Glycosylphosphatidylinositol-specific phospholipase D immunoreactivity is present in islet amyloid in type 2 diabetes.
Numerous apolipoproteins associate with amyloid plaques. A minor high-density lipoprotein-associated protein, glycosylphosphatidylinositol-specific phospholipase D (GPI-PLD), has recently been described by the authors and others. Since GPI-PLD is synthesized by, and secreted from, pancreatic islet beta cells, the present study examined the hypothesis that GPI-PLD associates with islet amyloid. GPI-PLD immunoreactivity was examined in pancreatic tissues from type 2 diabetic and non-diabetic humans. GPI-PLD binding to heparan sulphate proteoglycan was determined in the absence or presence of heparan sulphate or heparin. Fibril formation from human islet amyloid polypeptide was determined in the absence or presence of GPI-PLD. In non-diabetics, GPI-PLD immunoreactivity was present and co-localized with insulin, as opposed to co-localizing with amyloid in diabetics. No immunoreactivity for apolipoprotein A-I was present in islet cells or islet amyloid. Heparan sulphate proteoglycan, which is commonly present in most amyloid, bound GPI-PLD in vitro. GPI-PLD inhibited the formation of amyloid fibrils from synthetic islet amyloid polypeptide in vitro. GPI-PLD is therefore present in islet amyloid and appears to derive from local production from islets. This localization likely derives from interaction between GPI-PLD and heparan sulphate proteoglycan. Since GPI-PLD also inhibited islet amyloid polypeptide fibril formation in vitro, it is concluded that GPI-PLD may play a role in islet amyloid formation in type 2 diabetes.
Larson
D M
DM
Departments of Medicine and of Biochemistry and Molecular Biology, Indiana University and the Richard L Roudebush Veterans Affairs Medical Center, Indianapolis, IN, USA.
Kennedy
M A
MA
Bowen
R F
RF
Verchere
C B
CB
Deeg
M A
MA
D000682:Amyloid / Q000096:biosynthesis / Q000187:drug effects / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology*; D019812:Heparan Sulfate Proteoglycans / Q000378:metabolism; D006801:Humans; D058228:Islet Amyloid Polypeptide; D007515:Islets of Langerhans / Q000201:enzymology*; D018613:Microscopy, Confocal; D010739:Phospholipase D / Q000378:metabolism* / Q000494:pharmacology
D000682:Amyloid; D019812:Heparan Sulfate Proteoglycans; D058228:Islet Amyloid Polypeptide; D010739:Phospholipase D; C065017:glycoprotein phospholipase D