The following quotation is from a research grant proposal by Mark Huising, Ph.D., Staff Scientist at the Salk Institute.
“In recent years and with the support of the Breakthrough T1D we have uncovered in the islet the presence of a network consisting of corticotropin-releasing factor (CRF) receptor type 1 and type 2 (CRFR1 and CRFR2). These receptors respond to CRF and to related peptide hormones called Urocortins. We have demonstrated that the stimulation of these receptors can induce an array of beneficial actions, which includes the stimulations of beta cell division, the prevention of beta cell death and the maintenance of insulin secretion in mouse models of diabetes”.
Meet Mark Huising, Ph.D., recipient of a two-year Breakthrough T1D grant to establish proof of principle of the ability of Urocortins to promote the regeneration of beta cells in T1D with his research colleagues Elena Caceres and Talitha van Der Meulen, Ph.D.
The complexity of life in the islet
Biologist Mark Huising Ph.D., who hails from the Netherlands, wants to know how things work in the islet cells of the pancreas. These tiny cell clusters are home to insulin-producing beta cells as well as other cells (alpha, delta, etc.) and a family of peptide hormones that serve as messengers, telling the various cells in the islet what to do and how to act.
Dr. Huising’s research is focused on these peptides – to understand their signals ““ what seems to be the source of cells’ actions and reactions in the islets – so that he can better understand the role of the islets in maintaining tight glycemic control and overall metabolic homeostasis. By getting a clearer, more specific picture of the complicated process of metabolism, Dr. Huising aims to find new targets for treating and curing type 1 diabetes.
The research efforts of Dr. Huising and his team at Salk Institute for Biological Studies have been focused on an interconnected network of these signaling molecules, some of which act within the pancreas while others signal to and from the brain, liver, skeletal muscle, GI tract and fat. Specifically, there is a group of neuropeptide hormones named after corticotropin-releasing factor (CRF). This peptide, discovered in 1981 by Dr. Huising’s mentor, the late Dr. Wylie Vale, is best known for its central role in the body’s reaction to stress and has been implicated in addiction, anxiety, obesity, and Alzheimer’s disease.
In 2010, Dr. Huising and Dr. Vale found that beta cells in the pancreas express the CRFR1 receptor. When exposed to CRF the beta cells multiply and secrete insulin when glucose is present. This intriguing discovery that the CRF family of peptides ““ together with their receptors – have a role in the body’s production of insulin-producing beta cells, and in the release of insulin ““ kept Dr. Huising delving deeper.
The receptors CRFR1 and 2 in the islets do more than respond to CRF in promising ways. In the presence of another member of the CRF family called Urocortin 3, CRFR1 and CRFR2 cause three responses: Beta cell division, prevention of beta cell death, and regulation of insulin secretion.
Recently, Dr. Huising turned to Urocortin 3 to examine its role in the regeneration of beta cells. Specifically he looked at when Urocortin 3 became involved in the formation of beta cells 1) in embryonic mice 2) in human embryonic stem cells 3) in progenitor cells in the pancreas (mice and hman) ““ these progenitor cells are those cells that haven’t yet differentiated themselves and have the “opportunity” to become a number of cell types.
What he discovered was surprising.
In a paper published in December, 2012, Dr. Huising’s team, along with collaborators at UC San Diego and ViaCyte Inc., demonstrated that in the mouse, Urocortin 3 is exclusively present in beta cells. In human islets however, Urocortin 3 is expressed in alpha cells in addition to beta cells. Beta cells make insulin. Alpha cells make glucagon ““ the antithesis to insulin. Therefore, to find the same hormone, Urocortin 3, expressed in both opposing cell types is a little bit unexpected. Nevertheless, it is clear that Urocortin 3 is restricted to mature alpha and beta cells; those cells that are capable of responding appropriately to changes in blood glucose by regulating their insulin and glucagon secretion.
This finding is not merely academic. It is of immediate use in generating beta cells from stem cells. The ‘beta cells’ that scientists have been able to grow from stem cells in a culture dish have some characteristics of actual beta cells, but are clearly not yet as good as our own beta cells. However, when these human pre-beta cells are transplanted in diabetic mice, they can mature to cure diabetes. Sometime during this maturation, they start to express Urocortin 3. Dr. Huising’s work establishes that Urocortin 3 expression coincides with the ability of beta cells to cure diabetes. The door now opens to screen for drugs that promote the appearance of Urocortin 3 as a proxy for beta cell maturity in ongoing efforts to generate mature human beta cells from stem cells in a dish.
What does this mean for people with type 1 diabetes?
For one, it seems we are finally getting to the brains behind our bodies’ ability to control blood sugar. Numerous molecular signals in the islets are involved in the life, reproduction and function of beta cells. CRF, Urocortins and these receptors may be the targets for therapies aimed at keeping beta cells healthy, multiplying and producing insulin in response to elevated blood glucose. Secondly, if we can determine Urocortin’s role in the life of a beta cell, we can add this to the complicated sequence of events that is required to coax stem cells and other cells into becoming insulin-producing beta cells.
Of course, the ultimate goal is to find ways to restore the body’s ability to make insulin and reduce the risk of complications from type 1 diabetes, either through the regeneration or replacement of insulin producing beta cells. Urocortin 3 is a road sign on the path to the programming of new alpha and beta cells.
Dr. Huising has looked at Urocortin 1 and Urocortin 3 in isolation with their receptors in the beta cells. In the months ahead, Dr. Huising is eager to make fireworks in the islets, simultaneously triggering both types of CRF receptors in the islets to to maximize the ensuing effects.
We need scientists to look outside the box. If scientists can turn a liver cell or an alpha cell into an insulin producing cell ““ do it!” – Mark Huising, Ph.D.
Dr. Huising has been funded by Breakthrough T1D since 2008. He hopes his legacy is in uncovering what goes on in the islets ““ to produce insulin, to grow and regenerate islets, and to understand the role of other hormones in the process. A new picture of what is happening in the islets gives a glimpse of ways other than insulin that we can address the disease.
The rate at which we have come to understand how things work in the islets has increased tremendously in the last decade. Still, there is unchartered territory within the islets that needs to be explored. Breakthrough T1D funding has a crucial impact ““ it keeps a base of scientists focused on type 1 diabetes in an ever-shrinking funding environment. Breakthrough T1D offers the opportunity for passionate, dedicated experts to stay the course in finding new therapies and a cure for type 1 diabetes.
This article was written by Breakthrough T1D Volunteers Barbara Donnell and Michele Huie.
Barbara Donnell is a long time supporter of Breakthrough T1D since her daughter was diagnosed more than 10 years ago. She has served on various committees, the Board of Directors and is now a National Research Information Volunteer representing the San Diego Chapter. Barbara supports Breakthrough T1D T1D research through personal giving and fundraising for The Promise Ball, The Breakthrough T1D Research Challenge and The Walk to Cure Diabetes.
Michele Huie has been actively involved with Breakthrough T1D since 2009. She has served on the Marketing & Communication committee, the website development working group and has recently joined the National Research Information Volunteer Committee. Michele supports Breakthrough T1D T1D research through personal giving and fundraising for The Ride to Cure Diabetes and The Walk to Cure Diabetes.
