nPOD. Beta Cell Physiology and Dysfunction

Lipid droplet distribution study in human pancreas

In collaboration with Dr. Alvin Powers’ at Vanderbilt University, we showed by electron microscopy (EM) that transplanted human islets have a much higher level of lipid droplets (LDs) than transplanted mouse islets (1). Moreover, we found that the number of LDs in transplanted human islets was increased in high fat diet (HFD) fed mouse recipients. We were intrigued by this observation, since we also observed that the high LD accumulation in human islets correlated with the unresponsiveness of the transplanted human islet β cells to the proliferation and insulin secretion signals observed in mouse islets (e.g. HFD & hyperglycemia (1)). Consequently, we extended this analysis by using both EM and the BODIPY 493/503 dye (i.e. a green fluorescent dye with hydrophobic properties that specifically stains neutral lipids and other lipophilic compounds) to analyze the LD content in intact human primary pancreas tissue sections. BODIPY 493/503 has the advantage over EM of allowing visualization of LD content/redistribution within a larger pancreatic area. BODIPY 493/503+ LD signals were shown to be: 1) randomly distributed between the acinar and endocrine compartment in healthy human samples; 2) in the α- and β-like cells generated from human embryonic stem cells; and strikingly, 3) enriched within T2D islets and longstanding T1D residual α cells in relation to the acinar space. These findings suggested the pancreatic LD accumulation patterns could be a marker of dysfunctional endocrine cells, and were published in Diabetes with Dr. Powers’ group (2). Dr. Xin Tong, the lead investigator on this project, also received a postdoctoral fellowship supporting this project through JDRF in 2019. We now propose in Aim 1 to use frozen OCT embedded slides to obtain insight into the effect of gender and BMI on pancreatic LD distribution. While low LD levels were previously found in healthy juvenile/young samples, we never tested T1D donors within this age range, which could have a novel LD enriched endotype. Consequently, we propose in Aim 2 to perform a pilot study exploring the pancreatic LD accumulation patterns in juvenile – young adult T1D donors (i.e. 10-20 years). Successful assessment of the LD accumulation pattern in these conditions will help determine the relationship of LDs to islet function, and guide the human islet selection process for transplantation therapy.

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