The role of intramuscular lipid in insulin resistance

Abstract

There is interest in how altered lipid metabolism could contribute to muscle insulin resistance. Many animal and human states of insulin resistance have increased muscle triglyceride content, and there are now plausible mechanistic links between muscle lipid accumulation and insulin resistance, which go beyond the classic glucose-fatty acid cycle. We postulate that muscle cytosolic accumulation of the metabolically active long-chain fatty acyl CoAs (LCACoA) is involved, leading to insulin resistance and impaired insulin signalling or impaired enzyme activity (e.g. glycogen synthase or hexokinase) either directly or via chronic translocation/activation of mediators such as a protein kinase C (particularly PKC theta and epsilon ). Ceramides and diacylglycerols (DAGs) have also been implicated in forms of lipid-induced muscle insulin resistance. Dietary lipid-induced muscle insulin resistance in rodents is relatively easily reversed by manipulations that lessen cytosolic lipid accumulation (e.g. diet change, exercise or fasting). PPAR agonists (both gamma and alpha) also lower muscle LCACoA and enhance insulin sensitivity. Activation of AMP-activated protein kinase (AMPK) by AICAR leads to muscle enhancement (especially glycolytic muscle) of insulin sensitivity, but involvement of altered lipid metabolism is less clear cut. In rodents there are similarities in the pattern of muscle lipid accumulation/PKC translocation/altered insulin signalling/insulin resistance inducible by 3-5-h acute free fatty acid elevation, 1-4 days intravenous glucose infusion or several weeks of high-fat feeding. Recent studies extend findings and show relevance to humans. Muscle cytosolic lipids may accumulate either by increased fatty acid flux into muscle, or by reduced fatty acid oxidation. In some circumstances muscle insulin resistance may be an adaptation to optimize use of fatty acids when they are the predominant available energy fuel. The interactions described here are fundamental to optimizing therapy of insulin resistance based on alterations in muscle lipid metabolism.

Human triglyceride-rich lipoproteins impair glucose metabolism and insulin signalling in L6 skeletal muscle cells independently of non-esterified fatty acid levels

“…The IMCL content, which in many [1][2][3][4] but not all studies [45,46] has been shown to be increased in insulin resistance, was also one focus of our experiments. The effects of TGRLs on insulin signalling and glucose homeostasis followed a time-dependent fashion.…”

“…high plasma levels of NEFAs, dyslipidaemia and pronounced postprandial lipaemia. A fourth lipid abnormality suggested to be a determinant of insulin resistance is the increase of intramyocellular lipid (IMCL) content in skeletal muscle [1][2][3][4].…”

Globular adiponectin increases GLUT4 translocation and glucose uptake but reduces glycogen synthesis in rat skeletal muscle cells

“…The accumulation of lipid in muscle and other tissues has been linked to the development of insulin resistance [35]. Previous work has shown that adiponectin increases fat oxidation in muscle and liver, and that AMP kinase appears to play a central role in the regulation of lipid metabolism by adiponectin [6,9,10].…”

Substrate cycling between de novo lipogenesis and lipid oxidation: a thermogenic mechanism against skeletal muscle lipotoxicity and glucolipotoxicity

“…12 Furthermore, there is also evidence that as chronic hyperglycemia develops, the oversupply of glucose could also, by inhibiting fatty acid oxidation, lead to the accumulation of intramyocellular lipid metabolites that further inhibit glucose uptake/metabolism and hence exacerbate the state of insulin resistance. [13][14][15] Since Randle's proposal in 1963 of a glucose-fatty acid cycle that embodies direct competition between substrates for mitochondrial oxidation, a plethora of mechanisms have been put forward to explain how fuel substrates could interfere with glucose disposal in skeletal muscle. 12,15 Particularly striking is that oversupply of each of the three main fuel substrates canFas depicted in Figure 1Fconverge towards the accumulation of triglycerides.…”

“…[13][14][15] Since Randle's proposal in 1963 of a glucose-fatty acid cycle that embodies direct competition between substrates for mitochondrial oxidation, a plethora of mechanisms have been put forward to explain how fuel substrates could interfere with glucose disposal in skeletal muscle. 12,15 Particularly striking is that oversupply of each of the three main fuel substrates canFas depicted in Figure 1Fconverge towards the accumulation of triglycerides. This can occur not only when the supply of circulating free fatty acid (FFA) is in excess of its oxidation, but also when the supply of amino acids or glucose exceeds the oxidation of these fuels, thereby resulting in the formation of malonyl-CoA which, by inhibiting carnitine palmitoyltransferase-1 (CPT-1), reduces the entry of long-chain fatty acyl-CoAs (FA-CoA) into mitochondrial b-oxidation.…”