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  • 1
    Language: English
    In: Annals of internal medicine, 16 March 2010, Vol.152(6), pp.346-57
    Description: Salsalate, a nonacetylated prodrug of salicylate, has been shown to decrease blood glucose concentration in small studies. To compare the efficacy and safety of salsalate at different doses in patients with type 2 diabetes. Parallel randomized trial with computer-generated randomization and centralized allocation. Patients and investigators, including those assessing outcomes and performing analyses, were masked to group assignment. (ClinicalTrials.gov registration number: NCT00392678) 3 private practices and 14 universities in the United States. Persons aged 18 to 75 years with fasting plasma glucose concentrations of 12.5 mmol/L or less (〈 or = 225 mg/dL) and hemoglobin A1c (HbA1c) levels of 7.0% to 9.5% treated by diet, exercise, and oral medication at stable doses for at least 8 weeks. After a 4-week, single-masked run-in period, patients were randomly assigned to receive placebo or salsalate in dosages of 3.0, 3.5, or 4.0 g/d for 14 weeks (27 patients each) in addition to their current therapy. Change in HbA1c was the primary outcome. Adverse effects and changes in measures of coronary risk and renal function were secondary outcomes. Higher proportions of patients in the 3 salsalate treatment groups experienced decreases in HbA1c levels of 0.5% or more from baseline (P = 0.009). Mean HbA1c changes were -0.36% (P = 0.02) at 3.0 g/d, -0.34% (P = 0.02) at 3.5 g/d, and -0.49% (P = 0.001) at 4.0 g/d compared with placebo. Other markers of glycemic control also improved in the 3 salsalate groups, as did circulating triglyceride and adiponectin concentrations. Mild hypoglycemia was more common with salsalate; documented events occurred only in patients taking sulfonylureas. Urine albumin concentrations increased in all salsalate groups compared with placebo. The drug was otherwise well tolerated. The number of patients studied and the trial duration were insufficient to warrant recommending the use of salsalate for type 2 diabetes at this time. Salsalate lowers HbA1c levels and improves other markers of glycemic control in patients with type 2 diabetes and may therefore provide a new avenue for treatment. Renal and cardiac safety of the drug require further evaluation. National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health.
    Keywords: Blood Glucose -- Metabolism ; Diabetes Mellitus, Type 2 -- Blood ; Hypoglycemic Agents -- Administration & Dosage ; Prodrugs -- Administration & Dosage ; Salicylates -- Administration & Dosage
    ISSN: 00034819
    E-ISSN: 1539-3704
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  • 2
    Language: English
    In: Barzilay, Joshua I., Kathleen A. Jablonski, Vivian Fonseca, Steven E. Shoelson, Allison B. Goldfine, Christopher Strauch, and Vincent M. Monnier. 2014. “The Impact of Salsalate Treatment on Serum Levels of Advanced Glycation End Products in Type 2 Diabetes.” Diabetes Care 37 (4): 1083-1091. doi:10.2337/dc13-1527. http://dx.doi.org/10.2337/dc13-1527.
    Description: OBJECTIVE Salsalate is a nonacetylated salicylate that lowers glucose levels in people with type 2 diabetes (T2D). Here we examined whether salsalate also lowered serum-protein-bound levels of early and advanced glycation end products (AGEs) that have been implicated in diabetic vascular complications. RESEARCH DESIGN AND METHODS Participants were from the Targeting Inflammation Using Salsalate for Type 2 Diabetes (TINSAL-T2D) study, which examined the impact of salsalate treatment on hemoglobin A1c (HbA1c) and a wide variety of other parameters. One hundred eighteen participants received salsalate, 3.5 g/day for 48 weeks, and 109 received placebo. Early glycation product levels (HbA1c and fructoselysine [measured as furosine]) and AGE levels (glyoxal and methylglyoxal hydroimidazolones [G-1H, MG-1H], carboxymethyllysine [CML], carboxyethyllysine [CEL], pentosidine) were measured in patient serum samples. RESULTS Forty-eight weeks of salsalate treatment lowered levels of HbA1c and serum furosine (P 〈 0.001) and CML compared with placebo. The AGEs CEL and G-1H and MG-1H levels were unchanged, whereas pentosidine levels increased more than twofold (P 〈 0.001). Among salsalate users, increases in adiponectin levels were associated with lower HbA1c levels during follow-up (P 〈 0.001). Changes in renal and inflammation factor levels were not associated with changes in levels of early or late glycation factors. Pentosidine level changes were unrelated to changes in levels of renal function, inflammation, or cytokines. CONCLUSIONS Salsalate therapy was associated with a reduction in early but not late glycation end products. There was a paradoxical increase in serum pentosidine levels suggestive of an increase in oxidative stress or decreased clearance of pentosidine precursor.
    Keywords: Pathophysiology/Complications;
    ISSN: 0149-5992
    E-ISSN: 19355548
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  • 3
    Language: English
    In: Sullivan, Shannon D., Kathleen A. Jablonski, Jose C. Florez, Dana Dabelea, Paul W. Franks, Sam Dagogo-Jack, Catherine Kim, William C. Knowler, Costas A. Christophi, and Robert Ratner. 2014. “Genetic Risk of Progression to Type 2 Diabetes and Response to Intensive Lifestyle or Metformin in Prediabetic Women With and Without a History of Gestational Diabetes Mellitus.” Diabetes Care 37 (4): 909-911. doi:10.2337/dc13-0700. http://dx.doi.org/10.2337/dc13-0700.
    Description: OBJECTIVE The Diabetes Prevention Program (DPP) trial investigated rates of progression to diabetes among adults with prediabetes randomized to treatment with placebo, metformin, or intensive lifestyle intervention. Among women in the DPP, diabetes risk reduction with metformin was greater in women with prior gestational diabetes mellitus (GDM) compared with women without GDM but with one or more previous live births. RESEARCH DESIGN AND METHODS We asked if genetic variability could account for these differences by comparing β-cell function and genetic risk scores (GRS), calculated from 34 diabetes-associated loci, between women with and without histories of GDM. RESULTS β-Cell function was reduced in women with GDM. The GRS was positively associated with a history of GDM; however, the GRS did not predict progression to diabetes or modulate response to intervention. CONCLUSIONS These data suggest that a diabetes-associated GRS is associated with development of GDM and may characterize women at risk for development of diabetes due to β-cell dysfunction.
    Keywords: Randomised Controlled Trial ; Quantitative Research ; Diabetes ; Diabetes : Health Promotion ; Pre-Diabetes ; Pregnancy : Complications ; Genetics ; Patients Education ; Disease Management ; Patient Education ; Insulin Resistance ; Pregnancy ; Pregnancy Complications ; Clinical Trials ; United States–Us;
    ISSN: 0149-5992
    E-ISSN: 19355548
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  • 4
    Language: English
    In: Diabetes care, May 2014, Vol.37(5), pp.e112
    Description: In our study to target inflammation using salsalate in patients with type 2 diabetes, we demonstrate improvement in glycemia but no change in either flow-mediated, endothelium-dependent (FMD) or nitroglycerin-mediated, endothelium-independent dilation over 6 months in salsalate (3.5 g/day) compared with placebo-treated patients (1). It is important to note that no adverse cardiovascular safety signal for endothelial function was demonstrated. Our findings differ from Pierce and colleagues (2,3), who demonstrated improvement in vascular function and …
    Keywords: Blood Glucose -- Metabolism ; Diabetes Mellitus, Type 2 -- Blood ; Endothelium, Vascular -- Physiopathology ; Inflammation -- Drug Therapy ; Salicylates -- Administration & Dosage ; Vasodilation -- Drug Effects
    E-ISSN: 1935-5548
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  • 5
    Language: English
    In: Diabetologia, 2014, Vol.57(3), pp.485-490
    Description: Byline: Paul W. Franks (1,2,3,4), Costas A. Christophi (4), Kathleen A. Jablonski (4), Liana K. Billings (5,6), Linda M. Delahanty (5,6), Edward S. Horton (6,7), William C. Knowler (8), Jose C. Florez (5,6,9) Keywords: Cholesterol; Dyslipidaemia; Gene x environment interaction; Gene x lifestyle interaction; Genetics; Lifestyle intervention; Metformin; Pharmacogenetics; PPARGC1A; PPARGC1B; Randomised controlled trial; Triacylglycerol Abstract: Aims/hypothesis PPARGC1A and PPARGCB encode transcriptional coactivators that regulate numerous metabolic processes. We tested associations and treatment (i.e. metformin or lifestyle modification) interactions with metabolic traits in the Diabetes Prevention Program, a randomised controlled trial in persons at high risk of type 2 diabetes. Methods We used Tagger software to select 75 PPARGCA1 and 94 PPARGC1B tag single-nucleotide polymorphisms (SNPs) for analysis. These SNPs were tested for associations with relevant cardiometabolic quantitative traits using generalised linear models. Aggregate genetic effects were tested using the sequence kernel association test. Results In aggregate, PPARGC1A variation was strongly associated with baseline triacylglycerol concentrations (p=2.9x10.sup.-30), BMI (p=2.0x10.sup.-5) and visceral adiposity (p=1.9x10.sup.-4), as well as with changes in triacylglycerol concentrations (p=1.7x10.sup.-5) and BMI (p=9.9x10.sup.-5) from baseline to 1 year. PPARGC1B variation was only associated with baseline subcutaneous adiposity (p=0.01). In individual SNP analyses, Gly482Ser (rs8192678, PPARGC1A) was associated with accumulation of subcutaneous adiposity and worsening insulin resistance at 1 year (both p〈0.05), while rs2970852 (PPARGC1A) modified the effects of metformin on triacylglycerol levels (p .sub.interaction=0.04). Conclusions/interpretation These findings provide several novel and other confirmatory insights into the role of PPARGC1A variation with respect to diabetes-related metabolic traits. Trial registration ClinicalTrials.gov NCT00004992 Author Affiliation: (1) Department of Clinical Science, Genetic and Molecular Epidemiology Unit, Lund University, Malmo, Sweden (2) Department of Public Health and Clinical Medicine, Umea University, Umea, Sweden (3) Department of Nutrition, Harvard School of Public Health, Boston, MA, USA (4) Diabetes Prevention Program Coordinating Center, The Biostatistics Center, George Washington University, 6110 Executive Blvd, Suite 750, Rockville, MD, 20852, USA (5) Department of Medicine, Harvard Medical School, Boston, MA, USA (6) Diabetes Research Center (Diabetes Unit), Department of Medicine, Massachusetts General Hospital, Boston, MA, USA (7) Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA (8) Diabetes Epidemiology and Clinical Research Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, AZ, USA (9) Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA Article History: Registration Date: 26/11/2013 Received Date: 23/09/2013 Accepted Date: 19/11/2013 Online Date: 07/12/2013 Article note: A full list of Diabetes Prevention Program investigators is shown in the electronic supplementary material (ESM) Disclosure A previous version of this paper (doi 10.1007/s00125-013-2911-3) was retracted because of an inadvertent overlap with an earlier broader study (Jablonski et al, Diabetes, 2010 doi: 10.2337/db10-0543). In the retracted article one of the key findings had been reported in the supplementary materials of Jablonski et al. The article was retracted at the request of the authors before it was published in print form. The retracted paper has now been completely replaced by this version. Electronic supplementary material The online version of this article (doi: 10.1007/s00125-013-3133-4) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
    Keywords: Cholesterol ; Dyslipidaemia ; Gene × environment interaction ; Gene × lifestyle interaction ; Genetics ; Lifestyle intervention ; Metformin ; Pharmacogenetics ; PPARGC1A ; PPARGC1B ; Randomised controlled trial ; Triacylglycerol
    ISSN: 0012-186X
    E-ISSN: 1432-0428
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  • 6
    Language: English
    In: Delahanty, Linda M., Qing Pan, Kathleen A. Jablonski, Karol E. Watson, Jeanne M. McCaffery, Alan Shuldiner, Steven E. Kahn, William C. Knowler, Jose C. Florez, and Paul W. Franks. 2012. Genetic predictors of weight loss and weight regain after intensive lifestyle modification, metformin treatment, or standard care in the diabetes prevention program. Diabetes Care 35(2): 363-6.
    Description: OBJECTIVE: We tested genetic associations with weight loss and weight regain in the Diabetes Prevention Program, a randomized controlled trial of weight loss–inducing interventions (lifestyle and metformin) versus placebo. RESEARCH DESIGN AND METHODS: Sixteen obesity-predisposing single nucleotide polymorphisms (SNPs) were tested for association with short-term (baseline to 6 months) and long-term (baseline to 2 years) weight loss and weight regain (6 months to study end). RESULTS: Irrespective of treatment, the Ala12 allele at PPARG associated with short- and long-term weight loss (−0.63 and −0.93 kg/allele, P ≤ 0.005, respectively). Gene–treatment interactions were observed for short-term (LYPLAL1 rs2605100, P\(_{lifestyle*SNP}\) = 0.032; GNPDA2 rs10938397, P\(_{lifestyle*SNP}\) = 0.016; MTCH2 rs10838738, P\(_{lifestyle*SNP}\) = 0.022) and long-term (NEGR1 rs2815752, P\(_{metformin*SNP}\) = 0.028; FTO rs9939609, P\(_{lifestyle*SNP}\) = 0.044) weight loss. Three of 16 SNPs were associated with weight regain (NEGR1 rs2815752, BDNF rs6265, PPARG rs1801282), irrespective of treatment. TMEM18 rs6548238 and KTCD15 rs29941 showed treatment-specific effects (P\(_{lifestyle*SNP}\) 〈 0.05). CONCLUSIONS: Genetic information may help identify people who require additional support to maintain reduced weight after clinical intervention.
    Keywords: Pathophysiology/Complications
    ISSN: 0149-5992
    E-ISSN: 19355548
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  • 7
    In: Obesity, September 2013, Vol.21(9), pp.E520-E526
    Description: OBJECTIVE: To assess associations and genotype × treatment interactions for melanocortin 4 receptor (MC4R) locus variants and obesity-related traits.DESIGN AND METHODS: Diabetes prevention program (DPP) participants (N = 3,819, of whom 3,356 were genotyped for baseline and 3,234 for longitudinal analyses) were randomized into intensive lifestyle modification (diet, exercise, weight loss), metformin or placebo control. Adiposity was assessed in a subgroup (n = 909) using computed tomography. All analyses were adjusted for age, sex, ethnicity and treatment.RESULTS: The rs1943218 minor allele was nominally associated with short-term (6 month; P = 0.032) and long-term (2 year; P = 0.038) weight change. Eight SNPs modified response to treatment on short-term (rs17066856, rs9966412, rs17066859, rs8091237, rs17066866, rs7240064) or long-term (rs12970134, rs17066866) reduction in body weight, or diabetes incidence (rs17066829) (all Pinteraction 〈 0.05).CONCLUSION: This is the first study to comprehensively assess the role of MC4R variants and weight regulation in a weight loss intervention trial. One MC4R variant was directly associated with obesity-related traits or diabetes; numerous other variants appear to influence body weight and diabetes risk by modifying the protective effects of the DPP interventions.
    Keywords: Medicine;
    ISSN: 1930-7381
    E-ISSN: 1930-739X
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  • 8
    Language: English
    In: Florez, Jose C., Kathleen A. Jablonski, Jarred B. McAteer, Paul W. Franks, Clinton C. Mason, Kieren Mather, Edward Horton et al. 2012. Effects of genetic variants previously associated with fasting glucose and insulin in the Diabetes Prevention Program. PLoS ONE 7(9): e44424.
    Description: Common genetic variants have been recently associated with fasting glucose and insulin levels in white populations. Whether these associations replicate in pre-diabetes is not known. We extended these findings to the Diabetes Prevention Program, a clinical trial in which participants at high risk for diabetes were randomized to placebo, lifestyle modification or metformin for diabetes prevention. We genotyped previously reported polymorphisms (or their proxies) in/near G6PC2, MTNR1B, GCK, DGKB, GCKR, ADCY5, MADD, CRY2, ADRA2A, FADS1, PROX1, SLC2A2, GLIS3, C2CD4B, IGF1, and IRS1 in 3,548 Diabetes Prevention Program participants. We analyzed variants for association with baseline glycemic traits, incident diabetes and their interaction with response to metformin or lifestyle intervention. We replicated associations with fasting glucose at MTNR1B (P〈0.001), G6PC2 (P = 0.002) and GCKR (P = 0.001). We noted impaired β-cell function in carriers of glucose-raising alleles at MTNR1B (P〈0.001), and an increase in the insulinogenic index for the glucose-raising allele at G6PC2 (P〈0.001). The association of MTNR1B with fasting glucose and impaired β-cell function persisted at 1 year despite adjustment for the baseline trait, indicating a sustained deleterious effect at this locus. We also replicated the association of MADD with fasting proinsulin levels (P〈0.001). We detected no significant impact of these variants on diabetes incidence or interaction with preventive interventions. The association of several polymorphisms with quantitative glycemic traits is replicated in a cohort of high-risk persons. These variants do not have a detectable impact on diabetes incidence or response to metformin or lifestyle modification in the Diabetes Prevention Program.
    Keywords: Biology ; Anatomy And Physiology ; Endocrine System ; Endocrine Physiology ; Insulin ; Genetics ; Human Genetics ; Genetic Association Studies ; Population Genetics ; Genetic Polymorphism ; Medicine ; Clinical Research Design ; Clinical Trials ; Endocrinology ; Diabetic Endocrinology ; Diabetes Mellitus Type 2
    ISSN: 1932-6203
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  • 9
    Language: English
    In: PLoS ONE, 2011, Vol.6(7), p.e21518
    Description: TCF7L2 variants have been associated with type 2 diabetes, body mass index (BMI), and deficits in proinsulin processing and insulin secretion. Here we sought to test whether these effects were apparent in high-risk individuals and modify treatment responses. ; We examined the potential role of the rs7903146 variant in predicting resistance to weight loss or a lack of improvement of proinsulin processing during 2.5-years of follow-up participants (N = 2,994) from the Diabetes Prevention Program (DPP), a randomized controlled trial designed to prevent or delay diabetes in high-risk adults. ; We observed no difference in the degree of weight loss by rs7903146 genotypes. However, the T allele (conferring higher risk of diabetes) at rs7903146 was associated with higher fasting proinsulin at baseline (〈0.001), higher baseline proinsulin∶insulin ratio (p〈0.0001) and increased proinsulin∶insulin ratio over a median of 2.5 years of follow-up ( = 0.003). Effects were comparable across treatment arms. ; The combination of a lack of impact of the genotypes on the ability to lose weight, but the presence of a consistent effect on the proinsulin∶insulin ratio over the course of DPP, suggests that high-risk genotype carriers at this locus can successfully lose weight to counter diabetes risk despite persistent deficits in insulin production.
    Keywords: Research Article ; Medicine ; Diabetes And Endocrinology
    E-ISSN: 1932-6203
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  • 10
    Language: English
    In: Annals of internal medicine, 02 July 2013, Vol.159(1), pp.1-12
    Description: Short-duration studies show that salsalate improves glycemia in type 2 diabetes mellitus (T2DM). To assess 1-year efficacy and safety of salsalate in T2DM. Placebo-controlled, parallel trial; computerized randomization and centralized allocation, with patients, providers, and researchers blinded to assignment. (ClinicalTrials.gov: NCT00799643). 3 private practices and 18 academic centers in the United States. Persons aged 18 to 75 years with fasting glucose levels of 12.5 mmol/L or less (≤225 mg/dL) and hemoglobin A1c (HbA1c) levels of 7.0% to 9.5% who were treated for diabetes. 286 participants were randomly assigned (between January 2009 and July 2011) to 48 weeks of placebo (n = 140) or salsalate, 3.5 g/d (n = 146), in addition to current therapies, and 283 participants were analyzed (placebo, n = 137; salsalate, n = 146). Change in hemoglobin A1c level (primary outcome) and safety and efficacy measures. The mean HbA1c level over 48 weeks was 0.37% lower in the salsalate group than in the placebo group (95% CI, -0.53% to -0.21%; P 〈 0.001). Glycemia improved despite more reductions in concomitant diabetes medications in salsalate recipients than in placebo recipients. Lower circulating leukocyte, neutrophil, and lymphocyte counts show the anti-inflammatory effects of salsalate. Adiponectin and hematocrit levels increased more and fasting glucose, uric acid, and triglyceride levels decreased with salsalate, but weight and low-density lipoprotein cholesterol levels also increased. Urinary albumin levels increased but reversed on discontinuation; estimated glomerular filtration rates were unchanged. Trial duration and number of patients studied were insufficient to determine long-term risk-benefit of salsalate in T2DM. Salsalate improves glycemia in patients with T2DM and decreases inflammatory mediators. Continued evaluation of mixed cardiorenal signals is warranted.
    Keywords: Anti-Inflammatory Agents, Non-Steroidal -- Administration & Dosage ; Diabetes Mellitus, Type 2 -- Drug Therapy ; Salicylates -- Administration & Dosage
    ISSN: 00034819
    E-ISSN: 1539-3704
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