Overexpression of muscle lipoprotein lipase and insulin sensitivity.
OBJECTIVE
The number of people affected with obesity and type 2 diabetes has reached epidemic proportions worldwide. Insulin resistance, a common feature of both conditions, has come under intense investigation. This review focuses on our current understanding of the insulin signaling cascade and potential mechanisms of regulation.


RESULTS
Recent studies have concentrated on inhibition of insulin-stimulated glucose uptake by free fatty acids as the primary cause of insulin resistance, particularly in muscle, a major site of insulin-stimulated glucose disposal. Mouse models of muscle-specific lipoprotein lipase overexpression permit closer examination of the consequences of lipid oversupply to muscle. Such mice exhibit whole-body and muscle insulin resistance, accompanied by increased accumulation of intramyocellular triglyceride and other fatty acid metabolites (i.e. long-chain acyl coenzyme A, diacylglycerol, and ceramide). These molecules may impede glucose transport by interfering with insulin signal transduction. The mechanisms for the inhibitory effect of free fatty acids on insulin-stimulated glucose transport are complex, and multiple pathways may be involved. Although key molecules have been identified, no single, clearly defined pathway has been established.


CONCLUSIONS
The mouse model of muscle-specific lipoprotein lipase overexpression allows closer examination of increased free fatty acid delivery to the muscle and of effects on insulin sensitivity. Further study of this model may provide additional insight into the role that lipids play in the development of insulin resistance, and may possibly help to identify novel approaches to prevention or treatment.
Pulawa
Leslie K
LK
Division of Endocrinology, Metabolism and Diabetes, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA. Leslie.Pulawa@UCHSC.edu
Eckel
Robert H
RH
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D005230:Fatty Acids, Nonesterified / Q000097:blood*; D015971:Gene Expression Regulation, Enzymologic; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology*; D008071:Lipoprotein Lipase / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D023421:Models, Animal; D018482:Muscle, Skeletal / Q000201:enzymology* / Q000378:metabolism; D015398:Signal Transduction
D001786:Blood Glucose; D005230:Fatty Acids, Nonesterified; D007328:Insulin; D008071:Lipoprotein Lipase