Epidemiological, physiological and pharmacological evidence support a potential pathogenic link leading sequentially from obesity-inflammation-""""""""insulin resistance->type 2 diabetes (T2D) and cardiovascular disease. Our basic science findings indicate that the inflammatory link is mediated by activation of the transcriptional master switch, NF-KB. Following our goals to translate basic findings to the clinic, we have identified anti-inflammatory salicylates as a potential new class of drugs for the treatment of these disorders through inhibition of the IKK?/NF-?B pathway. Preliminary results from 2- to 4-week long, single-site clinical trials in T2D patients showed that high-doses of either aspirin (7 g/day) or salsalate (3.0 to 4.5 g/day) have pronounced and highly significant effects on many metabolic parameters, including reductions in fasting and postprandial glucose, total cholesterol, triglycerides, free fatty acids and hepatic glucose production and improvements in insulin-stimulated glucose disposal. This application aims to progress past the 'proof-of-principle'stage to determine whether IKK?/NF-?B inhibition in general and salsalate therapy in particular might provide new avenues for treating patients with diabetes. We propose a double-masked, placebo-controlled trial for assessing the efficacy of salsalate, a safe and FDA-approved drug, initially dosed at 3.0 g/day and escalating as tolerated to 4.0 g/day. Patients with documented but poorly controlled T2D (7.0%

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01DK074556-05
Application #
7893157
Study Section
Special Emphasis Panel (ZDK1-GRB-2 (J1))
Program Officer
Linder, Barbara
Project Start
2006-09-04
Project End
2013-06-30
Budget Start
2010-07-01
Budget End
2013-06-30
Support Year
5
Fiscal Year
2010
Total Cost
$1,500,000
Indirect Cost
Name
Joslin Diabetes Center
Department
Type
DUNS #
071723084
City
Boston
State
MA
Country
United States
Zip Code
02215
Goldfine, Allison B; Shoelson, Steven E (2017) Therapeutic approaches targeting inflammation for diabetes and associated cardiovascular risk. J Clin Invest 127:83-93
Rubin, Mishaela R; Goldfine, Allison B; McMahon, Donald J et al. (2015) Effects of the anti-inflammatory drug salsalate on bone turnover in type 2 diabetes mellitus. Endocrine 50:504-7
Barzilay, Joshua I; Jablonski, Kathleen A; Fonseca, Vivian et al. (2014) The impact of salsalate treatment on serum levels of advanced glycation end products in type 2 diabetes. Diabetes Care 37:1083-91
Goldfine, Allison B; Jablonski, Kathleen A; Shoelson, Steven E et al. (2014) Response to comment on Goldfine et al. Targeting inflammation using salsalate in patients with type 2 diabetes: effects on flow-mediated dilation (TINSAL-FMD). Diabetes care 2013;36:4132-4139. Diabetes Care 37:e112
Goldfine, Allison B; Fonseca, Vivian; Jablonski, Kathleen A et al. (2013) Salicylate (salsalate) in patients with type 2 diabetes: a randomized trial. Ann Intern Med 159:1-12
Goldfine, Allison B; Buck, J Stewart; Desouza, Cyrus et al. (2013) Targeting inflammation using salsalate in patients with type 2 diabetes: effects on flow-mediated dilation (TINSAL-FMD). Diabetes Care 36:4132-9
Romeo, Giulio R; Lee, Jongsoon; Shoelson, Steven E (2012) Metabolic syndrome, insulin resistance, and roles of inflammation--mechanisms and therapeutic targets. Arterioscler Thromb Vasc Biol 32:1771-6
Goldfine, Allison B; Fonseca, Vivian; Shoelson, Steven E (2011) Therapeutic approaches to target inflammation in type 2 diabetes. Clin Chem 57:162-7
Mathis, Diane; Shoelson, Steven E (2011) Immunometabolism: an emerging frontier. Nat Rev Immunol 11:81
Goldfine, Allison B; Fonseca, Vivian; Jablonski, Kathleen A et al. (2010) The effects of salsalate on glycemic control in patients with type 2 diabetes: a randomized trial. Ann Intern Med 152:346-57

Showing the most recent 10 out of 15 publications