A hitherto unknown hormonal complex that regulates extracellular energy production in pancreatic islet (beta) cells could be a novel target to not only treat both type 1 and type 2 diabetes but also potentially to prevent their development in the first place, suggests basic science research led by US investigators.
Fatty-acid-binding protein 4 (FABP4), a recently identified hormone, was known to be elevated in type 2 diabetes, but the researchers now show that it is not only increased in type 1 diabetes but also that those increases predate its development.
They also show that antibodies against the hormone in mice models prevent type 1 diabetes and improve glycemic control in type 2 disease.
Moreover, it forms a complex with two other proteins that the researchers termed “Fabkin.”
The research, published in Nature this month, indicates that increased levels of the complex blunts beta cell function, while antibody treatment improves beta cell function.
“For many decades, we have been searching for the signal that communicates the status of energy reserves in adipocytes (fat cells) to generate appropriate endocrine responses, such as the insulin production from pancreatic beta cells,” said senior author Gökhan S. Hotamisligil, MD, PhD, in a press release.
“We now have identified Fabkin as a novel hormone that controls this critical function through a very unusual molecular mechanism.”
Still a Long Way to Go
Speaking to Medscape Medical News, Hotamisligil, who is director of the Sabri Ülker Center for Metabolic Research at Harvard T. H. Chan School of Public Health, Boston, Massachusetts, explained that taking the findings to the clinic entails answering a number of questions.
“That will keep us busy for a long time, and there are also translational questions, which are extremely exciting,” but the team is very “optimistic” that the findings will transfer well into humans, he said.
One reason is that in mice and humans with type 1 and type 2 diabetes, “we see exactly the same pattern of regulation” of Fabkin levels and that, “equally importantly,” sustained high levels of the hormone “correlate with poor diabetes control” in type 1 diabetes and disease severity in type 2 disease.
“This is the first strong indication that it will translate well, and the second is that, if we take human islets…and then apply this hormone into those islets, we see the same suppression of insulin secretion and viability that we see in mice islets.”
Moreover, blocking the hormone prevents the “negative effects” that we see on the islets, which is a “really critical” factor in suggesting that Fabkin could be a viable treatment target in humans, Hotamisligil explained.
He continued that, encouragingly, “nature has done some experiments in humans” with Fabkin, showing that “you can have a safe and healthy life with a mutation in the components of this complex…that reduces levels of the hormone.
“These individuals have a greatly reduced risk for both diabetes and cardiovascular disease, so this tells us that, if we can establish a safe agent that can be used in humans, this will be well-tolerated for life, and it will have beneficial effects.”
Lastly, Hotamisligil said that such an agent already exists, “so it’s really just a matter of making it suitable for human use and taking it through the testing procedures.”
He cautioned, however, that “these are important pillars” for translational research “that we rarely, if ever, find in many of our projects,” and there is still a long way to go.
Study Details: FABP4 Levels Associated With Glycemic Control
The team says the research was “inspired” by previous studies showing that Fabp4 knockout mice had higher beta-cell mass in the pancreas and significantly increased glucose-stimulated insulin secretion.
While it is “well established” that FABP4 is increased in type 2 diabetes, they initially examined whether levels are also regulated in type 1 diabetes, independently of adiposity and insulin resistance.
Looking at serum samples from normoglycemic individuals and those with new-onset type 1 diabetes in the BABYDIAB and DiMELLI cohorts, they found that FABP4 was increased approximately 1.6-fold in the latter.
In another cohort of older patients with type 1 diabetes of variation durations, serum FABP4 levels were correlated with A1c levels (P = .005), “which suggests that FABP4 is associated with glycemic control.”
Mouse studies indicate that FABP4 levels are increased both shortly before and during new-onset type 1 diabetes, implying that the hormone “may have a role in beta-cell failure and pathogenesis” in both type 1 and type 2 diabetes.
Antibody targeting of FABP4 levels in mice also revealed that treatment from 10 weeks of age protected against the development of type 1 diabetes, while antibody-treated mice with diabetes had significantly reduced blood glucose and increased plasma insulin levels vs mice given control antibodies.
This, the team says, “suggests that these mice had a less severe diabetes phenotype” with the protection against type 1 diabetes similar to that seen in Fabp4 knockout mice.
Mice with diet-induced obesity and non-obese mice with diabetes treated with anti-FABP4 antibodies had improved glucose tolerance tests and a significant increase in islet number and beta cell mass vs controls.
Further work enabled the team to identify a complex formed by circulating FABP4–adenosine kinase (ADK)–and nucleoside diphosphate kinase (NDPK), which could be targeted by anti-FABP4 antibodies via both FABP4 and NPDK.
“We propose the name Fabkin for this new hormone complex formed by NDPK to indicate its unique constitution of a fatty-acid-binding protein and kinases,” the researchers write.
The team then found that the Fabkin complex alters calcium homeostasis in the endoplasmic reticulum (ER).
This, “results in ER dysfunction, increased sensitivity to environmental stress and potentiation of beta-cell death in vitro,” which are mechanisms “critical” to the pathogenesis of both type 1 and 2 diabetes.
Finally, they showed that targeting Fabkin with anti-FABP4 antibodies “preserves beta-cell mass and enhances beta-cell function to protect against diabetes in multiple models.”
Funding for this study came from National Institutes of Health and Juvenile Diabetes Research Foundation grants. The Hotamisligil Lab has generated intellectual property (assigned to Harvard University) related to hormonal FABP4 and its therapeutic targeting and receives funding for this project from Lab1636, LLC, an affiliate of Deerfield Management. Gökhan S. Hotamisligil is on the Scientific Advisory Board of Crescenta Pharmaceuticals and holds equity. Other authors have no conflicts of interest to declare.
Nature. 2021. doi: 10.1038/s41586-021-04137-3. Abstract