Pathophysiology & Molecular Pharmacology

How We're Advancing Care

The laboratories in this section aim to identify potential pathophysiological mechanisms contributing to type 2 diabetes, including insulin resistance and beta β-cell dysfunction, and associated conditions and complications, including hyperuricemia and cardiovascular disease.

While members of the section attempt to elucidate the mechanisms themselves, this is not necessary as the goal is to identify any mechanism that might be exploited for therapeutic purposes. An example of the approach is the section member's identification of inflammation as a potential pathological mediator in insulin resistance and target for its reversal. Ongoing studies that spun off from TINSAL-T2D and studies of salicylate's mechanism of action include:

1. Once we knew that salicylate binds and activates AMPK, we found that AMPK activation is required for salicylate's anti-inflammatory effects through AMPK mediated inhibition of NF-kB. This occurs through canonical inhibition of mTORC1 via TSC1/2 and Rheb. KLF2 activation downstream of mTORC1 is required NFkB inhibition.
2. Using basic biochemical principles, we identified another route to activating AMPK with approved drugs, in this case for treating gout. By inhibiting of xanthine oxidase (XO), the final step in purine metabolism, XO inhibitors including allopurinol raise levels of upstream purines, including AMP, which activate AMPK. Basic and clinical studies are expanding on this important discovery.
3. We initially studied HSF1 because salicylate had been shown to activate it, but we found this was not relevant to salicylate's metabolic actions in mammals. However, we discovered that feeding activates the HSF1 transcriptional program in liver to maintain protein folding homeostasis in the face of mTOR driven increases in protein synthesis and growth. This is the first demonstration of a normal physiological function for HSF1, as opposed to a stress response, in mammals.
4. Studies on inflammation in the pathogenesis of T2D lead to us to hypothesize potential roles of leukotrienes in the recruitment of specific leukocytes to adipose tissue or liver, potentially including neutrophils and NK cells.
5. We have found that externalized phosphatidylinositides (PIPs) represent a new "eat me" expressed on apoptotic cells that is recognized by phagocyte CD14. Manuscripts in each of these 5 areas are being prepared for submission.

Recent Accomplishments

• The TINSAL-T2D, TINSAL-CVD and TINSAL-IGT clinical trials translated the Section's basic discoveries on inflammation by showing that the salicylate pro-drug, salsalate, improves blood glucose and lipid levels in persons with type 2 diabetes or prediabetes; cardiovascular effects of salsalate are thus far indeterminate. Annals Intern Med 2010; PLoS One 2013; Annals Intern Med 2013; JAMA Cardiol. 2016.
• Having determined that inflammation was a potential mediator in type 2 diabetes, studies were focused on determining which cells and tissues are responsible, which include macrophages, regulatory T cells and natural killer (NK) cells in adipose tissues. Nat. Med. 2009; PNAS 2010; Nature 2012; Cell Metab. 2016.