Tissue-specific overexpression of lipoprotein lipase causes tissue-specific insulin resistance

Abstract

Insulin resistance in skeletal muscle and liver may play a primary role in the development of type 2 diabetes mellitus, and the mechanism by which insulin resistance occurs may be related to alterations in fat metabolism. Transgenic mice with muscle-and liver-specific overexpression of lipoprotein lipase were studied during a 2-h hyperinsulinemic-euglycemic clamp to determine the effect of tissue-specific increase in fat on insulin action and signaling. Muscle-lipoprotein lipase mice had a 3-fold increase in muscle triglyceride content and were insulin resistant because of decreases in insulin-stimulated glucose uptake in skeletal muscle and insulin activation of insulin receptor substrate-1-associated phosphatidylinositol 3-kinase activity. In contrast, liver-lipoprotein lipase mice had a 2-fold increase in liver triglyceride content and were insulin resistant because of impaired ability of insulin to suppress endogenous glucose production associated with defects in insulin activation of insulin receptor substrate-2-associated phosphatidylinositol 3-kinase activity. These defects in insulin action and signaling were associated with increases in intracellular fatty acid-derived metabolites (i.e., diacylglycerol, fatty acyl CoA, ceramides). Our findings suggest a direct and causative relationship between the accumulation of intracellular fatty acid-derived metabolites and insulin resistance mediated via alterations in the insulin signaling pathway, independent of circulating adipocytederived hormones.skeletal muscle ͉ liver

Overexpression of lipoprotein lipase improves insulin resistance induced by a high-fat diet in transgenic rabbits

“…n=5 and n=4 for transgenic and control rabbits respectively though we cannot exclude the possibility that transgenic rabbits may have (locally) hepatic insulin resistance associated with the fatty liver [30,31,32], overall effect of LPL overexpression on insulin sensitivity was apparently beneficial. These findings in transgenic rabbits contrast with the results in transgenic mice that showed insulin resistance accompanied by accumulation of TG in their skeletal muscle [16] or liver [4]. Nevertheless, one study reported that there is no effect of the accumulation of TG in skeletal muscle on insulin-stimulated whole-body and muscle-specific glucose uptake [18].…”

“…Several previous studies have shown that an imbalance of LPL activity may alter the partitioning of plasma TG between muscle and adipose tissue, and thus influence insulin resistance and obesity. For example, increased LPL in muscle and liver might lead to the over-production of NEFA, to accumulation of TG, and to the subsequent impairment of the insulin signal, resulting in a state of insulin resistance [4]. In addition, LPL activity was found to be higher in visceral adipose tissue of obese mice and humans, which could lead to increased NEFA influx through the portal vein into the liver, and could again result in a state of insulin resistance [5,6].…”

“…One of the best experimental approaches is to use transgenic animals that overexpress LPL. Several lines of transgenic mice that overexpress human LPL have been created, and although the sites of overexpression differ, all transgenic mice show decreased plasma levels of TG [4,13,14,15,16,17,18]. However, studies on transgenic mice have also generated conflicting results regarding the effects of LPL on insulin resistance.…”

“…However, studies on transgenic mice have also generated conflicting results regarding the effects of LPL on insulin resistance. For example, two studies on LPL transgenic mice have shown that overexpression of human LPL in mouse muscle is associated with insulin resistance [4,17], whereas one group (even using the same transgenic mice as in the above study) failed to show a correlative or causal relationship between increased LPL activity and insulin resistance even though there was increased TG content in the muscles [18]. In addition, one study reported that LPL transgenic mice were protected against diet-induced obesity regardless of slight hyperglycaemia [16].…”

Predictors of graft and patient survival in subjects transplanted for HCV infection

“…Intracellular fat accumulation alters insulin signaling and causes insulin resistance and overactive hepatic gluconeogenesis. 10 Hyperinsulinemia is also a potential mechanism for this fibrosis through direct stimulation of hepatic stellate cell mitogenesis and collagen synthesis. 11 The association between DM and graft cirrhosis was recently analyzed in another study carried out by Burra et al 12 on the use of steatotic grafts in HCVpositive recipients, but they did not confirm a similar correlation.…”