Lipid Droplet Accumulation in Human Pancreatic Islets Is Dependent On Both Donor Age and Health

Abstract

Human but not mouse islets transplanted into immunodeficient NSG mice effectively accumulate lipid droplets (LDs). Because chronic lipid exposure is associated with islet β-cell dysfunction, we investigated LD accumulation in the intact human and mouse pancreas over a range of ages and states of diabetes. Very few LDs were found in normal human juvenile pancreatic acinar and islet cells, with numbers subsequently increasing throughout adulthood. While accumulation appeared evenly distributed in postjuvenile acinar and islet cells in donors without diabetes, LDs were enriched in islet α- and β-cells from donors with type 2 diabetes (T2D). LDs were also found in the islet β-like cells produced from human embryonic cell–derived β-cell clusters. In contrast, LD accumulation was nearly undetectable in the adult rodent pancreas, even in hyperglycemic and hyperlipidemic models or 1.5-year-old mice. Taken together, there appear to be significant differences in pancreas islet cell lipid handling between species, and the human juvenile and adult cell populations. Moreover, our results suggest that LD enrichment could be impactful to T2D islet cell function.

β-Cell Dysfunction, Hepatic Lipid Metabolism, and Cardiovascular Health in Type 2 Diabetes: New Directions of Research and Novel Therapeutic Strategies

“…(II) Adipocyte infiltration in close proximity to the pancreatic islets in T2DM and hydrolysis of triglyceride content are other sources of fatty acids for the β-cells [ 65 , 85 ]. (III) Formation of lipid droplet within the β-cell was found in T2DM [ 86 ], and high expression of HSL in β-cell has decreased insulin secretion after feeding mice on a high fat diet, and this was associated with lower triglyceride accumulation within the islets of the transgenic mice compared with the wild-type mice [ 87 ]. Furthermore, toxic lipid intermediates derived from fatty acid metabolism including diacylglycerides and ceramides were confirmed to cause damage to insulin signaling within the hepatocytes and myocytes [ 88 , 89 ], but less is known about how such toxic metabolites can affect β-cells [ 7 , 57 ].…”

“…It has been reported that lipid droplets are more common within acinar cells of human donors with T2DM [ 86 ], and higher expression of the CD36 fatty acid transporter protein was associated with defective insulin secretion [ 39 ]. Recently, we have demonstrated that remission of T2DM and recovery of β-cell function were associated with gradual normalization of the pancreas morphology ( Figure 3 ) [ 172 ].…”

Ectopic Fat Accumulation in Pancreas and Heart

“…The pancreas is roughly divided into pancreatic islets that secrete endocrine hormones such as insulin and glucagon, and exocrine regions that secrete digestive enzymes, and is composed of lobes separated by connective tissues. Pancreatic fat includes interlobular or intralobular infiltration of adipocytes [ 12 ] as well as accumulation of intracellular lipid droplets of pancreatic endocrine or exocrine cells [ 13 , 14 , 15 ]. So far, it has been said that pancreatic fat increases physiologically with age, obesity, diabetes mellitus, excess alcohol intake, and viral infections [ 14 , 16 , 17 ].…”

“…Pancreatic fat includes interlobular or intralobular infiltration of adipocytes [ 12 ] as well as accumulation of intracellular lipid droplets of pancreatic endocrine or exocrine cells [ 13 , 14 , 15 ]. So far, it has been said that pancreatic fat increases physiologically with age, obesity, diabetes mellitus, excess alcohol intake, and viral infections [ 14 , 16 , 17 ]. Fat accumulation in the pancreas is called pancreatic steatosis, fatty pancreas, etc.…”

Perilipin2 down-regulation in β cells impairs insulin secretion under nutritional stress and damages mitochondria

“…One consequence of nutritional overload is the increased production of lipids including triglycerides (TG) that are stored in lipid droplets (LDs) (5). While the accumulation of LDs is closely tied to tissue dysfunction in non-alcoholic fatty liver disease, insulin resistant skeletal muscle, atherosclerosis, and diabetic cardiomyopathy, a role of LD under nutritional stress in b cell dysfunction has been underappreciated due to difficulty demonstrating LDs in mouse b cells (3,6,7). Importantly, LDs are easily identifiable in adult human b cells (6,8,9).…”