|Pilot Study||Regulation of human bile acid metabolism in reversible insulin resistance|
|Awardee||Joshua Cook MD PhD|
Bile acids (BA) have emerged as promising and manipulatable mediators of the dual threats posed by insulin resistance (IR) underlying type 2 diabetes: chronic hyperglycemia and cardiovascular disease. Levels of 12ahydroxylated bile acids (12-HBA) strongly correlate with measures of IR in humans and depletion of 12-HBA in animals improves glucose tolerance. However, hepatic IR also appears to cause increased 12-HBA in animals. Better understanding the mechanisms behind this apparent pathologic cycle in humans is essential for developing novel cardioprotective diabetes treatments. We propose short-circuiting this cycle with two complementary patient-oriented research studies of growth hormone (GH) excess, a secondary cause of insulin resistance featuring both clear pathogenesis and reversibility, and its consequences for BA metabolism. First, we will prospectively study patients with acromegaly (“GH-oma”), measuring IR indices and BA profiles before and after surgical and/or medical treatment. Second, we will conduct a randomized, placebo-controlled prospective clinical trial in which we administer recombinant human GH (rhGH) to healthy volunteers in order to evaluate the impact of temporarily induced IR on BA metabolism – especially 12-HBA content. We will also assess the ability of the BA sequestrant colesevelam to mitigate rhGH-induced IR by offsetting adverse BA reprogramming. In each case we will perform our BA analysis using advanced mass spectrometric techniques capable of identifying >150 individual BA species, most as yet unstudied. These patient-oriented studies will yield new mechanistic insights into the direction(s) of causality in the relationship between IR and BA, particularly 12-HBA, with major implications for drug design.