Relative Hypoglycemia and Hyperinsulinemia in Mice with Heterozygous Lipoprotein Lipase (LPL) Deficiency

Abstract

Lipoprotein lipase (LPL) provides tissues with fatty acids, which have complex effects on glucose utilization and insulin secretion. To determine if LPL has direct effects on glucose metabolism, we studied mice with heterozygous LPL deficiency (LPL؉/؊). LPL؉/؊ mice had mean fasting glucose values that were up to 39 mg/dl lower than LPL؉/؉ littermates. Despite having lower glucose levels, LPL؉/؊ mice had fasting insulin levels that were twice those of ؉/؉ mice. Hyperinsulinemic clamp experiments showed no effect of genotype on basal or insulin-stimulated glucose utilization. LPL message was detected 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 human islets incubated in vitro. In mice, ؉/؊ islets expressed half the enzyme activity of ؉/؉ islets. Islets isolated from ؉/؉ mice secreted less insulin in vitro than ؉/؊ and ؊/؊ islets, suggesting that LPL suppresses insulin secretion. To test this notion directly, LPL enzyme activity was manipulated in INS-1 cells. INS-1 cells treated with an adeno-associated virus expressing human LPL had more LPL enzyme activity and secreted less insulin than adeno-associated virus-␤-galactosidase-treated cells. INS-1 cells transfected with an antisense LPL oligonucleotide had less LPL enzyme activity and secreted more insulin than cells transfected with a control oligonucleotide. These data suggest that islet LPL is a novel regulator of insulin secretion. They further suggest that genetically determined levels of LPL play a role in establishing glucose levels in mice. Lipoprotein lipase (LPL)1 catalyzes the rate-limiting step for clearance of triglycerides from the blood. Hydrolysis of lipoprotein-associated triglycerides in the capillary beds of peripheral tissues such as muscle and adipose tissue produces free fatty acids that are available for local uptake (1). LPL enzyme activity is probably the major factor controlling movement of exogenous fatty acids into peripheral tissues. The overexpression of LPL in mouse muscle (2) increases tissue lipid as well as mitochondria and peroxisomes, the sites of fatty acid metabolism. Mice with homozygous LPL deficiency (LPLϪ/Ϫ) (3, 4) die soon after birth with minimal tissue lipid. Mice deficient in adipose tissue LPL develop adipose tissue lipid stores but only by inducing de novo fatty acid biosynthesis from glucose (5). These results suggest that tissue lipid content plays important roles in normal physiology and that LPL is essential for the acquisition of exogenous fatty acids by tissues.Fatty acids and glucose compete as respiratory substrates in many tissues (6). In muscle, fatty acids inhibit glucose utilization and oxidation. In liver, fatty acids inhibit glucose oxidation and promote gluconeogenesis. In the pancreatic beta cell (7), fatty acids have complex effects that differ depending on the duration of exposure. Since LPL is the dominant provider of fatty acids to tissues and fatty acids alter insulin secretion and glucose utilizatio...

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