Regulation of human bile acid metabolism in reversible insulin resistance

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.