Pancreatic islet cells distinct in mice and humans
By Cassandra Awgulewitsch
Researchers in the lab of Roland Stein (Molecular Physiology & Biophysics), along with collaborators at UCSF, NC State, and UPenn, have shown distinct changes in human pancreatic islet cells throughout the course of life and the progression of type 2 diabetes. They also discovered distinct phenotypes in human islet cells compared to a mouse model.
This work, published in Diabetes, was led by Xin Tong, a postdoctoral researcher who, along with her colleagues, sought insight into pancreatic islet (hormone-producing cells in the pancreas) biology in the context of type 2 diabetes. This disease is characterized by high blood glucose and lipid levels, dysregulation of islet cells, and generalized insulin resistance. Beta cells within the pancreatic Islets of Langerhans are critical for producing and secreting insulin, a hormone key in regulating glucose levels throughout the body.
Historically, much of the work has been done in mouse models due to the difficulty of obtaining human pancreatic samples and the genetic similarities between mice and humans. In this study, Tong and colleagues obtained pancreatic and islet samples from healthy and diabetic human donors of ages 2 to 67. They found increased levels of lipid droplets—cellular structures that regulate the storage and breakdown of lipids, among other functions—in islet beta cells from older as compared to younger donors and in diabetic as opposed to nondiabetic donors.
The group also transplanted human islets from both the young and adult donors into immunodeficient mice. They found that LDs were elevated in transplants from adult donor samples but were absent from those of juvenile, or young, donors.
Tong and her colleagues then used a human embryonic stem cell line to generate and isolate a group of cells called embryonic-derived beta cell clusters (eBCs) for their experiments. Although, as their name implies, they are derived from embryonic cells, eBCs strongly resemble adult beta cells. Transplanting them into the same immunodeficient mice showed that these mature-like eBCs accumulated LDs. This result echoed those of previous experiments, and suggests that older human beta cells tend to acquire more LDs than younger beta cells.
The Stein group also explored LD accumulation in several different mouse and rat models of type 2 diabetes and, in contrast with the human samples, noted very low levels or a complete lack of LDs regardless of the age and diabetes state of the rodents. They also noted distinct mRNA expression profiles (the complete list of genes that are set to be made into proteins in a particular cell type) between human and mouse islets, pointing to key differences between the species.
Altogether, these results highlight the importance of using human models to explore lipid biology in the context of type 2 diabetes, and emphasize the increasing importance of translational work in a variety of fields in adequately and effectively representing human phenotypes.
This work was supported by the Human Islet Research Network, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institutes of Health, the Vanderbilt Diabetes Research and Training Center, JDRF, the Leona M. and Harry B. Helmsley Charitable Trust, the U.S. Department of Veteran Affairs, and a Kraft Family Fellowship.