Dynamic PET Imaging Reveals Heterogeneity of Skeletal Muscle Insulin Resistance

Ng, Jason; Bertoldo, Alessandra; Minhas, Davneet; Helbling, Nicole L.; Coen, Paul M.; Price, Julie C.; Cobelli, Claudio; Kelley, David E.; Goodpaster, Bret H.

doi:10.1210/jc.2013-2095

Cited by 18 publications

(19 citation statements)

References 17 publications

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“…In support, HKII content was higher in type I compared with type II fibers. The influence of HKII protein levels on glucose uptake is controversial and has recently been estimated to control ;10% of human skeletal muscle glucose metabolism during insulin-stimulated conditions (42). In the current study, fiber type-specific HKII levels were not different between groups investigated.…”

Section: Discussioncontrasting

confidence: 39%

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

et al. 2014

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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), ...

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Section: Discussioncontrasting

confidence: 39%

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

et al. 2014

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“…Previously, we showed similar trends in MRglu in gluteus and calf muscle [2]. It is, however, possible that skeletal muscle in other parts of the body may show a different association with the M-value as previously suggested [29]. The current study was not designed to investigate the underlying intracellular mechanisms, but previous research suggests the lower glucose uptake rate in the muscle of T2D subjects may be due to a combination of mechanisms.…”

Section: Musclementioning

confidence: 51%

Altered Glucose Uptake in Muscle, Visceral Adipose Tissue, and Brain Predict Whole-Body Insulin Resistance and may Contribute to the Development of Type 2 Diabetes: A Combined PET/MR Study

et al. 2018

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We assessed glucose uptake in different tissues in type 2 diabetes (T2D), prediabetes, and control subjects to elucidate its impact in the development of whole-body insulin resistance and T2D. Thirteen T2D, 12 prediabetes, and 10 control subjects, matched for age and BMI, underwent OGTT and abdominal subcutaneous adipose tissue (SAT) biopsies. Integrated whole-body F-FDG PET and MRI were performed during a hyperinsulinemic euglycemic clamp to asses glucose uptake rate (MRglu) in several tissues. MRglu in skeletal muscle, SAT, visceral adipose tissue (VAT), and liver was significantly reduced in T2D subjects and correlated positively with M-values (r=0.884, r=0.574, r=0.707 and r=0.403, respectively). Brain MRglu was significantly higher in T2D and prediabetes subjects and had a significant inverse correlation with M-values (r=-0.616). Myocardial MRglu did not differ between groups and did not correlate with the M-values. A multivariate model including skeletal muscle, brain and VAT MRglu best predicted the M-values (adjusted r=0.85). In addition, SAT MRglu correlated with SAT glucose uptake ex vivo (r=0.491). In different stages of the development of T2D, glucose uptake during hyperinsulinemia is elevated in the brain in parallel with an impairment in peripheral organs. Impaired glucose uptake in skeletal muscle and VAT together with elevated glucose uptake in brain were independently associated with whole-body insulin resistance, and these tissue-specific alterations may contribute to T2D development.

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“…2C), and insulin blockade had modest effects on glucose uptake in these tissues. Soleus muscle, which is known to have a decreased insulin-stimulated glucose uptake capacity in insulin-resistant human individuals (17), displayed a reduction in glucose accumulation (44% less accumulated 18 F-FDG) in the insulin-blocked animals versus controls (Fig. 2D).…”

Section: Discussionmentioning

confidence: 99%

“…In Vivo Glucose Distribution in Insulin-Resistant DIO mice: PET-CT Scanning PET combined with X-ray CT scan analysis is a noninvasive in vivo imaging approach that has been used to study glucose disposal in lean healthy adults (16), and in insulin-resistant individuals (17) and in individuals with type 2 diabetes (18), as well as to study glucose disposal in rodents (19). We here used PET-CT scanning together with the glucose tracer molecule 18 F-FDG to study tissuespecific accumulation of glucose in HFD-fed animals.…”

Section: Discussionmentioning

confidence: 99%

Dual Actions of Apolipoprotein A-I on Glucose-Stimulated Insulin Secretion and Insulin-Independent Peripheral Tissue Glucose Uptake Lead to Increased Heart and Skeletal Muscle Glucose Disposal

et al. 2016

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Apolipoprotein A-I (apoA-I) of HDL is central to the transport of cholesterol in circulation. ApoA-I also provides glucose control with described in vitro effects of apoA-I on β-cell insulin secretion and muscle glucose uptake. In addition, apoA-I injections in insulin-resistant diet-induced obese (DIO) mice lead to increased glucose-stimulated insulin secretion (GSIS) and peripheral tissue glucose uptake. However, the relative contribution of apoA-I as an enhancer of GSIS in vivo and as a direct stimulator of insulin-independent glucose uptake is not known. Here, DIO mice with instant and transient blockade of insulin secretion were used in glucose tolerance tests and in positron emission tomography analyses. Data demonstrate that apoA-I to an equal extent enhances GSIS and acts as peripheral tissue activator of insulin-independent glucose uptake and verify skeletal muscle as an apoA-I target tissue. Intriguingly, our analyses also identify the heart as an important target tissue for the apoA-I–stimulated glucose uptake, with potential implications in diabetic cardiomyopathy. Explorations of apoA-I as a novel antidiabetic drug should extend to treatments of diabetic cardiomyopathy and other cardiovascular diseases in patients with diabetes.

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Dynamic PET Imaging Reveals Heterogeneity of Skeletal Muscle Insulin Resistance

Abstract: Lower glucose transport rates are the major feature underlying IR preceding type 2 diabetes, although substantial heterogeneity in insulin action across muscle types highlight the complexity of skeletal muscle IR.

Cited by 18 publications

References 17 publications

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

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

Altered Glucose Uptake in Muscle, Visceral Adipose Tissue, and Brain Predict Whole-Body Insulin Resistance and may Contribute to the Development of Type 2 Diabetes: A Combined PET/MR Study

Dual Actions of Apolipoprotein A-I on Glucose-Stimulated Insulin Secretion and Insulin-Independent Peripheral Tissue Glucose Uptake Lead to Increased Heart and Skeletal Muscle Glucose Disposal

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