Effect of salsalate on insulin action, secretion, and clearance in nondiabetic, insulin-resistant individuals: a randomized, placebo-controlled study

Sun H Kim, Alice Liu, Danit Ariel, Fahim Abbasi, Cindy Lamendola, Kaylene Grove, Vanessa Tomasso, Hector Ochoa, Gerald Reaven, Sun H Kim, Alice Liu, Danit Ariel, Fahim Abbasi, Cindy Lamendola, Kaylene Grove, Vanessa Tomasso, Hector Ochoa, Gerald Reaven

Abstract

Objective: Salsalate treatment has been shown to improve glucose homeostasis, but the mechanism remains unclear. The aim of this study was to evaluate the effect of salsalate treatment on insulin action, secretion, and clearance rate in nondiabetic individuals with insulin resistance.

Research design and methods: This was a randomized (2:1), single-blind, placebo-controlled study of salsalate (3.5 g daily for 4 weeks) in nondiabetic individuals with insulin resistance. All individuals had measurement of glucose tolerance (75-g oral glucose tolerance test), steady-state plasma glucose (SSPG; insulin suppression test), and insulin secretion and clearance rate (graded-glucose infusion test) before and after treatment.

Results: Forty-one individuals were randomized to salsalate (n = 27) and placebo (n = 14). One individual from each group discontinued the study. Salsalate improved fasting (% mean change -7% [95% CI -10 to -14] vs. 1% [-3 to 5], P = 0.005) but not postprandial glucose concentration compared with placebo. Salsalate also lowered fasting triglyceride concentration (-25% [-34 to -15] vs. -6% [-26 to 14], P = 0.04). Salsalate had no effect on SSPG concentration or insulin secretion rate but significantly decreased insulin clearance rate compared with placebo (-23% [-30 to -16] vs. 3% [-10 to 15], P < 0.001). Salsalate was well tolerated, but four individuals needed a dose reduction due to symptoms.

Conclusions: Salsalate treatment in nondiabetic, insulin-resistant individuals improved fasting, but not postprandial, glucose and triglyceride concentration. These improvements were associated with a decrease in insulin clearance rate without change in insulin action or insulin secretion.

Trial registration: ClinicalTrials.gov NCT02007577.

© 2014 by the American Diabetes Association.

Figures

Figure 1
Figure 1
Changes during the OGTT in glucose (A and B) and insulin (C and D) profile following salsalate (A and C) and placebo (B and D) treatment. Curves at baseline (closed circles) and 4 weeks (open circles) after treatment are shown. Glucose AUC was significantly lower after placebo (P = 0.004), and insulin AUC was significantly higher after salsalate (P = 0.001). P values represent within-group difference in AUC.
Figure 2
Figure 2
Change in MCR-I during the IST (A) and GGIT (B). Salsalate significantly decreased MCR-I during both the IST and GGIT.

References

    1. Williamson RT. On the treatment of glycosuria and diabetes mellitus with sodium salicylate. Br Med J 1901;1:760–762
    1. Yuan M, Konstantopoulos N, Lee J, et al. Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of Ikkbeta. Science 2001;293:1673–1677
    1. Shoelson SE, Lee J, Goldfine AB. Inflammation and insulin resistance. J Clin Invest 2006;116:1793–1801
    1. Möhlig M, Freudenberg M, Bobbert T, et al. Acetylsalicylic acid improves lipid-induced insulin resistance in healthy men. J Clin Endocrinol Metab 2006;91:964–967
    1. Fleischman A, Shoelson SE, Bernier R, Goldfine AB. Salsalate improves glycemia and inflammatory parameters in obese young adults. Diabetes Care 2008;31:289–294
    1. Faghihimani E, Aminorroaya A, Rezvanian H, Adibi P, Ismail-Beigi F, Amini M. Reduction of insulin resistance and plasma glucose level by salsalate treatment in persons with prediabetes. Endocr Pract 2012;18:826–833
    1. Fernández-Real JM, López-Bermejo A, Ropero AB, et al. Salicylates increase insulin secretion in healthy obese subjects. J Clin Endocrinol Metab 2008;93:2523–2530
    1. 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
    1. 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
    1. Newman WP, Brodows RG. Aspirin causes tissue insensitivity to insulin in normal man. J Clin Endocrinol Metab 1983;57:1102–1106
    1. Bratusch-Marrain PR, Vierhapper H, Komjati M, Waldhäusl 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
    1. Matsuda M, DeFronzo RA. Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp. Diabetes Care 1999;22:1462–1470
    1. DeFronzo RA, Matsuda M. Reduced time points to calculate the composite index. Diabetes Care 2010;33:e93.
    1. Greenfield MS, Doberne L, Kraemer F, Tobey T, Reaven G. Assessment of insulin resistance with the insulin suppression test and the euglycemic clamp. Diabetes 1981;30:387–392
    1. Knowles JW, Assimes TL, Tsao PS, et al. Measurement of insulin-mediated glucose uptake: direct comparison of the modified insulin suppression test and the euglycemic, hyperinsulinemic clamp. Metabolism 2013;62:548–553
    1. Facchini FS, Hua N, Abbasi F, Reaven GM. Insulin resistance as a predictor of age-related diseases. J Clin Endocrinol Metab 2001;86:3574–3578
    1. Kim SH, Abbasi F, Chu JW, et al. Rosiglitazone reduces glucose-stimulated insulin secretion rate and increases insulin clearance in nondiabetic, insulin-resistant individuals. Diabetes 2005;54:2447–2452
    1. Jones CN, Pei D, Staris P, Polonsky KS, Chen YD, Reaven GM. Alterations in the glucose-stimulated insulin secretory dose-response curve and in insulin clearance in nondiabetic insulin-resistant individuals. J Clin Endocrinol Metab 1997;82:1834–1838
    1. 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
    1. McLaughlin T, Carter S, Lamendola C, et al. Effects of moderate variations in macronutrient composition on weight loss and reduction in cardiovascular disease risk in obese, insulin-resistant adults. Am J Clin Nutr 2006;84:813–821
    1. Reaven GM. What do we learn from measurements of HOMA-IR? Diabetologia 2013;56:1867–1868
    1. Faghihimani E, Aminorroaya A, Rezvanian H, Adibi P, Ismail-Beigi F, Amini M. Salsalate improves glycemic control in patients with newly diagnosed type 2 diabetes. Acta Diabetol 2013;50:537–543
    1. Hundal RS, Petersen KF, Mayerson AB, et al. Mechanism by which high-dose aspirin improves glucose metabolism in type 2 diabetes. J Clin Invest 2002;109:1321–1326
    1. Hawley SA, Fullerton MD, Ross FA, et al. The ancient drug salicylate directly activates AMP-activated protein kinase. Science 2012;336:918–922
    1. Din FV, Valanciute A, Houde VP, et al. Aspirin inhibits mTOR signaling, activates AMP-activated protein kinase, and induces autophagy in colorectal cancer cells. Gastroenterology 2012;142:1504–1515.e3
    1. Steinberg GR, Dandapani M, Hardie DG. AMPK: mediating the metabolic effects of salicylate-based drugs? Trends Endocrinol Metab 2013;24:481–487

Source: PubMed

Sponsorer og samarbejdspartnere

Medicinske tilstande

Narkotikainterventioner

3
Abonner