Zigman Lab Expands Understanding of Ghrelin’s Impact on Islet Physiology

New research findings published in Endocrinology about the hormone ghrelin’s impact on islet size in non-pregnant and pregnant female mice could provide a platform for potential new treatments for type 1, type 2, and gestational 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 investigating the effects of the hormone ghrelin on islet size and pancreatic beta-cell mass in female mice is noteworthy because it extends our understanding of effects of ghrelin on islet physiology and blood glucose control to both sexes and to the setting of pregnancy and has implications for treatment of type 1, type 2, and gestational diabetes.

What are the top takeaways from the research?

1. Experimentally reducing ghrelin leads to increased pancreatic islet size, percentage of very large islets, and β-cell mass in female mice, similar to what we had previously demonstrated in male mice.
2. Neither islet size nor β-cell mass correlated with plasma ghrelin levels, although they positively correlated with plasma levels of LEAP2 – a hormone that blocks ghrelin action
3. Thus, despite observed pregnancy-associated reductions in ghrelin, other factors – possibly including LEAP2, the levels of which increases in pregnancy -- appear to govern islet enlargement and changes to insulin sensitivity and glucose tolerance in the setting of pregnancy.

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

Yes – Previous work in the Zigman lab demonstrated a similar effect of ghrelin to increase islet size and β-cell mass in male mice, also showing that high fat diet-induced reductions in plasma ghrelin contributed to (but were not wholly responsible for) the increase in islet size associated with obesity.

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., 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 pregnancy as an adaptive strategy. This research reveals clues regarding differential roles for the related hormones ghrelin and LEAP2 in regulating the islet size enlargement associated with diet-induced obesity vs. pregnancy. This research provides a platform for potential new treatments for type 1, type 2, and gestational 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.

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.