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, also are 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 macrophages that express heme oxygenase-1 (HO-1) and produce interleukin-10 (IL-10), together with activation of macrophages that produce pro-inflammatory factors. Furthermore, upregulating HO-1 expression by giving hemin, by giving inhaled carbon monoxide or by giving IL-10 reverses the ICC-related cellular defects and restores normal gastric emptying in diabetic animals. This is a completely new paradigm and for the first time provides a potential mechanistic basis for the cellular changes in diabetic gastroparesis and a novel therapeutic approach.
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 Lab recently showed that the changes in macrophage polarization patterns that were demonstrated in animal models also occur in humans with diabetic gastroparesis.
The Cellular and Molecular Physiology of Gastrointestinal Disorders Lab has also applied analysis of genomic variants, proteomic and transcriptomic profiling to understand why some people with diabetes get gastroparesis and others do not. These studies found that the longer repeats in the human HO-1 (HMOX1) gene promoter associate with more-severe symptoms of gastroparesis, especially nausea.
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 macrophages in the development of 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.