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After nearly 10 years of follow-up in the VA Diabetes Trial, patients with type 2 diabetes who had 5.6 years of intensive glucose control had 8.6 fewer major cardiovascular events per 1000 person-years than those assigned to standard control but no improvement in overall survival. Patients with type 2 diabetes have a greatly increased risk of cardiovascular events. 1 Although end-stage microvascular events (such as end-stage renal disease and blindness) represent important complications of diabetes, the morbidity and mortality related to cardiovascular events are an order of magnitude greater than that related to microvascular events. 2 Therefore, whether improved glucose control reduces the rate of cardiovascular events is an important clinical question. Most observational studies have shown an association between glucose control and cardiovascular disease. 3 – 6 Among the four large, randomized, controlled trials of improved glucose control in patients with type 2 diabetes — the United Kingdom . . .

Cardiovascular disease (CVD) risk in type 2 diabetes (T2DM) is only partially reduced by intensive glycemic control. Diabetic dyslipidemia is suggested to be an additional important contributor to CVD risk in T2DM. Multiple lipid lowering medications effectively reduce fasting LDL cholesterol and triglycerides concentrations and several of them routinely reduce CVD risk. However, in contemporary Western societies the vasculature is commonly exposed to prolonged postprandial hyperlipidemia. Metabolism of these postprandial carbohydrates and lipids yields multiple proatherogenic products. Even a transient increase in these factors may worsen vascular function and induces impaired endothelial dependent vasodilatation, a predictor of atherosclerosis and future cardiovascular events. There is a recent increased appreciation for the role of gut-derived incretin hormones in controlling the postprandial metabolic milieu. Incretin-based medications have been developed and are now used to control postprandial hyperglycemia in T2DM. Recent data indicate that these medications may also have profound effects on postprandial lipid metabolism and may favorably influence several cardiovascular functions. This review discusses (1) the postprandial state with special emphasis on postprandial lipid metabolism and its role in endothelial dysfunction and cardiovascular risk, (2) the ability of incretins to modulate postprandial hyperlipidemia and (3) the potential of incretin-based therapeutic strategies to improve vascular function and reduce CVD risk.

Aims Low C-peptide levels, indicating beta-cell dysfunction, are associated with increased within-day glucose variation and hypoglycemia. In advanced type 2 diabetes, severe hypoglycemia and increased glucose variation predict cardiovascular (CVD) risk. The present study examined the association between C-peptide levels and CVD risk and whether it can be explained by visit-to-visit glucose variation and severe hypoglycemia. Materials and methods Fasting C-peptide levels at baseline, composite CVD outcome, severe hypoglycemia, and visit-to-visit fasting glucose coefficient of variation (CV) and average real variability (ARV) were assessed in 1565 Veterans Affairs Diabetes Trial participants. Results There was a U-shaped relationship between C-peptide and CVD risk with increased risk with declining levels in the low range (< 0.50 nmol/l, HR 1.30 [95%CI 1.05–1.60], p = 0.02) and with rising levels in the high range (> 1.23 nmol/l, 1.27 [1.00–1.63], p = 0.05). C-peptide levels were inversely associated with the risk of severe hypoglycemia (OR 0.68 [0.60–0.77]) and visit-to-visit glucose variation (CV, standardized beta-estimate − 0.12 [SE 0.01]; ARV, − 0.10 [0.01]) (p < 0.0001 all). The association of low C-peptide levels with CVD risk was independent of cardiometabolic risk factors (1.48 [1.17–1.87, p = 0.001) and remained associated with CVD when tested in the same model with severe hypoglycemia and glucose CV. Conclusions Low C-peptide levels were associated with increased CVD risk in advanced type 2 diabetes. The association was independent of increases in glucose variation or severe hypoglycemia. C-peptide levels may predict future glucose control patterns and CVD risk, and identify phenotypes influencing clinical decision making in advanced type 2 diabetes.

IntroductionThis scoping review synthesises the existing literature on racial and ethnic disparities in the utilisation of continuous glucose monitors (CGMs) among adults and children with diabetes in the USA. The primary objective is to describe the extent and nature of these disparities, with the broader goal of informing future research and interventions to address health inequities.Methods and analysisGuided by the Joanna Briggs Institute methodological framework, this review will systematically search PubMed, Embase and Scopus for relevant studies. Included studies will focus on individuals diagnosed with type 1 or type 2 diabetes in the USA. Selection criteria will prioritise studies reporting demographic factors, CGM usage patterns and associated health outcomes. The primary outcome is the extent of racial and ethnic disparities in CGM utilisation. Data synthesis will use the National Institute on Minority Health and Health Disparities Framework (NIMHD) to uncover patterns of CGM utilisation among racial–ethnic groups. The NIMHD facilitates a multilevel examination of the factors influencing CGM initiation, continued use and attrition by integrating individual, interpersonal, community and societal level influences. This comprehensive approach provides a nuanced understanding of the barriers and facilitators shaping CGM usage across diverse populations. By applying the NIMHD framework, this review aims to identify existing disparities, uncover gaps in the literature and offer direction for future research and interventions.Ethics and disseminationAs this study involves a review of previously published literature and does not involve human subjects research, institutional review board approval will not be pursued. Findings will be disseminated through peer-reviewed publications, conference presentations and lay summaries.Literature review registration number https://doi.org/10.17605/OSF.IO/RGW6M.

Discrimination Between Obesity and Insulin Resistance in the Relationship With Adiponectin Fahim Abbasi 1 , James W. Chu 1 , Cindy Lamendola 1 , Tracey McLaughlin 1 , John Hayden 2 , Gerald M. Reaven 1 and Peter D. Reaven 2 1 Divisions of Cardiovascular Medicine and Endocrinology and Metabolism, Department of Medicine, Stanford University School of Medicine, Stanford, California 2 Division of Endocrinology and Metabolism, Department of Medicine, Carl T. Hayden Veterans Affairs Medical Center, Phoenix, Arizona Address correspondence reprint requests to Peter Reaven MD, Division of EndocrinologyMetabolism, Department of Medicine (CS-111E), Carl T. Hayden Veterans Affairs Medical Center, 650 East Indian School Rd., Phoenix, AZ 85012. E-mail: peter.reaven{at}med.va.gov Abstract Insulin resistance and obesity are both associated with lower plasma adiponectin concentrations. Since insulin resistance and obesity are related, the extent to which the association of adiponectin with insulin resistance is dependent on its relationship with obesity is unclear. To address this issue, fasting plasma adiponectin concentrations were measured in 60 nondiabetic subjects, stratified into four equal groups on the basis of both their degree of adiposity and insulin resistance. Insulin resistance was quantified by determining the steady-state plasma glucose (SSPG) concentration in response to an infusion of octreotide, glucose, and insulin, and degree of adiposity was assessed by BMI. Subjects were defined as obese (BMI ≥30.0 kg/m 2 ) or nonobese (<27.0 kg/m 2 ) and as either insulin sensitive (SSPG <100 mg/dl) or insulin resistant (>190 mg/dl). Insulin-resistant subjects had significantly ( P <0.001) lower (mean ± SD) adiponectin concentrations, whether they were obese (17.1 ± 5.9 μg/ml) or nonobese (16.3 ± 7.5 μg/ml) as compared with either obese, insulin-sensitive (34.3 ± 13.1 μg/ml) or nonobese, insulin-sensitive (29.8 ± 15.3 μg/ml) subjects. Finally, adiponectin levels in insulin-sensitive subjects varied to a significantly greater degree than in insulin-resistant subjects. These results suggest that adiponectin concentrations are more closely related to differences in insulin-mediated glucose disposal than obesity. FFA, free fatty acid SSPG, steady-state plasma glucose Footnotes Accepted December 15, 2003. Received June 30, 2003. DIABETES

Apolipoprotein C-III (apoC-III) regulates triglyceride (TG) metabolism. In plasma, apoC-III exists in non-sialylated (apoC-III0a without glycosylation and apoC-III0b with glycosylation), monosialylated (apoC-III1) or disialylated (apoC-III2) proteoforms. Our aim was to clarify the relationship between apoC-III sialylation proteoforms with fasting plasma TG concentrations. In 204 non-diabetic adolescent participants, the relative abundance of apoC-III plasma proteoforms was measured using mass spectrometric immunoassay. Compared with the healthy weight subgroup (n = 16), the ratios of apoC-III0a, apoC-III0b, and apoC-III1 to apoC-III2 were significantly greater in overweight (n = 33) and obese participants (n = 155). These ratios were positively correlated with BMI z-scores and negatively correlated with measures of insulin sensitivity (Si). The relationship of apoC-III1 / apoC-III2 with Si persisted after adjusting for BMI (p = 0.02). Fasting TG was correlated with the ratio of apoC-III0a / apoC-III2 (r = 0.47, p<0.001), apoC-III0b / apoC-III2 (r = 0.41, p<0.001), apoC-III1 / apoC-III2 (r = 0.43, p<0.001). By examining apoC-III concentrations, the association of apoC-III proteoforms with TG was driven by apoC-III0a (r = 0.57, p<0.001), apoC-III0b (r = 0.56. p<0.001) and apoC-III1 (r = 0.67, p<0.001), but not apoC-III2 (r = 0.006, p = 0.9) concentrations, indicating that apoC-III relationship with plasma TG differed in apoC-III2 compared with the other proteoforms. We conclude that apoC-III0a, apoC-III0b, and apoC-III1, but not apoC- III2 appear to be under metabolic control and associate with fasting plasma TG. Measurement of apoC-III proteoforms can offer insights into the biology of TG metabolism in obesity.

Intensive Glucose-Lowering Therapy Reduces Cardiovascular Disease Events in Veterans Affairs Diabetes Trial Participants With Lower Calcified Coronary Atherosclerosis Peter D. Reaven 1 , Thomas E. Moritz 2 , Dawn C. Schwenke 1 , Robert J. Anderson 2 , 3 , Michael Criqui 4 , Robert Detrano 5 , Nicholas Emanuele 6 , Moti Kayshap 7 , Jennifer Marks 8 , Sunder Mudaliar 9 , R. Harsha Rao 10 , Jayendra H. Shah 11 , Steven Goldman 11 , Domenic J. Reda 2 , Madeline McCarren 2 , Carlos Abraira 8 and William Duckworth 1 1 Phoenix Veterans Affairs Health Care System, Phoenix, Arizona; 2 Cooperative Studies Program Coordinating Center, Hines Veterans Affairs Hospital, Hines, Illinois; 3 School of Public Health, University of Illinois at Chicago, Chicago, Illinois; 4 University of California, San Diego, San Diego, California; 5 University of California, Irvine, Irvine, California; 6 Hines Veterans Affairs Medical Center, Hines, Illinois; 7 Long Beach Veterans Affairs Medical Center, Long Beach, California; 8 Miami Veterans Affairs Medical Center, Miami, Florida; 9 Veterans Affairs San Diego Health System, San Diego, California; 10 School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania; 11 Southern Arizona Veterans Affairs Health Care System, Tucson, Arizona. Corresponding author: Peter Reaven, peter.reaven{at}va.gov . Abstract OBJECTIVE This study investigated the hypothesis that baseline calcified coronary atherosclerosis may determine cardiovascular disease events in response to intensive glycemic control within the Veterans Affairs Diabetes Trial (VADT). RESEARCH DESIGN AND METHODS At baseline, 301 type 2 diabetic participants in the VADT, a randomized trial comparing the effects of intensive versus standard glucose lowering on cardiovascular events, had baseline coronary atherosclerosis assessed by coronary artery calcium (CAC) measured by computed tomography. Participants were followed over the 7.5-year study for development of cardiovascular end points. RESULTS During a median follow-up duration of 5.2 years, 89 cardiovascular events occurred. Although intensive glucose-lowering therapy did not significantly reduce cardiovascular events in the substudy cohort as a whole, there was evidence that the response was modified by baseline CAC, as indicated by significant P values for treatment by log(CAC + 1) interaction terms in unadjusted and multivariable-adjusted models (0.01 and 0.03, respectively). Multivariable-adjusted hazard ratios (HRs) for the effect of treatment indicated a progressive diminution of benefit with increasing CAC. Subgroup analyses were also conducted for clinically relevant CAC categories: those above and below an Agatston score of 100. Among those randomized to intensive treatment, for the subgroup with CAC >100, 11 of 62 individuals had events, while only 1 of 52 individuals with CAC ≤100 had an event. The multivariable HR for intensive treatment for those with CAC >100 was 0.74 (95% CI 0.46–1.20; P = 0.21), while for the subgroup with CAC ≤100, the corresponding HR was 0.08 (0.008–0.77; P = 0.03), with event rates of 39 and 4 per 1,000 person-years, respectively. CONCLUSIONS These data indicate that intensive glucose lowering reduces cardiovascular events in those with less extensive calcified coronary atherosclerosis. Footnotes Clinical trial reg. no. NCT00032487, clinicaltrials.gov. The contents of this article do not represent the views of the Department of Veterans Affairs or the U.S. government. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. See accompanying commentary, p. 2448 . . Received April 27, 2009. Accepted July 12, 2009. © 2009 American Diabetes Association

Using mass spectrometric immunoassay, the abundance of SAA truncations relative to the native variants was examined in plasma of 91 participants with type 2 diabetes and chronic kidney disease and 69 participants without diabetes. The ratio of SAA 1.1 (missing N-terminal arginine) to native SAA 1.1 was lower in diabetics compared to non-diabetics (p = 0.004), and in males compared to females (p<0.001). This ratio was negatively correlated with glycated hemoglobin (r = -0.32, p<0.001) and triglyceride concentrations (r = -0.37, p<0.001), and positively correlated with HDL cholesterol concentrations (r = 0.32, p<0.001). The relative abundance of the N-terminal arginine truncation of SAA1.1 is significantly decreased in diabetes and negatively correlates with measures of glycemic and lipid control.

The goal of the VA Diabetes Trial (VADT) was to determine the effect of intensive glucose control on macrovascular events in subjects with difficult-to-control diabetes. No significant benefit was found. This report examines predictors of the effect of intensive therapy on the primary outcome in this population. This trial included 1791 subjects. Baseline cardiovascular risk factors were collected by interview and the VA record. The analyses were done by intention to treat. Univariate analysis at baseline of predictors of a primary cardiovascular (CV) event included a prior CV event, age, insulin use at baseline, and duration of diagnosed diabetes (all P<.0001). Multivariable modeling revealed a U-shaped relationship between duration of diabetes and treatment. Modeled estimates for the hazard ratios (HRs) for treatment show that subjects with a short duration (3 years or less) of diagnosed diabetes have a nonsignificant increase in risk (HR >1.0) after which the HR is below 1.0. From 7 to 15 years' duration at entry, subjects have HRs favoring intensive treatment. Thereafter the HR approaches 1.0 and over-21-years' duration approaches 2.0. Duration over 21 years resulted in a HR of 1.977 (CI 1.77–3.320, P<.01). Baseline c-peptide levels progressively declined up to 15 years and were stable subsequently. In difficult-to-control older subjects with type 2 DM, duration of diabetes altered the response to intensive glucose control. Intensive therapy may reduce CV events in subjects with a duration of 15 years or less and may increase risks in those with longer duration.

Insulin-like growth factor 1 (IGF1) is an important biomarker for the management of growth hormone disorders. Recently there has been rising interest in deploying mass spectrometric (MS) methods of detection for measuring IGF1. However, widespread clinical adoption of any MS-based IGF1 assay will require increased throughput and speed to justify the costs of analyses, and robust industrial platforms that are reproducible across laboratories. Presented here is an MS-based quantitative IGF1 assay with performance rating of >1,000 samples/day, and a capability of quantifying IGF1 point mutations and posttranslational modifications. The throughput of the IGF1 mass spectrometric immunoassay (MSIA) benefited from a simplified sample preparation step, IGF1 immunocapture in a tip format, and high-throughput MALDI-TOF MS analysis. The Limit of Detection and Limit of Quantification of the resulting assay were 1.5 μg/L and 5 μg/L, respectively, with intra- and inter-assay precision CVs of less than 10%, and good linearity and recovery characteristics. The IGF1 MSIA was benchmarked against commercially available IGF1 ELISA via Bland-Altman method comparison test, resulting in a slight positive bias of 16%. The IGF1 MSIA was employed in an optimized parallel workflow utilizing two pipetting robots and MALDI-TOF-MS instruments synced into one-hour phases of sample preparation, extraction and MSIA pipette tip elution, MS data collection, and data processing. Using this workflow, high-throughput IGF1 quantification of 1,054 human samples was achieved in approximately 9 hours. This rate of assaying is a significant improvement over existing MS-based IGF1 assays, and is on par with that of the enzyme-based immunoassays. Furthermore, a mutation was detected in ∼1% of the samples (SNP: rs17884626, creating an A→T substitution at position 67 of the IGF1), demonstrating the capability of IGF1 MSIA to detect point mutations and posttranslational modifications.