Electrospray ionization mass spectrometric analyses of changes in tissue phospholipid molecular species during the evolution of hyperlipidemia and hyperglycemia in Zucker diabetic fatty rats

The Zucker diabetic fatty (ZDF) rat is a genetic model of type II diabetes mellitus in which males homozygous for nonfunctional leptin receptors (fa/f a) develop obesity, hyper lipidemia, and hyperglycemia, but rats homozygous for normal receptors (+/+) remain lean and normoglycemic. Insulin resistan ce develops in young fa/fa rats and is followed by evolution of an insulin secretory defect that triggers hyperglycemia. Because insulin secretion and insulin sensitivity are affected by membrane phospholipid fatty acid compo sition, we have determined whether metabolic abnormalities in fa/fa rats ar e associated with changes in tissue phospholipids. Electrospray ionization mass spectrometric analyses of glycerophosphocholine (GPC) and glycerophosp hoethanolamine (GPE) molecular species from tissues of prediabetic (6 wk of age) and overtly diabetic (12 wk) fa/fa rats and from +/+ rats of the same ages indicate that arachidonate-containing species from heart, aorta, and liver of prediabetic fa/fa rats made a smaller contribution to GPC total io n current than was the case for +/+ rats. There was a correspondingly large r contribution from species with sn-2 oleate or linoleate substituents in f a/fa. heart and aorta. The relative contributions of arachidonate-containin g GPC species increased in these tissues as fa/fa rats aged and were Equal to or greater than those for +/+ rats by 12 wk. For heart and aorta, relati ve contributions from GPE species with sn-2 arachidonate or docosahexaenoat e substituents to the total ion current increased and those from species wi th sn-2 oleate or linoleate substituents fell as fa/fa rats aged, but these tissue lipid profiles changed little with age in +/+ rats. GPC and CPT pro files for brain, kidney, sciatic nerve, and red blood cells were similar am ong fa/fa and +/+ rats at 6 and 12 wk of age, and pancreatic islets from fa /fa and +/+ rats exhibited similar GPC and GPE profiles at 12 wk of age. Un der-representation of arachidonate-containing GPC and GPT species in some f a/fa rat tissues at 6 wk could contribute to insulin resistance, but deplet ion of islet arachidonate-containing GPC and GPE species is unlikely to exp lain the evolution of the insulin secretory defect that is well-developed b y 12 wk of age.