Systems Physiology of Obesity and Diabetes
Can we cure type 2 diabetes and reverse obesity?
Obesity stretches the limits of metabolism, resulting in chronic and often fatal diseases such as hypertension and type 2 diabetes. It is not clear why it is so difficult to lose weight and maintain weight-loss, and the mechanistic links between obesity and diabetes remain obscure. We believe that to solve these questions and cure diabetes, we must take a wholistic approach and study how different organs and systems in the body interact in both health and disease.
Bariatric surgery, also known as metabolic or weight-loss surgery, is currently the most effective weight-loss treatment for obese and frequently diabetic patients. Surgery leads to rapid diabetes remission through yet unknown mechanisms independent of weight loss. This challenges many basic views of physiology and metabolism. Therefore, understanding bariatric surgery presents opportunities for both improving our basic understanding of physiology as well as identifying novel clinical approaches toward diabetes and obesity.
L-cells (red) in the intestinal epithelium (green) are a rare endocrine cell type that secreted the hormones Glp1, Glp2. Diabetes and weight loss drugs are based on Glp1 analogs, and on ways to increase the half life of endogenous Glp1.
Surgical, genetic, pharmacological, stem-cell and mathematical models
We use surgical mouse models for Roux and Y Gastric Bypass and Sleeve Gastrectomy to study how anatomy changes physiology to bring about diabetes remission and weight loss. Using these models we generate hypotheses regarding the mechanisms by which surgery works, and how can we affect physiology without surgical intervention. We use genetic models and metabolic drugs to test and refine our hypotheses and discover new biology toward this end. The intestine can also be modeled using 3D organoid culture derived from mouse or human intestinal stem-cells, or from human embryonic stem-cells. These cultures allow direct visualization of intestinal processes and large numbers of samples for experiments. In parallel, we use mathematical modeling to crystalize our ideas, explain data and generate new hypotheses which can be tested experimentally.
Hormonal regulation of metabolism
Hormones convey information between tissues from one tissue to the next, and all metabolic diseases involve some dysregulation of hormonal systems. It is perhaps not so surprising that bariatric surgeries change the levels and dynamics of many metabolic hormones. Hormone pathways are especially attractive to us because their activation or inhibition has therapeutic potential. Additionally, they are amenable to mathematical modeling and can be studied by established pharmacological and genetic tools. At present, we are most interested in the dynamics and function of the hormones glucagon, somatostatin and growth hormone in the regulation of metabolism.
Organismal allocation of nutrients and energy storage
Where does food go after we eat? Absorbed nutrients are somehow distributed to the various tissues of our body: some are stored as glycogen in the muscle, some as fat in adipose tissue while some are metabolized in the liver to create new metabolites altogether. Hormones such as insulin control how nutrients are allocated and how energy is spent. Bariatric surgeries work in part because they change this allocation. We are interested in quantitatively “following the food” in healthy and disease states to understand the logic and control of this process and ultimately to manipulate it through bio-medical devices or pharmacological agents.
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