Zigman Lab Demonstrates Effects of Ghrelin Reduction on Pancreatic Islets

New research findings published in The Journal of Clinical Investigation about the hormone ghrelin’s role in regulating blood glucose could have implications for the treatment of type 1 and type 2 diabetes.

We asked Jeffrey Zigman, M.D., Ph.D., a Professor in the Center for Hypothalamic Research, to explain his team’s findings.

Why is this research noteworthy?

Our research demonstrating that reducing levels of the hormone ghrelin alone can relatively markedly and rapidly increase pancreatic beta-cell mass is noteworthy because the findings are novel, the findings partially explain the changed physiology of islets in the setting of obesity, the findings contribute to our understanding of how ghrelin regulates blood glucose, and the findings have implications for treatment of type 1 and type 2 diabetes.

What are the top takeaways from the research?

1. Reducing ghrelin – by gene knockout, conditional ghrelin-cell ablation, or high-fad diet feeding – is associated with increased mean pancreatic islet size, percentage of large islets, and β-cell mass.
2. Higher β-cell numbers from decreased β-cell apoptosis contributes to the increased β-cell mass.
3. A negative correlation between islet size and plasma ghrelin in high fat diet-fed plus chow-fed wildtype mice together with even higher islet size in high fat diet-fed ghrelin-knockout mice than in high fat diet-fed wildtype mice suggest reduced ghrelin contributes to, but is not solely responsible for diet-induced obesity-associated islet enlargement.

Does this build on previous findings from you or your lab, or other researchers at UTSW?

Yes – Previous work in the Brown/Goldstein lab has highlighted the essential role of ghrelin in preventing life-threatening drops in blood glucose in the setting of severe caloric restriction. Previous work in the Zigman lab has demonstrated key roles for different brain regions in ghrelin’s glucoregulatory actions. The Zigman lab has published papers that help clarify the pancreatic islet celltypes mediating ghrelin action.  Also, the Zigman lab has also previously demonstrated that ghrelin permits the normal counterregulatory response to insulin-induced hypoglycemia.

Are there any distinctive tools, technology, training, grants, development initiatives or state or federal funding such as NIH that deserve mentioning?

This work was supported by the David and Teresa Disiere Foundation, the Diana and Richard C. Strauss Professorship in Biomedical Research, the Mr. and Mrs. Bruce G. Brookshire Professorship in Medicine, the Kent and Jodi Foster Distinguished Chair in Endocrinology, in Honor of Daniel Foster, M.D., the American Diabetes Association, and the National Institutes of Health. 

How does this research advance the field?

This research expands our understanding of how ghrelin’s actions to regulate blood glucose, which are thought to be essential in the setting of severe caloric restriction, are mediated. This research expands our understanding of how islet size and insulin levels are regulated in the setting of diet-induced obesity as a defensive strategy against insulin resistance. This research reveals clues regarding potential mechanisms by which reducing ghrelin increases islet size.  This research provides a platform for potential new treatments for type 1 and type 2 diabetes.

How does it tie into/advance toward clinical solutions for patients?

Such a relatively marked and rapid effect of conditional ghrelin reduction could potentially be harnessed to increase beta-cell mass as a treatment for type 1 diabetes mellitus (T1DM). One could envision a therapeutic strategy whereby neutralizing ghrelin or decreasing ghrelin signaling in other ways  could be used to increase beta-cell numbers within donor islets, optimize proliferation of cultured beta-cell lines, and/or favor expansion of beta-cells within islet organoids prior to or following beta-cell transplantation. Decreasing ghrelin signaling within patients who have undergone islet cell transplantation also presumably would favorably impact glycemic control in other ways, for instance by enhancing insulin sensitivity, directly and indirectly promoting insulin secretion, and increasing islet vascularity, all of which previously have been documented. It remains to be seen if islets or beta-cells from low ghrelin environments also would exhibit improved survival following transplantation, as for instance has been shown for enlarged islets derived as a result of other manipulations.

Neutralizing ghrelin additionally might show efficacy as a T1DM prevention strategy and in management of type 2 diabetes mellitus (T2DM). For instance, in the non-obese diabetic (NOD) mouse model, enhancing beta-cell proliferation prior to islet infiltration by immune cells alters the immunogenic identity of beta-cells, protecting the mice from developing T1DM. One wonders if enhancing β-cell numbers by neutralizing ghrelin would have the same effect. Also, during the pathogenesis of T2DM, longstanding insulin resistance causes beta-cells to become dysfunctional and/or dormant, eventually leading to deterioration of glycemic control. This results at least in part from inactivation of key beta-cell transcriptional complexes. Neutralizing ghrelin conceivably could serve as a novel means to replenish β-cells in patients with T2DM.

How do UTSW’s education, clinical care, or other research missions tie into this research?

This research was conducted within UT Southwestern’s Center for Hypothalamic Research, which was established in 2006 to bring together scientists interested in understanding the mechanisms by which the hypothalamus regulates eating, body weight, blood glucose, and related metabolic processes. The Center is unique among academic institutions in that it is the only one with a primary focus on the hypothalamus. By studying the hypothalamus plus interconnected brain regions, peripheral organ systems such as the pancreatic islets, and hormonal networks along the gut-brain axis, we hope to better understand the pathogenesis of obesity, diabetes, and related metabolic/mood disorders. 

This research also is aligned with the UT Southwestern’s Nutrition and Obesity Research Center’s mission to support research infrastructure, enrichment programs, and collaborative activities for investigators conducting research in the causal factors of nutrition and obesity-related health problems, including consequences, prevention, and alleviation.

Further, this research has been facilitated by the mission of the Division of Endocrinology at UT Southwestern, with its diverse faculty whose expertise spans the spectrum of endocrine diseases, including obesity and diabetes.

 

Dr. Zigman holds the Kent and Jodi Foster Distinguished Chair in Endocrinology, in Honor of Daniel Foster, M.D.; the Mr. and Mrs. Bruce G. Brookshire Professorship in Medicine; and the Diana and Richard C. Strauss Professorship in Biomedical Research.

To learn more about Dr. Zigman’s research, visit the Zigman Lab site.