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Background and Purpose: A promising, yet lengthy measure to identify mastery of patient-identified stress is Younger’s (1991, 1993) Mastery of Stress Instrument (MSI). With a goal for a parsimonious and valid measure, this study determined the psychometric properties of a reduced item instrument with adults diagnosed with type 2 diabetes. Methods: First, an expert content analysis was completed. Second, item and confirmatory factor analysis were completed with a sample of 200 adults with a diagnosis of type 2 diabetes. Results: Eight items were removed through content validity and seven items were removed with Item analysis. Factor analysis supported Younger’s four sub-concepts. Conclusions: Future research with this revised MSI scale is advocated to identify those who may need strategies to increase their mastery of stress.

Context Observational studies suggest that low vitamin D status may be a risk factor for cancer. Objective In a population with prediabetes and overweight/obesity that is at higher risk of cancer than the general population, we sought to determine if vitamin D supplementation lowers the risk of cancer and precancers. Methods The Vitamin D and type 2 diabetes (D2d) cancer outcomes study (D2dCA) is an ancillary study to the D2d study, which was conducted at 22 academic medical centers in the United States. Participants had prediabetes and overweight/obesity and were free of cancer for the previous 5 years. Participants were randomized to receive vitamin D3 4000 IU daily or placebo. At scheduled study visits (4 times/year), cancer and precancer events were identified by questionnaires. Clinical data were collected and adjudicated for all reported events. Cox proportional hazard models compared the hazard ratio (HR) of incident cancers and precancers between groups. Results Over a median follow-up period of 2.9 years, among 2385 participants (mean age 60 years and 25-hydroxyvitamin D 28 ng/mL), there were 89 cases of cancer. The HR of incident cancer for vitamin D vs placebo was 1.07 (95% CI 0.70, 1.62). Of 241 participants with incident precancers, 239 had colorectal adenomatous polyps. The HR for colorectal polyps for vitamin D vs placebo was 0.83 (95% CI 0.64, 1.07). Conclusion In the D2d population of participants with prediabetes and overweight/obesity, not selected for vitamin D insufficiency, vitamin D supplementation did not have a significant effect on risk of incident cancer or colorectal polyps.

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.

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).

Objective: Our goal is to measure real-world effects of at-risk driver physiology on safety-critical tasks like driving by monitoring driver behavior and physiology in real-time. Drivers with type ...

Animal models of obesity have shown that the expression of Thromboxane A2 Receptor (tbxa2r) and thromboxane synthase (Tbxas1) are increased in adipose tissue (AT) and are associated with insulin resistance and inflammation. Objective: To compare Tbxa2r gene expression in the AT of human subjects with different degrees of obesity and to determine the association between AT Tbxa2r with BMI and markers of AT inflammation. Methods: Subcutaneous AT samples were collected from lean (BMI 40) subjects. Gene expression of Tbxa2r was analyzed in AT and compared among different groups. Correlation analysis to determine the association between AT Tbxa2r and obesity and obesity-related inflammation. Results: The mRNA levels of Tbxa2r were significantly higher in obese compared to normal subjects (P Conclusion: Signaling of TxA2 is higher in AT in obesity and is associated with BMI as well as inflammatory genes. Tbxa2r may be a potential therapeutic target for obesity-linked diseases including type 2 DM and CV disease. Disclosure D. Alcaraz alvarez: None. S. Viswanathan: None. T. Gopal: None. N. Kumar: None. K. Kelley: None. C. Desouza: Advisory Panel; Self; Bayer AG, Novo Nordisk, Consultant; Self; AstraZeneca.

Background: Islet autoimmunity may contribute to beta-cell dysfunction in type 2 diabetes (T2D). Its prevalence and clinical significance have not been rigorously determined. We investigated the prevalence of cellular and humoral islet autoimmunity in T2D and their relation to beta-cell function. Methods: The study was nested in the Glycemia Reduction Approaches in Diabetes – A Comparative Effectiveness (GRADE) study. Participants included 419 T2D patients (age 57·4±10·3 y [mean±SD], body mass index 33·6±6·2 kg/m2, diabetes duration 4·0±3·0 y, HbA1c 7·5±0·5%). We measured humoral (autoantibodies against GAD65, IA2, ZnT8) and cellular (T-cell autoreactivity against islet antigens) autoimmunity, beta-cell function (ratio of incremental area under the curve of C-peptide to that of glucose from 0–120 min of an oral glucose tolerance test [iAUC-CG]), and ratio of C-peptide to glucose from 0–30 min (∆C-peptide(0–30)/∆glucose(0–30)), and glycemic parameters. Findings: Cellular islet autoimmunity was present in 41·3%, humoral islet autoimmunity in 13·5%, and both in 5·3%. iAUC-CG and ∆C-peptide(0–30)/∆glucose(0–30) were lower among T-cell-positives than -negatives using two different adjustments for insulin sensitivity (iAUC-CG: 13·2% [95% CI 0·3, 24·4%] or 11·4% [95% CI 0·4, 21·2%] lower; ∆C-peptide(0–30)/∆glucose(0–30)) 19% [95% CI 3·1, 32·3%] or 17·7% [95% CI 2·6, 30·5%] lower). T-cell-positives had 0·17% higher HbA1c (95% CI 0·07,0·28) and 7·7 mg/dL higher fasting plasma glucose levels (95% CI 0·2,15·3) than T-cell-negatives. Interpretation: Islet autoimmunity is highly prevalent in patients with T2D. T-cell-mediated autoimmunity is associated with diminished beta-cell function and worse glycemic control. Funding Information: This study was funded by the NIH. This ancillary study to the GRADE study was independently funded by grant R01DK104832 (to AB and JPP) from the National Institute of Diabetes and Digestive and Kidney Diseases. The GRADE study is supported by a grant from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health under Award Number U01DK098246. The planning of GRADE was supported by a U34 planning grant from the NIDDK (U34-DK-088043). The American Diabetes Association supported the initial planning meeting for the U34 proposal. The National Heart, Lung, and Blood Institute and the Centers for Disease Control and Prevention also provided funding support. The Department of Veterans Affairs provided resources and facilities. Additional support was provided by grant numbers P30 DK017047, P30 DK020541-44, P30 DK020572, P30 DK072476, P30 DK079626, P30 DK092926, U54 GM104940, UL1 TR000439, UL1 TR000445, UL1 TR001108, UL1 TR001409, UL1 TR001449, UL1 TR002243, UL1 TR002345, UL1 TR002378, UL1 TR002489, UL1 TR002489, UL1 TR002529, UL1 TR002535, UL1 TR002537, and UL1 TR002548. Educational materials have been provided by the National Diabetes Education Program. Material support in the form of donated medications and supplies has been provided by Becton, Dickinson an Company, Bristol-Myers Squibb, Merck, NovoNordisk, Roche Diagnostics, and Sanofi. Declaration of Interests: The authors declare no conflicts of interest. Ethics Approval Statement: Nineteen centers obtained local Institutional Review Board approval for the ancillary study and contributed participants.

Coconut oil, rich in medium-chain saturated fatty acids (MCSFA), in particular, lauric acid (LA), is known to exert beneficial metabolic effects. Although LA is the most abundant saturated fatty acid in coconut oil, the specific role of LA in altering obesity-related metabolic disorders remains unknown. Here, we examined the effects of supplementing a high fat (HF) diet with purified LA on obesity-associated metabolic derangements in comparison with palmitic acid (PA), a long-chain saturated fatty acid. Male C57BL/6 mice were fed a control chow diet (CD) or an HF diet supplemented with 3% LA (HF + LA) or PA (HF + PA) for 12 wk. Markers of adipose tissue (AT) inflammation, systemic insulin resistance (IR), and hepatic steatosis, were assessed. The body weight and total fat mass were significantly higher in both HF + LA and HF + PA diet-fed groups compared to CD controls. However, the visceral adipose tissue (VAT) mass was significantly higher (p &lt, 0.001) in HF + LA-fed mice compared to both CD as well as HF + PA-fed mice. Interestingly, markers of AT inflammation were promoted to a lesser extent in HF + LA-fed mice compared to HF + PA-fed mice. Thus, immunohistochemical analysis of VAT showed an increase in MCP-1 and IL-6 staining in HF + PA-fed mice but not in HF + LA-fed mice compared to CD controls. Further, the mRNA levels of macrophage and inflammatory markers were significantly higher in HF + PA-fed mice (p &lt, 0.001) whereas these markers were increased to a lesser extent in HF + LA-fed group. Of note, the insulin tolerance test revealed that IR was significantly increased only in HF + PA-fed mice but not in HF + LA-fed group compared to CD controls. While liver triglycerides were increased significantly in both HF + PA and HF + LA-fed mice, liver weight and plasma markers of liver injury such as alanine aminotransferase and aspartate aminotransferase were increased significantly only in HF + PA-fed mice but not in HF + LA-fed mice. Taken together, our data suggest that although both LA and PA increased AT inflammation, systemic IR, and liver injury, the extent of metabolic derangements caused by LA was less compared to PA in the setting of high fat feeding.

IntroductionMost patients with type 2 diabetes require sequential addition of glucose-lowering agents to maintain long-term glycemic control. In this retrospective, observational study, we compared intensification with a glucagon-like peptide-1 receptor agonist (GLP-1 RA), oral antidiabetic drugs (OADs), and insulin in patients receiving two OADs, using US electronic health records and claims data.Research design and methodsFor inclusion, patients in the IBM MarketScan Explorys database were required to have claims for two different OADs in the 180-day baseline period and ≥1 claim for a different OAD/GLP-1 RA/insulin at index date (treatment intensification). Changes in glycated hemoglobin (HbA1c) and weight from baseline were assessed at 180 days postindex. Patients were propensity score-matched by baseline characteristics and exact-matched by HbA1c category (HbA1c cohort and weight/composite outcomes cohort) and body mass index (BMI) category (weight/composite outcomes cohort only) to obtain balanced treatment arms. The primary endpoint was the percentage of patients reaching target HbA1c ResultsSignificantly more patients intensifying with a GLP-1 RA achieved HbA1c 1c and weight decreases from baseline; and a significantly greater chance of HbA1c ConclusionsIn propensity score-matched cohorts, GLP-1 RAs demonstrated significant benefits for both glycemic control and weight management over additional OAD(s) or insulin, respectively, indicating that they may represent the optimal choice at these points in the treatment pathway.

Background: Thromboxane A2 (TxA2), a lipid mediator plays a critical role in cardiovascular disease and chronic inflammatory disorders. TxA2 signaling is regulated by TxA2 synthase (Tbxas1), an enzyme that produces TxA2, and TxA2 receptor (Tbxa2r). Objective: To determine if Tbxa2r gene expression in adipose tissue (AT) is higher in obese insulin resistant (IR) subjects compared to overweight non-IR subjects. Methods: Insulin resistance was measured via a homeostatic model assessment of insulin resistance (HOMA-IR). Subcutaneous AT biopsies were obtained from overweight (BMI between ≥25 to 2.5) subjects. Gene expression of Tbxa2r and Tbxas1 were analyzed in tissue samples and compared between groups. Results: The mRNA levels of Tbxa2r and Tbxas1 were significantly higher in obese IR subjects compared to overweight subjects (P Conclusion: Our data suggest that TxA2 signaling is activated in AT in obesity and is associated with the development of insulin resistance in obesity. Tbxas1 and/or Tbxa2r may be a potential therapeutic target for obesity-linked metabolic diseases. Disclosure D. Alcaraz Alvarez: None. S. Viswanathan: None. T. Thangavelu: None. N. Kumar: None. K. Kelley: None. C. Desouza: Consultant; Self; AstraZeneca, Bayer AG, Novo Nordisk A/S.

We hypothesized that islet autoimmunity, hitherto considered the pathophysiologic basis of type 1 diabetes (T1D) and latent autoimmune diabetes of adults (LADA), could contribute to ß cell dysfunction in patients with type 2 diabetes (T2D). To evaluate this question, the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness (GRADE) Study - Beta Cell Ancillary Study Network measured humoral islet autoimmunity (autoantibodies against 65 kDa glutamic acid decarboxylase (GAD65-Ab), islet autoantigen-2 (IA2-Ab) and zinc transporter-8 (ZnT8-Ab)) in 392 participants (age 57.2 ± 10.1 y; BMI 33.5 ± 6.2 kg/m2; diabetes duration 4.0 ± 3.0 y; HbA1c 7.5 ± 0.5 %; on metformin as the sole glucose-lowering medication), and cellular islet autoimmunity (T cell autoreactivity against a broad range of islet antigens) in 322 of the same participants. 41.4% had evidence of cellular islet autoimmunity and 13.5% had evidence of humoral islet autoimmunity, but only 5.4% had both. T cell autoreactivity to islet antigens, but not autoantibody-positivity, was associated with diminished ß cell function, as assessed by the ratio of incremental area under the curve (iAUC) of C-peptide to iAUC of glucose during 0-120 min of an OGTT (ß = -0.1403; se = 0.0612; p = 0.0219) or ∆C-peptide/∆glucose during 0-30 min of an OGTT (ß = -0.2113; se = 0.0728; p = 0.0037), adjusted for insulin sensitivity. T cell positive participants also had higher fasting plasma glucose (p = 0.045) and HbA1c (p = 0.001) than T cell negative participants. These findings indicate that islet autoimmunity in T2D patients is far more prevalent than previously recognized; T cell mediated islet autoimmunity is associated with diminished ß cell function. Disclosure B. Brooks-Worrell: None. C.S. Hampe: None. E.V. Gonzalez: None. B.M. Palomino: None. S.Z. Zangeneh: None. K. Utzschneider: Other Relationship; Self; Medtronic. S.E. Kahn: Advisory Panel; Self; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Intarcia Therapeutics, Janssen Scientific Affairs, LLC., Merck & Co., Inc., Novo Nordisk A/S, Pfizer Inc. M.E. Larkin: None. M.L. Johnson: Consultant; Self; Jaeb Center for Health Research. Research Support; Self; Abbott, Dexcom, Inc., Insulet Corporation, JDRF, Lilly Diabetes, Medtronic, National Institute of Diabetes and Digestive and Kidney Diseases, Novo Nordisk Inc. K.J. Mather: Research Support; Self; Abbott, Merck & Co., Inc., Novo Nordisk Inc., Sanofi. N. Younes: None. N. Rasouli: Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Novo Nordisk Inc. Research Support; Self; Allergan plc., Novo Nordisk Inc. C. Desouza: Consultant; Self; AstraZeneca, Bayer AG, Novo Nordisk A/S. R.M. Cohen: Stock/Shareholder; Self; Bristol-Myers Squibb. J.Y. Park: None. H. Florez: None. W. Valencia: None. A. Shojaie: None. J.P. Palmer: None. A. Balasubramanyam: None. Funding National Institutes of Health (R01DK104832, U01DK098246)

Our goal is to address the need for driver-state detection using wearable and in-vehicle sensor measurements of driver physiology and health. To address this goal, we deployed in-vehicle systems, wearable sensors, and procedures capable of quantifying real-world driving behavior and performance in at-risk drivers with insulin-dependent type 1 diabetes mellitus (DM). We applied these methodologies over 4 weeks of continuous observation to quantify differences in real-world driver behavior profiles associated with physiologic changes in drivers with DM (N=19) and without DM (N=14). Results showed that DM driver behavior changed as a function of glycemic state, particularly hypoglycemia. DM drivers often drive during at-risk physiologic states, possibly due to unawareness of impairment, which in turn may relate to blunted physiologic responses (measurable heart rate) to hypoglycemia after repeated episodes of hypoglycemia. We found that this DM driver cohort has an elevated risk of crashes and citations, which our results suggest is linked to the DM driver's own momentary physiology. Overall, our findings demonstrate a clear link between at-risk driver physiology and real-world driving. By discovering key relationships between naturalistic driving and parameters of contemporaneous physiologic changes, like glucose control, this study directly advances the goal of driver-state detection through wearable physiologic sensors as well as efforts to develop "gold standard" metrics of driver safety and an individualized approach to driver health and wellness.

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 HbA1c 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 HbA1c from baseline to week 26. RESULTS In total, 705 randomized patients were exposed to trial products. At week 26, a dose-dependent change in HbA1c 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 HbA1c compared with liraglutide or placebo but with a higher frequency of GI AEs.

Aim: To evaluate the potential for semaglutide to help people with type 2 diabetes (T2D) achieve glycated haemoglobin (HbA1c) targets while avoiding unwanted outcomes, such as weight gain, hypoglycaemia and gastrointestinal (GI) side effects. Materials and methods: Data from the phase IIIa SUSTAIN 1 to 5 clinical trials were analysed. Participants had inadequately controlled T2D and were drug-naïve (SUSTAIN 1) or on a range of background treatments (SUSTAIN 2 to 5). The main protocol-specified composite endpoint was the proportion of participants achieving HbA1c

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 (D3) 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 A1c (HbA1c) 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 60 (9.9) years and BMI 32.1 (4.5) kg/m2. Thirty-five percent met all three prediabetes criteria, 49% met the FPG/HbA1c criteria only, 9.5% met the 2hPG/FPG criteria only, and 6.3% met the 2hPG/HbA1c criteria only. Black participants had the highest mean HbA1c 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 HbA1c 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.

This pilot study tackles the overarching need for driver-state detection through real-world measurements of driver behavior and physiology in at-risk drivers with type 1 diabetes mellitus (DM). 35 drivers (19 DM, 14 comparison) participated. Real-time glucose levels were measured over four weeks with continuous glucose monitor (CGM) wearable sensors. Contemporaneous real-world driving performance and behavior were measured with in-vehicle video and electronic sensor instrumentation packages. Results showed clear links between at-risk glucose levels (particularly hypoglycemia) and changes in driver performance and behavior. DM participants often drove during at-risk glucose levels (low and high) and showed cognitive impairments in key domains for driving, which are likely linked to frequent hypoglycemia. The finding of increased driving risk in DM participants was mirrored in state records of crashes and traffic citations. Combining sensor data and phenotypes of driver behavior can inform patients, caregivers, safety interventions, policy, and design of supportive in-vehicle technology that is responsive to driver state.

AIMS: The Glycemia Reduction Approaches in Diabetes - A Comparative Effectiveness (GRADE) trial is a randomized clinical trial comparing glycemic effects of four diabetes medications added to metformin in type 2 diabetes (T2D). Microvascular and macrovascular diseases are secondary outcomes. We evaluated the prevalence and risk factor relationships for microvascular and macrovascular complications in the GRADE cohort at study entry. METHODS: Complication prevalence and risk factors were analyzed based on data from screening in all consenting participants meeting GRADE eligibility. Logistic regression and Z-statistics were used to assess risk factor relationships with complications. RESULTS: We enrolled 5047 T2D participants [mean age 57 years; 36% female; mean knownT2D duration 4 years (all

Aims Both fasting (FPG) and postprandial plasma glucose (PPG) contribute to HbA1c levels. We investigated the relationship between achievement of American Diabetes Association (ADA) and American Association of Clinical Endocrinologists (AACE) recommended FPG and/or PPG targets and glycaemic efficacy outcomes in two trials. Methods In this post hoc analysis, data from participants with Type 2 diabetes in the phase 3 LixiLan‐O (NCT 02058147) and LixiLan‐L (NCT 02058160) trials were evaluated to compare the relationship between achievement of society‐recommended FPG and/or PPG targets and efficacy (HbA1c change, HbA1c goal attainment, weight change) and safety outcomes in the treatment groups. Results Across treatment arms, iGlarLixi achieved the highest proportion of participants meeting both ADA‐ and AACE‐recommended FPG and PPG targets at study end in both trials. A higher proportion of participants in the iGlarLixi (fixed‐ratio combination of insulin glargine and lixisenatide) vs. insulin glargine alone or lixisenatide alone treatment arms achieved HbA1c goals (P, What's new? Achievement of both fasting (FPG) and postprandial plasma glucose (PPG) targets is important for optimal glycaemic control in Type 2 diabetes.This post hoc analysis of the LixiLan‐O and LixiLan‐L trials shows that targeting both FPG and PPG results in improved glycaemic control, with weight neutrality and a low risk of hypoglycaemia.It is clinically desirable to achieve control of FPG and PPG. More people treated with iGlarLixi achieved control, and those who did so reached an HbA1c target of

Background: Oral semaglutide is the first oral glucagon-like peptide-1 (GLP-1) receptor agonist for glycaemic control in patients with type 2 diabetes. Type 2 diabetes is commonly associated with renal impairment, restricting treatment options. We aimed to investigate the efficacy and safety of oral semaglutide in patients with type 2 diabetes and moderate renal impairment. Methods: This randomised, double-blind, phase 3a trial was undertaken at 88 sites in eight countries. Patients aged 18 years and older, with type 2 diabetes, an estimated glomerular filtration rate of 30–59 mL/min per 1·73 m2, and who had been receiving a stable dose of metformin or sulfonylurea, or both, or basal insulin with or without metformin for the past 90 days were eligible. Participants were randomly assigned (1:1) by use of an interactive web-response system, with stratification by glucose-lowering medication and renal function, to receive oral semaglutide (dose escalated to 14 mg once daily) or matching placebo for 26 weeks, in addition to background medication. Participants and site staff were masked to assignment. Two efficacy-related estimands were defined: treatment policy (regardless of treatment discontinuation or rescue medication) and trial product (on treatment without rescue medication) in all participants randomly assigned. Endpoints were change from baseline to week 26 in HbA1c (primary endpoint) and bodyweight (confirmatory secondary endpoint), assessed in all participants with sufficient data. Safety was assessed in all participants who received at least one dose of study drug. This trial is registered on ClinicalTrials.gov, number NCT02827708, and the European Clinical Trials Registry, number EudraCT 2015-005326-19, and is now complete. Findings: Between Sept 20, 2016, and Sept 29, 2017, of 721 patients screened, 324 were eligible and randomly assigned to oral semaglutide (n=163) or placebo (n=161). Mean age at baseline was 70 years (SD 8), and 168 (52%) of participants were female. 133 (82%) participants in the oral semaglutide group and 141 (88%) in the placebo group completed 26 weeks on treatment. At 26 weeks, oral semaglutide was superior to placebo in decreasing HbA1c (estimated mean change of −1·0 percentage point (SE 0·1; −11 mmol/mol [SE 0·8]) vs −0·2 percentage points (SE 0·1; −2 mmol/mol [SE 0·8]); estimated treatment difference [ETD]: −0·8 percentage points, 95% CI −1·0 to −0·6; p1c −1·1 percentage points (SE 0·1; −12 mmol/mol [SE 0·8] versus −0·1 percentage points (SE 0·1; −1 mmol/mol [SE 0·8]; ETD −1·0 percentage points, 95% CI −1·2 to −0·8; p

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 (P0.05) 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.

BACKGROUND: Observational studies support an association between a low blood 25-hydroxyvitamin D level and the risk of type 2 diabetes. However, whether vitamin D supplementation lowers the risk of diabetes is unknown. METHODS: We randomly assigned adults who met at least two of three glycemic criteria for prediabetes (fasting plasma glucose level, 100 to 125 mg per deciliter; plasma glucose level 2 hours after a 75-g oral glucose load, 140 to 199 mg per deciliter; and glycated hemoglobin level, 5.7 to 6.4%) and no diagnostic criteria for diabetes to receive 4000 IU per day of vitamin D(3) or placebo, regardless of the baseline serum 25-hydroxyvitamin D level. The primary outcome in this time-to-event analysis was new-onset diabetes, and the trial design was event-driven, with a target number of diabetes events of 508. RESULTS: A total of 2423 participants underwent randomization (1211 to the vitamin D group and 1212 to the placebo group). By month 24, the mean serum 25-hydroxyvitamin D level in the vitamin D group was 54.3 ng per milliliter (from 27.7 ng per milliliter at baseline), as compared with 28.8 ng per milliliter in the placebo group (from 28.2 ng per milliliter at baseline). After a median follow-up of 2.5 years, the primary outcome of diabetes occurred in 293 participants in the vitamin D group and 323 in the placebo group (9.39 and 10.66 events per 100 person-years, respectively). The hazard ratio for vitamin D as compared with placebo was 0.88 (95% confidence interval, 0.75 to 1.04; P = 0.12). The incidence of adverse events did not differ significantly between the two groups. CONCLUSIONS: Among persons at high risk for type 2 diabetes not selected for vitamin D insufficiency, vitamin D(3) supplementation at a dose of 4000 IU per day did not result in a significantly lower risk of diabetes than placebo. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; D2d ClinicalTrials.gov number, .)

Context Variations in the prevalence and etiology of type 2 diabetes (T2D) across race and ethnicity may affect treatment responses. Semaglutide is a glucagon-like peptide-1 analog approved for once-weekly, subcutaneous treatment of T2D. Objective To compare semaglutide efficacy and safety in race and ethnicity subgroups across the SUSTAIN trials. Design Post hoc analysis of data from phase 3 randomized SUSTAIN 1–5 and 7 (pooled), and SUSTAIN 6 trials. Participants 3074 subjects (SUSTAIN 1–5 and 7) and 1648 subjects (SUSTAIN 6). Interventions Semaglutide 0.5 or 1.0 mg, placebo, or active comparator (sitagliptin 100 mg, exenatide extended release 2.0 mg, insulin glargine 100IU/ml and dulaglutide 0.75 or 1.5 mg). Main Outcome Measures Change in hemoglobin A1C (HbA1c) and body weight from baseline to weeks 30, 40 and 104, and other efficacy and safety endpoints. Results HbA1c was reduced from baseline by 1.0 to 1.5 percentage points and 1.3 to 2.0 percentage points, and body weight was reduced by 2.3 to 4.7 kg and 3.6 to 6.1 kg with semaglutide 0.5 and 1.0 mg, respectively, across race and ethnicity subgroups. Minor changes in blood pressure and lipid profiles were observed. Adverse events (AEs) were reported in similar proportions of subjects across trials. More Asian versus other race subgroups discontinued treatment prematurely due to AEs. The most commonly reported AEs were gastrointestinal disorders. Conclusions In this SUSTAIN trials post hoc analysis, semaglutide was associated with consistent and clinically relevant reductions in HbA1c and body weight in subjects with T2D, with minor variations in efficacy and safety outcomes associated with race or ethnicity.

Background: Thromboxane-Prostanoid Receptor (TP-R) is implicated in several chronic inflammatory disorders. Our preclinical animal studies showed that TP-R plays a critical role in obesity linked Insulin Resistance (IR). Aim: To determine the link between TP-R and obesity and/or obesity-associated inflammation/IR in human subjects. Methods: We collected PBMCs from lean normal and obese IR subjects and analyzed the expression of various inflammatory genes including TP-R, Thromboxane A2 Synthase (TXA2S), TNFα, and MCP-1. We obtained subcutaneous adipose tissue biopsies from obese subjects and analyzed the TP-R mRNA expression and its correlation with inflammatory cytokines mediating IR. Results: TP-R mRNA expression is significantly increased in PBMCs of obese IR subjects compared to lean normal subjects (P Conclusion: Our data demonstrate that TP-R expression is positively correlated with markers of obesity and/or IR and support our hypothesis that TP-R can be used as a biomarker or a therapeutic target for obesity related IR. Disclosure T. Thangavelu: None. S. Viswanathan: None. C. Desouza: Consultant; Self; Novo Nordisk A/S, Sanofi US. Funding National Institute of General Medical Sciences; Great Plains Institutional Developmental Award for Clinical and Translational Research

Type 1 diabetes affects the structure and function of the brain, with psychomotor speed as the most commonly reported deficit. The current study sought to uncover the dynamics underlying motor processing in the brain of adults with type 1 diabetes using an arrow-based Flanker task. Adults (ages 19-35, N = 39) with type 1 diabetes and no major complications and a matched control group (N = 40) underwent magnetoencephalography (MEG) while performing the task. During the task, participants were presented with a row of five arrows facing right or left, and participants were instructed to respond by button press to the direction of the middle arrow. Analyses focused on the time period around movement execution to examine motor-related dynamics. Time series analyses were performed on the peak beta and gamma responses from the motor cortices. An ANOVA model and follow-up regression analyses were used to delineate the predictive value of each neural response in driving behavioral outcomes. Subsequent t-tests between frequent (3+ episodes per week) and infrequent (0-1 episodes per week) hypoglycemic groups were performed to examine response differences within the adults with type 1 diabetes. Responses driving behavior differed between adults with and without type 1 diabetes. In adults with type 1 diabetes, beta frequency responses were significant predictors of reaction time, where greater ipsilateral recruitment led to faster reaction times (b = .58, t = 3.64, p = .001). In contrast, gamma drove behavioral outcomes in the control group (b = -.43, t = -2.96, p = .005). Further, within group analyses revealed that more frequent episodes of hypoglycemia were associated with alterations specific to beta responses during the pre-movement baseline period (p < .05). These results show frequency specific alterations in motor dynamics in adults with type 1 diabetes, with an added effect of increased hypoglycemia. These findings strongly indicate that diabetes directly impacts motor control components in the brain, regulating behavioral outcomes. Disclosure C.M. Embury: None. V.A. Were: None. G.H. Lord: None. A. Drincic: Board Member; Self; Corcept Therapeutics. C. Desouza: Consultant; Self; Novo Nordisk A/S, Sanofi US. T.W. Wilson: None. Funding National Institutes of Health (R01MH103220, R01MH116782)

Patients (pts) with T2D and renal impairment have limited glucose-lowering treatment options. Oral semaglutide (sema) 14 mg once daily (N=163) was compared with placebo (pbo, N=161) in a 26-week, randomized, phase 3a trial (NCT02827708) in pts with T2D and moderate renal impairment (eGFR 30-59 mL/min/1.73 m2), receiving 1-2 glucose-lowering agents (could include basal insulin). Endpoints: change in HbA1c (primary) and body weight (BW, secondary) to week 26. Two estimands were defined: treatment policy (regardless of trial product discontinuation or rescue medication) and trial product (on trial product without rescue medication) in all randomized pts. Oral sema was superior to (treatment policy) and significantly better than (trial product) pbo in reducing HbA1c and BW (Table). More pts reached HbA1c, BW loss, and composite targets with oral sema. At follow-up, eGFR was unchanged. Fewer pts on oral sema required rescue medication (4 vs. 10%). Adverse events were more frequent with oral sema (74 vs. 65%), most often mild/moderate nausea (19 vs. 7%). More patients on oral sema prematurely discontinued trial product (15 vs. 5%), mainly due to nausea and vomiting. In conclusion, in pts with T2D and moderate renal impairment, oral sema provided superior glycemic control and BW loss compared to pbo at 26 weeks, did not appear to affect renal function, and was well tolerated in line with the population and GLP-1RA class. Disclosure O. Mosenzon: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk Inc., Sanofi. Research Support; Self; AstraZeneca, Novo Nordisk Inc. Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk Inc., Sanofi-Aventis. S. Rosenlund: Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. J.W. Eriksson: Advisory Panel; Self; AstraZeneca. Consultant; Self; AstraZeneca, Bayer AG, Merck Sharp & Dohme Corp., Novo Nordisk A/S. Research Support; Self; AstraZeneca, Novo Nordisk A/S. S.R. Heller: Advisory Panel; Self; Eli Lilly and Company, Novo Nordisk A/S, Sanofi-Aventis, Takeda Pharmaceutical Company Limited, Zealand Pharma A/S. Consultant; Self; Novo Nordisk A/S. Speaker's Bureau; Self; Eli Lilly and Company, Novo Nordisk A/S. R.E. Pratley: Consultant; Self; Sanofi US. Other Relationship; Self; AstraZeneca, Eli Lilly and Company, GlaxoSmithKline plc., Janssen Global Services, LLC., Janssen Research & Development, Lexicon Pharmaceuticals, Inc., Ligand Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Mundipharma, Novo Nordisk Inc., Pfizer Inc., Sanofi, Takeda Development Center Americas, Inc. T. Sathyapalan: Speaker's Bureau; Self; Novo Nordisk Foundation. Other Relationship; Self; Bristol-Myers Squibb Company, Eli Lilly and Company, Sanofi-Aventis. T.M. Blicher: Employee; Self; Novo Nordisk A/S. O.H. Hels: Employee; Self; Novo Nordisk A/S. C. Desouza: Consultant; Self; Novo Nordisk A/S, Sanofi US. Funding Novo Nordisk A/S

Aims To establish recruitment approaches that leverage electronic health records in multicenter prediabetes/diabetes clinical trials and compare recruitment outcomes between electronic health record–supported and conventional recruitment methods. Methods Observational analysis of recruitment approaches in the vitamin D and type 2 diabetes (D2d) study, a multicenter trial in participants with prediabetes. Outcomes were adoption of electronic health record–supported recruitment approaches by sites, number of participants screened, recruitment performance (proportion screened who were randomized), and characteristics of participants from electronic health record–supported versus non–electronic health record methods. Results In total, 2423 participants were randomized: 1920 from electronic health record (mean age of 60 years, 41% women, 68% White) and 503 from non–electronic health record sources (mean age of 56.9 years, 58% women, 61% White). Electronic health record–supported recruitment was adopted by 21 of 22 sites. Electronic health record–supported recruitment was associated with more participants screened versus non–electronic health record methods (4969 vs 2166 participants screened), higher performance (38.6% vs 22.7%), and more randomizations (1918 vs 505). Participants recruited via electronic health record were older, included fewer women and minorities, and reported higher use of dietary supplements. Electronic health record–supported recruitment was incorporated in diverse clinical environments, engaging clinicians either at the individual or the healthcare system level. Conclusion Establishing electronic health record–supported recruitment approaches across a multicenter prediabetes/diabetes trial is feasible and can be adopted by diverse clinical environments.

Digital, Background: Two glucagon-like peptide-1 (GLP-1) receptor agonists reduced renal outcomes in people with type 2 diabetes at risk for cardiovascular disease. We assessed the long-term effect of the GLP-1 receptor agonist dulaglutide on renal outcomes in an exploratory analysis of the REWIND trial of the effect of dulaglutide on cardiovascular disease. Methods: REWIND was a multicentre, randomised, double-blind, placebo-controlled trial at 371 sites in 24 countries. Men and women aged at least 50 years with type 2 diabetes who had either a previous cardiovascular event or cardiovascular risk factors were randomly assigned (1:1) to either weekly subcutaneous injection of dulaglutide (1·5 mg) or placebo and followed up at least every 6 months for outcomes. Urinary albumin-to-creatinine ratios (UACRs) and estimated glomerular filtration rates (eGFRs) were estimated from urine and serum values measured in local laboratories every 12 months. The primary outcome (first occurrence of the composite endpoint of non-fatal myocardial infarction, non-fatal stroke, or death from cardiovascular causes), secondary outcomes (including a composite microvascular outcome), and safety outcomes of this trial have been reported elsewhere. In this exploratory analysis, we investigate the renal component of the composite microvascular outcome, defined as the first occurrence of new macroalbuminuria (UACR >33·9 mg/mmol), a sustained decline in eGFR of 30% or more from baseline, or chronic renal replacement therapy. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01394952. Findings: Between Aug 18, 2011, and Aug 14, 2013, 9901 participants were enrolled and randomly assigned to receive dulaglutide (n=4949) or placebo (n=4952). At baseline, 791 (7·9%) had macroalbuminuria and mean eGFR was 76·9 mL/min per 1·73 m2 (SD 22·7). During a median follow-up of 5·4 years (IQR 5·1-5·9) comprising 51 820 person-years, the renal outcome developed in 848 (17·1%) participants at an incidence rate of 3·5 per 100 person-years in the dulaglutide group and in 970 (19·6%) participants at an incidence rate of 4·1 per 100 person-years in the placebo group (hazard ratio [HR] 0·85, 95% CI 0·77-0·93; p=0·0004). The clearest effect was for new macroalbuminuria (HR 0·77, 95% CI 0·68-0·87; p, Ciencias Médicas y de la Salud

Digital, Background Three different glucagon-like peptide-1 (GLP-1) receptor agonists reduce cardiovascular outcomes in people with type 2 diabetes at high cardiovascular risk with high glycated haemoglobin A1c (HbA1c) concentrations. We assessed the effect of the GLP-1 receptor agonist dulaglutide on major adverse cardiovascular events when added to the existing antihyperglycaemic regimens of individuals with type 2 diabetes with and without previous cardiovascular disease and a wide range of glycaemic control. Methods This multicentre, randomised, double-blind, placebo-controlled trial was done at 371 sites in 24 countries. Men and women aged at least 50 years with type 2 diabetes who had either a previous cardiovascular event or cardiovascular risk factors were randomly assigned (1:1) to either weekly subcutaneous injection of dulaglutide (1·5 mg) or placebo. Randomisation was done by a computer-generated random code with stratification by site. All investigators and participants were masked to treatment assignment. Participants were followed up at least every 6 months for incident cardiovascular and other serious clinical outcomes. The primary outcome was the first occurrence of the composite endpoint of non-fatal myocardial infarction, non-fatal stroke, or death from cardiovascular causes (including unknown causes), which was assessed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01394952. Findings Between Aug 18, 2011, and Aug 14, 2013, 9901 participants (mean age 66·2 years [SD 6·5], median HbA1c 7·2% [IQR 6·6–8·1], 4589 [46·3%] women) were enrolled and randomly assigned to receive dulaglutide (n=4949) or placebo (n=4952). During a median follow-up of 5·4 years (IQR 5·1–5·9), the primary composite outcome occurred in 594 (12·0%) participants at an incidence rate of 2·4 per 100 person-years in the dulaglutide group and in 663 (13·4%) participants at an incidence rate of 2·7 per 100 person-years in the placebo group (hazard ratio [HR] 0·88, 95% CI 0·79–0·99; p=0·026). All-cause mortality did not differ between groups (536 [10·8%] in the dulaglutide group vs 592 [12·0%] in the placebo group; HR 0·90, 95% CI 0·80–1·01; p=0·067). 2347 (47·4%) participants assigned to dulaglutide reported a gastrointestinal adverse event during follow-up compared with 1687 (34·1%) participants assigned to placebo (p, Ciencias Médicas y de la Salud

In recent years, Cardiovascular Outcome Event Trials (CVOTs) in type 2 diabetes mellitus (T2DM) have demonstrated that sodium glucose transporter 2 inhibitors (SGLT2i) could reduce major adverse cardiovascular events (MACE) and cardiovascular mortality independent of a glucose lowering mechanism. SGLT2i trials reported significant results that have generated biologically plausible theories with regard to the macrovascular benefit. In this review, we have summarized and discussed the results of the CANVAS program. The CANVAS program is unique as it is an analysis of two aggregated cohorts. The two cohorts were similar at baseline but had different durations of exposure to canagliflozin. It showed a 14% reduction in the primary MACE composite. However, the individual components of the MACE composite were not significantly different from placebo. Initial analysis also indicated a reno-protective effect. The results of the CANVAS program are similar overall yet different when compared to the EMPA-REG OUTCOMES trial, especially with regard to cardiovascular mortality and adverse event profile. This could possibly be due to the differences in the cardiovascular risk profile of the enrolled population in the two trials. Other possibilities include drug-specific effects and different mechanisms of lowering overall MACE. In addition, a brief comparison of CANVAS to the CVD-REAL indicates that the CANVAS trial results may apply to a larger, more generalized population than those in the CANVAS program.

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 non-diabetic controls, who completed an Eriksen flanker task while undergoing magnetoencephalography (MEG). 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 were 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.

Microvascular and macrovascular complications drive morbidity, mortality, and health care costs in type 2 diabetes (T2D). The GRADE trial enrolled 5047 participants with T2D 2), 5.1% for myocardial infarction (self-report); and 2.0% for stroke (self-report). The Table describes age- and sex-adjusted associations between individual risk factors and complications as odds ratios comparing the presence vs. absence of the complication. Notable features include associations of HbA1c, obesity and blood pressure with micro- but not macrovascular disease; association of triglycerides with microvascular disease only; and associations of smoking and HDL with both micro- and macrovascular disease. These data reveal unexpected patterns in the clustering of risk factors with complications in GRADE patients with short T2D duration. ACR≥30eGFR2MIStrokeORpORpORpORpORpORpHBA1C at screening (%)1.0380.30660.6580.00300.8370.28541.0940.00170.9960.95910.9370.5605BMI (kg/m2)1.040 Disclosure K.J. Mather: Research Support; Self; Merck & Co., Inc., Sanofi-Aventis, Novo Nordisk A/S, Abbott. Advisory Panel; Self; Merck & Co., Inc. R. Pop-Busui: Research Support; Self; AstraZeneca. I. Bebu: None. C. Baker: None. R.M. Cohen: Stock/Shareholder; Self; Bristol-Myers Squibb Company. J.P. Crandall: None. C. Desouza: Consultant; Self; Novo Nordisk A/S, Sanofi. Research Support; Self; Merck & Co., Inc.. Advisory Panel; Self; Medscape. J.B. Green: Consultant; Self; Merck Sharp & Dohme Corp.. Research Support; Self; AstraZeneca. Consultant; Self; Daiichi Sankyo Company, Limited. Research Support; Self; GlaxoSmithKline plc., Intarcia Therapeutics, Inc.. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Novo Nordisk Inc. M. Kirkman: Research Support; Self; Bayer AG, Theracos, Inc.. Consultant; Self; National Institutes of Health. Research Support; Self; National Institutes of Health, Centers for Disease Control and Prevention. H. Krause-Steinrauf: None. M.E. Larkin: None. J. Pettus: Advisory Panel; Self; Sanofi, Novo Nordisk Inc.. Consultant; Self; MannKind Corporation. Advisory Panel; Self; Insulet Corporation. Consultant; Self; Senseonics. E.R. Seaquist: Advisory Panel; Self; Eli Lilly and Company. Consultant; Self; Eli Lilly and Company, Sanofi, Zucera, InfoMed, 360 consulting. Other Relationship; Self; Novo Nordisk Inc.. E.Z. Soliman: None. E.B. Schroeder: None. D.J. Wexler: None. G. Research Group: Research Support; Self; National Institute of Diabetes and Digestive and Kidney Diseases, National Heart, Lung, and Blood Institute. Other Relationship; Self; Bristol-Myers Squibb Company, Merck & Co., Inc., Novo Nordisk Inc., Sanofi-Aventis, Roche Diagnostics Corporation, Becton, Dickinson and Company, Centers for Disease Control and Prevention, National Diabetes Education Program.

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.

Patients with type 2 diabetes (T2DM) and chronic kidney disease (CKD) have impaired endothelial function. Vitamin D and its analogs may play a role in regulation of endothelial function and inflammation. We studied effects of paricalcitol compared to placebo on endothelial function and markers of inflammation and oxidative stress in patients with T2DM and CKD.A double blind, randomized, placebo-controlled trial was conducted in 60 patients with T2DM and stage 3 or 4 CKD. Paricalcitol 1 mcg or placebo was administered orally once daily for three months. Brachial artery flow mediated dilatation (FMD), nitroglycerine mediated dilation (NMD), and plasma concentrations of inflammatory cytokines, tumor necrosis factor -α and interleukin-6, highly-sensitive C-reactive protein; endothelial surface proteins, intercellular adhesion molecule -1 and monocyte chemo attractant protein-1, and plasma glucose, insulin, free fatty acids, and urinary isoprostane were measured at baseline and end of three months.27 patients in the paricalcitol group and 28 patients in the control group completed the study, though analysis of FMD at both time points was possible in 23 patients in each group. There was no significant difference in the change in FMD, NMD or the biomarkers examined after paricalcitol or placebo treatment.Treatment with paricalcitol at this dose and duration did not affect brachial artery FMD or biomarkers of inflammation and oxidative stress. The lack of significance may be due to the fact that the study patients had advanced CKD and that effects of paricalcitol are not additive to the effects of glycemic, lipid and anti-hypertensive therapies.

BACKGROUND Overweight and obesity are growing problems for primary care. Although effective weight management programs exist, these programs experience significant attrition, which limits effectiveness. OBJECTIVES This study examined provider and staff perceptions of attrition from the Veterans Health Administration MOVE!(®) Weight Management Program as an initial step toward understanding attrition from primary care-based programs. PARTICIPANTS MOVE!(®) clinicians, primary care providers, and other staff members who interacted with patients about participating in MOVE!(®) (n=754) from Department of Veterans Affairs medical centers throughout the United States. Respondents were predominantly female (80.8%), Caucasian (79.2%), and trained as nurses (L.P.N., R.N., or N.P.; 50%). MEASURE Participants completed a web-mediated survey; items assessed agreement with personal and programmatic reasons for dropout, and allowed respondents to indicate the number one reason for dropout in an open-ended format. This survey was adapted from an existing tool designed to capture patient perceptions. RESULTS Respondents indicated that veterans experienced practical barriers to attendance (eg, transportation and scheduling difficulties) and desire for additions to the program (eg, a live exercise component). Low motivation was the primary factor identified by respondents as associated with dropout, particularly as noted by MOVE!(®) clinicians (versus other providers/staff; P

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.

Aims: Cognitive decline disproportionately affects older adult type 2 diabetes. We tested whether randomized intensive glucose-lowering reduces the rate(s) of cognitive decline in adults with advanced type 2 diabetes (mean: age, 60 years; diabetes duration, 11 years) from the Veterans Affairs Diabetes Trial. Methods: A battery of neuropsychological tests (digit span, digit symbol substitution (DSym), and Trails-making Part B (TMT-B)) was administered at baseline in ~1700 participants and repeated at year 5. Thirty-six risk factors were evaluated as predictors of cognitive decline in multivariable regression analyses.Results: The mean age-adjusted, DSym or TMT-B declined significantly in all study participants (P < 0.001). Randomized intensive glucose-lowering did not significantly alter the rate of cognitive decline. The final model of risk factors associated with 5-year decline in age-adjusted TMT-B included as significant predictors: longer baseline diabetes duration (beta = -0.028; P = 0.0057), lower baseline diastolic blood pressure (beta = 0.028; P < 0.001), and baseline calcium channel blocker medication use (beta = -0.639; P < 0.001). Higher baseline pulse pressure was significantly associated with decline in age-adjusted TMT-B suggesting a role for both higher systolic and lower diastolic blood pressure. Baseline thiazide diuretic use (beta= -0.549; P =0.015) was an additional significant predictor of 5-year decline in age-adjusted digit symbol score. Post-baseline systolic blood pressure-lowering was significantly associated (P < 0.001) with decline in TMT-B performance. There was a significant inverse association between post-baseline plasma triglyceride- lowering (P = 0.045) and decline in digit symbol substitution task performance.Conclusions: A five-year period of randomized intensive glucose-lowering did not significantly reduce the rate of cognitive decline in older-aged adults with type 2 diabetes. Systolic and diastolic blood pressure as well as plasma triglycerides were modifiable risk factors of the rate of cognitive decline in older adult type 2 diabetes.

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.

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.

Diabetes is at epidemic proportions in the U.S. Patients with diabetes are at increased risk for micro- and macrovascular complications. The benefit of glycemic control in decreasing the risk for microvascular disease is well established. However, the role of glycemic control in decreasing macrovascular complications has been controversial. Several large clinical trials looking at this issue have either shown no benefit or even potential harm. The possibility of hypoglycemia as a risk factor for cardiovascular events is a topic of much debate. In this review article, we discuss the evidence for and against this hypothesis and the possible mechanisms that might be involved. Patients with diabetes have an increased risk of cardiovascular disease. The link between glycemic control and microvascular complications has been firmly established (1,2). However, the association between glycemic control and macrovascular disease is mainly obtained from epidemiological studies, and intensive glucose control has often failed to reduce macrovascular events. Intensive glucose control invariably increases the risk of hypoglycemia and sometimes the severity of hypoglycemia (2) Several epidemiological studies and smaller prospective studies have linked hypoglycemia to increased cardiovascular risk (3⇓–5). Recent large randomized trials looking at intensive glycemic control have either shown no benefit (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation [ADVANCE] and Veterans Affairs Diabetes Trial [VADT]) or increased all cause mortality (Action to Control Cardiovascular Risk in Diabetes [ACCORD]) (6). While the reason for the increased mortality is unclear and hypoglycemia has not been implicated as a cause of death, these studies have increased the debate about the degree of glycemic control required to decrease diabetes complications and the role of hypoglycemia in cardiovascular morbidity and mortality. The modern definition of hypoglycemia is plasma glucose

Cyrus v Desouza1,2, Lindsey Rentschler1, Vivian Fonseca31University of Nebraska Medical Center, 2Omaha VA Medical Center, Omaha, NE, USA; Scott & White Medical Clinic/Texas A & M College of Medicine, Temple, TX, USAAbstract: 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.Keywords: PPAR, VEGF, angiogenesis, cardiovascular

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.

Evaluate the performance of glycated albumin (GA) monitoring by comparing it to other measures of glycemic control during intensification of antidiabetic therapy.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.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).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) inflammation characterized by macrophage accumulation and secretion of inflammatory mediators is considered to play a critical role in the pathogenesis of obesity-linked metabolic disorders, in particular, insulin resistance. Although an intimate relationship exists between inflammation and metabolism, there is a lack of consistent therapeutic success in targeting inflammatory pathways to treat obesity-linked metabolic diseases suggesting that certain immunoregulatory genes can exert differential effects on metabolic regulation. The objective of this study is to determine the role of cyclooxygenase-2 (COX-2), an inducible inflammatory gene, abundantly upregulated in macrophages upon exposure to inflammatory stimuli, in modulating AT inflammation and systemic metabolic homeostasis in obesity. Methods Wild type (WT) and COX-2 knock-out (COX-2-/-) mice were fed a standard chow diet (CD) or a high fat (HF, 45% fat calories) diet for 13 wk. The expression of macrophage and inflammatory markers were determined in visceral AT and macrophage-rich stromal cells collected from visceral AT. In addition, various metabolic tests including insulin and glucose tolerance tests and energy expenditure measurements were performed to determine the impact of COX-2 deletion in modulating metabolic homeostasis. Results Consistent with its role in inducing an inflammatory response, deletion of COX-2 resulted in a decrease in markers of AT inflammation. For example, the markers of M1 pro-inflammatory macrophages were reduced and that of M2 anti-inflammatory macrophages were increased in the visceral AT of COX-2−/− compared to WT mice on a HF diet. Moreover, the mRNA expression of inflammatory genes such as MIP1α and TNFα was significantly lower (P Conclusion Taken together, deletion of COX-2 attenuated AT inflammation but increased adiposity and impaired metabolic homeostasis in a state of nutrient excess. Although inflammation is intricately linked to metabolism, our study suggests that a considerable discordance exists between these two processes and that COX-2 derived eicosanoids can exert differential effects in modulating inflammatory and metabolic processes.

Background: Patients with type 2 diabetes mellitus have a higher rate of restenosis following angioplasty. Peroxisome proliferator activator receptor-x (PPAR) and y 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-y ligand rosiglitazone, but not the PPAR-x ligand fenofibrate, decreases intimal hyperplasia following balloon injury in both fatty and lean Zucker rats. This effect of the PPAR-y ligand was independent of glycemia, insulin, and lipid levels, and was more pronounced in insulin-resistant rats.

OBJECTIVE—In some studies intensive diabetes treatment in patients with type 2 diabetes may be associated with increased cardiovascular events. It is not clear whether these events are related to hypoglycemic episodes. To determine whether episodes of hypoglycemia were more likely to be associated with cardiac ischemia than normoglycemia or hyperglycemia, we carried out a study in 21 patients with coronary artery disease (CAD) and type 2 diabetes treated with insulin who had good glycemic control. RESEARCH DESIGN AND METHODS—We carried out 72-h continuous glucose monitoring along with simultaneous cardiac Holter monitoring for ischemia. Patients also recorded symptoms of cardiac ischemia (chest pain) and symptoms of hypoglycemia. RESULTS—Satisfactory continuous glucose monitoring system recordings were obtained in 19 patients. We recorded 54 episodes of hypoglycemia (blood glucose 200 mg/dl; none symptomatic). Of the 54 episodes of hypoglycemia, 10 were associated with symptoms of chest pain, during 4 of which electrocardiographic abnormalities were documented. In contrast, only 1 episode of chest pain occurred during 59 episodes of hyperglycemia. No chest pain or electrocardiographic abnormalities occurred when the blood glucose was within the normal range. The difference between the frequency of ischemia during hypoglycemia and the frequency during both hyperglycemia and normoglycemia was statistically significant (P < 0.01). There were 50 episodes during which the blood glucose changed by >100 mg over a 60-min period, and ischemic symptoms occurred during 9 of these episodes (P < 0.01 compared with stable normoglycemia or hyperglycemia). CONCLUSIONS—Hypoglycemia is more likely to be associated with cardiac ischemia and symptoms than normoglycemia and hyperglycemia, and it is particularly common in patients who experience considerable swings in blood glucose. These data may be important in the institution of insulin treatment and attempting near-normal glycemia in patients with known CAD. Further research is needed to determine strategies to prevent ischemia associated with hypoglycemia.

OBJECTIVE—Flow-mediated dilatation (FMD), induced by occlusion of the brachial artery, is an index of nitric oxide-dependent endothelial function that is impaired in patients with type 2 diabetes. Sildenafil (Viagra) is an inhibitor of phosphodiesterase 5 (PDE-5), which is used for management of erectile dysfunction in a broad range of patients, including those with type 2 diabetes. Its effects on endothelial function in these patients have not been previously assessed.RESEARCH DESIGN AND METHODS—We assessed the acute and prolonged effects of a low dose of sildenafil (25 mg) on FMD in patients with type 2 diabetes. We performed a double-blind, placebo-controlled cross-over trial in 16 patients (14 of whom completed the study) with type 2 diabetes who had erectile dysfunction without overt clinical heart disease.RESULTS—In these patients, the mean ± SD brachial artery diameter (BAD) measured by ultrasound was 4.33 ± 0.6 mm. After inducing FMD, the BAD increased 8% to 4.66 ± 0.6 mm (P = 0.2). One hour after oral administration of sildenafil 25 mg, FMD increased the BAD significantly by 15% to 4.99 ± 0.5 mm (P ≤ 0.01), whereas it did not change with placebo (4.6 ± 0.6 mm, P = 0.1). After treatment with sildenafil 25 mg daily for 2 weeks and testing 24 h after the last dose, the mean FMD was 14% (P = 0.01). In contrast, the mean FMD with placebo was 9% (P = 0.45).CONCLUSIONS—We conclude that acute and prolonged sildenafil treatment has a favorable effect on brachial artery flow-mediated dilatation that persists for at least 24 h after the last dose. Further investigation is needed to determine whether this prolonged effect has clinical implications in patients with type 2 diabetes.