The Impact of Salsalate Treatment on Serum Levels of Advanced Glycation End Products in Type 2 Diabetes

Abstract

OBJECTIVESalsalate 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 METHODSParticipants 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.RESULTSForty-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.CONCLUSIONSSalsalate 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.

Salsalate (Salicylate) Uncouples Mitochondria, Improves Glucose Homeostasis, and Reduces Liver Lipids Independent of AMPK-β1

“…This is the first study to suggest that salicylate-driven mitochondrial uncoupling is the primary mechanism of action to explain the host of beneficial effects associated with salicylate (11,49,50) and salsalate (6)(7)(8)14,51,52). Data from the present study and previous investigations suggest that mitochondrial uncoupling resulting from the protonophoric properties of salicylate explains the consistently observed increases in energy expenditure in murine models and human subjects treated with salicylate-based compounds (6,10,11,14,15,(52)(53)(54)(55)(56)(57)(58).…”

The Receptor for Advanced Glycation Endproducts (RAGE) and Mediation of Inflammatory Neurodegeneration

“…While the primary risk factor for AD is advanced age, recent insights from genomic technology implicate inflammatory lipid and cytokine signaling in microglia, the myeloid cells of the CNS, as a prominent correlate of disease. Specifically, human GWAS suggest a powerful link between inflammatory pathways, including complement, chemokines and influential lipid and cholesterol molecules, such as Triggering Receptor Expressed on Myeloid Cells 2 (TREM2), ABCA7, Apolipoprotein E variant 4 (APOE4) and others with AD susceptibility [14,20,[41][42][43][44][45][46][47][48][49]. Additional analyses within animal models have illuminated various molecules critical to the innate immune system as major contributors to increased or decreased rate of AD progression, such as Chemokine Receptor Type 2 (CCR2), Chemokine Receptor 1 (CX3CR1 or GPR1), complement components (C1q and C3) and Chemokine Ligand 8 (CXCL8) [43,[50][51][52][53][54][55][56][57][58][59][60][61][62][63].…”

Anti-inflammatory therapy in the treatment of cardiovascular diseases

“…In the Targeting Inflammation Using Salsalate for Type 2 Diabetes (TINSAL-T2D) study, these compounds showed an inhibitory effect on inflammatory process by reducing the number of circulating leukocytes, neutrophils, and lymphocytes [8]. Thus, these inexpensive and relatively safe drugs still require careful evaluation of their potential use in the treatment of CVD.…”