Roux-en-Y gastric bypass (RYGB) improves glycemic control within days after surgery, and changes in insulin sensitivity and β-cell function are likely to be involved. We studied 10 obese patients with type 2 diabetes (T2D) and 10 obese glucose-tolerant subjects before and 1 week, 3 months, and 1 year after RYGB. Participants were included after a preoperative diet-induced total weight loss of −9.2 ± 1.2%. Hepatic and peripheral insulin sensitivity were assessed using the hyperinsulinemic- euglycemic clamp combined with the glucose tracer technique, and β-cell function was evaluated in response to an intravenous glucose-glucagon challenge as well as an oral glucose load. Within 1 week, RYGB reduced basal glucose production, improved basal hepatic insulin sensitivity, and increased insulin clearance, highlighting the liver as an important organ responsible for early effects on glucose metabolism after surgery. Insulin-mediated glucose disposal and suppression of fatty acids did not improve immediately after surgery but increased at 3 months and 1 year; this increase likely was related to the reduction in body weight. Insulin secretion increased after RYGB only in patients with T2D and only in response to oral glucose, underscoring the importance of the changed gut anatomy.

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), ...

Keypointsr AMP-activated protein kinase (AMPK) is an important regulator of cellular energy status during exercise.r Most human studies investigating skeletal muscle protein signalling have been performed in whole muscle biopsy samples, yet recent studies suggest muscle fibre type-specific AMPK expression with potential fibre type-specific regulation of AMPK during exercise.r This study provides novel and comprehensive data on human muscle fibre type-specific expression levels of AMPK subunits and downstream targets of AMPK.r We show a differentiated response to exercise of key metabolic signalling proteins in human type I and type II muscle fibres during interval exercise, not evident during continuous exercise. These differences between exercise types were not present in whole muscle biopsy samples.r Our findings highlight the importance of performing fibre type-specific measurements and the increased activation of AMPK in interval vs. continuous exercise could be important for exercise type-specific adaptations, i.e. metabolism, insulin sensitivity and mitochondrial density in human skeletal muscle.Abstract AMP-activated protein kinase (AMPK) is a regulator of energy homeostasis during exercise. Studies suggest muscle fibre type-specific AMPK expression. However, fibre type-specific regulation of AMPK and downstream targets during exercise has not been demonstrated. We hypothesized that AMPK subunits are expressed in a fibre type-dependent manner and that fibre type-specific activation of AMPK and downstream targets is dependent on exercise intensity. Pools of type I and II fibres were prepared from biopsies of vastus lateralis muscle from healthy men before and after two exercise trials: (1) continuous cycling (CON) for 30 min at 69 ± 1% peak rate of O 2 consumption (V O 2 peak ) or (2) interval cycling (INT) for 30 min with 6 × 1.5 min high-intensity bouts peaking at 95 ± 2%V O 2 peak . In type I vs. II fibres a higher β 1 AMPK (+215%) and lower γ 3 AMPK expression (−71%) was found. and ACC Ser221 ) or higher (GS 2+2a ). Exercise-induced glycogen degradation in type I vs. II fibres was similar (CON) or lower (INT). In conclusion, a differentiated response to exercise of metabolic signalling/effector proteins in human type I and II fibres was evident during interval exercise. This

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Supplementary key words fatty acid metabolism • fatty acid translocase CD36 • traffi cking • AMP-dependent protein kinaseDuring submaximal exercise, plasma FAs are an important source of energy, accounting for ‫ف‬ 60% of total substrate utilization in human subjects ( 1-3 ). Increases in FA utilization during exercise are facilitated by a rapid and sustained upregulation of skeletal muscle FA uptake by 5-15-fold ( 1, 4 ). This increase in skeletal muscle FA uptake during exercise results from a coordinated increase in rates of FA delivery, surface membrane FA transport, and intracellular substrate fl ux through mitochondrial ␤ -oxidation or storage as intracellular lipids [for review, see ( 5 )]. Skeletal muscle expresses multiple lipid binding proteins [for review, see ( 6 )], such as the membrane-bound FA binding protein ( 7 ), the FA transport proteins (FATP1 and FATP4) ( 8, 9 ), and the FA translocase CD36 (FAT/ CD36) ( 10 ), all of which have been implicated in the transsarcolemmal transport of FA uptake ( 9,11,12 ). The functional role of FAT/CD36 in long-chain FA plasma membrane transport is supported by studies reporting blunted uptake of the palmitic acid analog ␤ -methyl-piodophenylpendadecanoic acid (

Sixty breeding pairs of captive American kestrels (Falco sparverius) were exposed to a range of sublethal dietary concentrations of mercury (Hg), in the form of methylmercuric chloride, and their subsequent reproduction was measured. Egg production, incubation performance, and the number and percent of eggs hatched decreased markedly between 3.3 and 4.6 mg/kg dry weight of Hg (1.2 and 1.7 mg/kg wet wt), in the diet. The number of fledglings and the percent of nestlings fledged were reduced markedly at 0.7 mg/kg dry weight (0.3 mg/kg wet wt) and declined further between 2 and 3.3 mg/kg dry weight (0.7 and 1.2 mg/kg wet wt). Dietary concentrations of >or=4.6 mg/kg dry weight (1.7 mg/kg wet wt) were associated with total fledging failure. The estimated decline in fledged young per pair (24%, Bayesian regression) for kestrels consuming 0.7 mg/kg dry weight (0.3 mg/ kg wet wt) raises concerns about population maintenance in areas subject to high inputs of anthropogenic Hg. Mercury concentrations in 20 second-laid eggs collected from all groups were related to dietary concentrations of Hg, and the Hg concentrations in 19 of these eggs were related to eggs laid and young fledged. Concentrations of Hg in eggs from the highest diet group (5.9 mg/kg dry wt; 2.2 mg/kg wet wt) were higher than egg concentrations reported for either wild birds or for captive birds (nonraptors) fed dry commercial food containing 5 mg/kg methylmercury. Accumulation ratios of Hg from diets to eggs were higher than those reported for feeding studies with other species.

. Enhanced insulin signaling in human skeletal muscle and adipose tissue following gastric bypass surgery.

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