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Purpose To evaluate the safety and potential efficacy of LLF580, a genetically engineered variant of human fibroblast growth factor-21, for triglyceride lowering, weight loss, and hepatic fat reduction. Methods A multicenter, double-blind, parallel design trial in obese, mildly hypertriglyceridemic adults randomized (1:1) to LLF580 300 mg or placebo subcutaneously every 4 weeks for 3 doses. Results Of 64 randomized study participants, 61 (mean ± SD: age 45 ± 11 years, 49% male, 80/15/5% Caucasian/African American/other, body mass index 36.1 ± 3.8 kg/m2) received LLF580 (n = 30) or placebo (n = 31) at 7 research sites in the United States. LLF580 lowered serum triglycerides by 54% (least square mean placebo adjusted change from baseline), total cholesterol 7%, low-density lipoprotein cholesterol 12%, and increased high-density lipoprotein cholesterol 36% compared with placebo (all P < 0.001) over 12 weeks. Substantial reduction of liver fat of 52% over placebo (P < 0.001) was also demonstrated in the setting of improved liver function tests including alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase, the composite enhanced liver fibrosis score, and N-terminal type III collagen propeptide (all P < 0.05). Insulin and C-peptide levels and insulin resistance by homeostatic model assessment for insulin resistance were all lower, and adiponectin higher with LLF580 treatment compared with placebo, whereas fasting glucose and glycated hemoglobin were unchanged. Reductions in biomarkers of bone formation without differences in markers of bone resorption were observed. LLF580 was generally safe and well tolerated, except for higher incidence of generally mild to moderate gastrointestinal adverse effects. Conclusions In obese, mildly hypertriglyceridemic adults, LLF580 was generally safe and demonstrated beneficial effects on serum lipids, liver fat, and biomarkers of liver injury, suggesting it may be effective for treatment of select metabolic disorders including hypertriglyceridemia and nonalcoholic fatty liver disease. Assessments of longer term safety and efficacy are warranted. ClinicalTrials.gov Identifier NCT03466203

BACKGROUND: Higher serum urate levels are associated with an increased risk of diabetic kidney disease. Lowering of the serum urate level with allopurinol may slow the decrease in the glomerular filtration rate (GFR) in persons with type 1 diabetes and early-to-moderate diabetic kidney disease. METHODS: In a double-blind trial, we randomly assigned participants with type 1 diabetes, a serum urate level of at least 4.5 mg per deciliter, an estimated GFR of 40.0 to 99.9 ml per minute per 1.73 m(2) of body-surface area, and evidence of diabetic kidney disease to receive allopurinol or placebo. The primary outcome was the baseline-adjusted GFR, as measured with iohexol, after 3 years plus a 2-month washout period. Secondary outcomes included the decrease in the iohexol-based GFR per year and the urinary albumin excretion rate after washout. Safety was also assessed. RESULTS: A total of 267 patients were assigned to receive allopurinol and 263 to receive placebo. The mean age was 51.1 years, the mean duration of diabetes 34.6 years, and the mean glycated hemoglobin level 8.2%. The mean baseline iohexol-based GFR was 68.7 ml per minute per 1.73 m(2) in the allopurinol group and 67.3 ml per minute per 1.73 m(2) in the placebo group. During the intervention period, the mean serum urate level decreased from 6.1 to 3.9 mg per deciliter with allopurinol and remained at 6.1 mg per deciliter with placebo. After washout, the between-group difference in the mean iohexol-based GFR was 0.001 ml per minute per 1.73 m(2) (95% confidence interval [CI], −1.9 to 1.9; P= 0.99). The mean decrease in the iohexol-based GFR was −3.0 ml per minute per 1.73 m(2) per year with allopurinol and −2.5 ml per minute per 1.73 m(2) per year with placebo (between-group difference, −0.6 ml per minute per 1.73 m(2) per year; 95% CI, −1.5 to 0.4). The mean urinary albumin excretion rate after washout was 40% (95% CI, 0 to 80) higher with allopurinol than with placebo. The frequency of serious adverse events was similar in the two groups. CONCLUSIONS: We found no evidence of clinically meaningful benefits of serum urate reduction with allopurinol on kidney outcomes among patients with type 1 diabetes and early-to-moderate diabetic kidney disease. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; PERL ClinicalTrials.gov number, NCT02017171.)

OBJECTIVE The overall aim of the Alliance of Randomized Trials of Medicine versus Metabolic Surgery in Type 2 Diabetes (ARMMS-T2D) consortium is to assess the durability and longer-term effectiveness of metabolic surgery compared with medical/lifestyle management in patients with type 2 diabetes (NCT02328599). RESEARCH DESIGN AND METHODS A total of 316 patients with type 2 diabetes previously randomly assigned to surgery (N = 195) or medical/lifestyle therapy (N = 121) in the STAMPEDE, TRIABETES, SLIMM-T2D, and CROSSROADS trials were enrolled into this prospective observational cohort. The primary outcome was the rate of diabetes remission (hemoglobin A1c [HbA1c] ≤6.5% for 3 months without usual glucose-lowering therapy) at 3 years. Secondary outcomes included glycemic control, body weight, biomarkers, and comorbidity reduction. RESULTS Three-year data were available for 256 patients with mean 50 ± 8.3 years of age, BMI 36.5 ± 3.6 kg/m2, and duration of diabetes 8.8 ± 5.7 years. Diabetes remission was achieved in more participants following surgery than medical/lifestyle intervention (60 of 160 [37.5%] vs. 2 of 76 [2.6%], respectively; P < 0.001). Reductions in HbA1c (Δ = −1.9 ± 2.0 vs. −0.1 ± 2.0%; P < 0.001), fasting plasma glucose (Δ = −52 [−105, −5] vs. −12 [−48, 26] mg/dL; P < 0.001), and BMI (Δ = −8.0 ± 3.6 vs. −1.8 ± 2.9 kg/m2; P < 0.001) were also greater after surgery. The percentages of patients using medications to control diabetes, hypertension, and dyslipidemia were all lower after surgery (P < 0.001). CONCLUSIONS Three-year follow-up of the largest cohort of randomized patients followed to date demonstrates that metabolic/bariatric surgery is more effective and durable than medical/lifestyle intervention in remission of type 2 diabetes, including among individuals with class I obesity, for whom surgery is not widely used.

AIMS: Insulin potentiates glucose-stimulated insulin secretion. These effects are attenuated in beta cell–specific insulin receptor knockout mice and insulin resistant humans. This investigation examines whether short duration insulin exposure regulates beta cell responsiveness to arginine, a non-glucose secretagogue. MATERIALS AND METHODS: Arginine-stimulated insulin secretion was studied in 10 healthy humans. In each subject arginine was administered as a bolus followed by continuous infusion on two occasions one month apart, after sham/saline or hyperinsulinemic-isoglycemic clamp, respectively providing low and high insulin pre-exposure conditions. Arginine-stimulated insulin secretion was measured by C-peptide deconvolution, and by a selective immunogenic (DAKO) assay for direct measurement of endogenous but not exogenous insulin. RESULTS: Pre-exposure to exogenous insulin augmented arginine-stimulated insulin secretion. The effect was seen acutely following arginine bolus (endogenous DAKO insulin incremental AUC(240–255min) 311.6±208.1 (post-insulin exposure) versus 120.6±42.2 μU/ml•min (sham/saline) (t-test P=0.021)), as well as in response to continuous arginine infusion (DAKO insulin incremental AUC(260–290min) 1095.3±592.1 (sham/saline) versus 564.8±207.1 μU/ml•min (high insulin)(P=0.009)). Findings were similar when beta cell response was assessed using C-peptide, insulin secretion rates by deconvolution, and the C-peptide to glucose ratio. CONCLUSIONS: We demonstrate a physiologic role of insulin in regulation of the beta cell secretory response to arginine.

The regulation of cell-cholesterol efflux is not completely understood. Our aim was to assess the role of HDL- and non-HDL-related parameters in ATP-binding cassette transporter-A1 (ABCA1) and scavenger receptor class B-type-I (SRBI) cell-cholesterol efflux capacity (CEC) in coronary heart disease (CHD) cases and controls.Lipids and apoA-I-containing HDL particles (by 2D gel-electrophoresis and immunodetection) were measured in 534 statin-treated CHD patients and in 1076 age-, gender-, and BMI-matched controls. ABCA1-CEC and SRBI-CEC were measured in apoB-depleted serum of 100 cases and 100 controls.Cases had significantly higher concentrations of preβ-1 particles (88%) and ABCA1-CEC (34%) compared to controls. ABCA1-CEC was positively correlated with the concentrations of preβ-1 particles, triglycerides, small-dense (sd) LDL-C, and LDL-C in both cases and controls. Moreover, both the concentration and the functionality of preβ-1 particles (ABCA1-CEC/mg preβ-1) were positively associated with the concentrations of sdLDL-C and triglycerides. Cases had 27% lower levels of large HDL particles but similar SRBI-CEC compared to controls. SRBI-CEC was correlated positively with HDL-C, apoA-I, and large-HDL particle levels. However, the functionality of large-HDL particles (SRBI-CEC/mg large particles) was significantly and positively correlated with the preβ-1/α-1 ratio, sdLDL-C, and triglycerides.CHD patients have significantly higher concentration, but less functional preβ-1 particles in term of cholesterol efflux capacity compared to controls. Triglyceride-rich lipoproteins have significant influence on either the concentration or the functionality or both of HDL particles and consequently HDL-CEC.

Few randomized trials have compared surgical versus lifestyle and pharmacologic approaches for type 2 diabetes (T2D) patients with mild to moderate obesity.This study examined resolution of hyperglycemia (A1C6.5% and fasting glucose126 mg/dL) 3 years after randomization to either a laparoscopic adjustable gastric band (LAGB) or 1-year diabetes and weight management (DWM) program.University medical center, United States.Forty T2D patients (mean ± SD: age, 51.3 ±10.0 yr; weight 109.5 ± 15.0 kg; body mass index [BMI] 36.5 ± 3.7 kg/mAt 3 years, 13% of 16 patients in LAGB and 5% of 17 patients in DWM achieved resolution of hyperglycemia (P = .601), with a modestly greater reduction in antidiabetic medications in the surgical group (P = .054). Reductions from baseline in A1C were sustained at 3 years in LAGB (-.82% [95% CI: -1.62 to -.01], P = .046) compared with DWM (+.23% [95% CI: -.57 to 1.03], P = .567). The surgical group had greater weight loss (-12.0 kg [95% CI: -15.9 to -8.1] versus -4.8 [95% CI: -8.6 to -.9], P = .010). HDL-cholesterol increased more after surgery (P = .003), but changes in triglycerides, LDL-cholesterol, and blood pressure did not differ between treatments. Diabetes- and obesity-specific quality of life improved comparably with both therapies.Achievement of American Diabetes Association targets for glucose, lipids, and blood pressure was similar with both treatment strategies. LAGB leads to greater sustained weight loss and higher HDL cholesterol compared with a DWM program. These findings may help guide patients with T2D and obesity when exploring options for diabetes and weight management.

OBJECTIVE Higher serum uric acid (SUA) is associated with diabetic kidney disease (DKD). Preventing Early Renal Loss in Diabetes (PERL) evaluates whether lowering SUA with allopurinol slows glomerular filtration rate (GFR) loss in people with type 1 diabetes (T1D) and mild to moderate DKD. We present the PERL rationale, design, and baseline characteristics. RESEARCH DESIGN AND METHODS This double-blind, placebo-controlled, multicenter trial randomized 530 participants with T1D, estimated GFR (eGFR) of 40–99.9 mL/min/1.73 m2, SUA ≥4.5 m/dL, and micro- to macroalbuminuric DKD or normoalbuminuria with declining kidney function (NDKF) (defined as historical eGFR decline ≥3 mL/min/1.73 m2/year) to allopurinol or placebo. The primary outcome is baseline-adjusted iohexol GFR (iGFR) after 3 years of treatment plus a 2-month washout period. RESULTS Participants are 66% male and 84% white. At baseline, median age was 52 years and diabetes duration was 35 years, 93% of participants had hypertension, and 90% were treated with renin-angiotensin system inhibitors (median blood pressure 127/71 mmHg). Median HbA1c was 8%, SUA 5.9 mg/dL, iGFR 68 mL/min/1.73 m2, and historical eGFR slope −3.5 mL/min/1.73 m2/year. Compared with participants with albuminuria (n = 419), those with NDKF (n = 94) were significantly older (56 vs. 52 years), had lower HbA1c (7.7 vs. 8.1%) and SUA (5.4 vs. 6.0 mg/dL), and had higher eGFR (82 vs. 74 mL/min/1.73 m2) and historical eGFR loss (−4.7 vs. −2.5 mL/min/1.73 m2/year). These differences persisted when comparing groups with similar rates of historical eGFR loss. CONCLUSIONS PERL will determine the effect of allopurinol on mild to moderate DKD in T1D, with or without albuminuria. Participants with normoalbuminuria and rapid GFR loss manifested many DKD risk factors of those with albuminuria, but with less severity.

Background: Several glucagon-like peptide receptor agonists (GLP-1RA) and sodium-glucose cotransporter-2 inhibitors (SGLT2i) have demonstrated cardiovascular benefit in type 2 diabetes in large randomized controlled trials in patients with established cardiovascular disease or multiple risk factors. However, few trial participants were on both agents, and it remains unknown whether the addition of SGLT2i to GLP-1RA therapy has further cardiovascular benefits. Methods: Patients adding either SGLT2i or sulfonylureas to baseline GLP-1RA were identified within 3 US claims datasets (2013–2018) and were 1:1 propensity score–matched, adjusting for >95 baseline covariates. The primary outcomes were a composite cardiovascular end point (comprising myocardial infarction, stroke, and all-cause mortality) and heart failure hospitalization. Adjusted hazard ratios (HRs) and 95% CIs were estimated in each dataset and pooled through fixed-effects meta-analysis. Results: Among 12 584 propensity score–matched pairs (mean [SD] age, 58.3 [10.9] years; 48.2% male) across the 3 datasets, there were 107 composite cardiovascular end point events (incidence rate per 1000 person-years, 9.9 [95% CI, 8.1–11.9]) among SGLT2i initiators compared with 129 events (incidence rate, 13.0 [95% CI, 10.9–15.3]) among sulfonylurea initiators, corresponding to an adjusted pooled HR of 0.76 (95% CI, 0.59–0.98); this decrease in composite cardiovascular end point was driven by numeric decreases in the risk of myocardial infarction (HR, 0.71 [95% CI, 0.51–1.003]) and all-cause mortality (HR, 0.68 [95% CI, 0.40–1.14]) but not stroke (HR, 1.05 [95% CI, 0.62–1.79]). For the outcome of heart failure hospitalization, there were 141 events (incidence rate, 13.0 [95% CI, 11.0–15.2]) among SGLT2i initiators versus 206 events (incidence rate, 20.8 [95% CI, 18.1–23.8]) among sulfonylurea initiators, corresponding to an adjusted pooled HR of 0.65 (95% CI, 0.50–0.82). Conclusions: Risk of residual confounding cannot be fully excluded. Individual therapeutic agents within each class may have different magnitudes of effect. In this large real-world cohort of patients with diabetes already on GLP-1RA, addition of SGLT2i conferred greater cardiovascular benefit compared with addition of sulfonylurea. The magnitude of the cardiovascular risk reduction was comparable with the benefit seen in cardiovascular outcome trials of SGLT2i versus placebo, where baseline GLP-1RA use was minimal.

SGLT2 inhibitors (SGLT2i) may provide cardiovascular (CV) benefit when added to GLP-1 receptor agonists (GLP-1RA) given the orthogonal mechanisms of action, although combined use is incompletely understood. Patients adding either SGLT2i or sulfonylureas to baseline GLP-1RA were identified within 3 U.S. datasets (2013-2018) and were 1:1 propensity score matched (PSM) adjusting for >95 baseline covariates. Primary outcomes were 1) a composite CV endpoint (comprised of myocardial infarction, stroke, or all-cause mortality) and 2) heart failure hospitalization. We estimated pooled hazard ratios (HR) and 95% confidence intervals (CI). Among 12,584 1:1 PSM pairs (mean [SD] age 58.3 [10.9]; male (48.2%)), there were 102 composite CV events (incidence rate per 1,000 person-years (IR) = 9.4) among SGLT2i initiators compared to 124 events (IR = 12.5) among sulfonylurea initiators, with an adjusted HR of 0.76 (95% CI: 0.59, 0.99), over a mean 10-month follow-up (Table). For the outcome of heart failure hospitalization, there were 141 (IR = 13.0) v 206 (IR = 20.8) events, with an adjusted HR of 0.65 (95% CI: 0.52, 0.80). Thus, adding SGLT2i to GLP-IRA therapy confers greater CV benefit compared to adding sulfonylureas, with a magnitude of risk reduction comparable to the benefit seen in CV outcome trials of SGLT2i vs. usual care in patients with minimal background GLP-IRA use. Disclosure C. Dave: None. S.C. Kim: Research Support; Self; AbbVie Inc., Bristol-Myers Squibb. A. Goldfine: Employee; Self; Novartis AG. R. Glynn: Research Support; Self; Amarin Corporation, AstraZeneca, Kowa Research Institute, Inc., Novartis Pharmaceuticals Corporation, Pfizer Inc. E. Patorno: Other Relationship; Self; Boehringer Ingelheim International GmbH.

To improve the power of mediation in high-throughput studies, here we introduce High-throughput mediation analysis (Hitman), which accounts for direction of mediation and applies empirical Bayesian linear modeling. We apply Hitman in a retrospective, exploratory analysis of the SLIMM-T2D clinical trial in which participants with type 2 diabetes were randomized to Roux-en-Y gastric bypass (RYGB) or nonsurgical diabetes/weight management, and fasting plasma proteome and metabolome were assayed up to 3 years. RYGB caused greater improvement in HbA1c, which was mediated by growth hormone receptor (GHR). GHR’s mediation is more significant than clinical mediators, including BMI. GHR decreases at 3 months postoperatively alongside increased insulin-like growth factor binding proteins IGFBP1/BP2; plasma GH increased at 1 year. Experimental validation indicates (1) hepatic GHR expression decreases in post-bariatric rats; (2) GHR knockdown in primary hepatocytes decreases gluconeogenic gene expression and glucose production. Thus, RYGB may induce resistance to diabetogenic effects of GH signaling. Trial Registration: Clinicaltrials.gov NCT01073020., Factors underlying the effects of gastric bypass surgery on glucose homeostasis are incompletely understood. Here the authors developed and applied high-throughput mediation analysis to identify proteome/metabolome mediators of improved glucose homeostasis after to gastric bypass surgery, and report that improved glycemia was mediated by the growth hormone receptor.

ContextPlasma betaine correlates with insulin sensitivity in humans. Betaine supplementation improves metabolic effects in mice fed a high-fat diet.ObjectiveTo assess metabolic effects of oral betaine in obese participants with prediabetes.DesignA 12-week, parallel arm, randomized, double-masked, placebo-controlled trial.SettingUniversity-affiliated hospital.Participants and InterventionsPersons with obesity and prediabetes (N = 27) were randomly assigned to receive betaine 3300 mg orally twice daily for 10 days, then 4950 mg twice daily for 12 weeks, or placebo.Main Outcome MeasuresChanges from baseline in insulin sensitivity, glycemia, hepatic fat, and endothelial function.ResultsThere was a 16.5-fold increase in plasma dimethylglycine [dimethylglycine (DMG); P < 0.0001] levels, but modest 1.3- and 1.5-fold increases in downstream serine and methionine levels, respectively, in the betaine vs placebo arm. Betaine tended to reduce fasting glucose levels (P = 0.08 vs placebo) but had no other effect on glycemia. Insulin area under curve after oral glucose was reduced for betaine treatment compared with placebo (P = 0.038). Insulin sensitivity, assessed by euglycemic hyperinsulinemic clamp, was not improved. Serum total cholesterol levels increased after betaine treatment compared with placebo (P = 0.032). There were no differences in change in intrahepatic triglyceride or endothelial function between groups.ConclusionDMG accumulation supports DMG dehydrogenase as rate limiting for betaine metabolism in persons with prediabetes. Betaine had little metabolic effect. Additional studies may elucidate mechanisms contributing to differences between preclinical and human responses to betaine, and whether supplementation of metabolites downstream of DMG improves metabolism.

OBJECTIVE To compare the effect of Roux-en-Y gastric bypass (RYGB) surgery versus intensive medical diabetes and weight management (IMWM) on clinical and patient-reported outcomes in obese patients with type 2 diabetes. RESEARCH DESIGN AND METHODS We prospectively randomized 38 obese patients with type 2 diabetes (15 male and 23 female, with mean ± SD weight 104 ± 16 kg, BMI 36.3 ± 3.4 kg/m2, age 52 ± 6 years, and HbA1c 8.5 ± 1.3% [69 ± 14 mmol/mol]) to laparoscopic RYGB (n = 19) or IMWM (n = 19). Changes in weight, HbA1c, cardiovascular risk factors (UKPDS risk engine), and self-reported health status (the 36-Item Short-Form [SF-36] survey, Impact of Weight on Quality of Life [IWQOL] instrument, and Problem Areas in Diabetes Survey [PAID]) were assessed. RESULTS After 3 years, the RYGB group had greater weight loss (mean −24.9 kg [95% CI −29.5, −20.4] vs. −5.2 [−10.3, −0.2]; P < 0.001) and lowering of HbA1c (−1.79% [−2.38, −1.20] vs. −0.39% [−1.06, 0.28] [−19.6 mmol/mol {95% CI −26.0, −13.1} vs. −4.3 {−11.6, 3.1}]; P < 0.001) compared with the IMWM group. Changes in cardiometabolic risk for coronary heart disease and stroke were all more favorable in RYGB versus IMWM (P < 0.05 to P < 0.01). IWQOL improved more after RYGB (P < 0.001), primarily due to subscales of physical function, self-esteem, and work performance. SF-36 and PAID scores improved in both groups, with no difference between treatments. A structural equation model demonstrated that improvement in overall quality of life was more strongly associated with weight loss than with improved HbA1c and was manifest by greater improvements in IWQOL than with either SF-36 or PAID. CONCLUSIONS Three years after randomization to RYGB versus IMWM, surgery produced greater weight loss, lower HbA1c, reduced cardiovascular risk, and improvements in obesity-related quality of life in obese patients with type 2 diabetes.

OBJECTIVE The rs7903146 T allele in transcription factor 7 like 2 (TCF7L2) is strongly associated with type 2 diabetes (T2D), but the mechanisms for increased risk remain unclear. We evaluated the physiologic and hormonal effects of TCF7L2 genotype before and after interventions that influence glucose physiology. RESEARCH DESIGN AND METHODS We genotyped rs7903146 in 608 individuals without diabetes and recorded biochemical data before and after 1) one dose of glipizide (5 mg) on visit 1 and 2) a 75-g oral glucose tolerance test (OGTT) performed after administration of metformin 500 mg twice daily over 2 days. Incretin levels were measured in 150 of the 608 participants. RESULTS TT risk-allele homozygotes had 1.6 mg/dL higher baseline fasting glucose levels and 2.5 pg/mL lower glucagon levels per T allele than carriers of other genotypes at baseline. In a subset of participants, the T allele was associated with higher basal glucagon-like peptide 1 (GLP-1) levels at visit 1 (β = 1.52, P = 0.02 and β = 0.96, P = 0.002 for total and active GLP-1, respectively), and across all points of the OGTT after metformin administration. Regarding drug response, the T allele was associated with a shorter time (β = −7.00, P = 0.03) and a steeper slope (β = 0.23, P = 0.04) to trough glucose levels after glipizide administration, and lower visit 2 fasting glucose level adjusted for visit 1 fasting glucose level (β = −1.02, P = 0.04) and a greater decline in glucose level between visits (β = −1.61, P = 0.047) after metformin administration. CONCLUSIONS Our findings demonstrate that common variation at TCF7L2 influences acute responses to both glipizide and metformin in people without diabetes and highlight altered incretin signaling as a potential mechanism by which TCF7L2 variation increases T2D risk.

Summary: Liver-specific disruption of the type 2 deiodinase gene (Alb-D2KO) results in resistance to both diet-induced obesity and liver steatosis in mice. Here, we report that this is explained by an ∼60% reduction in liver zinc-finger protein-125 (Zfp125) expression. Zfp125 is a Foxo1-inducible transcriptional repressor that causes lipid accumulation in the AML12 mouse hepatic cell line and liver steatosis in mice by reducing liver secretion of triglycerides and hepatocyte efflux of cholesterol. Zfp125 acts by repressing 18 genes involved in lipoprotein structure, lipid binding, and transport. The ApoE promoter contains a functional Zfp125-binding element that is also present in 17 other lipid-related genes repressed by Zfp125. While liver-specific knockdown of Zfp125 causes an “Alb-D2KO-like” metabolic phenotype, liver-specific normalization of Zfp125 expression in Alb-D2KO mice rescues the phenotype, restoring normal susceptibility to diet-induced obesity, liver steatosis, and hypercholesterolemia. : Mice with liver-specific disruption of the type 2 deiodinase gene are resistant to both diet-induced obesity and hepatosteatosis. Fernandes et al. show that this is due to a reduction in liver expression of zinc-finger protein-125, a Foxo1-inducible transcriptional repressor that causes lipid accumulation by reducing hepatic secretion of VLDL. Keywords: deiodinase, steatosis, cholesterol, triglycerides, zinc finger protein 125, liver, hepatocytes, transcriptional repressor

To assess long-term efficacy and safety of salsalate to improve glycemia in persons with diabetes risk, who are overweight with statin-treated, stable coronary heart disease.Glycemic status was assessed in 192 persons without diabetes at baseline in a pre-specified secondary analysis from Targeting INflammation Using SALsalate in CardioVascular Disease (TINSAL-CVD), a multi-center, double-masked, randomized (1:1), placebo-controlled, parallel clinical trial.Participants were mostly Caucasian males, age 60±7 years, BMI 31.4±3.0 kg/mSalsalate improves glycemia in obese persons at increased risk for diabetes, and hence may decrease risk of incident type 2 diabetes. Salsalate may inform new therapeutic approaches for diabetes prevention, but renal safety may limit clinical utility.

AIMS: To examine whether the presence of two common missense variants in the CYP2C9 gene (rs1799853, encoding Arg144Cys and denoted as *2, and rs1057910, encoding Ile359Leu and denoted as *3) influences the acute physiological response to a single glipizide dose in individuals naïve to diabetes medications. METHODS: In the Study to Understand the Genetics of the Acute Response to Metformin and Glipizide in Humans (SUGAR-MGH), 786 individuals genotyped for rs1799853/rs41291560 (*2) and rs1057910/rs9332214 (*3) were treated with 5 mg glipizide in the fasting state. Glucose and insulin levels were measured at baseline, 30, 60, 90, 120, 180 and 240 min for calculation of phenotypic endpoints of glipizide response. The challenge was aborted as a result of hypoglycaemia, defined as glucose

Molecular mechanisms by which Roux-en-Y gastric bypass (RYGB) improves glycemic control and metabolism in type 2 diabetes (T2D) remain incompletely understood. In the SLIMM-T2D trial, participants with T2D were randomized to RYGB or nonsurgical management and their fasting plasma proteome and metabolome were analyzed for up to 3 years. To identify analytes that mediate improvement in outcomes, we developed a high-throughput mediation analysis method (Hitman), which is significantly more powerful than existing methods. Top-ranking analyte mediators of glycemia improvement were growth hormone receptor and prolylhydroxyproline, which were more significant than any clinical mediator, including BMI. Beta-alanine and Histidine Metabolism (both including CNDP1) were top differentially regulated pathways, and Valine, Leucine and Isoleucine Degradation was also a top differentially-regulated pathway and a top mediator of improvement in insulin resistance. The identified analytes may serve as novel targets for T2D therapy. More broadly, Hitman can identify analyte mediators of outcomes in randomized trials for which high-throughput data are available.

OBJECTIVE: Insulin resistance is associated with increased lipolysis and elevated concentrations of free fatty acids, which in turn contribute to impaired vascular function. We hypothesized that lowering free fatty acids with acipimox, a nicotinic acid derivative that impairs free fatty acid efflux, would improve endothelial function, measured by flow-mediated dilation, in individuals with metabolic syndrome. METHODS: Eighteen subjects with metabolic syndrome and 17 healthy controls were enrolled and treated with acipimox 250 mg orally every 6 hours, or placebo, for 7 days in a randomized, double-blind, crossover trial. RESULTS: Acipimox reduced free fatty acid concentrations among individuals with metabolic syndrome to near normal levels (P=0.01), but there was no change among healthy controls (P=0.17). Acipimox did not improve endothelial-dependent flow-mediated dilation in either group (metabolic syndrome: P=0.42, and healthy controls: P=0.16), although endothelial-independent nitroglycerin-mediated dilation among those with metabolic syndrome tended to increase (20.3%, P=0.06). There were no changes in blood lipids or markers of inflammation following therapy. There was minimal correlation between change in flow-mediated dilation and baseline measures of body-mass index (ρ=−.09) or waist circumference (ρ=−0.15). CONCLUSIONS: In groups with normal or elevated baseline free fatty acids, short-term reductions do not improve endothelial function assessed by flow-mediated dilation.

BACKGROUND: Hypoglycemia is an increasingly recognized complication of bariatric surgery. Mechanisms contributing to glucose lowering remain incompletely understood. We aimed to identify differentially abundant plasma proteins in patients with post-bariatric hypoglycemia (PBH) after roux-en-Y gastric bypass (RYGB), compared to asymptomatic post-RYGB. METHODS: Proteomic analysis of blood samples collected after overnight fast and mixed meal challenge in individuals with PBH, asymptomatic RYGB, severe obesity, or overweight recruited from outpatient hypoglycemia or bariatric clinics. RESULTS: The top-ranking differentially abundant protein at 120 minutes after mixed meal was fibroblast growth factor 19 (FGF-19), an intestinally-derived hormone regulated by bile acid/FXR signaling; levels were 2.4-fold higher in PBH vs. asymptomatic post-RYGB (mean ± SEM: 1094±141 vs. 428±45, P

Background The purpose of this study was to compare effects of Roux-en-Y gastric bypass versus a multidisciplinary, group-based medical diabetes and weight management program on physical fitness and behaviors. Methods Physical behavior and fitness were assessed in participants of the study Surgery or Lifestyle With Intensive Medical Management in the Treatment of Type 2 Diabetes (SLIMM-T2D) (NCT01073020), a randomized, parallel-group trial conducted at a US academic hospital and diabetes clinic with 18- to 24-month follow-up. Thirty-eight type 2 diabetes patients with hemoglobin A 1c ≥6.5% and body mass index 30-42 kg/m 2 were randomized to Roux-en-Y gastric bypass or the medical program. A 6-minute walk test to evaluate fitness, self-reported physical activity, standardized physical surveys, and cardiometabolic risk assessment were performed at baseline and after intervention. Results Both groups similarly improved 6-minute walk test distance, with greater improvements in oxygen saturation and reduced heart rate after surgery. Self-reported physical activity improved similarly at 18-24 months after interventions, although exercise increased gradually after surgery, whereas early substantial increases in the medical group were not fully sustained. Self-reported total and physical health were similar by Short Form-36 but improved more in the Impact of Weight on Quality of Life survey after surgery. Improvement in cardiovascular risk scores, HbA 1c , and body mass index were greater after surgery. Conclusion In this small, randomized study, both interventions led to therapeutic lifestyle changes and improved objective and self-reported physical fitness. Greater improvements in heart rate, oxygen saturation, and perceived impact of weight on health were seen after surgery, which could be attributable to greater weight loss. The clinical importance of these improvements with greater weight loss warrants further investigation.

Objective Plasma levels of branched-chain amino acids (BCAA) are consistently elevated in obesity and type 2 diabetes (T2D) and can also prospectively predict T2D. However, the role of BCAA in the pathogenesis of insulin resistance and T2D remains unclear. Methods To identify pathways related to insulin resistance, we performed comprehensive gene expression and metabolomics analyses in skeletal muscle from 41 humans with normal glucose tolerance and 11 with T2D across a range of insulin sensitivity (SI, 0.49 to 14.28). We studied both cultured cells and mice heterozygous for the BCAA enzyme methylmalonyl-CoA mutase (Mut) and assessed the effects of altered BCAA flux on lipid and glucose homeostasis. Results Our data demonstrate perturbed BCAA metabolism and fatty acid oxidation in muscle from insulin resistant humans. Experimental alterations in BCAA flux in cultured cells similarly modulate fatty acid oxidation. Mut heterozygosity in mice alters muscle lipid metabolism in vivo, resulting in increased muscle triglyceride accumulation, increased plasma glucose, hyperinsulinemia, and increased body weight after high-fat feeding. Conclusions Our data indicate that impaired muscle BCAA catabolism may contribute to the development of insulin resistance by perturbing both amino acid and fatty acid metabolism and suggest that targeting BCAA metabolism may hold promise for prevention or treatment of T2D., Highlights • Human insulin resistance is associated with perturbed muscle BCAA metabolism. • Experimental modulation of BCAA metabolic flux alters fatty acid oxidation in vitro. • Mut heterozygosis leads to increased body weigh and muscle TAG accumulation in mice.

We aimed to compare metabolic control in adults with diabetes in the general population to those newly referred to a diabetes center and after 1 year of specialty care.We performed a retrospective comparison of adults with diabetes aged ≥20 years data from the National Health and Nutrition Examination Survey (NHANES, n = 1,674) and a diabetes center (n = 3,128) from 2005-2010. NHANES participants represented the civilian, non-institutionalized U.S.Diabetes center referrals lived primarily around eastern Massachusetts. The proportion attaining targets for glycated hemoglobin A1c (A1c), blood pressure (BP), low-density lipoprotein (LDL) cholesterol, or all 3 (ABC control) and the proportion prescribed medications to lower A1c, BP, or cholesterol were evaluated.Compared to the general sample, a smaller proportion of new diabetes center referrals had A1c7% (53 mmol/mol, 24% vs. 53%, P.001), BP130/80 mm Hg (38% vs. 50%, P.001), and ABC control (5.6% vs. 17%, P.001) but not LDL100 mg/dL (2.6 mmol/L, 54% vs. 53%, P = .65). After 1 year, more diabetes center referrals attained targets for A1c (40%), BP (38%), LDL (67%), and ABC control (15%) (P.001 for all versus baseline). ABC control was not different between the general sample and diabetes center referrals at 1 year (P = .16). After 1 year, a greater percentage of diabetes center referrals compared to the general sample were prescribed medications to lower glucose (95% vs. 72%), BP (79% vs. 64%), and cholesterol (77% vs. 54%)(all P.001).Compared to the general population, glycemic control was significantly worse for adults newly referred to the diabetes center. Within 1 year of specialty care, ABC control increased 270% in the setting of significant therapy escalation.A1c = glycated hemoglobin A1c ABC = composite of A1c, blood pressure, and cholesterol ACEi = angiotensin-converting enzyme inhibitor ARB = angiotensin receptor blocker BMI = body mass index BP = blood pressure EHR = electronic health record LDL = low-density lipoprotein NCHS = National Center for Health Statistics NHANES = National Health and Nutrition Examination Survey PCP = primary care provider.

The U.S. Food and Drug Administration (FDA) issued a Guidance for Industry in 2008 defining preapproval and postapproval requirements for the demonstration of cardiovascular safety for all new medications developed for glycemic management in type 2 diabetes. Seventeen large, prospective, randomized, controlled clinical trials involving more than 140,000 subjects thus far have been completed or are ongoing in accordance with this guidance. All five of the completed trials, involving three different drug classes, have met their primary objective to exclude an unacceptable level of ischemic cardiovascular risk as defined in the FDA guidance. Additionally, one trial found an increased risk of hospitalization for heart failure, and another demonstrated decreases in cardiovascular mortality and hospitalization for heart failure. Given that a heightened risk of cardiovascular ischemic events has not been demonstrated across several classes of new diabetes drugs, we believe it is time for the scientific community and the FDA to consider a more targeted approach to what is, in effect, a global cardiovascular safety trial requirement for all new type 2 diabetes medications in development.

BACKGROUND: Mechanisms of metabolic improvement after bariatric surgery remain incompletely understood. Intestinal glucose uptake is increased after gastric bypass in rodents, potentially contributing to reduced blood glucose and type 2 diabetes remission. OBJECTIVE: We assessed whether intestinal glucose uptake is increased in humans after gastric surgery. SETTING: University Hospital, United States. METHODS: In a retrospective, case-control cohort study, positron emission tomography-computerized tomography scans performed for clinical indications were analyzed to quantify intestinal glucose uptake in patients with or without history of gastric surgery. We identified 19 cases, defined as patients over age 18 with prior gastric surgery (Roux-en-Y gastric bypass [n = 10], sleeve gastrectomy [n = 1], or Billroth I [n = 2] or II gastrectomy [n = 6]), and 43 controls without gastric surgery, matched for age, sex, and indication for positron emission tomography-computerized tomography. Individuals with gastrointestinal malignancy or metformin treatment were excluded. Images were obtained 60 minutes after (18) F-fluorodeoxyglucose injection (4.2 MBq/kg), and corrected by attenuation; noncontrast low-dose computerized tomography was obtained in parallel. Fused and nonfused images were analyzed; standardized uptake values were calculated for each region by volumes of interest at the region of highest activity. RESULTS: Both standardized uptake values maximum and mean were significantly increased by 41% to 98% in jejunum, ascending, and transverse colon in patients with prior gastric surgery (P < .05 versus controls). CONCLUSION: Intestinal glucose uptake is increased in patients with prior gastric surgery. Prospective studies are important to dissect the contributions of weight loss, dietary factors, and systemic metabolism, and to determine the relationship with increased insulin-independent glucose uptake and reductions in glycemia. (Surg Obes Relat Dis 2019;000:1–7.) © 2019 American Society for Bariatric Surgery. Published by Elsevier Inc. All rights reserved.

To identify molecular mechanisms contributing to postoperative metabolic improvements after Roux-en-Y gastric bypass (RYGB), we performed comprehensive proteomic analysis of fasting human plasma samples obtained from the SLIMM-T2D longitudinal clinical trial, which randomized obese individuals with T2D to RYGB surgery or a one-year intensive medical diabetes and weight management (DWM) program, and followed them for 3 years. Somalogic proteomic analysis was performed on plasma collected in the fasting state at baseline and during longitudinal follow-up, and proteins differentially abundant in RYGB vs. DWM at each time point were identified. The protein with highest magnitude of differential abundance at 3 years was insulin-like growth factor binding protein 2 (IGFBP2), upregulated by 2.2-fold in RYGB vs. DWM (p=4.37E-06); differences were confirmed by ELISA. IGFBP2 inversely correlated at 3 years with BMI (r=-0.74, p=5.31E-05) and HbA1c (r=-0.68, p=0.00004). Notably, IGFBP2 levels were increased at the first postoperative study visit (10% weight loss) following RYGB or at similar weight loss for the DWM group, suggesting an early weight-independent contribution. IGFBP2 is predominantly expressed in liver and upregulated after RYGB in mice (2.8-fold at 8 weeks, GSE68812). To identify IGFBP2-dependent mechanisms contributing to improved hepatic metabolism, we overexpressed mouse IGFBP2 or control vector in mouse AML12 hepatocytes, achieving a 6-fold increase in IGFPB2 protein. qPCR revealed 15-30% downregulation of lipogenic genes (e.g., Fasn, Srebp1) with a 2-fold increase in expression of genes regulating fatty acid oxidation (e.g., Ppara, Ppargc1a). Analysis of metabolism (Seahorse flux analyzer) revealed increased fatty acid oxidation (3-fold, p In conclusion, increased IGFBP2 expression may contribute to improved hepatic lipid oxidative metabolism, and thus induce systemic metabolic improvement after RYGB surgery. Disclosure Y. Yuchi: None. W. Cai: None. T. Takagi: None. H. Pan: None. J. Dreyfuss: None. K. Foster: None. A.H. Vernon: None. D.C. Simonson: Advisory Panel; Self; GI Windows, Inc.. Stock/Shareholder; Self; GI Windows, Inc.. Stock/Shareholder; Spouse/Partner; Phase V Technologies, Inc. A. Goldfine: Employee; Self; Novartis AG. A. Hoeflich: None. M.E. Patti: Research Support; Self; Janssen Pharmaceuticals, Inc.. Other Relationship; Self; Xeris Pharmaceuticals, Inc.. Research Support; Self; Ethicon US, LLC., Coviden, MedImmune. Other Relationship; Self; Novo Nordisk Inc., XOMA Corporation, AstraZeneca, Nestlé. Research Support; Self; Dexcom, Inc.. Consultant; Self; Eiger BioPharmaceuticals.

Background: Dietary supplement use is widespread in the United States. Although it has been suggested in both in vitro and small in vivo human studies that chromium has potentially beneficial effects in type 2 diabetes (T2D), chromium supplementation in diabetes has not been investigated at the population level. Objective: The objective of this study was to examine the use and potential benefits of chromium supplementation in T2D by examining NHANES data. Methods: An individual was defined as having diabetes if he or she had a glycated hemoglobin (HbA1c) value of ≥6.5%, or reported having been diagnosed with diabetes. Data on all consumed dietary supplements from the NHANES database were analyzed, with the OR of having diabetes as the main outcome of interest based on chromium supplement use. Results: The NHANES for the years 1999–2010 included information on 62,160 individuals. After filtering the database for the required covariates (gender, ethnicity, socioeconomic status, body mass index, diabetes diagnosis, supplement usage, and laboratory HbA1c values), and when restricted to adults, the study cohort included 28,539 people. A total of 58.3% of people reported consuming a dietary supplement in the previous 30 d, 28.8% reported consuming a dietary supplement that contained chromium, and 0.7% consumed supplements that had “chromium” in the title. Compared with nonusers, the odds of having T2D (HbA1c ≥6.5%) were lower in persons who consumed chromium-containing supplements within the previous 30 d than in those who did not (OR: 0.73; 95% CI: 0.62, 0.86; P = 0.001). Supplement use alone (without chromium) did not influence the odds of having T2D (OR: 0.89; 95% CI: 0.77, 1.03; P = 0.11). Conclusions: Over one-half the adult US population consumes nutritional supplements, and over one-quarter consumes supplemental chromium. The odds of having T2D were lower in those who, in the previous 30 d, had consumed supplements containing chromium. Given the magnitude of exposure, studies on safety and efficacy are warranted.

Wound healing is impaired in diabetes, resulting in significant morbidity and mortality. Neutrophils are the main leukocytes involved in the early phase of healing. As part of their anti-microbial defense, neutrophils form extracellular traps (NETs) by releasing decondensed chromatin lined with cytotoxic proteins. NETs, however, can also induce tissue damage. Here we show that neutrophils isolated from type 1 and type 2 diabetic humans and mice were primed to produce NETs (a process termed NETosis). Expression of peptidylarginine deiminase 4 (PAD4, encoded by Padi4 in mice), an enzyme important in chromatin decondensation, was elevated in neutrophils from individuals with diabetes. When subjected to excisional skin wounds, wild-type (WT) mice produced large quantities of NETs in wounds, but this was not observed in Padi4(-/-) mice. In diabetic mice, higher levels of citrullinated histone H3 (H3Cit, a NET marker) were found in their wounds than in normoglycemic mice and healing was delayed. Wound healing was accelerated in Padi4(-/-) mice as compared to WT mice, and it was not compromised by diabetes. DNase 1, which disrupts NETs, accelerated wound healing in diabetic and normoglycemic WT mice. Thus, NETs impair wound healing, particularly in diabetes, in which neutrophils are more susceptible to NETosis. Inhibiting NETosis or cleaving NETs may improve wound healing and reduce NET-driven chronic inflammation in diabetes.

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.

Objective Hyperinsulinemic hypoglycemia with neuroglycopenia is a rare complication following Roux-en-Y gastric bypass (RYGB) surgery for weight management. Insulin secretion and action in response to oral and intravenous stimuli in persons with and without neuroglycopenia following RYGB are evaluated in this study. Methods Cross-sectional cohort studies were performed at a single academic institution to assess insulin secretion and action during oral mixed meal tolerance test and intravenous glucose tolerance test (IVGTT). Results Insulin secretion was increased more following oral mixed meal than intravenous glucose in individuals with neuroglycopenia compared to the asymptomatic group. Reduced insulin clearance did not contribute to higher insulinemia. Glucose effectiveness at zero insulin, estimated during the IVGTT, was also higher in those with neuroglycopenia. Insulin sensitivity did not differ between groups. Conclusions Increased beta-cell response to oral stimuli and insulin-independent glucose disposal may both contribute to severe hypoglycemia after RYGB.

Higher hemoglobin A1c (HbA1c) is associated with lower cognitive function in type 2 diabetes. To determine whether associations persist at lower levels of dysglycemia in patients who have established cardiovascular disease, cognitive performance was assessed in the Targeting INflammation Using SALsalate in CardioVascular Disease (TINSAL-CVD) trial.The age-adjusted relationships between HbA1c and cognitive performance measured by the Mini-Mental State Examination, Digit Symbol Substitution Test, Rey Auditory Verbal Learning Test, Trail Making Test, and Categorical Verbal Fluency were assessed in 226 men with metabolic syndrome and established stable coronary artery disease.Of the participants, 61.5% had normoglycemia, 20.8% had impaired fasting glucose, and 17.7% had type 2 diabetes. HbA1c was associated with cognitive function tests of Digit Symbol Substitution Test, Rey Auditory Verbal Learning Test, Trail Making Test, and Categorical Verbal Fluency (all P.02), but not the Mini-Mental State Examination. In an age-adjusted model, a 1% (11 mmol/mol) higher HbA1c value was associated with a 5.9 lower Digit Symbol Substitution Test score (95% confidence interval [CI], -9.58 to -2.21; P.0001); a 2.44 lower Rey Auditory Verbal Learning Test score (95% CI, -4.00 to -0.87; P.0001); a 15.6 higher Trail Making Test score (95% CI, 5.73 to 25.6; P.0001); and a 3.71 lower Categorical Verbal Fluency score (95% CI, -6.41 to -1.01; P.02). In a multivariate model adjusting for age, education, and cardiovascular covariates, HbA1c remained associated with cognitive function tests of Rey Auditory Verbal Learning Test (R(2) = 0.27, P.0001), Trail Making Test (R(2) = 0.18, P.0001), and Categorical Verbal Fluency (R(2) = 0.20, P.0001), although association with the Digit Symbol Substitution Test was reduced.Higher HbA1c is associated with lower cognitive function performance scores across multiple domain tests in men with metabolic syndrome and coronary artery disease. Future studies may demonstrate whether glucose lowering within the normative range improves cognitive health.

Objectives This study sought to evaluate differential effects of visceral fat (VF) and subcutaneous fat and their effects on metabolic syndrome (MetS) risk across body mass index (BMI) categories. Background The regional distribution of adipose tissue is an emerging risk factor for cardiometabolic disease, although serial changes in fat distribution have not been extensively investigated. VF and its alterations over time may be a better marker for risk than BMI in normal weight and overweight or obese individuals. Methods We studied 1,511 individuals in the MESA (Multi-Ethnic Study of Atherosclerosis) with adiposity assessment by computed tomography (CT). A total of 253 participants without MetS at initial scan underwent repeat CT (median interval 3.3 years). We used discrete Cox regression with net reclassification to investigate whether baseline and changes in VF area are associated with MetS. Results Higher VF was associated with cardiometabolic risk and coronary artery calcification, regardless of BMI. After adjustment, VF was more strongly associated with incident MetS than subcutaneous fat regardless of weight, with a 28% greater MetS hazard per 100 cm 2 /m VF area and significant net reclassification (net reclassification index: 0.44, 95% confidence interval [CI]: 0.29 to 0.60) over clinical risk. In individuals with serial imaging, initial VF (hazard ratio: 1.24 per 100 cm 2 /m, 95% CI: 1.08 to 1.44 per 100 cm 2 /m, p = 0.003) and change in VF (hazard ratio: 1.05 per 5% change, 95% CI: 1.01 to 1.08 per 5% change, p = 0.02) were associated with MetS after adjustment. Changes in subcutaneous fat were not associated with incident MetS after adjustment for clinical risk and VF area. Conclusions VF is modestly associated with BMI. However, across BMI, a single measure of and longitudinal change in VF predict MetS, even accounting for weight changes. Visceral adiposity is essential to assessing cardiometabolic risk, regardless of age, race, or BMI, and may serve as a marker and target of therapy in cardiometabolic disease.

Two recent randomized controlled trials of type 2 diabetes mellitus (T2DM) patients with history of, or at high risk of, cardiovascular disease (CVD) showed no risk of ischemic cardiovascular events associated with dipeptidyl peptidase-4 inhibitors (DPP4i), but an increased risk of heart failure (HF) with saxagliptin. We evaluated the risk of CVD including myocardial infarction (MI), stroke, coronary revascularization, and HF associated with DPP4i in T2DM patients with and without baseline CVD as used in the community.Using US commercial insurance claims data (2005-2012), we conducted a cohort study that included initiators of DPP4i and non-DPP4i treatments. Composite CVD endpoints including MI, stroke, coronary revascularization, and HF were defined with a hospital discharge diagnosis or procedure code. Cox proportional hazards models compared the risk of composite and individual CVD endpoints in propensity score (PS)-matched initiators of DPP4 versus non-DPP4i.We included 79,538 (18 % with baseline CVD) persons in PS-matched pairs of DPP4i and non-DPP4i initiators. The incidence rate per 1,000 person-years for composite CVD was 30.30 (95 % CI 28.24-32.51) in DPP4i and 34.76 (95 % CI 32.34-37.36) in non-DPP4i. The PS-matched hazard ratio (HR) for composite CVD was 0.87 (95 % CI 0.79-0.96) in DPP4i versus non-DPP4i. The PS-matched HR for HF was 0.81 (95 % CI 0.70-0.94) in DPP4i versus non-DPP4i. Among patients with baseline CVD, there was no increased risk of CVD or HF associated with DPP4i use.Among T2DM patients, initiating DPP4i was not associated with a greater risk of CVD or HF compared to non-DPP4i initiators.

Impact of weight loss on cardiac structure has not been extensively investigated in large, multi-ethnic, community-based populations. We investigated the longitudinal impact of weight loss on cardiac structure by cardiac magnetic resonance (CMR).2351 participants in the Multi-Ethnic Study of Atherosclerosis (MESA) who underwent CMR at Exam 1 (2002) and Exam 5 (2011) were included. Primary outcomes were percentage change in LV mass (indexed to height) and LV mass-to-volume ratio (concentric LV remodelling). Multivariable linear regression was used to measure the association between outcomes and weight change. At median 9.4 years' follow-up, 639 individuals (27%) experienced5% weight loss (median 6.9 kg) and 511 (22%) had5% weight gain (median 6.4 kg). A5% weight gain was associated with the greatest increase in LV mass (+5.4% median) and LV mass-to-volume ratio (+12.2% median). Adjusting for medications, hypertension/diabetes (and change in these risk factors), age, race and other risk factors, every 5% weight loss was associated with a 1.3% decrease in height-indexed LV mass and 1.3% decrease in LV mass-to-volume ratio (p0.0001). There was no effect modification/confounding by age, race, gender or baseline BMI. Change in LV mass-to-volume ratio was roughly linear, specifically for modest degrees of weight loss (-10% to +10%). Change in LV mass was linear with weight loss, suggesting no threshold of weight loss is needed for LV mass regression.In a large multi-ethnic population, weight loss is associated with beneficial effects on cardiac structure, independent of age, race, gender, BMI and obesity-related cardiometabolic risk. There is no threshold of weight loss required to produce these effects.

Objective Dipeptidyl peptidase-4 (DPP4), also known as CD26, is a transmembrane glycoprotein that has a costimulatory function in the immune response. DPP4 inhibitors (DPP4i) are oral glucose-lowering drugs for type 2 diabetes mellitus (T2DM). This study evaluated the risk of incident rheumatoid arthritis (RA) and other autoimmune diseases (AD) such as systemic lupus erythematosus, psoriasis, multiple sclerosis and inflammatory bowel disease, associated with DPP4i in patients with T2DM. Methods Using US insurance claims data (2005–2012), we conducted a population-based cohort study that included initiators of combination therapy with DPP4i (DPP4i plus metformin) and non-DPP4i (non-DPP4i plus metformin). RA and other AD were identified with ≥2 diagnoses and ≥1 dispensing for AD-specific immunomodulating drugs or steroids. Composite AD includes RA or other AD. Propensity score (PS)-stratified Cox proportional hazards models compared the risk of AD in DPP4i initiators versus non-DPP4i, controlling for potential confounders. Results After asymmetric trimming on the PS, 73 928 patients with T2DM starting DPP4i combination therapy and 163 062 starting non-DPP4i combination therapy were selected. Risks of incident RA and composite AD were lower in the DPP4i group versus non-DPP4i with the PS-stratified HR of 0.66 (95% CI 0.44 to 0.99) for RA, 0.73 (0.51 to 1.03) for other AD and 0.68 (95% CI 0.52 to 0.89) for composite AD. Conclusions In this large cohort of diabetic patients, those initiating DPP4i combination therapy appear to have a decreased risk of incident AD including RA compared with those initiating non-DPP4i combination therapy. These results may suggest possible pharmacological pathways for prevention or treatment of AD.

OBJECTIVE To test whether inhibiting inflammation with salsalate improves endothelial function in patients with type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS We conducted an ancillary study to the National Institutes of Health–sponsored, multicenter, randomized, double-masked, placebo-controlled trial evaluating the safety and efficacy of salsalate in targeting inflammation to improve glycemia in patients with T2D. Flow-mediated, endothelium-dependent dilation (FMD) and endothelium-independent, nitroglycerin-mediated dilation (NMD) of the brachial artery were assessed at baseline and 3 and 6 months following randomization to either salsalate 3.5 g/day or placebo. The primary end point was change in FMD at 6 months. RESULTS A total of 88 participants were enrolled in the study, and data after randomization were available for 75. Patients in the treatment and control groups had similar ages (56 years), BMI (33 kg/m2), sex (64% male), ethnicity, current treatment, and baseline HbA1c (7.7% [61 mmol/mol]). In patients treated with salsalate versus placebo, HbA1c was reduced by 0.46% (5.0 mmol/mol; P < 0.001), fasting glucose by 16.1 mg/dL (P < 0.001), and white blood cell count by 430 cells/µL (P < 0.02). There was no difference in the mean change in either FMD (0.70% [95% CI −0.86 to 2.25%]; P = 0.38) or NMD (−0.59% [95% CI −2.70 to 1.51%]; P = 0.57) between the groups treated with salsalate and placebo at 6 months. Total and LDL cholesterol were 11 and 16 mg/dL higher, respectively, and urinary albumin was 2.0 µg/mg creatinine higher in the patients treated with salsalate compared with those treated with placebo (all P < 0.009). CONCLUSIONS Salsalate does not change FMD in peripheral conduit arteries in patients with T2D despite lowering HbA1c. This finding suggests that salsalate does not have an effect on vascular inflammation, inflammation does not cause endothelial dysfunction in T2D, or confounding effects of salsalate mitigate favorable effects on endothelial function.

Obesity-related sub-acute chronic inflammation has been associated with incident type 2 diabetes and atherosclerotic cardiovascular disease. Inflammation is increasingly considered to be a pathologic mediator of these commonly co-occurring diseases. A growing number of preclinical and clinical studies support the inflammatory hypothesis, but clinical trials to confirm the therapeutic potential to target inflammation to treat or prevent cardiometabolic conditions are still ongoing. There are multiple inflammatory signaling pathways. Regulation is complex, with substantial crosstalk across these multiple pathways. The activity of select pathways may be differentially regulated in different tissues. Pharmacologic approaches to diabetes management may have direct or indirect antiinflammatory effects, the latter potentially attributable to an improved metabolic state. Conversely, some antiinflammatory approaches may affect glucose metabolism and cardiovascular health. To date, clinical trials suggest that targeting one portion of the inflammatory cascade may differentially affect dysglycemia and atherothrombosis. Understanding the underlying biological processes may contribute to the development of safe and effective therapies, although a single approach may not be sufficient for optimal management of both metabolic and athrothrombotic disease states.

Severe postprandial hypoglycemia with neuroglycopenia is an increasingly recognized, debilitating complication of Roux-en-Y gastric bypass (RYGB) surgery. Increased secretion of insulin and incretin hormones is implicated in its pathogenesis. Histopathologic examination of pancreas has demonstrated increased islet size and/or nuclear diameter in post-RYGB patients who underwent pancreatectomy for severe refractory hypoglycemia with neuroglycopenia (RYGB + NG). We aimed to determine whether β-cell proliferation or apoptosis is altered in RYGB + NG. We performed an observational study to analyze markers of proliferation, apoptosis, cell cycle, and transcription factor expression in pancreatic tissue from affected RYGB + NG patients (n = 12), normoglycemic patients undergoing pancreatic surgery for benign lesions (controls, n = 6), and individuals with hypoglycemia due to insulinoma (n = 52). Proliferative cell nuclear antigen (PCNA) expression was increased in insulin-positive cells in RYGB + NG patients (4.5-fold increase, p

Chronic sub-acute inflammation contributes to the pathogenesis of type 2 diabetes mellitus and cardiovascular disease. High doses of salicylate reduce inflammation, glucose and triacylglycerols, and may improve insulin sensitivity, suggesting therapeutic potential in impaired fasting glucose and/or impaired glucose tolerance. This trial aimed to evaluate the effect of salsalate vs placebo on insulin resistance and glycaemia in impaired fasting glucose and/or impaired glucose tolerance.We conducted a 12 week, two-centre, randomised, placebo-controlled study to evaluate the effect of salsalate (up to 4 g/day) vs placebo on systemic glucose disposal. Secondary objectives included treatment effects on glycaemia, inflammation and cardiovascular risk factors. Seventy-eight participants with impaired fasting glucose and/or impaired glucose tolerance from two VA healthcare systems were enrolled. Randomisation assignment was provided by the coordinating center directly to site pharmacists, and participants and research staff were blinded to treatment assignment.Seventy-one individuals were randomised to placebo (n = 36) or salsalate (n = 35). Glucose disposal did not change in either group (salsalate 1% [95% CI -39%, 56%]; placebo 6% [95% CI -20%, 61%], p = 0.3 for placebo vs salsalate). Fasting glucose was reduced by 6% during the study by salsalate (p = 0.006) but did not change with placebo. Declines in glucose were accompanied by declines in fasting C-peptide with salsalate. Insulin clearance was reduced with salsalate. In the salsalate group, triacylglycerol levels were lower by 25% (p = 0.01) and adiponectin increased by 53% (p = 0.02) at the end of the study. Blood pressure, endothelial function and other inflammation markers did not differ between groups. Adipose tissue nuclear factor κB (NF-κB) activity declined in the salsalate group compared with placebo (-16% vs 42%, p = 0.005), but was not correlated with metabolic improvements. The frequency of tinnitus was low but tended to be higher with salsalate therapy (n = 4 vs n = 2).In summary, salsalate therapy was well tolerated, lowered fasting glucose, increased adiponectin and reduced adipose tissue NF-κB activity. These changes were not related to changes in peripheral insulin sensitivity, suggesting additional mechanisms for metabolic improvement.ClinicalTrials.gov NCT00330733.Office of Research and Development, Medical Research Service, Department of Veterans Affairs and NIH K24 DK63214.

Background: The implementation of electronic health records (EHRs) may support evaluations of health care delivery, such as the prescription of newly approved medications, to adults with diabetes. We aimed to evaluate prescribing patterns of thiazolidinediones and novel glucose-lowering drug classes using electronic prescribing data contained in an outpatient EHR from 2002–2010. Methods: We identified adults with type 2 diabetes seen from 2002–2010 who were newly prescribed rosiglitazone (ROSI), pioglitazone (PIO), or a novel glucose-lowering drug class (other). The annual number of new prescriptions and their relative percentages (per 1000 patients) were calculated. Results: From 2002–2010, 6209 patients with type 2 diabetes were newly prescribed 8858 eligible medications. In 2006, ROSI and PIO accounted for 44% and 37% of new prescriptions, respectively. After 2007, the relative percentage of new ROSI prescriptions declined more rapidly than PIO prescriptions, falling to 7% and 47% of peak levels, respectively, by 2010. By 2010, the relative percentages of new ROSI, PIO, and other prescriptions were 2%, 18%, and 80%, respectively. Conclusions: Evaluations of EHR data represent a cost-effective method for evaluating diabetes medications with new Food and Drug Administration warnings or indications. Validation of demographic and clinical data will expand the scope of EHR-based evaluations of health care delivery and outcomes for adults with diabetes.

Importance Inflammation may contribute to pathological associations among obesity, diabetes mellitus, and cardiovascular disease. Objective To determine whether targeting inflammation using salsalate compared with placebo reduces progression of noncalcified coronary artery plaque. Design, Setting, and Participants In the Targeting Inflammation Using Salsalate in Cardiovascular Disease (TINSAL-CVD) trial participants were randomly assigned between September 23, 2008, and July 5, 2012, to 30 months of salsalate or placebo in addition to standard, guideline-based therapies. Randomization was computerized and centrally allocated, with patients, health care professionals, and researchers masked to treatment assignment. Participants were overweight and obese statin-using patients with established, stable coronary heart disease. Interventions Salsalate (3.5 g/d) or placebo orally over 30 months. Main Outcomes and Measures The primary outcome was progression of noncalcified coronary artery plaque assessed by multidetector computed tomographic angiography. Secondary outcomes were other measures of safety and efficacy. Results Two hundred fifty-seven participants were randomized to salsalate (n = 129) or placebo (n = 128). Their mean (SD) age was 60.8 (7.0) years, and 94.0% (236 of 251) were male. One hundred ninety participants (89 in the salsalate group and 101 in the placebo group) completed the study. Compared with baseline, there was no increase in noncalcified plaque volume in the placebo-treated patients and no difference in change between the salsalate and placebo groups (mean difference, −1 mm3; 95% CI, −11 to 9 mm3;P = .87). Salsalate treatment decreased total white blood cell, lymphocyte, monocyte, and neutrophil counts and increased adiponectin levels without change in C-reactive protein levels. Fasting glucose, triglycerides, uric acid, and bilirubin levels were decreased in the salsalate group compared with the placebo group, while hemoglobin levels were increased. Urinary albumin levels increased, with tinnitus and atrial arrhythmias more common, in the salsalate group compared with the placebo group. Conclusions and Relevance Salsalate when added to current therapies that include a statin does not reduce progression of noncalcified coronary plaque volume assessed by multidetector computed tomographic angiography in statin-using patients with established, stable coronary heart disease. The absence of progression of noncalcified plaque volume in the placebo group may limit interpretation of the trial results. Trial Registration clinicaltrials.gov Identifier:NCT00624923

Cardiovascular disease remains the principal cause of death and disability among patients with diabetes mellitus. Diabetes mellitus exacerbates mechanisms underlying atherosclerosis and heart failure. Unfortunately, these mechanisms are not adequately modulated by therapeutic strategies focusing solely on optimal glycemic control with currently available drugs or approaches. In the setting of multifactorial risk reduction with statins and other lipid-lowering agents, antihypertensive therapies, and antihyperglycemic treatment strategies, cardiovascular complication rates are falling, yet remain higher for patients with diabetes mellitus than for those without. This review considers the mechanisms, history, controversies, new pharmacological agents, and recent evidence for current guidelines for cardiovascular management in the patient with diabetes mellitus to support evidence-based care in the patient with diabetes mellitus and heart disease outside of the acute care setting.

Both decreased insulin secretion and action contribute to the pathogenesis of type 2 diabetes (T2D) in humans. The insulin receptor and insulin signalling proteins are present in the rodent and human β-cell and modulate cell growth and function. Insulin receptors and insulin signalling proteins in β-cells are critical for compensatory islet growth in response to insulin resistance. Rodents with tissue-specific knockout of the insulin receptor in the β-cell (βIRKO) show reduced first-phase glucose-stimulated insulin secretion (GSIS) and with aging develop glucose intolerance and diabetes, phenotypically similar to the process seen in human T2D. Expression of multiple insulin signalling proteins is reduced in islets of patients with T2D. Insulin potentiates GSIS in isolated human β-cells. Recent studies in humans in vivo show that pre-exposure to insulin increases GSIS, and this effect is diminished in persons with insulin resistance or T2D. β-Cell function correlates to whole-body insulin sensitivity. Together, these findings suggest that pancreatic β-cell dysfunction could be caused by a defect in insulin signalling within β-cell, and β-cell insulin resistance may lead to a loss of β-cell function and/or mass, contributing to the pathophysiology of T2D.

The Food and Drug Administration has added information to statin labels regarding an effect on diabetes, noting reported increases in glycated hemoglobin and fasting serum glucose levels but adding that it believes that the cardiovascular benefits outweigh the risks.