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Our Research

The main focus of our lab is to understand which pathways guide beta cell proliferation, to find approaches to make more beta cells, to prevent or treat diabetes.  Using knockout and transgenic mice, and human and mouse pancreatic tissue in culture systems, we are following two exciting leads.

Beta Cell Generation:

We are focused on finding ways to increase the number of insulin-secreting pancreatic beta cells, to prevent or treat diabetes. We recently learned that when beta cells ramp up production of insulin, beta cell proliferation is also triggered.  Now we are testing hypotheses to learn how this works. Our long term goal is to identify therapeutic pathways to expand human beta cell mass.

Workload-based tissue homeostasis in the pancreatic islet via the UPR 
We were the first to implicate the beta cell unfolded protein response (UPR) in determining beta cell mass through regulation of proliferation. READ MORE

Hyperglycemia increases mouse and human beta cell proliferation in vivo 
My first work in islet biology was to develop an in vivo mouse model in which hyperglycemia is induced by direct intravenous glucose infusion. This is useful to the diabetes research community because hyperglycemia is not caused by damage to a glucose-regulatory tissue, and because it applies a stimulus for beta cell proliferation (glucose) that can be studied in vitro and in vivo. We used this model for proof of principal experiments showing that in vivo hyperglycemia increases human beta cell proliferation in islets engrafted in mice.  READ MORE

Type 2 Diabetes Genetics:

We found an intriguing connection between blood lipid levels and a region of DNA that determines type 2 diabetes risk in people, and are sleuthing the mechanism of this connection.

Hyperlipidemia (high blood lipid levels) restricts beta cell proliferation, via the T2D risk locus called CDKN2A/B  
Our work described a novel form of beta cell lipotoxicity on the beta cell: reduced compensatory proliferation in response to high glucose. It was previously known that FFAs impair insulin secretion and increase beta cell death. Using our in vivo mouse intravenous chronic infusion system, we found that raising lipid levels prevented glucose-induced proliferation.  Studies in mouse islets suggest that high lipids slow beta cell proliferation by inducing a cell cycle inhibitor gene called p16, which is encoded at the CDKN2A/B locus.  READ MORE

Collaborations using our Infusion Model 
Our intravenous glucose and lipid infusion models are useful methods to alter circulating nutrient levels without relying on damaging or interfering with the function of a metabolic tissue. However, these models are not easy to implement, so I provide collaborative access to these samples and techniques.  READ MORE