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Consensus has not been reached on what constitutes an optimal diet in individuals with prediabetes and type 2 diabetes mellitus (T2DM), especially between low-carbohydrate options.We compared 2 low-carbohydrate diets with 3 key similarities (incorporating nonstarchy vegetables and avoiding added sugars and refined grains) and 3 key differences (incorporating compared with avoiding legumes, fruits, and whole, intact grains) for their effects on glucose control and cardiometabolic risk factors in individuals with prediabetes and T2DM.Keto-Med was a randomized, crossover, interventional trial. Forty participants aged ≥18 years with prediabetes or T2DM followed the well-formulated ketogenic diet (WFKD) and the Mediterranean-plus diet (Med-Plus) for 12 weeks each, in random order. The diets shared the 3 key similarities noted above. The Med-Plus incorporated legumes, fruits, and whole, intact grains, while the WFKD avoided them. The primary outcome was the percentage change in glycated hemoglobin (HbA1c) after 12 weeks on each diet. Secondary and exploratory outcomes included percentage changes in body weight, fasting insulin, glucose, and blood lipids; average glucose from continuous glucose monitor (CGM), and nutrient intake.The primary analysis was of 33 participants with complete data. The HbA1c values did not differ between diets at 12 weeks. Triglycerides decreased more for the WFKD [percentage changes, -16% (SEM, 4%) compared with -5% (SEM, 6%) for the Med-Plus; P = 0.02] and LDL cholesterol was higher for the WFKD [percentage changes, +10% (SEM, 4%) compared with -5% (SEM, 5%) for the Med-Plus; P = 0.01]. Weight decreased 8% (SEM, 1%) compared with 7% (SEM, 1%) and HDL cholesterol increased 11% (SEM, 2%) compared with 7% (SEM, 3%) for the WFKD compared with the Med-Plus, respectively; however, there was a significant interaction of diet × order for both. Participants had lower intakes of fiber and 3 nutrients on the WFKD compared with the Med-Plus. Twelve-week follow-up data suggest the Med-Plus is more sustainable.HbA1c values were not different between diet phases after 12 weeks, but improved from baseline on both diets, likely due to several shared dietary aspects. The WFKD led to a greater decrease in triglycerides, but also had potential untoward risks from elevated LDL cholesterol and lower nutrient intakes from avoiding legumes, fruits, and whole, intact grains, as well as being less sustainable. This trial was registered at clinicaltrials.gov as NCT03810378.

There is evidence suggesting that infection with SARS-CoV-2 can lead to several long-term sequelae including diabetes. This mini-review examines the rapidly evolving and conflicting literature on new-onset diabetes after COVID-19, which we term NODAC. We searched PubMed, MEDLINE, and medRxiv from inception until December 1, 2022 using both MeSH terms and free text words including “COVID-19,” “SARS-CoV-2,” “diabetes,” “hyperglycemia,” “insulin resistance,” and “pancreatic β-cell.” We also supplemented searches by examining reference lists from retrieved articles. Current evidence suggests that COVID-19 increases the risk of developing diabetes, but the attributable risk is uncertain due to limitations of study designs and the evolving nature of the pandemic, including new variants, widespread population exposure to the virus, diagnostic options for COVID-19 and vaccination status. The etiology of diabetes after COVID-19 is likely multifactorial and includes factors associated with host characteristics (e.g., age), social determinants of health (e.g., deprivation index), and pandemic-related effects both at the personal (e.g., psychosocial stress) and the societal-community level (e.g., containment measures). COVID-19 may have direct and indirect effects on pancreatic β-cell function and insulin sensitivity related to: the acute infection and its treatment (e.g., glucocorticoids); autoimmunity; persistent viral residency in multiple organs including adipose tissue; endothelial dysfunction; and hyperinflammatory state. While our understanding of NODAC continues to evolve, consideration should be given for diabetes to be classified as a post-COVID syndrome, in addition to traditional classifications of diabetes (e.g., type 1 or type 2), so that the pathophysiology, natural history and optimal management can be studied.

NAFLD is common in primary care. Liver fibrosis stage 2 or higher (≥F2) increases future risk of morbidity and mortality. We developed and validated a score to aid in the initial assessment of liver fibrosis for NAFLD in primary care.Data from patients with biopsy-proven NAFLD were extracted from the NASH Clinical Research Network observational study (n = 676). Using logistic regression and machine-learning methods, we constructed prediction models to distinguish ≥F2 from F0/1. The models were tested in participants in a trial ("FLINT," n = 280) and local patients with NAFLD with magnetic resonance elastography data (n = 130). The final model was applied to examinees in the National Health and Nutrition Examination Survey (NHANES) III (n = 11,953) to correlate with long-term mortality.A multivariable logistic regression model was selected as the Steatosis-Associated Fibrosis Estimator (SAFE) score, which consists of age, body mass index, diabetes, platelets, aspartate and alanine aminotransferases, and globulins (total serum protein minus albumin). The model yielded areas under receiver operating characteristic curves ≥0.80 in distinguishing F0/1 from ≥F2 in testing data sets, consistently higher than those of Fibrosis-4 and NAFLD Fibrosis Scores. The negative predictive values in ruling out ≥F2 at SAFE of 0 were 88% and 92% in the two testing sets. In the NHANES III set, survival up to 25 years of subjects with SAFE0 was comparable to that of those without steatosis (p = 0.34), whereas increasing SAFE scores correlated with shorter survival with an adjusted HR of 1.53 (p 0.01) for subjects with SAFE 100.The SAFE score, which uses widely available variables to estimate liver fibrosis in patients diagnosed with NAFLD, may be used in primary care to recognize low-risk NAFLD.

Objective: Statin treatment reduces the risk of atherosclerotic cardiovascular disease but is associated with a modest increased risk of type 2 diabetes, especially in those with insulin resistance or prediabetes. Our objective was to determine the physiological mechanism for the increased type 2 diabetes risk. Approach and Results: We conducted an open-label clinical trial of atorvastatin 40 mg daily in adults without known atherosclerotic cardiovascular disease or type 2 diabetes at baseline. The co-primary outcomes were changes at 10 weeks versus baseline in insulin resistance as assessed by steady-state plasma glucose during the insulin suppression test and insulin secretion as assessed by insulin secretion rate area under the curve (ISR AUC ) during the graded-glucose infusion test. Secondary outcomes included glucose and insulin, both fasting and during oral glucose tolerance test. Of 75 participants who enrolled, 71 completed the study (median age 61 years, 37% women, 65% non-Hispanic White, median body mass index, 27.8 kg/m 2 ). Atorvastatin reduced LDL (low-density lipoprotein)-cholesterol (median decrease 53%, P P =0.01) and insulin secretion (ISR AUC ) by a median of 9% ( P AUC (median increase, 0.05%; P =0.03) and fasting insulin (median increase, 7%; P =0.01). Conclusions: In individuals without type 2 diabetes, high-intensity atorvastatin for 10 weeks increases insulin resistance and insulin secretion. Over time, the risk of new-onset diabetes with statin use may increase in individuals who become more insulin resistant but are unable to maintain compensatory increases in insulin secretion. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02437084. Graphic Abstract: A graphic abstract is available for this article.

Context Vitamin D regulates glucose homeostasis pathways, but effects of vitamin D supplementation on β-cell function remain unclear. Objective To investigate the effects of vitamin D3 supplementation on insulin sensitivity and β-cell function. Methods This is a prespecified secondary analysis of the Vitamin D and Type 2 Diabetes study. Overweight/obese adults at high risk for type 2 diabetes (prediabetes) were randomly treated with vitamin D3 4000 IU or matching placebo daily for 24 months. Main Outcome Disposition index (DI), as an estimate of β-cell function, was calculated as the product of Homeostasis Model Assessment 2 indices derived from C-peptide values (HOMA2%Scpep) and C-peptide response during the first 30 minutes of a 75-g oral glucose tolerance test (OGTT). Results Mean age was 60.5 ± 9.8 years and body mass index was 31.9 ± 4.4 kg/m2. Mean serum 25(OH)D level increased from 27.9 ± 10.3 ng/mL at baseline to 54.9 ng/mL at 2 years in the vitamin D group and was unchanged (28.5 ± 10.0 ng/mL) in the placebo group. The baseline DI predicted incident diabetes independent of the intervention. In the entire cohort, there were no significant differences in changes in DI, HOMA2%Scpep, or C-peptide response between the 2 groups. Among participants with baseline 25(OH)D level Conclusions Supplementation with vitamin D3 for 24 months did not improve an OGTT-derived index of β-cell function in people with prediabetes not selected based on baseline vitamin D status; however, there was benefit among those with very low baseline vitamin D status.

BACKGROUND AND OBJECTIVES: Low serum 25-hydroxyvitamin D (25[OH]D) concentration has been associated with higher levels of proteinuria and lower levels of eGFR in observational studies. In the Vitamin D and Type 2 Diabetes (D2d) study, we investigated the effect of vitamin D supplementation on kidney outcomes in a population with prediabetes. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Overweight/obese adults with high risk for type 2 diabetes (defined by meeting two of three glycemic criteria for prediabetes) were randomized to vitamin D(3) 4000 IU per day versus placebo. Median duration of treatment was 2.9 years (interquartile range 2.0–3.5 years). Kidney outcomes included (1) worsening in Kidney Disease: Improving Global Outcomes (KDIGO ) risk score (low, moderate, high, very high) on two consecutive follow-up visits after the baseline visit and (2) mean changes in eGFR and urine albumin-to-creatinine ratio (UACR). RESULTS: Among 2166 participants (mean age 60 years, body mass index 32 kg/m(2), serum 25(OH)D 28 ng/ml, eGFR 87 ml/min per 1.73 m(2), UACR 11 mg/g, 79% with hypertension), 10% had moderate, high, or very high KDIGO risk score. Over a median follow-up of 2.9 years, there were 28 cases of KDIGO worsening in the vitamin D group and 30 in the placebo group (hazard ratio, 0.89; 95% confidence interval [95% CI], 0.52 to 1.52]). Mean difference in eGFR from baseline was −1.0 ml/min per 1.73 m(2) (95% CI, −1.3 to −0.7) in the vitamin D group and −0.1 ml/min per 1.73 m(2) (95% CI, −0.4 to 0.2) in the placebo group; between-group difference was −1.0 ml/min per 1.73 m(2) (95% CI, −1.4 to −0.6). Mean difference in UACR was 2.7 mg/g (95% CI, 1.2 to 4.3) in the vitamin D group and 2.0 (95% CI, 0.5 to 3.6) in the placebo group; between-group difference was 0.7 mg/g (95% CI, −1.5 to 2.9). CONCLUSIONS: Among persons with prediabetes, who were not preselected on the basis of serum 25(OH)D concentration, vitamin D supplementation did not affect progression of KDIGO risk scores and did not have a meaningful effect on change in UACR or eGFR.

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.

Background The independent role of pericardial adipose tissue (PAT) as an ectopic fat associated with cardiovascular disease (CVD) remains controversial. This study aimed to determine whether PAT is associated with left ventricular (LV) structure and function independent of other markers of general obesity. Methods We studied 2471 participants (50.9 % women) without known CVD from the Korean Genome Epidemiology Study, who underwent 2D-echocardiography with tissue Doppler imaging (TDI) and computed tomography measurement for PAT. Results Study participants with more PAT were more likely to be men and had higher cardiometabolic indices, including blood pressure, glucose, and cholesterol levels (all P P P = 0.015) and early diastolic (P P Conclusions PAT was associated with subclinical LV structural and functional deterioration, and these associations were independent of and stronger than with general and abdominal obesity measures.

Aim To examine how circulating glucagon-like peptide-1 (GLP-1) concentrations during liraglutide treatment relate to its therapeutic actions on glucose and weight, and to study the effects of liraglutide on other proglucagon-derived peptides (PGDPs), including endogenous GLP-1, glucagon-like peptide-2, glucagon, oxyntomodulin, glicentin and major proglucagon fragment, which also regulate metabolic and weight control. Materials and methods Adults who were overweight/obese (body mass index 27-40 kg/m2 ) with prediabetes were randomized to liraglutide (1.8 mg/day) versus placebo for 14 weeks. We used specific assays to measure exogenous (liraglutide, GLP-1 agonist [GLP-1A]) and endogenous (GLP-1E) GLP-1, alongside five other PGDP concentrations during a mixed meal tolerance test (MMTT) completed at baseline and at week 14 (liraglutide, n = 16; placebo, n = 19). Glucose during MMTT, steady-state plasma glucose (SSPG) concentration for insulin resistance and insulin secretion rate (ISR) were previously measured. MMTT area-under-the-curve (AUC) was calculated for ISR, glucose and levels of PGDPs. Results Participants on liraglutide versus placebo had significantly (P ≤ .004) decreased weight (mean -3.6%, 95% CI [-5.2% to -2.1%]), SSPG (-32% [-43% to -22%]) and glucose AUC (-7.0% [-11.5% to -2.5%]) and increased ISR AUC (30% [16% to 44%]). GLP-1A AUC at study end was significantly (P ≤ .04) linearly associated with % decrease in weight (r = -0.54) and SSPG (r = -0.59) and increase in ISR AUC (r = 0.51) in the liraglutide group. Treatment with liraglutide significantly (P ≤ .005) increased exogenous GLP-1A AUC (median 310 vs. 262 pg/mL × 8 hours at baseline but decreased endogenous GLP-1E AUC [13.1 vs. 24.2 pmol/L × 8 hours at baseline]), as well as the five other PGDPs. Decreases in the PGDPs processed in the intestines are independent of weight loss, indicating a probable direct effect of GLP-1 receptor agonists to decrease their endogenous production in contrast to weight loss-dependent changes in glucagon and major proglucagon fragment that are processed in pancreatic alpha cells. Conclusions Circulating GLP-1A concentrations, reflecting liraglutide levels, predict improvement in weight, insulin action and secretion in a linear manner. Importantly, liraglutide also downregulates other PGDPs, normalization of the levels of which may provide additional metabolic and weight loss benefits in the future.

Obesity is a well-known risk factor for infertility. However, the use of weight loss medications prior to conception is underutilized. The objectives of our study are to describe weight loss, pregnancy rates, and live birth rates after short-term phentermine use in women with obesity and infertility.This was a retrospective analysis of 55 women (18 to 45 years old) who were overweight or obese, diagnosed with infertility, and prescribed phentermine for weight loss in an ambulatory endocrinology clinic at a single, tertiary level academic medical center. Main outcome measures were mean percent weight change at 3 months after starting phentermine, and pregnancy, and live birth rates from start of phentermine to June 30, 2017.Median duration of phentermine use was 70 days (Q1, Q3lsqb;33, 129]). Mean ± SD percent weight change at 3 months after starting phentermine was -5.3 ± 4.1% (P.001). The pregnancy rate was 60% and the live birth rate was 49%. There was no significant difference in pregnancy rates (52% versus 68%; P = .23) or live birth rates (44% versus 54%; P = .50) in women who lost ≥5% versus5% of their baseline weight. The number of metabolic comorbidities was negatively associated with the pregnancy rate. Phentermine was generally well-tolerated with no serious adverse events.Phentermine can produce clinically significant weight loss in women with obesity during the preconception period. Higher pregnancy or live birth rates were not observed with a greater degree of weight loss with phentermine.

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.

AIMS –: To determine the association with cardiovascular (CV) outcomes of sodium glucose cotransporter-2 (SGLT-2) inhibitors compared with dipeptidyl peptidase-4 (DPP-4) inhibitors in patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD). MATERIALS AND METHODS –: We conducted a population-based cohort study of new users of SGLT-2 inhibitors and DPP-4 inhibitors with T2DM and CKD using data from Optum Clinformatics DataMart. We assembled three cohorts: T2DM/no CKD, T2DM/CKD 1–2, and T2DM/ CKD 3a. Study outcomes were 1) time to first heart failure (HF) hospitalization; and 2) time to a composite CV endpoint comprised of non-fatal myocardial infarction (MI) or stroke. After inverse probability of treatment weighting, we used proportional hazards regression to estimate hazard ratios (HR) and 95% confidence intervals (CI). RESULTS –: New users of SGLT-2 inhibitors versus of DPP-4 inhibitors had lower risks of HF hospitalization in the T2DM/no CKD (HR, 0.76; 95% CI, 0.70, 0.82) and T2DM/CKD 1–2 (HR, 0.63; 95% CI, 0.48, 0.84), but no significant association was present in the T2DM/CKD 3a cohort. Compared with prescription of DPP-4 inhibitors, SGLT-2 inhibitors were associated with lower risks of non-fatal MI or stroke of 23% (HR, 0.77; 95% CI, 0.70, 0.85) in the T2DM/no CKD cohort, but no significant associations were present in the T2DM/CKD 1–2 and T2DM/CKD 3a cohorts. CONCLUSIONS –: Incident prescription of SGLT-2 inhibitors was associated with lower risks of HF hospitalization but not with non-fatal MI or stroke despite suggesting benefit, relative to prescription of DPP-4 inhibitor across different stages of CKD.

Vitamin D is believed to regulate pathways in glucose homeostasis, but effects of vitamin D supplementation on insulin sensitivity and β-cell function in humans remain uncertain. We completed a secondary analysis of the Vitamin D and type 2 diabetes (D2d) study to investigate the effects of vitamin D supplementation on insulin sensitivity and β-cell function. Participants at high risk for type 2 diabetes, meeting at least 2-out-of-3 ADA criteria for prediabetes, were randomly assigned to 4000 IU/day of vitamin D3 or placebo. Insulin sensitivity and β-cell function were estimated using data from 75-gram oral glucose tolerance tests (OGTT). We used the University of Oxford HOMA2 Calculator to estimate insulin sensitivity from simultaneously measured fasting plasma glucose and C-peptide values. Early C-peptide and insulin responses were calculated as the ratio of C-peptide or insulin increment to glucose level changes during the first 30 minutes of the OGTT. The disposition index (DI) as an estimate of β-cell function was calculated as the product of C-peptide response and HOMA2%S. The response to vitamin D3 was evaluated in 1,774 participants over 24 months. Baseline characteristics [mean age 60.5±9.8 years, BMI 31.9±4.4 kg/m2, 56.4% male, 69.1% white, 25-hydroxyvitamin D (25-OH D) 28.2±10.2 ng/ml, HbA1c 5.9%±0.2, FPG 107.7±7.2 mg/dl, 2hrOGTT glucose 137.1±34.1 mg/dl] were similar between the vitamin D and placebo groups. Serum 25-OH D increased from 27.9±10.3 ng/ml to 54.9±14.4 ng/ml at 24 months in the vitamin D group and remained unchanged with placebo (p In conclusion, in this pre-specified analysis from the D2d study, supplementation with vitamin D for 24 months did not alter insulin sensitivity or β-cell function in people with prediabetes who were not selected based on their baseline vitamin D levels. Disclosure N. Rasouli: Consultant; Self; Novo Nordisk, Research Support; Self; Allergan plc, Lilly Diabetes, Novo Nordisk. I. Brodsky: None. R. Chatterjee: Research Support; Self; Bristol-Myers Squibb Company, Epigenomics AG, Verily Life Sciences. S. H. Kim: Advisory Panel; Self; Bayer U. S., GI Dynamics, Stock/Shareholder; Spouse/Partner; Dexcom, Inc. R. E. Pratley: Other Relationship; Self; Hanmi Pharmaceutical, Merck Sharp & Dohme Corp., Metavention, Monster Energy Company, Inc., Novo Nordisk, Pfizer Inc., Poxel SA, Sanofi, Scohia Pharma Inc., Sun Pharmaceutical Industries Ltd. M. Staten: None. J. P. Nelson: None. A. G. Pittas: None. D2d research group: n/a. Funding American Diabetes Association (1-14-D2d-01 to A.G.P.); National Institute of Diabetes and Digestive and Kidney Diseases (U34DK091958); Office of Dietary Supplements (U01DK098245)

The age-standardized prevalence of diabetes increased from 9.8% in 1988-1994, to 10.8% in 2001-2002, to 12.4% in 2011-2012 in the United States.1 According to the National Vital Statistics System data, diabetes-related mortality has remained stable as the seventh-leading cause of death nationally since 2006.2 However, the age-standardized diabetes-related mortality decreased from 112.2 per 100,000 individuals in 2007 to 104.3 per 100,000 individuals in 2017.3 In terms of cause-specific mortality, the age-standardized mortality for cardiovascular disease, complications of diabetes, and cancer among individuals with diabetes declined annually by approximately 1%.3 In contrast, chronic liver disease-related mortality has been reported to be increasing in individuals with diabetes.4,5 However, the trends in mortality due to chronic liver disease in the setting of diabetes remain unknown. In this study, we estimated the trends in chronic liver disease-related mortality among individuals with diabetes from 2007 to 2017 in the United States.

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of liver disease, and yet the natural course remains unclear. Study population included 36,195 individuals who participated in a health-screening program and diagnosed with fatty liver by abdominal ultrasound. Participants were provided written information regarding fatty liver and advised to make lifestyle changes. Ultrasound was repeated after at least 6 months. After a mean follow up of 4.9 years (±3.4), 19.6% resolved their fatty liver. Individuals who resolved were more likely female (22.9% vs. 12.3%), thinner (body mass index [BMI], 25.2 ± 2.7 vs. 26 ± 2.7), and with lower HOMA-IR (1.4 vs. 1.7) (P .70.001). Decrease in BMI predicted resolution of fatty liver with 42% of those in the top quartile of BMI decline resolving compared with 5.7% in the lowest quartile (odds ratio [OR] (95% confidence interval [CI]) 15.65 (14.13–17.34), P P

AIMS/HYPOTHESIS: The determination of diabetes as underlying cause of death by using the death certificate may result in inaccurate estimation of national mortality attributed to diabetes, because individuals who die with diabetes generally have other conditions that may contribute to their death. We investigated the trends in age-standardised mortality due to diabetes as underlying or contributing cause of death and cause-specific mortality from cardiovascular disease (CVD), complications of diabetes and cancer among individuals with diabetes listed on death certificates in the USA from 2007 to 2017. METHODS: Using the US Census and national mortality database, we calculated age-standardised mortality due to diabetes as underlying or contributing cause of death and cause-specific mortality rates among adults over 20 years with diabetes listed on death certificates. A total of 2,686,590 deaths where diabetes was underlying or contributing cause of death were analysed. We determined temporal mortality rate patterns by joinpoint regression analysis with estimates of annual percentage change (APC). RESULTS: Age-standardised diabetes mortality rates compared among underlying cause of death, contributing cause of death and all-cause mortality were 32.2 vs 75.7 vs 105.1 per 100,000 individuals during the study period. The age-standardised mortality rates due to diabetes as underlying or contributing cause of death declined from 112.2 per 100,000 individuals in 2007 to 104.3 per 100,000 individuals in 2017 with the most pronounced decline noted from 2007 to 2014 (APC −1.4%; 95% CI −1.9%, −1.0%) and stabilisation in decline from 2014 to 2017 (APC 1.1%; 95% CI −0.6%, 2.8%). In terms of cause-specific mortality among individuals with diabetes listed on death certificates, the age-standardised mortality rates for CVD declined at an annual rate of 1.2% with a marked decline of 2.3% between 2007 and 2014. Age-standardised diabetes-specific mortality rates as underlying cause of death decreased from 2007 to 2009 (APC −4.5%) and remained stable from 2009 to 2017. Age-standardised mortality rates for cancer steadily decreased with an average APC of −1.4% (95% CI −1.8%, −1.0%) during the 11-year period. Mortality in the subcategory of CVD demonstrated significant differences. CONCLUSIONS/INTERPRETATION: Current national estimates capture about 30% of all-cause mortality among individuals with diabetes listed as underlying or contributing cause of death on death certificates. The age-standardised mortality due to diabetes as underlying or contributing cause of death and cause-specific mortality from CVD in individuals with diabetes listed as underlying or contributing cause of death plateaued from 2014 onwards except for hypertensive heart disease and heart failure.

Gerald Reaven was often called the "father of insulin resistance." On the 1-year anniversary of his death in 2018, we challenge three myths associated with insulin resistance: metformin improves insulin resistance; measurement of waist circumference predicts insulin resistance better than body mass index; and insulin resistance causes weight gain. In this review, we highlight Reaven's relevant research that helped to dispel these myths associated with insulin resistance.

Objective: Insulin sensitivity affects plasma triglyceride concentration and both differ by race/ethnicity. The purpose of this study was to provide a comprehensive assessment of the variation in insulin sensitivity and its relationship to hypertriglyceridaemia between five race/ethnic groups. Research design and methods: In this cross-sectional study, clinical data for 1025 healthy non-Hispanic White, Hispanic White, East Asian, South Asian and African American individuals were analysed. Insulin-mediated glucose disposal (a direct measure of peripheral insulin sensitivity) was measured using the modified insulin suppression test. Statistical analysis was performed using analysis of co-variance. Results: Of the study participants, 63% were non-Hispanic White, 9% were Hispanic White, 11% were East Asian, 11% were South Asian and 6% were African American. Overall, non-Hispanic Whites and African Americans displayed greater insulin sensitivity than East Asians and South Asians. Triglyceride concentration was positively associated with insulin resistance in all groups, including African Americans. Nevertheless, for any given level of insulin sensitivity, African Americans had the lowest triglyceride concentrations. Conclusion: Insulin sensitivity, as assessed by a direct measure of insulin-mediated glucose disposal, and its relationship to triglyceride concentration vary across five race/ethnic groups. Understanding these relationships is crucial for accurate cardiovascular risk stratification and prevention.

Liraglutide is a glucagon-like peptide 1 receptor agonist (GLP-1ra) and has 97% homology to native GLP-1. Native GLP-1 derives from proglucagon, which is also a prohormone for other peptides including GLP-2, glucagon, oxytomodulin, glicentin, and major proglucagon fragment. Aside from GLP-1 and glucagon, the actions and roles of the other proglucagon-derived peptides remain unclear. In addition, the effect of liraglutide treatment on these peptides are unknown. The aim of this study was to evaluate the effect of treatment with liraglutide compared with placebo on proglucagon-derived peptides. Adults who were overweight/obese (BMI 27-40 kg/m2) with prediabetes were randomized to liraglutide 1.8mg daily vs placebo for 14 weeks. All participants met regularly with a registered dietitian and were advised to decrease calorie intake by 500 kcal/day. Proglucagon-derived peptides were measured during mixed-meal tolerance test (MMTT) at baseline and after 14 weeks in a subset of individuals with saved samples (n=16 on liraglutide, n=19 on placebo). The MMTT involved eating breakfast at 08:00 (20% of daily energy intake) and lunch at 12:00 (40% of daily energy intake). Blood was collected before breakfast and hourly from 08:00 to 16:00. The area-under-the curve (AUC) was calculated for all proglucagon-derived peptides using the trapezoidal method. Individuals treated with liraglutide lost twice as much weight as those assigned to placebo injections (mean ± SD, 6.1 ± 1.9 vs 3.2 ± 2.2 kg, 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 (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.

Recent years have seen a high incidence of mumps, which is generally diagnosed based on clinical features, especially parotitis, without laboratory confirmation in Korea. To better understand the epidemiology of mumps in Korean children, we investigated sporadic suspected mumps cases with parotitis. In total, 237 buccal swabs or throat swabs collected from children with parotitis who had been clinically diagnosed with mumps were tested using real-time PCR for the detection of six viruses (Epstein-Barr virus, Human herpesvirus 6, Mumps virus, Human parainfluenza virus-1, -2, -3, Human adenovirus, Human bocavirus). Among 237 parotitis cases, 87 (36.7%) were positive for at least one virus; a single infection was observed in 73 (83.9%) cases, and co-infections were detected in 14 (16.1%) cases. Epstein-Barr virus was most frequent (20.7%), followed by human herpesvirus 6 (8.0%), mumps virus (5.5%), human parainfluenza virus-3 (4.6%), human adenovirus (4.2%), and human bocavirus (0.4%). These data suggested that the sporadic suspected mumps in the children might be related to other respiratory viruses rather than to the mumps virus. Our findings also indicate the limitation of clinical diagnosis without laboratory confirmation for mumps and thus highlight the importance of laboratory testing in suspected mumps cases.

Prevalence of insulin resistance is increased in patients with obstructive sleep apnea (OSA). Since insulin resistance is an independent predictor of cardiovascular disease (CVD), this study was initiated to see if pioglitazone administration would improve insulin sensitivity, and thereby decrease risk of CVD in overweight/obese, nondiabetic, insulin-resistant patients with untreated OSA. Patients (n=30) were administered pioglitazone (45 mg/day) for 8 weeks, and measurements were made before and after intervention of insulin action (insulin-mediated glucose uptake by the insulin suppression test), C-reactive protein, lipid/lipoprotein profile, and gene expression profile of peri-umbilical subcutaneous fat tissue. Insulin sensitivity increased 31% (p

Metabolically dormant bacteria present a critical challenge to effective antimicrobial therapy because these bacteria are genetically susceptible to antibiotic treatment but phenotypically tolerant. Such tolerance has been attributed to impaired drug uptake, which can be reversed by metabolic stimulation. Here, we evaluate the effects of central carbon metabolite stimulations on aminoglycoside sensitivity in the pathogen Pseudomonas aeruginosa. We identify fumarate as a tobramycin potentiator that activates cellular respiration and generates a proton motive force by stimulating the tricarboxylic acid (TCA) cycle. In contrast, we find that glyoxylate induces phenotypic tolerance by inhibiting cellular respiration with acetyl-coenzyme A diversion through the glyoxylate shunt, despite drug import. Collectively, this work demonstrates that TCA cycle activity is important for both aminoglycoside uptake and downstream lethality and identifies a potential strategy for potentiating aminoglycoside treatment of P. aeruginosa infections. Keyword: aminoglycoside susceptibility; Pseudomonas aeruginosa; TCA cycle; respiration; electron transport chain; fumarate; glyoxylate; biochemical persistence; LC-MS metabolomics, Defense Threat Reduction Agency (DTRA) (Grant HDTRA1-15-1-0051), National Institutes of Health (U.S.) (Grant NIH K99GM118907)

Objective The aim of this study was to better delineate the complex interrelationship among insulin resistance (IR), secretion rate (ISR), and clearance rate (ICR) to increase plasma insulin concentrations in obesity. Methods Healthy volunteers (92 nondiabetic individuals) had an insulin suppression test to measure IR and graded-glucose infusion test to measure ISR and ICR. Obesity was defined as a body mass index (BMI) ≥30 kg/m2, and IR was defined as steady-state plasma glucose (SSPG) ≥10 mmol/L during the insulin suppression test. Plasma glucose and insulin concentrations, ISR, and ICR were compared in three groups: insulin sensitive/overweight; insulin sensitive/obesity; and insulin resistant/obesity. Results Compared with the insulin-sensitive/overweight group, the insulin-sensitive/obesity had significantly higher insulin area under the curve (AUC) and ISR AUC during the graded-glucose infusion test (P < 0.001). Glucose AUC and ICR were similar. The insulin-resistant/obesity group had higher insulin AUC and ISR AUC compared with the insulin-sensitive/obesity but also had higher glucose AUC and decreased ICR (P < 0.01). In multivariate analysis, both BMI and SSPG were significantly associated with ISR. Conclusions Plasma insulin concentration and ISR are increased in individuals with obesity, irrespective of degree of IR, but a decrease in ICR is confined to the subset of individuals with IR.

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, .)

Objective: Although reported to be independent of obesity, the longitudinal changes of left ventricular structure and function have not been well characterized in normal-weight individuals with type 2 diabetes compared with overweight/obese individuals with type 2 diabetes. Methods: A total of 558 participants in the Korean Genome and Epidemiology Study who underwent tissue Doppler echocardiography at baseline (cycle 4) and after 8 years (cycle 8) were classified into three groups based on body mass index and diabetes status: (1) normal-weight individuals without type 2 diabetes, (2) normal-weight individuals with type 2 diabetes and (3) overweight/obese individuals with type 2 diabetes. Results: Only overweight/obese individuals with type 2 diabetes group had higher adjusted left ventricular mass index and lower tissue Doppler imaging early diastolic velocity and E/Em ratio compared with the normal-weight individuals without type 2 diabetes group at baseline and after 8 years. Participants in overweight/obese individuals with type 2 diabetes group also showed the higher prevalence and odds of left ventricular hypertrophy (16.0%; adjusted odds ratio: 2.24; 95% confidence interval: 1.22–5.06) and left ventricular diastolic dysfunction (49.1%; 3.45; 1.01–4.32). Among participants with normal left ventricular structure and function at baseline, only overweight/obese individuals with type 2 diabetes group was associated with greater incidence of left ventricular hypertrophy (relative risk: 2.28; 1.04–4.98) over 8 years but not diastolic dysfunction. Conclusion: Cross-sectional and longitudinal observations suggest that increasing body mass index category and its associated metabolic abnormalities at baseline are associated with an increased risk for left ventricular hypertrophy and greater impairment in left ventricular diastolic parameters.

Plasma glucose concentrations are tightly regulated and maintained within a narrow range in non-diabetic individuals. Maintenance of this physiological state is primarily a function of the ability of the pancreatic β-cells to modify insulin secretion rate (ISR), thus preventing wide-swings in plasma glucose concentrations. As a consequence, and in contrast to plasma glucose concentrations, plasma insulin concentrations vary substantially in non-diabetic individuals. Although differences in ISR are primarily responsible for the variability in plasma insulin concentration, there is increasing evidence that differences in insulin clearance rate (ICR) also play a role in regulation of plasma insulin concentration. The goal of this mini-review is to highlight situations that demonstrate the important role of ICR in both insulin and glucose homeostasis.

Biphasic reacting systems contain effectively immiscible aqueous and organic liquid phases in which reactants, products, and catalysts can partition. These conditions allow novel synthesis paths, higher yields, and faster reactions, as well as facilitate product(s) separation. A systematic modeling framework of three modules has been developed to describe phase equilibria, reactions, mass transfer, and material balances of such processes. The recently developed group-contribution electrolyte model, e-KT-UNIFAC, is used to predict the partitioning and equilibria of electrolyte and nonelectrolyte species for a wide variety of reacting substances. Reaction kinetics and mass transfer are described by nonelementary reaction rate laws. Extents of reaction are used to calculate the species material balances. The resulting mathematical model contains only a few rate parameters to be regressed to a minimum of time-dependent data. In addition to describing the behavior of such systems, predictions can be made of th...

Background High fasting insulin levels have been reported to predict development of observed apneas, suggesting that insulin resistance may contribute to the pathogenesis of obstructive sleep apnea (OSA). The aim of this study was to determine whether enhancing insulin sensitivity in individuals with OSA would improve sleep measures. Patients/Methods Insulin-resistant, nondiabetic individuals with untreated OSA were randomized (2:1) to pioglitazone (45 mg/day) or placebo for eight weeks in this single-blind study. All individuals had repeat measurements pertaining to sleep (overnight polysomnography and functional outcomes of sleep questionnaire) and insulin action (insulin suppression test). Results A total of 45 overweight/obese men and women with moderate/severe OSA were randomized to pioglitazone ( n = 30) or placebo ( n = 15). Although insulin sensitivity increased 31% among pioglitazone-treated compared with no change among individuals receiving placebo ( p 0.001 for between-group difference), no improvement in quantitative or qualitative sleep measurements was observed. Conclusions Pioglitazone administration increased insulin sensitivity in otherwise untreated individuals with OSA, without any change in polysomnographic sleep measures over an eight-week period. These findings do not support a causal role for insulin resistance in the pathogenesis of OSA.

Objective Several studies have shown decreased insulin clearance rate (ICR) in individuals with obesity, but it remains unclear whether this is predominately due to obesity-associated insulin resistance (IR) or obesity itself. We aimed to clarify the complex interrelationship that exists between obesity, IR and ICR.

Aims To quantify patterns of conventional and newer antidiabetic medication use in patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD). Methods We used data from a large claims and integrated dataset that includes employed and commercially insured patients in the US to select patients who had T2DM and CKD with information on laboratory values and prescriptions for antidiabetic medications from January 1, 2014 to January 1, 2015. We stratified the analyses by sociodemographic variables. Results In a cohort of 38,577 patients with T2DM and CKD, we found wide variation in the treatment of T2DM by CKD stage as well as by several sociodemographic factors. Although metformin was the most commonly prescribed medication, only about half of patients in the cohort and fewer than two-thirds of patients with early stage CKD were prescribed metformin. Approximately 10.6% of patients with CKD stage 4 and 2.1% of the patients with CKD stage 5 were prescribed metformin. Sulfonylureas with active metabolites that accumulate with impaired kidney function were prescribed in more than one-third of patients with CKD stages 3b, 4, and 5. Only 3.4% and 12.3% of patients were prescribed GLP-1 and DPP-4 respectively. Conclusions Prescriptions for metformin were lower than expected among patients with mild to moderate CKD. Prescriptions for newer antidiabetic medications with known safety and efficacy across the spectrum of CKD remained low. Prescriptions for agents contraindicated in advanced CKD continued to be written in a sizeable fraction of patients.

Hispanics and Asians have a higher risk for type 2 diabetes than non-Hispanic whites (NHW); however, the mechanisms remain unclear. We evaluated differences in insulin physiology and the relationship between obesity and insulin action between NHWs (n=68) compared with Hispanics (n=33) and Asians (n=36). All participants were part of our ongoing registry. All were nondiabetic and had the following measurements: 1) insulin resistance (steady-state plasma glucose, SSPG, using the insulin suppression test, IST); 2) insulin secretion rate (using the graded-glucose infusion test, GGIT); and 3) insulin clearance rate (GGIT). Relationships were compared between measures of obesity (BMI, waist circumference) and SSPG, and between SSPG and insulin secretion rate and clearance rate using multivariate regression. Compared with NHWs, both Hispanics and Asians had higher degrees of insulin resistance than predicted by BMI or WC (Figure, p In conclusion, higher risk for diabetes in Hispanics and Asians may relate to greater risk for obesity-associated insulin resistance. Disclosure S.H. Kim: None.

Objective: Describe baseline characteristics of the NIH/ADA-supported D2d study, the first diabetes prevention trial in the U.S. to apply current ADA diagnostic glycemia criteria. Research Design and Methods: Multicenter (22 sites), randomized, double-blind, placebo-controlled, primary prevention trial testing efficacy of oral daily 4000 IU cholecalciferol (D3) compared to placebo on incident diabetes in adults at high risk. Eligible participants met at least 2-of-3 2010 ADA glycemic criteria for prediabetes: fasting plasma glucose (FPG) 100-125 mg/dL, 2-hour glucose post-75g oral glucose load (2hPG) 140-199 mg/dL, and/or hemoglobin A1c (HbA1c) 5.7-6.4%. Results: 2423 participants (45% women, 33% non-white) were randomized. Mean (±SD) age was 59 (±9.9) years, and BMI was 32 (±4.5) kg/m2. Thirty-five percent met 3 prediabetes criteria, 49% met FPG/HbA1c criteria only, 9.5% met 2hPG/FPG criteria only, and 6.3% met 2hPG/HbA1c criteria only. Black participants had higher HbA1c and lower FPG concentration than white, Asian, and other races (P Conclusions: D2d will establish the efficacy and safety of vitamin D supplementation for diabetes prevention and inform on the natural history of prediabetes per contemporary ADA criteria. Disclosure E. LeBlanc: None. R.E. Pratley: Other Relationship; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eisai Inc., GlaxoSmithKline plc., Janssen Pharmaceuticals, Inc., Lexicon Pharmaceuticals, Inc., Ligand Pharmaceuticals, Inc., Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk Inc., Pfizer Inc., Sanofi-Aventis, Takeda Development Center Americas, Inc.. B. Dawson-Hughes: None. M.A. Staten: None. P.R. Sheehan: None. M.R. Lewis: None. A.L. Peters: Advisory Panel; Self; Abbott, Bigfoot Biomedical. Research Support; Self; Dexcom, Inc.. Advisory Panel; Self; Eli Lilly and Company, Insulin Algorithms, JDRF, Lexicon Pharmaceuticals, Inc., Livongo Health. Research Support; Self; MannKind Corporation. Other Relationship; Self; Medscape. Advisory Panel; Self; Merck & Co., Inc.. Research Support; Self; National Institute of Diabetes and Digestive and Kidney Diseases. Speaker's Bureau; Self; Novo Nordisk Inc.. Advisory Panel; Self; Novo Nordisk Inc., Omada Health, Inc., Optum Rx, Inc., Sanofi. Research Support; Self; T1D Exchange. Advisory Panel; Self; The Endocrine Society. Research Support; Self; The Leona M. and Harry B. Helmsley Charitable Trust. Advisory Panel; Spouse/Partner; Johnson & Johnson Diabetes Institute, LLC.. S.H. Kim: None. R. Chatterjee: None. V. Aroda: Consultant; Self; Novo Nordisk Inc.. Research Support; Self; Novo Nordisk Inc., AstraZeneca, Calibra Medical, Eisai Inc., Sanofi. Consultant; Self; Sanofi. Research Support; Self; Theracos, Inc.. Employee; Spouse/Partner; Merck & Co., Inc.. Other Relationship; Self; American Diabetes Association. Consultant; Self; ADOCIA. C. Chadha: None. A. Pittas: None.

Background While inflammation is associated with obesity and insulin resistance, their inter-relationships in the development of type 2 diabetes or hypertension are not clear. Aim of the study To evaluate inflammatory markers in prediction of type 2 diabetes and hypertension. Methods The study population of this retrospective cohort study consisted of individuals who participated in a comprehensive health screening program with measurement of white blood cell count and C-reactive protein from 2002–2010 (N = 96,606) in nondiabetic and normotensive Koreans. Median follow up time were 3.7 years for incident type 2 diabetes and 3.3 years for hypertension. Multivariate Cox proportional hazards models were performed to assess risk for type 2 diabetes or hypertension by white blood cell or C-reactive protein quartiles with adjustment of various possible confounding factors including insulin resistance. Results During the follow-up period, 1448 (1.5%) developed type 2 diabetes and 10,405 (10.8%) developed hypertension. Among men, comparison of adjusted hazard ratios (HR) for incident type 2 diabetes in the highest versus lowest white blood cell or C-reactive protein quartiles were 1.48 [95% confidence interval (CI), 1.20–1.83] and 1.30 (95% CI, 1.07–1.57), respectively. Among women, white blood cell but not C-reactive protein was significantly associated with type 2 diabetes [HR 1.79 (95% CI 1.24–2.57)]. White blood cell and C-reactive protein quartiles were also modestly associated with incident hypertension in both sexes. Conclusions Although white blood cell and C-reactive protein are associated with adiposity and insulin resistance, these inflammatory markers also independently predict type 2 diabetes and/or hypertension.

Sleep apnoea severity in overweight men may be more closely related to insulin resistance than degree of obesity http://ow.ly/S1LC5

Background and Objective Although salsalate administration consistently lowers plasma triglyceride concentrations in patients with type II diabetes, prediabetes, and/or insulin resistance, changes in low-density lipoprotein cholesterol (LDL-C) concentrations have been inconsistent; varying from no change to a significant increase. To evaluate the clinical relevance of this discordance in more detail, we directly measured LDL-C and obtained a comprehensive assessment of changes in lipid, lipoprotein, and apoprotein concentrations associated with salsalate use in insulin-resistant individuals, overweight or obese, but without diabetes, using vertical auto profile method. Methods A single-blind, randomized, placebo-controlled study was performed in volunteers who were overweight or obese, without diabetes, and insulin resistant on the basis of their steady-state plasma glucose concentration during an insulin suppression test. Participants were randomized 2:1 to receive salsalate 3.5 g/d (n = 27) or placebo (n = 14) for 4 weeks. Comprehensive lipid, lipoprotein, and apoprotein analysis by vertical auto profile was obtained after an overnight fast, before and after study intervention. Results There was no change in directly measured LDL-C concentration in salsalate-treated individuals. However, salsalate administration was associated with various changes considered to decrease atherogenicity; including decreases in triglyceride and total very low–density lipoprotein cholesterol (VLDL-C) concentrations, a shift from small denser LDL lipoproteins toward larger, more buoyant LDL particles, decreases in VLDL 1+2 -C and LDL 4 -C, and nonsignificant decreases in non–high-density lipoprotein cholesterol and apolipoprotein B. No significant changes occurred in the placebo-treated group. Conclusions Atherogenicity of the lipid, lipoprotein, and apoprotein profile of insulin-resistant individuals who were overweight or obese improved significantly in association with salsalate treatment. The clinical importance of this finding awaits further study.