research letter
Diabetes, Obesity and Metabolism 17: 608–612, 2015. © 2015 John Wiley & Sons Ltd
RESEARCH LETTER
Salsalate has no effect on insulin secretion but decreases insulin clearance: a randomized, placebo-controlled trial in subjects without diabetes To elucidate whether increased insulin concentration after salsalate treatment (3 g/day for 7 days) is attributable to an increased insulin secretion rate (ISR) or to reduced metabolic clearance of endogenous insulin (MCI) during stepped glucose infusion (SGI). The analysis was performed in obese subjects who participated in a randomized double-blind, parallel, placebo-controlled clinical trial. A total of 27 participants (16 on salsalate, 11 on placebo) completed baseline and follow-up SGI. During SGI in the salsalate group, C-peptide concentrations were reduced by 11%, while plasma insulin concentrations were increased by 30%, corresponding to a 30% reduction in MCI (p < 0.0001). At molar increments of glucose, insulin concentrations were increased by 27% (p = 0.02), but ISR was unchanged. Salsalate did not alter insulin secretion, but lowered MCI, indicating that a reduction in insulin clearance is the principal mechanism for increased insulin levels after salsalate administration. Keywords: C-peptide, insulin secretion, salicylates, salsalate, stepped hyperglycaemia Date submitted 3 November 2014; date of first decision 4 December 2014; date of final acceptance 11 February 2015
Introduction
Research Design and Methods
Recent randomized trials have shown a glucose-lowering effect of salicylates in subjects without diabetes and with various degrees of glucose tolerance [1–4]. Studies in subjects without diabetes also showed that treatment with salicylates was associated with no changes or even worsening of peripheral and/or hepatic insulin sensitivity [2–6]. Hyperinsulinaemia as a potential underlying mechanism of the glucose-lowering action of salicylates had been supported by earlier data showing increased insulin responses to various secretagogues [7–9]. Increased insulin concentrations after administration of salicylates was also found during euglycaemic–hyperinsulinaemic clamp [2,3,6] or hyperglycaemic clamp [5,6]. These occurred in the settings of constant insulin infusion during euglycaemic–hyperinsulinaemic clamp and unchanged or lower C-peptide concentrations during hyperglycaemic clamp, indicating decreased insulin clearance. A more recent study showed reduced insulin clearance and unchanged insulin secretion after salsalate in insulin-resistant individuals without diabetes [4]. In the present paper, we report the results of an in vivo insulin secretion sub-study of a previously reported randomized study on the effect of the salicylate drug salsalate on glucose tolerance and insulin action (measured by euglycaemic–hyperinsulinaemic clamp) [2].
Details of the study design, including the inclusion and exclusion criteria of the original double-blinded, placebo-controlled study, have been reported previously [2]. In brief, participants had to be obese (BMI ≥ 30 kg/m2 ) and confirmed to be without diabetes by 75-g oral glucose tolerance test (1999 WHO criteria). All participants provided written informed consent before participation. An oral glucose tolerance test and euglycaemic–hyperinsulinaemic clamp were performed before and on days 6 and 7, respectively, of either salsalate (3 g/day in two daily doses) or placebo treatment. The same day, after finishing the euglycaemic–hyperinsulinaemic clamp, and after a 60-min wash-out period while maintaining euglycaemia using a variable rate of 20% glucose infusion, a stepped glucose infusion (SGI; five steps) was administered to assess insulin secretion (Supplementary methods, File S1) as described previously [10]. The insulin secretion rate (ISR) was calculated from C-peptide levels by the deconvolution method using standard values of C-peptide clearance with a two-compartment model for C-peptide distribution and degradation [11]. Metabolic clearance of endogenous insulin (MCI) was calculated as (i) basal MCI: the ratio of average plasma C-peptide and insulin concentrations before starting SGI (−10, −5 and 0 min); (ii) total MCI: the ratio of total SGI areas under the curve (AUCs) of C-peptide to insulin; and (iii) net MCI: the ratio of integral ISR to the incremental AUC of insulin during SGI. The effect of salsalate was evaluated using mixed-model procedures in the SAS statistical package (version 9.2; SAS
Correspondence to : A/Prof. Barbora de Courten, MD, PhD, MPH, Monash Centre for Health, Research and Implementation, School of Public Health and Preventive Medicine, Monash University, 43-51 Kanooka Grove, Clayton, Victoria 3186, Australia. E-mail: [email protected]
DIABETES, OBESITY AND METABOLISM
research letter
Figure 1. Plasma glucose (A), insulin (B) and C-peptide (C) concentrations during stepped glucose infusion. Data are expressed as means ± standard error. p values indicate differences from baseline after salsalate treatment versus placebo. Mixed models were adjusted for time, baseline value and glucose infusion rate (GIR).
Volume 17 No. 6 June 2015
doi:10.1111/dom.12450 609
research letter
DIABETES, OBESITY AND METABOLISM
Figure 2. Standardized dose–response curves of (A) insulin, (B) insulin secretion rate (ISR) at molar increments of plasma glucose concentrations, and (C) metabolic clearance of endogenous insulin [MCI; first two columns basal MCI = average C-peptide divided by average insulin before glucose infusion; second two columns: total MCI = ratio of C-peptide and insulin area under the curve (AUC) during stepped glucose infusion (SGI); third columns: net MCI – integrated ISR divided by incremental AUC of insulin during SGI]. Data are expressed as means ± standard error. p values indicate differences from baseline after salsalate treatment versus placebo [incremental AUCs for (A) and (B)] adjusted for baseline.
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DIABETES, OBESITY AND METABOLISM
Institute Inc, Cary, NC, USA). Follow-up differences in study outcomes were adjusted for measurements at baseline.
Results Of 40 subjects recruited for the original study, 27 completed the SGI part of the protocol (details on non-completion in the Supplementary results; File S1). The baseline clinical characteristics of these subjects were similar to those of the primary group [2] and were not different between those assigned to placebo and salsalate (Table S1, File S1). Similarly to the original group, salsalate treatment resulted in decreased fasting glucose concentrations and increased fasting insulin concentrations, decreased clearance of exogenous insulin and unchanged insulin-normalized peripheral insulin sensitivity compared with baseline, but only the decrease in exogenous insulin clearance was significantly different when compared with the placebo group (Table S2, File S1). Before SGI, glucose and C-peptide concentrations were unchanged, while insulin concentrations were elevated (by a median of 30% vs baseline; p = 0.006) after salsalate (Figure 1). During SGI, plasma glucose concentrations trended lower (by 2.5%; p = 0.09), serum insulin concentrations were increased and plasma C-peptide concentrations were decreased (both p < 0.0001) after salsalate treatment (Figure 1). Insulin and C-peptide concentrations after salsalate treatment also showed a significant interaction with time (p = 0.008) and (p = 0.0004), with greater differences toward the end of the glucose infusion (Figure 1B, C). The insulin concentration response at molar increments of plasma glucose was also augmented after salsalate treatment (p = 0.02; Figure 2A). By contrast, the ISR response at molar increments of plasma glucose concentrations was unchanged (p = 0.6; Figure 2B). The MCI was decreased by about one third after treatment with salsalate (all p < 0.0001; Figure 2C).
Discussion In the context of the present randomized double-blinded placebo-controlled trial in obese subjects without diabetes, a week-long treatment with salsalate did not increase insulin secretion, but appeared to decrease the MCI. Increased insulin concentrations after salicylates have been previously reported in various patterns and study settings, including increased early insulin peak after i.v. glucose load in both subjects with diabetes and healthy subjects without diabetes after 4 days [8] and increased early and delayed insulin response during hyperglycaemic clamp in healthy individuals after a single dose [5] of acetylsalicylic acid. Another study showed an increased acute insulin response during an intravenous glucose tolerance test in healthy obese individuals treated for 2 weeks with the salicylate derivative triflusal [1]. An enhanced insulin response to glucose load after salicylate administration was also reported in several other studies in people without diabetes [7,9]; however, as all of these studies reported peripheral insulin concentrations only, they did not provide information on whether increased
Volume 17 No. 6 June 2015
research letter insulin concentration resulted from increased insulin secretion or decreased insulin clearance. Recently, Kim et al. [4], by using a similar protocol to that used in the present study (SGI with estimation of ISR from C-peptide concentrations), showed unchanged insulin secretion after 4 weeks of salsalate treatment in predominantly white male, obese, individuals without diabetes. In the present study, insulin concentrations increased while plasma C-peptide concentrations decreased during the SGI protocol, indicating reductions in both insulin clearance and insulin secretion; however, the reduction in insulin secretion may be secondary to the glucose-lowering effect of salsalate rather than a decreased glucose sensitivity of 𝛽 cells because ISRs were unchanged when analysed as a function of molar increments in glucose concentrations. Decreased insulin clearance upon salicylate treatment has been indicated in the past by observations of higher insulin but unchanged plasma C-peptide concentrations during euglycaemic–hyperinsulinaemic clamp, and augmented insulin but unchanged C-peptide response during hyperglycaemic clamp [6]. Both the present data and those of Kim et al. [4], which are consistent with these previous studies, support reduced insulin clearance as the key mechanisms underlying increased insulin concentrations upon salicylate treatment. The mechanism of decreased insulin clearance is difficult to explore as insulin uptake and degradation is a complex and not yet completely understood process involving more than only insulin-sensitive tissues [12]. The liver and the kidney are the principal sites for insulin clearance. Insulin may also be cleared by muscle, adipocytes, gastrointestinal cells, fibroblasts, monocytes and lymphocytes, which contain insulin receptors [12]. To date, it is still unclear which of these tissues is predominantly affected by salicylates with regard to insulin clearance and by what mechanism. It should be noted that the present study was conducted as a secondary study, in a subset of the original cohort, and therefore lacks the statistical power to test the effect of salicylate treatment on the primary outcomes: measures of glycaemic control and insulin action; therefore, we were not able to determine whether the glucose-lowering effect of salsalate was related to increased insulin concentrations. In conclusion, we have shown that treatment with salsalate did not alter insulin secretion, but did appear to lower the MCI. As the reductions in insulin clearance were not accompanied by a worsening of insulin action and salsalate treatment had a significant glucose-lowering effect in our original larger cohort [2], salicylate drugs may represent a viable approach to the prevention and treatment of type 2 diabetes. A. Penesova1,2,† , J. Koska1,3,† , E. Ortega1,4 , J. C. Bunt1 , C. Bogardus1 & B. de Courten1,5 1 Obesity and Diabetes Clinical Research Section, Phoenix Epidemiology and Clinical Research Branch, NIDDK, NIH, DHHS, Phoenix, AZ, USA 2 Centre of Molecular Medicine, Institute of Experimental Endocrinology, Slovak Academy of Sciences, Bratislava, Slovakia 3 Phoenix VA Health Care System, Phoenix, AZ, USA
doi:10.1111/dom.12450 611
research letter 4 Department
of Endocrinology and Nutrition, ICMDM, Hospital Clinic, IDIBAPS, CIBEROBN, Barcelona, Spain 5 Monash Centre for Health, Research and Implementation (MCHRI), School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia †
These authors contributed equally to the work.
Acknowledgements We would like to thank John Graves, Carol Massengill, Jeanette Impson, metabolic kitchen, nursing and technical staff, and the individuals who volunteered for this study. The contents of this article do not represent the views of the Department of Health and Human Services, Department of Veterans Affairs or the US Government. All the research was supported by the National Institute of Diabetes and Digestive and Kidney Diseases intramural programme.
Conflict of Interest The authors have no conflicts of interest to declare. The author contributions were as follows: A. P. analysed the data and wrote the manuscript; J. K. conducted the study, collected and analysed the data and contributed to manuscript writing; E. O. contributed to study design, conducted the study and reviewed/edited the manuscript; J. C. B. contributed to study design, conducted the study and reviewed/edited the manuscript; C. B. contributed to study design and reviewed/edited the manuscript; B. de C. designed and initiated the trial and reviewed/edited manuscript.
Supporting Information
DIABETES, OBESITY AND METABOLISM
References 1. Fernandez-Real JM, Lopez-Bermejo A, Ropero AB et al. Salicylates increase insulin secretion in healthy obese subjects. J Clin Endocrinol Metab 2008; 93: 2523–2530. 2. Koska J, Ortega E, Bunt JC et al. The effect of salsalate on insulin action and glucose tolerance in obese non-diabetic patients: results of a randomised double-blind placebo-controlled study. Diabetologia 2009; 52: 385–393. 3. Goldfine AB, Conlin PR, Halperin F et al. A randomised trial of salsalate for insulin resistance and cardiovascular risk factors in persons with abnormal glucose tolerance. Diabetologia 2013; 56: 714–723. 4. Kim SH, Liu A, Ariel D et al. Effect of salsalate on insulin action, secretion, and clearance in nondiabetic, insulin-resistant individuals: a randomized, placebo-controlled study. Diabetes Care 2014; 37: 1944–1950. 5. Newman WP, Brodows RG. Aspirin causes tissue insensitivity to insulin in normal man. J Clin Endocrinol Metab 1983; 57: 1102–1106. 6. Bratusch-Marrain PR, Vierhapper H, Komjati M, Waldhausl WK. Acetyl-salicylic acid impairs insulin-mediated glucose utilization and reduces insulin clearance in healthy and non-insulin-dependent diabetic man. Diabetologia 1985; 28: 671–676. 7. Giugliano D, Torella R, Siniscalchi N, Improta L, D’Onofrio F. The effect of acetylsalicylic acid on insulin response to glucose and arginine in normal man. Diabetologia 1978; 14: 359–362. 8. Micossi P, Pontiroli AE, Baron SH et al. Aspirin stimulates insulin and glucagon secretion and increases glucose tolerance in normal and diabetic subjects. Diabetes 1978; 27: 1196–1204. 9. Chen M, Robertson RP. Restoration of the acute insulin response by sodium salicylate. A glucose dose-related phenomenon. Diabetes 1978; 27: 750–756. 10. Gautier JF, Wilson C, Weyer C et al. Low acute insulin secretory responses in adult offspring of people with early onset type 2 diabetes. Diabetes 2001; 50: 1828–1833. 11. Van Cauter E, Mestrez F, Sturis J, Polonsky KS. Estimation of insulin secretion rates from C-peptide levels. Comparison of individual and standard kinetic parameters for C-peptide clearance. Diabetes 1992; 41: 368–377. 12. Valera Mora ME, Scarfone A, Calvani M, Greco AV, Mingrone G. Insulin clearance in obesity. J Am Coll Nutr 2003; 22: 487–493.
Additional Supporting Information may be found in the online version of this article: File S1. Supplementary data.
612 Penesova et al.
Volume 17 No. 6 June 2015
Diabetes, Obesity and Metabolism 17: 608–612, 2015. © 2015 John Wiley & Sons Ltd
RESEARCH LETTER
Salsalate has no effect on insulin secretion but decreases insulin clearance: a randomized, placebo-controlled trial in subjects without diabetes To elucidate whether increased insulin concentration after salsalate treatment (3 g/day for 7 days) is attributable to an increased insulin secretion rate (ISR) or to reduced metabolic clearance of endogenous insulin (MCI) during stepped glucose infusion (SGI). The analysis was performed in obese subjects who participated in a randomized double-blind, parallel, placebo-controlled clinical trial. A total of 27 participants (16 on salsalate, 11 on placebo) completed baseline and follow-up SGI. During SGI in the salsalate group, C-peptide concentrations were reduced by 11%, while plasma insulin concentrations were increased by 30%, corresponding to a 30% reduction in MCI (p < 0.0001). At molar increments of glucose, insulin concentrations were increased by 27% (p = 0.02), but ISR was unchanged. Salsalate did not alter insulin secretion, but lowered MCI, indicating that a reduction in insulin clearance is the principal mechanism for increased insulin levels after salsalate administration. Keywords: C-peptide, insulin secretion, salicylates, salsalate, stepped hyperglycaemia Date submitted 3 November 2014; date of first decision 4 December 2014; date of final acceptance 11 February 2015
Introduction
Research Design and Methods
Recent randomized trials have shown a glucose-lowering effect of salicylates in subjects without diabetes and with various degrees of glucose tolerance [1–4]. Studies in subjects without diabetes also showed that treatment with salicylates was associated with no changes or even worsening of peripheral and/or hepatic insulin sensitivity [2–6]. Hyperinsulinaemia as a potential underlying mechanism of the glucose-lowering action of salicylates had been supported by earlier data showing increased insulin responses to various secretagogues [7–9]. Increased insulin concentrations after administration of salicylates was also found during euglycaemic–hyperinsulinaemic clamp [2,3,6] or hyperglycaemic clamp [5,6]. These occurred in the settings of constant insulin infusion during euglycaemic–hyperinsulinaemic clamp and unchanged or lower C-peptide concentrations during hyperglycaemic clamp, indicating decreased insulin clearance. A more recent study showed reduced insulin clearance and unchanged insulin secretion after salsalate in insulin-resistant individuals without diabetes [4]. In the present paper, we report the results of an in vivo insulin secretion sub-study of a previously reported randomized study on the effect of the salicylate drug salsalate on glucose tolerance and insulin action (measured by euglycaemic–hyperinsulinaemic clamp) [2].
Details of the study design, including the inclusion and exclusion criteria of the original double-blinded, placebo-controlled study, have been reported previously [2]. In brief, participants had to be obese (BMI ≥ 30 kg/m2 ) and confirmed to be without diabetes by 75-g oral glucose tolerance test (1999 WHO criteria). All participants provided written informed consent before participation. An oral glucose tolerance test and euglycaemic–hyperinsulinaemic clamp were performed before and on days 6 and 7, respectively, of either salsalate (3 g/day in two daily doses) or placebo treatment. The same day, after finishing the euglycaemic–hyperinsulinaemic clamp, and after a 60-min wash-out period while maintaining euglycaemia using a variable rate of 20% glucose infusion, a stepped glucose infusion (SGI; five steps) was administered to assess insulin secretion (Supplementary methods, File S1) as described previously [10]. The insulin secretion rate (ISR) was calculated from C-peptide levels by the deconvolution method using standard values of C-peptide clearance with a two-compartment model for C-peptide distribution and degradation [11]. Metabolic clearance of endogenous insulin (MCI) was calculated as (i) basal MCI: the ratio of average plasma C-peptide and insulin concentrations before starting SGI (−10, −5 and 0 min); (ii) total MCI: the ratio of total SGI areas under the curve (AUCs) of C-peptide to insulin; and (iii) net MCI: the ratio of integral ISR to the incremental AUC of insulin during SGI. The effect of salsalate was evaluated using mixed-model procedures in the SAS statistical package (version 9.2; SAS
Correspondence to : A/Prof. Barbora de Courten, MD, PhD, MPH, Monash Centre for Health, Research and Implementation, School of Public Health and Preventive Medicine, Monash University, 43-51 Kanooka Grove, Clayton, Victoria 3186, Australia. E-mail: [email protected]
DIABETES, OBESITY AND METABOLISM
research letter
Figure 1. Plasma glucose (A), insulin (B) and C-peptide (C) concentrations during stepped glucose infusion. Data are expressed as means ± standard error. p values indicate differences from baseline after salsalate treatment versus placebo. Mixed models were adjusted for time, baseline value and glucose infusion rate (GIR).
Volume 17 No. 6 June 2015
doi:10.1111/dom.12450 609
research letter
DIABETES, OBESITY AND METABOLISM
Figure 2. Standardized dose–response curves of (A) insulin, (B) insulin secretion rate (ISR) at molar increments of plasma glucose concentrations, and (C) metabolic clearance of endogenous insulin [MCI; first two columns basal MCI = average C-peptide divided by average insulin before glucose infusion; second two columns: total MCI = ratio of C-peptide and insulin area under the curve (AUC) during stepped glucose infusion (SGI); third columns: net MCI – integrated ISR divided by incremental AUC of insulin during SGI]. Data are expressed as means ± standard error. p values indicate differences from baseline after salsalate treatment versus placebo [incremental AUCs for (A) and (B)] adjusted for baseline.
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DIABETES, OBESITY AND METABOLISM
Institute Inc, Cary, NC, USA). Follow-up differences in study outcomes were adjusted for measurements at baseline.
Results Of 40 subjects recruited for the original study, 27 completed the SGI part of the protocol (details on non-completion in the Supplementary results; File S1). The baseline clinical characteristics of these subjects were similar to those of the primary group [2] and were not different between those assigned to placebo and salsalate (Table S1, File S1). Similarly to the original group, salsalate treatment resulted in decreased fasting glucose concentrations and increased fasting insulin concentrations, decreased clearance of exogenous insulin and unchanged insulin-normalized peripheral insulin sensitivity compared with baseline, but only the decrease in exogenous insulin clearance was significantly different when compared with the placebo group (Table S2, File S1). Before SGI, glucose and C-peptide concentrations were unchanged, while insulin concentrations were elevated (by a median of 30% vs baseline; p = 0.006) after salsalate (Figure 1). During SGI, plasma glucose concentrations trended lower (by 2.5%; p = 0.09), serum insulin concentrations were increased and plasma C-peptide concentrations were decreased (both p < 0.0001) after salsalate treatment (Figure 1). Insulin and C-peptide concentrations after salsalate treatment also showed a significant interaction with time (p = 0.008) and (p = 0.0004), with greater differences toward the end of the glucose infusion (Figure 1B, C). The insulin concentration response at molar increments of plasma glucose was also augmented after salsalate treatment (p = 0.02; Figure 2A). By contrast, the ISR response at molar increments of plasma glucose concentrations was unchanged (p = 0.6; Figure 2B). The MCI was decreased by about one third after treatment with salsalate (all p < 0.0001; Figure 2C).
Discussion In the context of the present randomized double-blinded placebo-controlled trial in obese subjects without diabetes, a week-long treatment with salsalate did not increase insulin secretion, but appeared to decrease the MCI. Increased insulin concentrations after salicylates have been previously reported in various patterns and study settings, including increased early insulin peak after i.v. glucose load in both subjects with diabetes and healthy subjects without diabetes after 4 days [8] and increased early and delayed insulin response during hyperglycaemic clamp in healthy individuals after a single dose [5] of acetylsalicylic acid. Another study showed an increased acute insulin response during an intravenous glucose tolerance test in healthy obese individuals treated for 2 weeks with the salicylate derivative triflusal [1]. An enhanced insulin response to glucose load after salicylate administration was also reported in several other studies in people without diabetes [7,9]; however, as all of these studies reported peripheral insulin concentrations only, they did not provide information on whether increased
Volume 17 No. 6 June 2015
research letter insulin concentration resulted from increased insulin secretion or decreased insulin clearance. Recently, Kim et al. [4], by using a similar protocol to that used in the present study (SGI with estimation of ISR from C-peptide concentrations), showed unchanged insulin secretion after 4 weeks of salsalate treatment in predominantly white male, obese, individuals without diabetes. In the present study, insulin concentrations increased while plasma C-peptide concentrations decreased during the SGI protocol, indicating reductions in both insulin clearance and insulin secretion; however, the reduction in insulin secretion may be secondary to the glucose-lowering effect of salsalate rather than a decreased glucose sensitivity of 𝛽 cells because ISRs were unchanged when analysed as a function of molar increments in glucose concentrations. Decreased insulin clearance upon salicylate treatment has been indicated in the past by observations of higher insulin but unchanged plasma C-peptide concentrations during euglycaemic–hyperinsulinaemic clamp, and augmented insulin but unchanged C-peptide response during hyperglycaemic clamp [6]. Both the present data and those of Kim et al. [4], which are consistent with these previous studies, support reduced insulin clearance as the key mechanisms underlying increased insulin concentrations upon salicylate treatment. The mechanism of decreased insulin clearance is difficult to explore as insulin uptake and degradation is a complex and not yet completely understood process involving more than only insulin-sensitive tissues [12]. The liver and the kidney are the principal sites for insulin clearance. Insulin may also be cleared by muscle, adipocytes, gastrointestinal cells, fibroblasts, monocytes and lymphocytes, which contain insulin receptors [12]. To date, it is still unclear which of these tissues is predominantly affected by salicylates with regard to insulin clearance and by what mechanism. It should be noted that the present study was conducted as a secondary study, in a subset of the original cohort, and therefore lacks the statistical power to test the effect of salicylate treatment on the primary outcomes: measures of glycaemic control and insulin action; therefore, we were not able to determine whether the glucose-lowering effect of salsalate was related to increased insulin concentrations. In conclusion, we have shown that treatment with salsalate did not alter insulin secretion, but did appear to lower the MCI. As the reductions in insulin clearance were not accompanied by a worsening of insulin action and salsalate treatment had a significant glucose-lowering effect in our original larger cohort [2], salicylate drugs may represent a viable approach to the prevention and treatment of type 2 diabetes. A. Penesova1,2,† , J. Koska1,3,† , E. Ortega1,4 , J. C. Bunt1 , C. Bogardus1 & B. de Courten1,5 1 Obesity and Diabetes Clinical Research Section, Phoenix Epidemiology and Clinical Research Branch, NIDDK, NIH, DHHS, Phoenix, AZ, USA 2 Centre of Molecular Medicine, Institute of Experimental Endocrinology, Slovak Academy of Sciences, Bratislava, Slovakia 3 Phoenix VA Health Care System, Phoenix, AZ, USA
doi:10.1111/dom.12450 611
research letter 4 Department
of Endocrinology and Nutrition, ICMDM, Hospital Clinic, IDIBAPS, CIBEROBN, Barcelona, Spain 5 Monash Centre for Health, Research and Implementation (MCHRI), School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia †
These authors contributed equally to the work.
Acknowledgements We would like to thank John Graves, Carol Massengill, Jeanette Impson, metabolic kitchen, nursing and technical staff, and the individuals who volunteered for this study. The contents of this article do not represent the views of the Department of Health and Human Services, Department of Veterans Affairs or the US Government. All the research was supported by the National Institute of Diabetes and Digestive and Kidney Diseases intramural programme.
Conflict of Interest The authors have no conflicts of interest to declare. The author contributions were as follows: A. P. analysed the data and wrote the manuscript; J. K. conducted the study, collected and analysed the data and contributed to manuscript writing; E. O. contributed to study design, conducted the study and reviewed/edited the manuscript; J. C. B. contributed to study design, conducted the study and reviewed/edited the manuscript; C. B. contributed to study design and reviewed/edited the manuscript; B. de C. designed and initiated the trial and reviewed/edited manuscript.
Supporting Information
DIABETES, OBESITY AND METABOLISM
References 1. Fernandez-Real JM, Lopez-Bermejo A, Ropero AB et al. Salicylates increase insulin secretion in healthy obese subjects. J Clin Endocrinol Metab 2008; 93: 2523–2530. 2. Koska J, Ortega E, Bunt JC et al. The effect of salsalate on insulin action and glucose tolerance in obese non-diabetic patients: results of a randomised double-blind placebo-controlled study. Diabetologia 2009; 52: 385–393. 3. Goldfine AB, Conlin PR, Halperin F et al. A randomised trial of salsalate for insulin resistance and cardiovascular risk factors in persons with abnormal glucose tolerance. Diabetologia 2013; 56: 714–723. 4. Kim SH, Liu A, Ariel D et al. Effect of salsalate on insulin action, secretion, and clearance in nondiabetic, insulin-resistant individuals: a randomized, placebo-controlled study. Diabetes Care 2014; 37: 1944–1950. 5. Newman WP, Brodows RG. Aspirin causes tissue insensitivity to insulin in normal man. J Clin Endocrinol Metab 1983; 57: 1102–1106. 6. Bratusch-Marrain PR, Vierhapper H, Komjati M, Waldhausl WK. Acetyl-salicylic acid impairs insulin-mediated glucose utilization and reduces insulin clearance in healthy and non-insulin-dependent diabetic man. Diabetologia 1985; 28: 671–676. 7. Giugliano D, Torella R, Siniscalchi N, Improta L, D’Onofrio F. The effect of acetylsalicylic acid on insulin response to glucose and arginine in normal man. Diabetologia 1978; 14: 359–362. 8. Micossi P, Pontiroli AE, Baron SH et al. Aspirin stimulates insulin and glucagon secretion and increases glucose tolerance in normal and diabetic subjects. Diabetes 1978; 27: 1196–1204. 9. Chen M, Robertson RP. Restoration of the acute insulin response by sodium salicylate. A glucose dose-related phenomenon. Diabetes 1978; 27: 750–756. 10. Gautier JF, Wilson C, Weyer C et al. Low acute insulin secretory responses in adult offspring of people with early onset type 2 diabetes. Diabetes 2001; 50: 1828–1833. 11. Van Cauter E, Mestrez F, Sturis J, Polonsky KS. Estimation of insulin secretion rates from C-peptide levels. Comparison of individual and standard kinetic parameters for C-peptide clearance. Diabetes 1992; 41: 368–377. 12. Valera Mora ME, Scarfone A, Calvani M, Greco AV, Mingrone G. Insulin clearance in obesity. J Am Coll Nutr 2003; 22: 487–493.
Additional Supporting Information may be found in the online version of this article: File S1. Supplementary data.
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