Obesity is an expanding global health problem. Obesity is associated with several co-morbidities; many of these conditions are mediated through insulin resistance and glucose intolerance, which can be partially attributed to an altered incretin response. The two incretin hormones GIP and GLP-1 enhance postprandial insulin secretion. Ingestion of nutrients strongly promote the release of both GIP and GLP-1 from the enteroendocrine cells K and L cells, respectively; however, the mechanisms underlying these processes are largely unestablished. Additionally, the relationship between diet-induced obesity and the postprandial release of GIP and GLP-1 has not been clearly demonstrated. It is unclear if the alterations are caused by obesity or the consumption of a high-energy diet that often induces obesity. Therefore, the goal of this dissertation was to investigate how incretin secretion is regulated by various macronutrients and how this process is altered following the chronic feeding of a high-fat diet using the lymph fistula rat model.
The dose-response relationships between the amount and type of ingested macronutrient and the secretion of incretins are not well-defined. Using the lymph fistula rat model, we determined that both GIP and GLP-1 respond dose dependently to increasing amounts of either acute carbohydrate or lipid in chow-fed Sprague-Dawley rats. However, there is minimal incretin response to dietary protein. We further demonstrate that lipid and carbohydrate are equally effective at stimulating GLP-1 release, while carbohydrate is the more potent GIP secretagogue.
In the second portion of this dissertation, we investigated the effects of chronic high-fat feeding on incretin secretion. Despite demonstrating no signs of obesity beyond hyperphagia, both the 3-week and 13-week HF-fed animals had elevated lymphatic GIP and GLP-1 concentrations compared to animals fed a LF diet following an identical mixed meal challenge with Ensure. Using our HF-PF group, we further demonstrate that, following chronic consumption of a HF diet, the elevated GIP concentration is driven by the greater percentage of fat intake, whereas the increased GLP-1 secretion is caused by the excess caloric intake.
These results may have important bearings on the nutritional and pharmacological regulation of GIP and GLP-1 secretion. Currently, GLP-1 mimetics are used for the treatment of type 2 diabetes. An additional potential therapeutic avenue is stimulating the release of the incretin hormones at the intestinal level; this would allow individuals to produce and secrete their own hormones, ideally replicating the physiological secretion time course and response to various nutrients. To accomplish this task, a greater understanding of the physiological and cellular mechanisms underlying nutrient-induced incretion secretion is needed. The results from the first portion of this dissertation provide steps in that direction. Furthermore, in order to provide incretin-based treatment to obese and type 2 diabetic patients, it is important to first understand the physiological defects in incretin secretion for both of these conditions. In regards to obesity, our findings suggest that mere consumption of a high-fat diet (for as little as 3 weeks) can result in significant changes in incretin secretion following an acute mixed nutrient challenge.