The primary focus of Dr. D'Alessio's research is the regulation of insulin secretion and glucose tolerance in type 2 diabetes, with a focus on the influence of proglucagon-derived peptides on these processes. Current efforts target the role of GLP-1 receptor signaling and proglucagon processing on islet function, and the effects of proG-peptides in the brain. The basic methodologic approach is systems physiology in rodent models and healthy and diabetic humans. Central themes that are common to this research is the interaction of ingested nutrients with endocrine signaling systems, and the interface between hormones and the nervous system. The overall goal of this work is to better understand the physiologic mechanisms underlying nutrient metabolism and apply this knowledge to the treatment of diabetes and obesity. Specific projects underway in Dr. D’Alessio’s lab include:

1. Regulation of insulin secretion by islet and intestinal glucagon-like peptide 1 (GLP-1).  These studies take advantage of mouse models with genetic alterations allowing deletion and re-expression of the GLP-1 receptor, proglucagon, and the glucagon receptor. These studies are designed to compare the effects of circulating and islet proG peptides on b-cell function (1).
2. Regulation of islet function by CNS GLP-1 signaling. This work extends initial observations that hypothalamic GLP-1 signaling increases insulin secretion. Current investigation is focused on regulation of islet function by specific GLP-1 receptor expressing neurons in the hypothalamus, interaction of GLP-1 signaling with the autonomic nervous system, and the balance of stress responses and glucoregulatory responses initiated by central GLP-1 (2,3,4). 
3. Interactions of GLP-1 and GIP to regulate insulin secretion and glucose tolerance. This project will use infusions of GLP-1 and GIP, and the GLP-1r antagonist exendin-(9-39), to determine the physiologic basis of the incretin effect. Pathophysiology will be tested in type 2 diabetic subjects before and after intensified glucose control (5).
4. Mechanisms of bariatric surgery to regulate insulin secretion. Humans and mice have marked changes in insulin secretory dynamics after gastric bypass or sleeve gastrectomy. In this project a mouse model of sleeve gastrectromy will be used to investigate systemic, islet, and b-cell factors that result in improved glucose tolerance. Findings in mice will be extended to studies of humans with bariatric surgery (6,7,8,9,10).

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