Fructose Metabolism Effects on the Liver: Unraveling the Role of Defective Intestinal GNG in Individuals with Obesity

"Fructose Metabolism Effects on the Liver: Unraveling the Role of Defective Intestinal GNG in Individuals With Obesity," is an interventional, randomized crossover study led by investigators at Touro University, California. The trial tests the hypothesis that, within a defined range of fructose intake, the small intestine's capacity to convert fructose to glucose via gluconeogenesis (intestinal GNG) serves a protective role for the liver, mitigating the harmful metabolic effects of dietary fructose. The study will determine whether this protective intestinal pathway is impaired in individuals with obesity compared with lean individuals, and will quantify the relative contributions of intestinal versus hepatic fructose conversion to circulating glucose and lipid synthesis.

Qualified adult participants, both lean (BMI 19 - 25 kg/m2) and obese (BMI 30 - 38 kg/m2) but otherwise healthy, will complete a baseline sugar tolerance test and then undergo four outpatient tracer/feeding study visits in randomized crossover fashion, each approximately three weeks apart. After an overnight fast, a six-hour fed tracer study will be initiated: participants will consume liquid meals at regular intervals while receiving tracer isotopes intravenously. Meal composition is standardized across visits except for fructose content (High: 16% of total carbohydrate; Low: 6% of total carbohydrate) and the route of tracer administration (oral 13C-labeled fructose in meals vs. intravenous 13C-labeled fructose). Blood and urine samples will be collected frequently during each six-hour study to measure tracer distribution and metabolic outcomes. Vital signs and anthropometrics are recorded at each clinic visit.

The trial's primary outcome measures quantify total fructose converted to glucose over six hours and partition this conversion between liver (hepatic GNG) and intestine (intestinal GNG). An additional primary measure assesses de novo lipogenesis (DNL), operationalized as the percentage of newly synthesized palmitate over the six-hour study period. These outcomes will clarify how fructose is metabolized systemically and whether defective intestinal fructose-to-glucose conversion in obesity shifts fructose fate toward hepatic glucose production or lipid synthesis, pathways implicated in fatty liver and metabolic disease.

This mechanistic study enrolls an estimated 40 participants and is designated as basic science in primary purpose. The interventional model is crossover with triple masking and four arms capturing combinations of high- and low-fructose meals and oral versus intravenous 13C-fructose tracers. Sponsor and institutional leadership are based at Touro University, California, with the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) listed as a collaborator; the study record includes an NIH grant/contract identifier (R01DK140477). Recruitment and conduct are taking place in Vallejo, California, under study contacts provided for coordination and oversight.

The study's investigators plan to share de-identified individual participant data and supporting documents with qualified academic investigators for at least five years from publication of the primary manuscript, enhancing transparency and enabling secondary analyses. Primary completion is estimated in mid-2030, offering an opportunity to inform mechanistic understanding of fructose metabolism and potential therapeutic or dietary strategies to protect the liver in populations with obesity.