Relative hypoglycemia and hyperinsulinemia in mice with heterozygous lipoprotein lipase (LPL) deficiency - Islet LPL regulates insulin secretion

Lipoprotein lipase (LPL) provides tissues with fatty acids, which have comp lex effects on glucose utilization and insulin secretion. To determine if L PL has direct effects on glucose metabolism, we studied mice with heterozyg ous LPL deficiency (LPL+/-), LPL+/- mice had mean fasting glucose values th at were up to 39 mg/dl lower than LPL+/+ littermates. Despite having lower glucose levels, LPL+/- mice had fasting insulin levels that were twice thos e of +/+ mice. Hyperinsulinemic clamp experiments showed no effect of genot ype on basal or insulin-stimulated glucose utilization. LPL message was det ected in mouse islets, INS-1 cells (a rat insulinoma cell line), and human islets, LPL enzyme activity was detected in the media from both mouse and h uman islets incubated in vitro. In mice, +/- islets expressed half the enzy me activity of +/+ islets, Islets isolated from +/+ mice secreted less insu lin in vitro than +/- and -/- islets, suggesting that LPL suppresses insuli n secretion. To test this notion directly, LPL enzyme activity was manipula ted in INS-1 cells. INS-1 cells treated with an adeno-associated virus expr essing human LPL had more LPL enzyme activity and secreted less insulin tha n adeno-associated virus-P-galactosidase-treated cells. INS-1 cells transfe cted with an antisense LPL oligonucleotide had less LPL enzyme activity and secreted more insulin than cells transfected with a control oligonucleotid e. These data suggest that islet LPL is a novel regulator of insulin secret ion. They further suggest that genetically determined levels of LPL play a role in establishing glucose levels in mice.