OBJECTIVE -We investigated whether alterations of glycolytic and oxidative enzyme capacity in skeletal muscle of patients with type 2 diabetes pertain to specific muscle fibers and are associated with changes in muscle fiber composition.RESEARCH DESIGN AND METHODS -Vastus lateralis muscle was obtained by percutaneous biopsy from 10 patients with type 2 diabetes and 15 age-and BMI-matched healthy volunteers. Using cytophotometry, muscle fiber composition and fiber type-specific glycolytic and oxidative enzyme activities were measured in slow oxidative, fast oxidative glycolytic, and fast glycolytic fibers.RESULTS -In the whole muscle, oxidative activity was decreased in patients with type 2 diabetes. The slow oxidative fiber fraction was reduced by 16%, whereas the fast glycolytic fiber fraction was increased by 49% in skeletal muscle from the diabetic patients. Both oxidative and glycolytic enzyme activities were significantly increased in fast glycolytic and fast oxidative glycolytic fibers of type 2 diabetic patients. However, the fiber-specific ratio of glycolytic enzyme activity relative to oxidative activity was not different between type 2 diabetic patients and the control subjects. The myofibrillic ATP activity was significantly lower in all fiber types of patients with type 2 diabetes and correlates with glucose infusion rate during the steady state of a euglycemic-hyperinsulinemic clamp and maximal aerobic capacity and negatively with HbA 1c values.CONCLUSIONS -Reduced oxidative enzyme activity in muscle of type 2 diabetic patients is most likely due to a reduction in slow oxidative fibers. Increased glycolytic and oxidative enzyme activities in individual muscle fibers are closely related to measures of long-term glycemic control and whole-body insulin sensitivity and could therefore represent a compensatory mechanism of the muscle in function of the altered glucose metabolism. Diabetes Care 29:895-900, 2006T ype 2 diabetes is characterized by severe insulin resistance of skeletal muscle associated with an impaired insulin-stimulated glucose disposal rate (1,2). Insulin resistance correlates with skeletal muscle fiber type distribution (3), a reduced percentage of slow oxidative type I fibers (4), and reduced oxidative enzyme capacity (5-7). Aging and physical inactivity, which are both associated with insulin resistance, also lead to diminished oxidative capacity of skeletal muscle (6). Simoneau and Kelley (6) showed that an increased ratio of glycolytic to oxidative enzymes contributes to insulin resistance in skeletal muscle of patients with type 2 diabetes. Interestingly, with singlefiber analysis, no differences have been found in the fiber type composition between lean, obese, and type 2 diabetic subjects (7). In this study, significant differences in oxidative but not in glycolytic enzyme activity and in the glycolytic-tooxidative ratio were reported for the comparison of lean and obese subjects and patients with type 2 diabetes (7). However, it is still not entirely understood whether metabolic...

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Three new thiostannates [Co(C8N5H23)]2Sn2S6 (I), [Fe(C8N5H23)]2Sn2S6 (II) and [Ni(C8N5H23)]2Sn2S6 (III) were synthesized under solvothermal conditions. In all compounds the [Sn2S6]4− anion acts as a bidentate or μ2 ligand bridging two symmetry related [M(C8N5H23)]2+ cations. Despite the identical building units only compounds I and II are isostructural crystallizing in the tetragonal space group I41/a, whereas compound III crystallizes in space group P21/n. A detailed analysis of the intermolecular interactions reveals remarkable differences between I/II and III which may be responsible for the crystallization in different symmetries and space groups. The slightly different bonding situations in the [Sn2S6]4− anion in I/II and III are reflected in the Raman spectra. For all three compounds the UV/Vis spectra show d‐d transitions energetically below the absorption edge.

Objective: Exercise training has been shown to have anti-inflammatory effects in patients with type 2 diabetes. Changes in interleukin-6 (IL-6) serum concentrations in response to training could contribute to these beneficial effects. However, there are heterogeneous data on whether circulating IL-6 is altered by exercise training. We therefore hypothesize that genetic factors modify the individual changes in IL-6 levels after long-term training. Research design and methods:The K174G/C variant in the IL-6 gene was genotyped in 60 subjects with impaired glucose tolerance. For a 12-month interventional study, patients were randomized into three groups: a control group (nZ16) was compared with one group, which underwent a standardized training program (nZ24) and another group, which was treated with 4 mg rosiglitazone once daily (nZ20). At baseline, after 1, 6, and 12 months, we measured anthropometric parameters and serum concentration of IL-6 and, at baseline and after 12 months, we determined glucose tolerance and fitness level. Results: Only in subjects carrying the SNP K174C allele did long-term exercise training result in significantly reduced IL-6 serum concentrations. Multivariate linear regression analysis identified the IL-6 genotype as a significant predictor of changes in IL-6 serum concentrations independent of age, gender and improvement in body mass index, hemoglobin (Hb)A 1c , and fitness level in response to training. Conclusions: Genetic variants in the IL-6 gene significantly modify changes in IL-6 serum concentrations in response to long-term exercise training programs. Our data suggest that genetic factors are important determinants for the individual response to anti-inflammatory effects of exercise training. 159 129-136 European Journal of Endocrinology

Brain accumulation and aggregation of amyloid-β (Aβ) peptides is a critical step in the pathogenesis of Alzheimer's disease (AD). Full-length Aβ peptides (mainly Aβ1-40 and Aβ1-42) are produced through sequential proteolytic cleavage of the amyloid precursor protein (APP) by β-and γ-secretases. However, studies of autopsy brain samples from AD patients have demonstrated that a large fraction of insoluble Aβ peptides are truncated at the N-terminus, with Aβ4-x peptides being particularly abundant. Aβ4-x peptides are highly aggregation prone, but their origin and any proteases involved in their generation are unknown. We have identified a recognition site for the secreted metalloprotease ADAMTS4 (a disintegrin and metalloproteinase with thrombospondin motifs 4) in the Aβ peptide sequence, which facilitates Aβ4-x peptide generation. Inducible overexpression of ADAMTS4 in HEK293 cells resulted in the secretion of Aβ4-40 but unchanged levels of Aβ1-x peptides. In the 5xFAD mouse model of amyloidosis, Aβ4-x peptides were present not only in amyloid plaque cores and vessel walls, but also in white matter structures co-localized with axonal APP. In the ADAMTS4 −/− knockout background, Aβ4-40 levels were reduced confirming a pivotal role of ADAMTS4 in vivo. Surprisingly, in the adult murine brain, ADAMTS4 was exclusively expressed in oligodendrocytes. Cultured oligodendrocytes secreted a variety of Aβ species, but Aβ4-40 peptides were absent in cultures derived from ADAMTS4 −/− mice indicating that the enzyme was essential for Aβ4-x production in this cell type. These findings establish an enzymatic mechanism for the generation of Aβ4-x peptides. They further identify oligodendrocytes as a source of these highly amyloidogenic Aβ peptides.