Selective lack of the C16:0 fatty acid isoform of sulfatide in pancreas of type II diabetic animal models

Abstract

Sulfatide (3'-sulfogalactosyl-ceramide) is a glycosphingolipid mainly located in the nervous system, but has also been found in the islets of Langerhans. Previous studies have suggested that sulfatide is involved in insulin processing and secretion. In this study, sulfatide expression and metabolism in pancreas and isolated islets of the type II diabetes models, ob/ob- and db/db mouse, was investigated using TLC-ELISA, metabolic labelling and electron microscopy. As in non-diabetic Lewis rat and human pancreas, sulfatide was located in secretory granules of the beta cells. However, the type II diabetic animal models and their background strains had an altered sulfatide expression, involving the lack of the C16:0 sulfatide fatty acid isoform, compared to non-diabetic Lewis rat, BALB/c mouse and human pancreatic tissue, in which the two dominating pancreatic sulfatide isoforms C16:0 and C24:0 are expressed. Correspondingly, in isolated ob/ob islets, sulfatide synthesis excluded the production of C16:0 sulfatide. Insulin administration to ob/ob mouse, which lowers beta cell activity, resulted in significantly increased sulfatide expression in pancreas (p=0.0003), but still no expression of the C16:0 sulfatide isoform. In vitro, the C16:0 sulfatide was shown to be the isomer involved in the preservation of insulin crystals. Thus, it is hypothesized that the selection of sulfatide isomers in pancreas might be a genetic factor contributing to disease development in type II diabetic animal models.

Involvement of sulfatide in beta cells and type 1 and type 2 diabetes

“…In the absence of sulfatide these crystals are broken down after a couple of days, even under optimal in vitro conditions, whereas in its presence the crystals have a lifespan of up to 3 weeks [13]. Interestingly, insulin crystals are preserved by the C16:0 fatty acid isoform of sulfatide [14] which is found in the pancreas, but neither the longchain isoform nor GalCer have this effect [13,14]. Finally, there are strong indications that sulfatide facilitates the instant monomerisation of insulin, which takes place during the secretion of this hormone from the beta cells [13].…”

“…The C16:0 isoform of sulfatide is present in substantial amounts in the pancreas of Lewis rats [4], BALB/c mice and humans [53], but ob/ob mice and db/db mice selectively lack this specific isoform of sulphatide [14]. In the Zucker rat, an animal model of type 2 diabetes, treatment with C16:0 sulfatide intraperitoneally twice a week almost doubled insulin secretion and improved the first-phase insulin response, as detected in a glucose tolerance test [54].…”

“…Type 2 diabetes animal models lack C16:0 sulfatide [14]. Insulin resistance is associated with low serum levels of sulfatide and/or the presence of another sulphated glycosphingolipid, SulphLacCer [51].…”

Role of sulfatide in normal and pathological cells and tissues

“…Incubation of ␤ TC3 cells with the C16:0 isoform of sulfatide (but not with the C24:0 isoform) inhibited glucose-induced insulin secretion by reducing ATP-sensitive potassium channel sensitivity ( 64 ). On the other hand, lack of the C16:0 isoform of sulfatide was also found in the pancreas of the type II diabetic mouse model, the db/db mouse ( 65 ). Sulfatide is required for normal insulin secretion through activation of ATP-sensitive potassium ion channels and stimulation of calcium ion-dependent exocytosis ( 66 ).…”

“…Sulfatide is required for normal insulin secretion through activation of ATP-sensitive potassium ion channels and stimulation of calcium ion-dependent exocytosis ( 66 ). The C16:0 isoform of sulfatide dramatically improves insulin crystal preservation, whereas the C24:0 isoform has almost no effect ( 65 ). Sulfatide facilitates the instant monomerization of insulin during its secretion from the ␤ cells of the pancreas.…”