Aims/Introduction Advanced glycation end‐products (AGEs), which are a major cause of diabetic vascular complications, accumulate in various tissues under chronic hyperglycemic conditions, as well as with aging in patients with diabetes. The loss of muscle mass and strength, so‐called sarcopenia and dynapenia, has recently been recognized as a diabetic complication. However, the influence of accumulated AGEs on muscle mass and strength remains unclear. The present study aimed to evaluate the association of sarcopenia and dynapenia with accumulated AGEs in patients with type 2 diabetes. Materials and Methods We recruited 166 patients with type 2 diabetes aged ≥30 years (mean age 63.2 ± 12.3 years; body mass index 26.3 ± 4.9 kg/m2; glycated hemoglobin 7.1 ± 1.1%). Skin autofluorescence as a marker of AGEs, limb skeletal muscle mass index, grip strength, knee extension strength and gait speed were assessed. Results Sarcopenia and dynapenia were observed in 7.2 and 13.9% of participants, respectively. Skin autofluorescence was significantly higher in patients with sarcopenia and dynapenia. Skin autofluorescence was the independent determinant for skeletal muscle mass index, grip strength, knee extension strength, sarcopenia and dynapenia. Conclusions Accumulated AGEs could contribute to reduced muscle mass and strength, leading to sarcopenia and dynapenia in patients with type 2 diabetes.

The eukaryotic translation initiation factor 2α (eIF2α) phosphorylation-dependent integrated stress response (ISR), a component of the unfolded protein response, has long been known to regulate intermediary metabolism, but the details are poorly worked out. We report that profiling of mRNAs of transgenic mice harboring a ligand-activated skeletal muscle–specific derivative of the eIF2α protein kinase R-like ER kinase revealed the expected up-regulation of genes involved in amino acid biosynthesis and transport but also uncovered the induced expression and secretion of a myokine, fibroblast growth factor 21 (FGF21), that stimulates energy consumption and prevents obesity. The link between the ISR and FGF21 expression was further reinforced by the identification of a small-molecule ISR activator that promoted Fgf21 expression in cell-based screens and by implication of the ISR-inducible activating transcription factor 4 in the process. Our findings establish that eIF2α phosphorylation regulates not only cell-autonomous proteostasis and amino acid metabolism, but also affects non–cell-autonomous metabolic regulation by induced expression of a potent myokine.—Miyake, M., Nomura, A., Ogura, A., Takehana, K., Kitahara, Y., Takahara, K., Tsugawa, K., Miyamoto, C., Miura, N., Sato, R., Kurahashi, K., Harding, H. P., Oyadomari, M., Ron, D., Oyadomari, S. Skeletal muscle–specific eukaryotic translation initiation factor 2α phosphorylation controls amino acid metabolism and fibroblast growth factor 21–mediated non–cell-autonomous energy metabolism.

We report an autopsy case of an 82-year-old woman with progressive dementia due to miliary brain metastasis from lung adenocarcinoma. The patient presented with dementia 5 months prior to death and suddenly died of pulmonary hemorrhage. Postmortem examination revealed normal appearance of the brain. However, there were numerous foci of cancer metastasis in all parts of the brain on light microscopic examination. The carcinoma cells were located in the perivascular (Virchow-Robin) space and did not invade to the brain parenchyma. The carcinoma cells were also found in the subpial space. In the cerebral cortex, foci of metastasis appeared to spread in the following way: tiny foci of metastasis initially occur in the middle cortical layer, then spread to all layers through the perivascular space, and finally reach the subpial space and subcortical white matter. Although the junction between gray and white matter is a preferred site for usual brain metastasis, middle cortical layer was considered to be the initial site for metastasis in our patient. The perivascular pial sheath plays an important role for the development of miliary brain metastasis.

Aim:The levels of fasting and postprandial plasma glucose, HbA1c and other risk factors for atherosclerosis have distinct effects in patients with and those without diabetes mellitus. The aim of this study was to determine the impact of diabetic surrogate markers on the endothelial function, arterial stiffness and carotid atherosclerosis in individuals with and without diabetes. Methods: A total of 320 Japanese subjects (mean age: 61.2±12.1 years) were recruited in this study. Demographic, clinical and laboratory parameters, including 75 g OGTT (155 subjects) results, were examined. The endothelial function was evaluated according to the flow-mediated vasodilation of the brachial artery (%FMD). In addition, arterial stiffness was evaluated according to the brachial-ankle pulse wave velocity (baPWV), and carotid atherosclerotic changes were estimated according to the maximum intima-media thickness (max-IMT) and resistive index of the common carotid artery (CCA-RI). A multiple regression analysis was performed to identify independent determinants of these vascular surrogate markers. Results: None of the glucose-related parameters were associated with the %FMD. In contrast, the presence of T2DM, the HbA1c level and an increased plasma glucose level at 60 minutes during 75 g OGTT were associated with an increased baPWV. The HbA1c level was also correlated with an increased max-IMT. The fasting plasma glucose (FPG) level and the presence of T2DM correlated with an increased CCA-RI. In the subjects with T2DM, the protective effects of high-density lipoprotein cholesterol (HDL-C) on the %FMD and baPWV were abolished. Conclusions: Various glucose metabolism parameters have different effects the degree of arterial stiffness and presence of carotid atherosclerosis, but not the endothelial function, suggesting that pharmacological intervention has the potential to preserve the endothelial function in diabetic individuals. In addition, the presence of T2DM blunts the vascular protective effects of HDL-C on the endothelial function and progression of arterial stiffness. Mizuho Kinouchi and Ken-ichi Aihara contributed equally to this work. J Atheroscler 487Diabetes and the Clinical Vascular Function twice and averaged. Hypertensive patients were defined as those with a systolic blood pressure (SBP) of ≥ 140 mmHg and/or a diastolic blood pressure of ≥ 90 mmHg and/or individuals receiving antihypertensive medications. Dyslipidemic patients were defined as those with a low-density lipoprotein cholesterol (LDL-C) level of ≥ 140 mg/dL, a triglyceride (TG) level of ≥ 150 mg/dL and/or a high-density lipoprotein cholesterol (HDL-C) level of ＜40 mg/dL and individuals receiving lipid-lowering medications. Diabetic patients were defined as individuals receiving insulin and/or oral hypoglycemic agents or those with a glycosylated hemoglobin A1c (HbA1c) level of ≥ 6.5%, fasting plasma glucose (FPG) level of ≥ 126 mg/dL or 2-hour plasma glucose level of ≥ 200 mg/dL during a 75g OGTT. The exclusion criteria were overt cardiac failure, known...

The binding of thrombin to its receptor stimulates inflammatory cytokines including IL-6 and monocyte chemoattractant protein-1 (MCP-1); both are associated with the development of insulin resistance. Because increased adiposity enhanced the expression of coagulation factor VII that stimulates the coagulation pathway in adipose tissue, we tested whether the inhibition of thrombin action ameliorates insulin resistance in obese diabetic (Lpr(-/-):db/db) mice. The 4-wk administration of argatroban, a selective thrombin inhibitor, reduced fasting plasma glucose and ameliorated insulin resistance in these mice. It also reduced adipocyte size and macrophage infiltration into adipose tissue. The aberrant gene expression of MCP-1, IL-6, adiponectin, and factor VII and suppressed insulin receptor substrate-1-Akt signaling in adipose tissue of db/db mice were reversed by argatroban treatment. These results demonstrate that increased adiposity enhances the production of thrombin in adipose tissue by stimulating factor VII expression and suggest that increased thrombin activity in adipose tissue plays an important role in the development of insulin resistance via enhancing MCP-1 production, leading to macrophage infiltration and insulin receptor substrate-1-Akt pathway inactivation.