Diabetic Gastroparesis

Diabetic gastroparesis can occur in both type 1 and type 2 diabetes and results in significant morbidity, often in young to middle-aged women. Beginning in 2001, Dr. Farrugia's lab set out to determine the cellular and molecular basis of diabetic gastroparesis, first in an animal model and then in people. This research allows scientists to design targeted therapies that improve patients' treatments and outcomes.

Dr. Farrugia's team first showed that the major cellular defect underlying diabetic gastroparesis in both animal models and in humans is loss of a cell type known as the interstitial cell of Cajal (ICC). Other cell types, including neurons, were also affected.

The lab then went on to show, in an animal model, that a critical change that precedes loss of ICC is a loss of alternatively activated M2 macrophages that express heme oxygenase 1 (HO-1) and produce interleukin-10 (IL-10), together with activation of M1 macrophages. Read more about the Cellular and Molecular Physiology of Gastrointestinal Disorders Lab's research on interstitial cells of Cajal.

Dr. Farrugia's Cellular and Molecular Physiology of Gastrointestinal Disorders Laboratory recently showed that the HO-1-related change that has been demonstrated in an animal model also occurs in humans. However, targeting HO-1 with hemin, giving inhaled carbon monoxide or giving IL-10 completely reverses the ICC-related cellular defects and restores normal gastric emptying.

Further, Dr. Farrugia's research team now uses the op/op mouse model lacking macrophages to show that without macrophages, cellular damage and delayed gastric emptying do not occur. This finding suggests that M2 macrophages are protective, and M1 macrophages are required for delayed gastric emptying to occur. This is a completely new paradigm and for the first time provides both a mechanistic and a therapeutic approach.

The Cellular and Molecular Physiology of Gastrointestinal Disorders Lab also studies why some people and animal models with diabetes get gastroparesis and others don't. Using a variety of techniques, including next-generation sequencing, the lab has shown that the length of repeats in the HO-1 (HMOX1) gene promoter affects the risk of developing the disease. The lab has also identified key molecules in the immune pathway that are involved in the development of gastroparesis.

This work is supported by two large grants from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). The program project grant, titled Pathobiology of the Enteric System, funds the lab's work on the role of HO-1 in diabetic gastroparesis.

The Cellular and Molecular Physiology of Gastrointestinal Disorders Lab is also part of the NIDDK's Gastroparesis Clinical Research Consortium, the largest-ever effort to understand the mechanisms underlying diabetic and idiopathic gastroparesis in the U.S. The consortium is based on collaborations with multiple academic medical centers across the country.