Ileal interposition surgery targets the hepatic TGF‐β pathway, influencing gluconeogenesis and mitochondrial bioenergetics in the UCD‐T2DM rat model of diabetes

Abstract

Ileal interposition (IT) is a surgical procedure that increases the delivery of incompletely digested nutrients and biliary and pancreatic secretions to the distal intestinal mucosa. Here, we investigated the metabolic impact of this intervention in 2‐mo‐old prediabetic University of California, Davis type 2 diabetes mellitus rats by assessing liver gene expression at 1.5 mo post‐IT surgery. Pathway analysis indicated decreased signaling via TGF‐β/Smad (a family of proteins named mothers against decapentaplegic homologs), peroxisome proliferator‐activated receptor (PPAR), and PI3K‐Akt‐AMPK–mechanistic target of rapamycin, likely targeting hepatic stellate cells because differentiation and activation of these cells is associated with decreased signaling via PPAR and TGF‐β/Smad. IT surgery up‐regulated the expression of genes involved in regulation of cholesterol and terpenoid syntheses and down‐regulated those involved in glycerophospholipid metabolism [including cardiolipin (CL)], lipogenesis, and gluconeogenesis. Consistent with the down‐regulation of the hepatic CL pathway, IT surgery produced a metabolic switch in liver, kidney cortex, and fat depots toward decreased mitochondrial fatty acid β‐oxidation, the process required to fuel high energy–demanding pathways (e.g., gluconeogenesis and glyceroneogenesis), whereas opposite effects were observed in skeletal and cardiac muscles. This study demonstrates for the first time the presence of metabolic pathways that complement the effects of IT surgery to maximize its benefits and potentially identify similarly effective, durable, and less invasive therapeutic options for metabolic disease, including inhibitors of TGF‐β signaling.—Hung, C., Napoli, E., Ross‐Inta, C., Graham, J., Flores‐Torres, A. L., Stanhope, K. L., Froment, P., Havel, P. J., Giulivi, C. Ileal interposition surgery targets the hepatic TGF‐β pathway, influencing gluconeogenesis and mitochondrial bioenergetics in the UCD‐T2DM rat model of diabetes. FASEB J. 33, 11270–11283 (2019). http://www.fasebj.org

Zucker Diabetic‐Sprague Dawley (ZDSD) rat: Type 2 diabetes translational research model

“…Studies with the UCD‐T2DM rat have investigated feeding regular rodent chows [e.g., Purina 5012 (Cummings et al., 2008, 2011)] and other diets containing nutritional supplementation [e.g., safflower oil (Cummings et al., 2008), fish oil and eicosapentaenoic acid (Cummings, Stanhope, Graham, Griffen, et al., 2010) and fructose (Cummings, Stanhope, Graham, Evans, et al., 2010)], in addition to dietary restrictions and various chemicals (Green et al., 2017; Hung, Kanke, et al., 2019) and drugs (Agrawal et al., 2014; Cummings, Stanhope, Graham, Baskin, et al., 2010; Cummings et al., 2014; Guglielmino et al., 2012), including leptin, which normalized plasma glucose (Cummings et al., 2011). Surgical interventions for obesity, for example, gastric sleeve gastrectomy, ileal interposition and Roux‐en‐Y gastric bypass, have also been explored in the UCD‐T2DM rat (Cummings, Strader, Stanhope, Graham, et al., 2010; Cummings et al., 2012; Cummings, Bettaieb, et al., 2013, Cummings, Graham, et al., 2013; Hansen et al., 2014; Hung et al., 2018; Hung, Napoli, et al., 2019), leading to evidence that, amongst other mechanisms, bile acids and changes in maternal weight contribute to the benefits of surgery in the experimental animals and, in some cases, even in the maternal offspring.…”

Alternative ways to correct poor glucose metabolism in patient with diabetes mellitus

“…The ileal transposition proved to be the most successful metabolic operation in the correction of severe forms of nonobese DM2 in the experiment [43].…”