Previous reports have shown that the paracrine system may be an important mediator in bone-marrow-derived mesenchymal stem cell (MSC) therapy for ischemic diseases. Hyperglycemia and hypoxia have been associated with increased levels of reactive oxygen species; oxidative stress may therefore influence the paracrine effects of MSCs under hypoxic conditions in diabetic patients, although the mechanism underlying this effect remains unknown. Hypoxia-inducible factor 1a (HIF-1a) regulates the transcription of hypoxia-inducible genes. We determined the effect of high-glucose concentrations on the production of angiogenic growth factors via HIF-1a induction in hypoxic MSCs. MSCs were cultured with different glucose concentration (5 . 6, 11, 20, or 30 mM) for 24 h. The cells were then incubated in a hypoxic chamber (5% O 2 ) or under normoxia (21% O 2 ) for 6 or 24 h. Protein levels of HIF-1a, vascular endothelial growth factor A 165 (VEGF-A 165 ), and platelet-derived growth factor B (PDGF-B) were attenuated by glucose in hypoxic MSCs in a dose-dependent manner. Treatment with MG132, a specific inhibitor of proteasome activity, significantly reversed the inhibitory effect of high-glucose concentrations in hypoxic MSCs. 4-Hydroxyl-tetramethylpiperidin-oxyl (a cell-permeable superoxide scavenger) or Apocynin (a NADPH oxidase inhibitor) significantly reversed glucose-induced attenuation of VEGF-A 165 , PDGF-B, and HIF-1a protein levels. Stimulation with a high-glucose concentration (30 mM) significantly increased intracellular superoxide levels in hypoxic MSCs. Our results suggest that in hypoxic MSCs the increase in intracellular superoxide levels induced by high-glucose concentrations may attenuate hypoxia-induced HIF-1a expression, which in turn attenuates hypoxiainduced VEGF-A 165 and PDGF-B transcription.
We present a case of cryptococcosis with adrenal insufficiency and meningitis in a healthy host without any risk factors. Antifungal therapy did not reduce the cryptococcal antigen titers of the cerebrospinal fluid and serum or the bilateral adrenal gland enlargement. It was suggested that the adrenal glands were the focus of persistent fungemia. Removal of both adrenal glands brought about a response to antifungal therapy. We conclude that if antifungal therapy is ineffective, bilateral adrenalectomy is an effective measure for treatment of such patients. Cryptococcosis is a possible cause of primary adrenal insufficiency in immunocompetent patients.
Abstract. Sodium-glucose cotransporter 2 inhibitors are commonly used to promote urinary glucose excretion (UGE). However, it remains unclear how UGE reflects glucose metabolism in the natural history of diabetes. Thus, we retrospectively reviewed the prediabetes medical records of 64 patients who had undergone 75-g oral glucose tolerance testing (OGTT) with measurements of UGE at 0 min, 60 min, and 120 min. The mean age and glycated hemoglobin levels were 46 ± 10 years and 5.6 ± 0.3%, respectively. The median UGE (60 min + 120 min) value was 16.8 mg ( The log-transformed insulinogenic index exhibited a significant inverse association with log-transformed UGE (60 min + 120 min) (r = -0.50, p < 0.001). The association between higher UGE and lower insulinogenic index was also observed in a subgroup analysis of patients with plasma glucose levels of ≥160 mg/ dL during the OGTT. Therefore, UGE measurements after OGTT may provide a useful clinical marker for detecting insulin secretion failure and advancing preventive and therapeutic interventions among populations with a high risk of developing diabetes.
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