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.

Flyvbjerg A, Langberg H, Kjaer M. Effect of estrogen on tendon collagen synthesis, tendon structural characteristics, and biomechanical properties in postmenopausal women. J Appl Physiol 106: 1385-1393, 2009. First published October 16, 2009 doi:10.1152/japplphysiol.90935.2008.-The knowledge about the effect of estradiol on tendon connective tissue is limited. Therefore, we studied the influence of estradiol on tendon synthesis, structure, and biomechanical properties in postmenopausal women. Nonusers (control, n ϭ 10) or habitual users of oral estradiol replacement therapy (ERT, n ϭ 10) were studied at rest and in response to one-legged resistance exercise. Synthesis of tendon collagen was determined by stable isotope incorporation [fractional synthesis rate (FSR)] and microdialysis technique (NH2-terminal propeptide of type I collagen synthesis). Tendon area and fibril characteristics were determined by MRI and transmission electron microscopy, whereas tendon biomechanical properties were measured during isometric maximal voluntary contraction by ultrasound recording. Tendon FSR was markedly higher in ERT users (P Ͻ 0.001), whereas no group difference was seen in tendon NH2-terminal propeptide of type I collagen synthesis (P ϭ 0.32). In ERT users, positive correlations between serum estradiol (sestradiol) and tendon synthesis were observed, whereas change in tendon synthesis from rest to exercise was negatively correlated to s-estradiol. Tendon area, fibril density, fibril volume fraction, and fibril mean area did not differ between groups. However, the percentage of medium-sized fibrils was higher in ERT users (P Ͻ 0.05), whereas the percentage of large fibrils tended to be greater in control (P ϭ 0.10). A lower Young's modulus (GPa/%) was found in ERT users (P Ͻ 0.05). In conclusion, estradiol administration was associated with higher tendon FSR and a higher relative number of smaller fibrils. Whereas this indicates stimulated collagen turnover in the resting state, collagen responses to exercise were negatively associated with s-estradiol. These results indicate a pivotal role for estradiol in maintaining homeostasis of female connective tissue. connective tissue; tendon fibrils; insulin-like growth factor-I; extracellular matrix; bone CROSS-SECTIONAL FINDINGS INDICATE that sex hormones influence tendon biomechanical properties (36), extracellular matrix adaptability in response to mechanical loading (11,21,36,41,59), and the risk of sustaining soft tissue injuries (11,24,25).Estrogen receptors have been localized in ligaments (32, 33), and tendons express transcripts for estrogen receptors (23). Nevertheless, the effect of estrogen on tendon and ligament turnover is not clarified. Thus an inhibiting effect (34, 60), no effect (51), and a stimulating effect (32) on collagen synthesis and fibroblast proliferation in vitro have been observed in anterior cruciate ligament (ACL) tissue samples. These contrasting findings are probably related to the variation between animal species and the applied methods. This ...

Lipid metabolism is important for health and insulin action, yet the fundamental process of regulating lipid metabolism during muscle contraction is incompletely understood. Here, we show that liver kinase B1 (LKB1) muscle-specific knockout (LKB1 MKO) mice display decreased fatty acid (FA) oxidation during treadmill exercise. LKB1 MKO mice also show decreased muscle SIK3 activity, increased histone deacetylase 4 expression, decreased NAD+ concentration and SIRT1 activity, and decreased expression of genes involved in FA oxidation. In AMP-activated protein kinase (AMPK)α2 KO mice, substrate use was similar to that in WT mice, which excluded that decreased FA oxidation in LKB1 MKO mice was due to decreased AMPKα2 activity. Additionally, LKB1 MKO muscle demonstrated decreased FA oxidation in vitro. A markedly decreased phosphorylation of TBC1D1, a proposed regulator of FA transport, and a low CoA content could contribute to the low FA oxidation in LKB1 MKO. LKB1 deficiency did not reduce muscle glucose uptake or oxidation during exercise in vivo, excluding a general impairment of substrate use during exercise in LKB1 MKO mice. Our findings demonstrate that LKB1 is a novel molecular regulator of major importance for FA oxidation but not glucose uptake in muscle during exercise.

No abstract

To understand the mechanisms in lipid-induced insulin resistance, a more physiological approach is to enhance fatty acid (FA) availability through the diet. Nine healthy men ingested two hypercaloric diets (in 75% excess of habitual caloric intake) for 3 days, enriched in unsaturated FA (78 energy % [E%] fat) (UNSAT) or carbohydrates (80 E% carbohydrate) (CHO) as well as a eucaloric control diet (CON). Compared with CON, the UNSAT diet reduced whole-body and leg glucose disposal during a hyperinsulinemic-euglycemic clamp, while decreasing hepatic glucose production. In muscle, diacylglycerol (DAG) and intramyocellular triacylglycerol were increased. The accumulated DAG was -1,3 DAG, which is known not to activate PKC, and insulin signaling was intact. UNSAT decreased PDH-E1α protein content and increased inhibitory PDH-E1α Ser phosphorylation and FA oxidation. CHO increased whole-body and leg insulin sensitivity, while increasing hepatic glucose production. After CHO, muscle PDH-E1α Ser phosphorylation was decreased, and glucose oxidation increased. After UNSAT, but not CHO, muscle glucose-6-phosphate content was 103% higher compared with CON during the clamp. Thus, PDH-E1α expression and covalent regulation, and hence the tricarboxylic acid cycle influx of pyruvate-derived acetyl-CoA relative to β-oxidation-derived acetyl-CoA, are suggested to impact on insulin-stimulated glucose uptake. Taken together, the oxidative metabolic fluxes of glucose and FA are powerful and opposite regulators of insulin action in muscle.