Human Muscle Fiber Type–Specific Insulin Signaling: Impact of Obesity and Type 2 Diabetes

Abstract

Skeletal muscle is a heterogeneous tissue composed of different fiber types. Studies suggest that insulinmediated glucose metabolism is different between muscle fiber types. We hypothesized that differences are due to fiber type-specific expression/regulation of insulin signaling elements and/or metabolic enzymes. Pools of type I and II fibers were prepared from biopsies of the vastus lateralis muscles from lean, obese, and type 2 diabetic subjects before and after a hyperinsulinemiceuglycemic clamp. Type I fibers compared with type II fibers have higher protein levels of the insulin receptor, GLUT4, hexokinase II, glycogen synthase (GS), and pyruvate dehydrogenase-E1a (PDH-E1a) and a lower protein content of Akt2, TBC1 domain family member 4 (TBC1D4), and TBC1D1. In type I fibers compared with type II fibers, the phosphorylation response to insulin was similar (TBC1D4, TBC1D1, and GS) or decreased (Akt and PDH-E1a). Phosphorylation responses to insulin adjusted for protein level were not different between fiber types. Independently of fiber type, insulin signaling was similar (TBC1D1, GS, and PDH-E1a) or decreased (Akt and TBC1D4) in muscle from patients with type 2 diabetes compared with lean and obese subjects. We conclude that human type I muscle fibers compared with type II fibers have a higher glucose-handling capacity but a similar sensitivity for phosphoregulation by insulin.Skeletal muscle is important for whole-body insulinstimulated glucose disposal (1), and skeletal muscle insulin resistance is a common phenotype of obesity and type 2 diabetes (T2D) (2). Skeletal muscle is a heterogeneous tissue composed of different fiber types, which can be divided according to myosin heavy chain (MHC) isoform expression. Studies in rodents show that insulin-stimulated glucose uptake in the oxidative type I fiber-dominant muscles is higher than in muscles with a high degree of glycolytic type II fibers (3-6). Whether this phenomenon is due to differences in locomotor activity of individual muscles or a direct consequence of the fiber-type composition is largely unknown. In incubated rat muscle, insulin-induced glucose uptake was higher (;100%) in type IIa (oxidative/glycolytic) compared with IIx and IIb (glycolytic) fibers (7,8), suggesting that insulin-mediated glucose uptake is related to the oxidative capacity of the muscle fiber. In humans, a positive correlation between proportions of type I fibers in muscle and whole-body insulin sensitivity has been demonstrated (9-11). Furthermore, insulin-stimulated glucose transport in human muscle strips was associated with the relative type I fiber content (12). Thus, it is likely that human type I fibers are more important than type II fibers for maintaining glucose homeostasis in response to insulin. Indeed, a decreased proportion of type I fibers has been found in various insulin resistant states such as the metabolic syndrome (9), obesity (13,14), T2D in some (10,13,14) but not all (12,15) studies and following bedrest (16), as well as in tetraplegic patients (17), ...

Skeletal Muscle Phospholipid Metabolism Regulates Insulin Sensitivity and Contractile Function

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Muscle Arnt/Hif1β Is Dispensable in Myofiber Type Determination, Vascularization and Insulin Sensitivity

“…ARNT is highly expressed in adipose tissues, heart, liver, and also skeletal muscle (Fig 1A). We further measured whether there is any difference in ARNT expression between the pre-dominantly oxidative slow-twitch muscles and the pre-dominantly glycolytic fast-twitch muscles, keeping in mind that oxidative slow-twitch muscles are metabolically efficient and relatively more insulin sensitive [27,28]. Expression of both ARNT gene (Fig 1B) and protein (Fig 1C and 1D) was relatively higher in pre-dominantly oxidative muscle (e.g.…”

Contributors to Metabolic Disease Risk Following Spinal Cord Injury

“…The transformation of muscles from a slow oxidative to a fast glycolytic phenotype following SCI yields a muscle tissue that is insulin resistant and metabolically inflexible. Recent research [58] confirmed that human SCI muscle has histochemical and biochemical properties that are very similar to that of human diabetic muscle, including fewer Type I fibers and a predominance of Type IIax+IIx fibers. These fibers have significantly reduced glucose handling capacity under insulin-stimulated conditions due to lower levels of the insulin receptor, glucose transporter 4 (GLUT 4), hexokinase II, glycogen synthase, and pyruvate dehydrogenase-E1α.…”