Lipid-Induced Insulin Resistance in Skeletal Muscle: The Chase for the Culprit Goes from Total Intramuscular Fat to Lipid Intermediates, and Finally to Species of Lipid Intermediates

Abstract

The skeletal muscle is the largest organ in the body. It plays a particularly pivotal role in glucose homeostasis, as it can account for up to 40% of the body and for up to 80%–90% of insulin-stimulated glucose disposal. Hence, insulin resistance (IR) in skeletal muscle has been a focus of much research and review. The fact that skeletal muscle IR precedes β-cell dysfunction makes it an ideal target for countering the diabetes epidemic. It is generally accepted that the accumulation of lipids in the skeletal muscle, due to dietary lipid oversupply, is closely linked with IR. Our understanding of this link between intramyocellular lipids (IMCL) and glycemic control has changed over the years. Initially, skeletal muscle IR was related to total IMCL. The inconsistencies in this explanation led to the discovery that particular lipid intermediates are more important than total IMCL. The two most commonly cited lipid intermediates for causing skeletal muscle IR are ceramides and diacylglycerol (DAG) in IMCL. Still, not all cases of IR and dysfunction in glycemic control have shown an increase in either or both of these lipids. In this review, we will summarise the latest research results that, using the lipidomics approach, have elucidated DAG and ceramide species that are involved in skeletal muscle IR in animal models and human subjects.

Obesity leads to impairments in the morphology and organization of human skeletal muscle lipid droplets and mitochondrial networks, which are resolved with gastric bypass surgery‐induced improvements in insulin sensitivity

“…Decrease in energy demand associated with reduced physical activity leads to skeletal muscle mitochondrial dynamics shift towards fragmented mitochondria in type II muscle fibres ( Figure 6A). 24 Impaired mitochondrial dynamics combined with increased lipid supply will decrease LD turnover in detriment of storage quality, such as uneven LD PLIN2-coats, potentially resulting in IMCL leakage into cellular organelles and cytoplasm, thereby exerting lipotoxic effects on different insulin cascade steps 40 (Figure 6C,D). 24 Impaired mitochondrial dynamics combined with increased lipid supply will decrease LD turnover in detriment of storage quality, such as uneven LD PLIN2-coats, potentially resulting in IMCL leakage into cellular organelles and cytoplasm, thereby exerting lipotoxic effects on different insulin cascade steps 40 (Figure 6C,D).…”

“…When sedentary lifestyle is combined with chronic oversupply of nutrients, the increased fasting plasma FFA will lead to IMCL accumulation ( Figure 6B), which is known to exacerbate mitochondrial fission rates. 24 Impaired mitochondrial dynamics combined with increased lipid supply will decrease LD turnover in detriment of storage quality, such as uneven LD PLIN2-coats, potentially resulting in IMCL leakage into cellular organelles and cytoplasm, thereby exerting lipotoxic effects on different insulin cascade steps 40 (Figure 6C,D). On the other hand, RYGB surgery leads to chronic negative energy balance, concomitant weight loss and decrease in plasma FFA (Table 1).…”

The Crucial Role of C18-Cer in Fat-Induced Skeletal Muscle Insulin Resistance

“…Although the exact mechanism that leads to the development of IR in skeletal muscle is not fully understood, increased uptake of FA, intracellular fat accumulation and bioactive lipids have been shown to play a key role in skeletal muscle IR [26][27][28]. Currently, research focus shifts from total intramyocellular fat accumulation to bioactive lipid classes, and further to individual lipid species [29]. With the use of stable isotope tracers and mass spectrometry we followed the fate of plasma FA in HFD-induced intramuscular fat accumulation and IR.…”

The effect of diet and exercise on lipid droplet dynamics in human muscle tissue

“…Moreover, the metabolism of lipid intermediates is highly intertwined, which complicates the identification of 'malign' insulin-desensitizing lipid moieties. Besides this, the role of specific lipid intermediates might be gender-, situation-, intervention-or even (epi)genetic-specific (Kitessa and Abeywardena, 2016).…”