/- mice. Finally, renal inflammation and markers of renal glucose release were increased in BM-COX-1-/- mice., Conclusion: Hematopoietic COX-1 deletion results in impairments in metabolic homeostasis which may be partly due to increased AT inflammation and dysregulated adipokine profile. An increase in renal glucose release and hepatic lipogenesis/lipid transport may also play a role, at least in part, in mediating hyperglycemia and dyslipidemia, respectively., (Published by Elsevier Inc.)

Endothelial progenitor cells (EPCs) are vital for the maintenance and repair of the endothelium. Decreased EPC number and function have been associated with increased cardiovascular (CVD) risk. Patients with diabetes have decreased number of circulating EPCs and decreased EPC function. This may account for some of the increased CVD risk seen in patients with diabetes that is not explained by traditional risk factors such as glycemic control, dyslipidemia and hypertension. Recent studies seem to indicate that drugs commonly used in diabetes patients such as metformin, thiazolidinediones, GLP-1 agonists, DPP-4 inhibitors, insulin, statins and ACE inhibitors may increase EPC number and improve EPC function. The mechanisms by which these drugs modulate EPC function may involve reduction in inflammation, oxidative stress and insulin resistance as well as an increase in nitric oxide (NO) bioavailability. This review will discuss the evidence in the literature regarding the above mentioned topics., (Published by Elsevier Inc.)

Aims: Obesity, which is at epidemic proportions in the USA, is associated with a higher risk of several co-morbid diseases including, cardiovascular disease, cancer and sleep apnea. Weight loss and weight maintenance programmmes are difficult to sustain for long term. Mental health problems such as apathy may be a major factor in patients unsuccessful in adhering to weight loss programmes. We propose that treating apathy will result in better weight loss in obese patients., Methods: This was a randomized prospective pilot study. Obese patients (n = 101) were randomized in a 1:2:2 ratio to either (i) standard nutrition counselling; or (ii) the Department of Veterans Affairs weight loss programme called 'motivate obese veterans everywhere ' (MOVE); or (iii) methylphenidate treatment plus the MOVE programme together. The intervention was for 6 months (26 weeks)., Results: For the within groups analysis, the absolute changes in weight (kg) are as follows, for MOVE (mean: -1.84; 95% confidence interval (CI): -4.56 to 0.87; p = 0.25), Methylphenidate (mean: -4.61; 95% CI: -7.90 to -1.33; p = 0.04), standard nutrition counselling (mean: -0.60; 95% CI: -2.59 to 1.39; p = 0.21), which indicates that although all three groups lost weight, only the methylphenidate group achieved statistical significance. The between group differences of the relative change in weight were not statistically different. The apathy evaluation score and the patient activation measure improved in all groups., Conclusion: Together these data suggest that treating apathy might be an important factor in the success of weight management programmes., (Published 2011. This article is a U.S. Government work and is in the public domain in the USA.)

Kidney transplantation is being performed more frequently for individuals with end stage renal disease (ESRD) due to improved survival and quality of life compared to long-term dialysis. Though rates decrease after transplant, cardiovascular disease (CVD) remains the most common cause of death after kidney transplant. New-onset diabetes after transplant (NODAT), a common complication following kidney transplantation, and pre-transplant diabetes both significantly increase the risk for CVD. Several other risk factors for CVD in kidney transplant recipients have been identified; however, optimal therapy for controlling the risk factors of CVD after kidney transplantation, including NODAT and pre-transplant diabetes, is not well defined. In the following review we will discuss the role of traditional and non-traditional risk factors in CVD after kidney transplant and the mechanisms involved therein. We will also examine the current literature regarding treatment of these risk factors for the prevention of CVD. Finally, we will review the current recommendations for pre- and post-transplant cardiovascular evaluation and management.

Objective: Endothelial progenitor cells (EPCs) are decreased in number and function in type 2 diabetes. Mechanisms by which this dysfunction occurs are largely unknown. We tested the hypothesis that a chronic inflammatory environment leads to insulin signaling defects in EPCs and thereby reduces their survival. Modifying EPCs by a knockdown of nuclear factor-κB (NF-κB) can reverse the insulin signaling defects, improve EPC survival, and decrease neointimal hyperplasia in Zucker fatty rats postangioplasty., Research Design and Methods: EPCs from Zucker fatty insulin-resistant rats were cultured and exposed to tumor necrosis factor-α (TNF-α). Insulin signaling defects and apoptosis were measured in the presence and absence of an NF-κB inhibitor, BAY11. Then, EPCs were modified by a knockdown of NF-κB (RelA) and exposed to TNF-α. For in vivo experiments, Zucker fatty rats were given modified EPCs post-carotid angioplasty. Tracking of EPCs was done at various time points, and neointimal hyperplasia was measured 3 weeks later., Results: Insulin signaling as measured by the phosphorylated-to-total AKT ratio was reduced by 56% in EPCs exposed to TNF-α. Apoptosis was increased by 71%. These defects were reversed by pretreatment with an NF-κB inhibitor, BAY11. Modified EPCs exposed to TNF-α showed a lesser reduction (RelA 20%) in insulin-stimulated AKT phosphorylation versus a 55% reduction in unmodified EPCs. Apoptosis was 41% decreased for RelA knockdown EPCs. Noeintimal hyperplasia postangioplasty was significantly less in rats receiving modified EPCs than in controls (intima-to-media ratio 0.58 vs. 1.62)., Conclusions: In conclusion, we have shown that insulin signaling and EPC survival is impaired in Zucker fatty insulin resistant rats. For the first time, we have shown that this defect can be significantly ameliorated by a knockdown of NF-κB and that these EPCs given to Zucker fatty rats decrease neointimal hyperplasia post-carotid angioplasty.

Objective: Salsalate is a dimeric form of salicylic acid that has been shown to have anti-inflammatory activity and to reduce glucose levels, insulin resistance, and cytokine expression. However, the effect of salsalate on vascular injury has not been determined. The objective of this study is to investigate the effect of salsalate on vascular injury and repair in a rat model of carotid artery balloon catheter injury., Research Design and Methods: Salsalate treatment was started in female Zucker fatty rats (insulin resistant) 1 week before carotid artery balloon catheter injury and continued for 21 days, at which time the animals were killed and studied., Results: Treatment with salsalate significantly decreased the intima-to-media ratio and upregulated the expression of aortic endothelial nitric oxide synthase (eNOS), phosphorylated eNOS (p-eNOS) (ser 1177), and manganese superoxide dismutase (MnSOD) and reduced serum interleukin (IL)-6 with concomitant downregulation of nuclear factor (NF) κB subunit p65 and vascular endothelial growth factor (VEGF) expression in the balloon-injured carotid artery of female Zucker fatty rats., Conclusions: The present study shows that salsalate treatment decreases vascular damage caused by balloon catheter injury in female Zucker fatty rats. The beneficial effect of salsalate on vascular injury was associated with upregulation of eNOS, p-eNOS, and MnSOD, which reduce oxidative stress and have anti-inflammatory properties, as evidenced by reduction in serum IL-6 and the downregulation of VEGF and NFκB, which promote inflammation without changing glucose levels. These results suggest that salsalate may be useful in reducing vascular injury and restenosis following interventional revascularization procedures.

Objectives: Novel interventions are needed for long-term maintenance of diabetes control. We studied the effects of a group diabetes clinic (GDC) on diabetes control when compared to usual care with primary care providers (PCP)., Research Design/methods: Data from the electronic medical records of 56 patients were collected. Twenty-nine patients were in the group diabetes clinic (GDC) while 27 patients followed with their PCP. Outcome variables, A1c, LDL, and blood pressure (BP) were measured at baseline and every 6 months for a 2 year period., Results: A1c, LDL and BP were no different at the end of 2 years in the GDC cohort and the PCP cohort. Slight upward trend in time was detected for A1c in both groups, but more so in the PCP group., Conclusion: GDC can lead to maintenance of diabetes control in a population with difficult to manage diabetes as effectively as and more efficiently than usual care., (Published by Elsevier Ltd.)

The incidence of type 2 diabetes is increasing at an alarming rate throughout the world. This is in large part due to the increase in obesity and the aging of the population. Therefore, new medications to combat type 2 diabetes are needed. Salicylates have been used as analgesics and antiinflammatory agents for several decades. Incidentally, in some studies it was noted that high-dose salicylate treatment reduced blood glucose concentrations. Recently, inflammation has been strongly associated with insulin resistance and diabetes. Some studies show that salsalate, which is a nonacetylated form of salicylate, reduces blood glucose concentrations in patients with type 2 diabetes, as well as in insulin-resistant patients without diabetes. Postulated mechanisms include the inhibition of nuclear factor NF-kappa-B. Discussed in this review are the efficacy, safety and mechanisms of salsalate relevant to the treatment of type 2 diabetes., (Copyright 2010 Prous Science, S.A.U. or its licensors. All rights reserved.)

The increase in obesity and the aging of the population has lead to an increase in the incidence of type 2 diabetes. This has led to the development of new drugs such as thiazolidinediones (TZDs) which are Peroxisome Proliferator-Activated Receptor (PPARgamma) agonists, to treat type 2 diabetes. TZDs have recently been at the center of a controversy with regards to their cardiovascular safety. Pioglitazone is a TZD which has been shown to be effective in glycemic control by lowering insulin resistance. Pioglitazone also has beneficial effects on lipid metabolism and cardiovascular risk. The safety and efficacy of pioglitazone including its pleotropic effects are discussed at length in this article.

The incidence of diabetes is directly related to the incidence of obesity, which is at epidemic proportions in the US. Cardiovascular disease is a common complication of diabetes, which results in high morbidity and mortality. Peroxisome proliferator-activated receptors (PPARs) are a group of nuclear hormone receptors that regulate lipid and glucose metabolism. PPAR-α agonists such as fenofibrate and PPAR-γ agonists such as the thiozolidinediones have been used to treat dyslipidemia and insulin resistance in diabetes. Over the past few years research has discovered the role of PPARs in the regulation of inflammation, proliferation, and angiogenesis. Clinical trials looking at the effect of PPAR agonists on cardiovascular outcomes have produced controversial results. Studies looking at angiogenesis and proliferation in various animal models and cell lines have shown a wide variation in results. This may be due to the differential effects of PPARs on proliferation and angiogenesis in various tissues and pathologic states. This review discusses the role of PPARs in stimulating angiogenesis. It also reviews the settings in which stimulation of angiogenesis may be either beneficial or harmful.

Objective: PPAR-gamma agonists such as thiazolidinediones, used in patients with insulin resistance have been shown to reduce neointimal hyperplasia in the short term. However recent studies suggest increased cardiovascular risk for some thiazolidinediones. Longer-term animal studies show inhibition of endothelial regrowth post endothelial injury which may account for some of the increased risk. We studied the effect of pioglitazone on VEGF, FGF and insulin stimulated endothelial cells to determine if this was a mechanism of inhibition of endothelial regrowth., Methods and Results: FGF/VEGF stimulated human umbilical vein endothelial cell (HUVEC) proliferation and apoptosis was measured, in vitro, in the presence and absence of hyperinsulinemia, with and without treatment with the PPAR-gamma agonist pioglitazone. Activation of ERK 1/2 and p38MAPK was measured under the same conditions. There was 40% decrease in proliferation with pioglitazone in VEGF stimulated cells, which was reversed by insulin. ERK 1/2 activation was decreased by pioglitazone in VEGF stimulated cells and was partially reversed by insulin. p38MAPK activation was increased by pioglitazone and was unaffected by insulin or VEGF. Pioglitazone also increased endothelial cell apoptosis., Conclusion: PPAR-gamma agonists may have detrimental cardiovascular effects post angioplasty especially in patients with insulin resistance. We have shown that one of the mechanisms may be inhibition of endothelial regrowth and re-endothelialization by inhibition of VEGF/FGF stimulation of the ERK 1/2 pathways in endothelial cells.

Diabetes is a complex disorder characterized by impaired insulin formation, release or action (insulin resistance), elevated blood glucose, and multiple long-term complications. It is a common endocrine disorder of humans and is associated with abnormalities of carbohydrate and lipid metabolism. There are two forms of diabetes, classified as type 1 and type 2. In type 1 diabetes, hyperglycemia is due to an absolute lack of insulin, whereas in type 2 diabetes, hyperglycemia is due to a relative lack of insulin and insulin resistance. More than 90% of people with diabetes have type 2 with varied degrees of insulin resistance. Insulin resistance is often associated with impaired insulin secretion, and hyperglycemia is a common feature in both types of diabetes, but failure to make a distinction between the types of diabetes in different animal models has led to confusion in the literature. This is particularly true in relation to cardiovascular disease in the presence of diabetes and especially the response to vascular injury, in which there are major differences between the two types of diabetes. Animal models do not completely mimic the clinical disease seen in humans. Animal models are at best analogies of the pathologic process they are designed to represent. The focus of this review is an analysis of intimal hyperplasia following catheter-induced vascular injury, including factors that may complicate comparisons between different animal models or between in vitro and in vivo studies. We examine the variables, pitfalls, and caveats that follow from the manner of induction of the injury and the diabetic state of the animal. The efficacy of selected antidiabetic drugs in inhibiting the development of the hyperplastic response is also discussed.

Objective: Diabetes mellitus is a major public health problem with a prevalence of 6-7%. Self-care behaviors play a major role in the control of diabetes. Apathy is characterized by loss of initiative and motivation. Apathy may interfere with self-care behavior and glycemic control. The primary objective was to determine the prevalence of apathy in patients with diabetes. The secondary objective was to determine if there was an association between clinically significant apathy and factors that affect glycemic control., Research Design and Methods: We conducted a cross-sectional study of 100 patients with diabetes who were assessed with the Apathy Evaluation Scale-Clinician version (AES-C), the Hamilton Depression Scale (HAM-D), and the Self-Care Inventory (SCI). For this study we defined clinically significant apathy as AES-C score of >30. We excluded patients with a HAM-D score of >14 (n=19) to avoid confounding from depression. T-tests were used to compare clinical characteristics between subjects with and without apathy. Multiple linear regression modeling was used to investigate the association between clinically significant apathy and factors that affect glycemic control., Results: Fifty (61.7% of 81) patients had clinically significant apathy. Compared to the non-apathetic patients, those with apathy had a higher mean BMI (30.5 kg/m(2) versus 34.1 kg/m(2) (p=0.03)) and were less likely to adhere to an exercise plan (p=0.01) or insulin regimen (p=0.003). After adjustment for age, BMI, cholesterol, mild depression and the average Self-Care Index score, the mean HbA1C level was 0.66% greater for apathetic compared to non-apathetic subjects (P=0.08)., Conclusion: Apathy is highly prevalent in patients with diabetes without depression. Apathy may have a negative impact on self-care behaviors and diabetes control.

Objective: Insulin resistance is an independent risk factor for cardiovascular disease. PPAR-gamma agonists like pioglitazone decrease insulin resistance and have been shown to reduce neointimal hyperplasia in the short-term. However long-term studies on endothelial regrowth and neointimal hyperplasia have not been done., Methods and Results: We used hyperinsulinemic, normoglycemic Zucker fatty rats. Rats were treated with either 10 mg/kg body wt. pioglitazone or placebo till the end of the experiment. Rats underwent carotid angioplasty at age 12-14 weeks, 1 week after treatment was begun. In one set of experiments rats were sacrificed at 6 months and neointimal hyperplasia and VEGF expression was assessed. In another set of experiments rats were sacrificed at 3 and 6 months. Endothelial regrowth was determined. The rats were all normoglycemic and hyperinsulinemic. Pioglitazone treated rats had a significantly lesser degree of neointimal hyperplasia than control rats. Treated rats also had decreased VEGF expression. Endothelial regrowth was decreased in the treated rats at 6 months., Conclusion: We conclude that although pioglitazone decreases neointimal hyperplasia even at 6 months, it retards endothelial regrowth, which could predispose the denuded vessel to thrombotic events. This may be modulated by a suppression of VEGF expression.

Objective: Insulin resistance is associated with a constellation of factors that enhance the artherosclerotic process. Vessel injury results in the formation of a markedly increased neointima in type 2 diabetes. Increased neointimal hyperplasia (NH) and vascular endothelial growth factor (VEGF) expression may lead to restenosis post angioplasty. We studied NH and VEGF expression in an obese, insulin resistant, but normoglycemic rat model, after carotid balloon injury., Methods and Results: Diabetic rats (ZDF, n=10), normoglycemic, insulin-resistant rats (ZDF-normoglycemic, n=6) as well as Zucker fatty rats (FZ, n=6), and lean Zucker rats (LZ, n=6), all 13-16 weeks old, were subjected to right carotid injury by an angioplasty catheter introduced via the femoral artery. Three weeks later the rats were sacrificed and serum and carotids obtained. The intima-media ratio (I/M) was then calculated. ZDF-normoglycemic, FZ and ZDF-diabetic rats were all hyperinsulinemic and hypertriglyceridemic when compared to LZ rats. ZDF diabetic rats were hyperglycemic while FZ, ZDF-normoglycemic and LZ rats were normoglycemic. The I/M ratio for ZDF and FZ rats were significantly greater than for LZ rats. The VEGF expression was significantly greater in ZDF and FZ rats than LZ rats., Conclusions: In conclusion, insulin resistance increases neointimal hyperplasia and VEGF expression even with normoglycemia, after carotid angioplasty in rats.

Background: Patients with type 2 diabetes mellitus have a higher rate of restenosis following angioplasty. Peroxisome proliferator activator receptor-alpha (PPAR) and gamma ligands such as fenofibrate and rosiglitazone, respectively, have been shown to have protective effects on the vessel wall. We studied the effect of fenofibrate and rosiglitazone on intimal hyperplasia in the Zucker rat, a model for insulin resistance and type 2 diabetes mellitus, following balloon catheter-induced injury., Methods and Results: Three groups of 13-week-old female fatty Zucker rats were administered an aqueous suspension of either 3 mg/kg/d rosiglitazone (n=7) or 150 mg/kg/d fenofibrate (n=6) by gavage, or served as controls (n=9). In addition, two groups of 13-week-old female lean Zucker rats were either administered 3 mg/kg/d rosiglitazone (n=6) or served as controls (n=6). Carotid balloon injury was induced 1 week after the drugs were started. The drug administration was continued for 3 weeks. A 2-mm balloon catheter was introduced through the femoral artery to the left carotid. The balloon was inflated to 4 atmospheres for 20 seconds and then was deflated to 2 atmospheres and dragged down to the aorta. The rats were killed 3 weeks after the injury. The carotid intima/media ratio was calculated. Intimal hyperplasia after carotid balloon-induced injury in the fatty Zucker rats was significantly reduced in the group treated with rosiglitazone (0.18 +/- 0.29) compared with the untreated group (0.97 +/- 0.13; P<.01). Plasma glucose, triglyceride, and insulin levels were elevated, indicative of the presence of insulin resistance; rosiglitazone treatment significantly reduced insulin and triglyceride levels without decreasing glucose. Rosiglitazone treatment also reduced, but to a lesser extent, the intimal hyperplasia in the lean Zucker rats (0.57 +/- 0.10 vs 1.06 +/- 0.12 treated and untreated, respectively; P<.01); however, it had no effect on insulin, triglyceride, or glucose levels in this group. The intimal hyperplasia in the fatty Zucker rats treated with fenofibrate was not reduced compared with controls (0.84 +/- 0.26 vs 0.97 +/- 0.13, respectively); fenofibrate reduced insulin and triglyceride, but not glucose levels, in these animals., Conclusions: The PPAR-gamma ligand rosiglitazone, but not the PPAR-alpha ligand fenofibrate, decreases intimal hyperplasia following balloon injury in both fatty and lean Zucker rats. This effect of the PPAR-gamma ligand was independent of glycemia, insulin, and lipid levels, and was more pronounced in insulin-resistant rats.