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Pilot & Feasibility Program Application Abstract

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Lymph Fistula Mouse: A novel model for studying incretin secretion

Phil Howles (Cincinnati, OH)

Pilot & Feasibility Program

With the prevalence of obesity, type 2 diabetes and other obesity related complications extending to well over half of the adult population of the United States, the need for mechanistic understanding and treatments for diabetes and its complications has become a priority for clinical and academic researchers alike. Incretins are secreted by the small intestine in response to nutrient stimulation and they promote insulin secretion. Incretins have gained considerable attention recently due to their important role in glucose homeostasis and their therapeutic potential for the treatment of type 2 diabetes. Genetic mouse models have been widely employed by diabetes investigators to understand the etiology and pathology of this disease. Despite the fact that mice are often used widely for metabolic research, incretin research has been hampered by low circulating levels of incretins coupled with the limited availability of blood volume for assay. In studies using the lymph fistula rat, we discovered that incretin levels in exist at levels 5-10 fold higher in intestinal lymph than in the portal blood (data to be published). Thus, the lymph fistula model can be potentially used for studying intestinal incretin secretion. We propose in this Pilot and Feasibility application to characterize the incretin response to the feeding of a lipid meal (Ensure) in C57BL/6J, FVB/N and 129/Sv, three mouse strains commonly used for metabolic studies as well as the generation of knockout and transgenic animals. If incretin secretion in response to ingestion of the Ensure is different between the 3 strains, future studies will be carried out to test if the difference between the strains can be attributed to a particular macronutrient component of the mixed meal. We believe that once the lymph fistula mouse model for studying incretin secretion is established, this phenotype testing will become an important and widely requested test for many diabetes investigators.

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