Re-aggregated human islets: The next gold-standard in 3D in vitro model for diabetes research?

Correlating human pancreas donor characteristics with 3D InSight™ Islet Microtissue functionality confirms reaggregated islets are a robust, physiologically relevant model for diabetes research.

With diabetes approaching epidemic proportions globally, there is an ever-increasing need for anti-diabetic drugs and therapies that help prevent the development of this disease. Human islet research is critical for our understanding of both type 1 diabetes and type 2 diabetes, thus there is also a growing demand for human islet models.

InSphero has perfected the art and science of producing uniform, functionally robust, and long-lived islets using a reaggregation technique that ensures minimal intra-assay and intra-donor variability. We recently completed our 90th production run of 3D InSight™ Islet Microtissues, and I want to share with you some of the data we've compiled over the past few years as well as key reasons why islet researchers can rely on our standardized model for studying human islet function, regeneration, and preservation.

Standard Models for Studying Islet Biology

For more than 30 years, laboratory animals have been used extensively in islet research to contribute to a vast knowledge base that has pushed the field forward. What seemed impossible only 10 years ago is now within the grasp of diabetes researchers. Production of beta-like cells from pluripotent sources (Pagliuca et al. 2014) and even induction of beta cell regeneration in situ through several strategies, including alpha to beta cell trans-differentiation (Ben-Othman et al. 2017) and stimulation of beta cell proliferation (Wang et al. 2015), or novel strategies to enhance the insulin secretory function of beta cells, have all been developed thanks to the research performed in islets from animal sources.

Unfortunately, implementing these strategies in humans has proven challenging due to interspecies differences between human and rodent islets and beta cells in terms of functionality, cell composition, and architecture, which highlights the importance of working with human tissue in the field of islet research and drug development. Access to human pancreatic islets is more vital than ever for researchers and pharmaceutical companies to advance towards novel therapeutic strategies for type 1 and type 2 diabetes.

Human beta cell research, however, is constrained by the limited availability of human pancreatic islets from living or cadaveric donors (April 2014 Islet Biology Keystone Meeting White Paper).

Beyond supply and demand for human islets in diabetes research

The field has been further stymied due to the short in vitro lifespan of donor islet cells, inherent heterogeneity in islet size and cellular composition, as well as the complexity of the isolation process (Kaddis et al. 2009). Moreover, islets obtained from various isolation centers can be heterogeneous in their purity and viability, depending on the quality of the donor material.

To overcome the myriad problems associated with primary islet fractions, InSphero developed a post-isolation protocol designed to take full advantage of the inherent ability of dispersed epithelial cells to re-establish cell-cell contact and assemble into spheroids. Under proper 3D cell culture conditions, such as gravity-induced cellular self-assembly, dispersed islet cells can form uniform, functionally robust, and long-lived human islet spheroids with preserved morphological features of native pancreatic islets.

Nonetheless, it is reasonable to think that a tissue that has undergone enzymatic disaggregation and has been put through a reaggregation process might have lost some of its original features. Some questions you might ask are: Is the functionality of the newly formed microtissues maintained? Do the endocrine cells re-establish cellular communications? Is paracrine signaling affected?

InSphero has now completed the production of islet microtissues from more than 90 donors, resulting in a valuable collection of data that offers the possibility of linking the functional performance of the newly formed islets with various donor characteristics

The insulin secretory function in response to glucose and other stimuli of reaggregated islet microtissues following our 3D Select™ Process for Islet Microtissues is not only sustained but is also prolonged with respect to short-lived, low-purity native islet fractions. Our customers, which include all top 10 pharmaceutical companies developing anti-diabetes drugs that target islets, have already tested their novel candidate compounds in 3D InSight™ Islet Microtissues with successful results.

Moreover, InSphero has now completed the production of islet microtissues from more than 90 donors, resulting in a valuable collection of data that offers the possibility of linking the functional performance of the newly formed islets with various donor characteristics.

Re-aggregated 3D human pancreatic islet organoids

Correlating human donor characteristics with islet microtissue functionality

We have observed that a positive correlation exists between the body weight of the donors, represented as Body Mass Index (BMI), and the levels of basal and glucose-stimulated insulin secretion of reaggregated 3D InSight™ Human Islet Microtissues. Increased body weight results in impaired insulin sensitivity in peripheral tissues, which forces the beta cells to increase their insulin secretory function to properly control the levels of glucose in the bloodstream.

The fact that islet microtissues produced from donors with higher BMI present enhanced insulin secretory function in both basal and stimulatory conditions indicates that beta cells still preserve their in vivo functionality, adapted to the degree of insulin resistance, after the process of enzymatic digestion and gravity-induced reaggregation.

An image depicting diagrams about Basal insulin secretion, BMI-GSIS, HbA1C - Basal Insulin, and Glucose-simulated insulin secretion

In a similar manner, we have detected that islet microtissues produced from individuals with a higher percentage of glycosylated HbA1C (higher levels of glycemia during the last 3 months) exhibit lower basal and glucose-stimulated insulin secretion than individuals with better glycemic control. This observation further supports the robustness of reaggregated islet microtissues as an ideal model for islet research.

The fact that 3D InSight™ Islet Microtissues accurately mimic the performance that their native original islets exhibited in their in vivo situation confirms that reaggregated islets are a reliable, homogeneous, and convenient model for human islet research and drug development.

Furthermore, with the data and experience accumulated after nearly 100 microtissue production runs, InSphero can adeptly address the needs of almost any experimental setting, even those that require donors and islet microtissues with predefined features.

I encourage you to learn more about our islet models and how you can apply them in your research. I'm confident you'll find our 3D InSight™ Human Islet Microtissues and Services are setting the new gold standard for diabetes research.

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