Luseogliflozin and caloric intake restriction increase superoxide dismutase 2 expression, promote antioxidative effects, and attenuate aortic endothelial dysfunction in diet-induced obese mice.

AIMS/INTRODUCTION: The mechanisms underlying the effect of sodium-glucose cotransporter 2 (SGLT2) inhibitors on aortic endothelial dysfunction in diet-induced obesity are not clearly understood. This study investigated whether SGLT2 inhibition by luseogliflozin improved free fatty acid (FFA)-induced endothelial dysfunction in high-fat diet (HFD)-induced obese mice. MATERIALS AND METHODS: Mice were fed a control diet or high-fat diet for 8 weeks, and then each diet with or without luseogliflozin was provided for an additional 8 weeks under free or paired feeding. Afterward, the thoracic aortas were removed and utilized for the experiments. RESULTS: Luseogliflozin treatment decreased body weight, fasting blood glucose, insulin, and total cholesterol in HFD-fed mice only under paired feeding but not under free feeding. Endothelial-dependent vasodilation under FFA exposure conditions was significantly lower in HFD-fed mice than in control diet-fed mice, and luseogliflozin treatment ameliorated FFA-induced endothelial dysfunction. Reactive oxygen species (ROS) production induced by FFA was significantly increased in HFD-induced obese mice. Luseogliflozin treatment increased the expression of superoxide dismutase 2 (SOD2), an antioxidative molecule, and reduced FFA-induced ROS production in the thoracic aorta. Superoxide dismutase reversed FFA-induced endothelial dysfunction in HFD-fed mice. CONCLUSIONS: It was shown that caloric restriction is important for the effect of luseogliflozin on metabolic parameters and endothelial dysfunction. Furthermore, SGLT2 inhibition by luseogliflozin possibly ameliorates FFA-induced endothelial dysfunction by increasing SOD2 expression and decreasing reactive oxygen species production in the thoracic aorta.

Basal insulin ameliorates post-breakfast hyperglycemia via suppression of post-breakfast proinsulin/C-peptide ratio and fasting serum free fatty acid levels in patients with type 2 diabetes.

BACKGROUND: In general, basal insulin targets fasting plasma glucose (FPG) levels, and prandial insulin targets postprandial glucose (PPG) levels. However, the effects of basal insulin on PPG levels are controversial. We investigated the effect of basal insulin on postprandial hyperglycemia using a test meal at breakfast as well as compared differences between degludec and glargine. METHODS: A total of 20 participants with type 2 diabetes were randomly assigned to degludec (n = 10) or glargine (n = 10). We initiated basal-bolus insulin therapy and titrated only basal insulin until FPG was < 6.1 mmol/L. We evaluated changes in post-breakfast glucose levels and changes in clinical parameters such as serum C-peptide (CPR), proinsulin (PI), and free fatty acids (FFA) levels between the pre- and post-titration periods. Differences between degludec and glargine in the post-titration period were also evaluated. RESULTS: Post-breakfast glucose levels significantly decreased by 46.1% in the post-titration period compared with the pre-titration period (n = 20, p < 0.001). These decreases correlated positively with decreases in the post-breakfast PI/CPR ratio (r = 0.692, p < 0.001) and in fasting FFA levels (r = 0.720, p < 0.001). There were no significant differences in post-breakfast glucose levels between degludec and glargine. However, the hypoglycemic rate with degludec was significantly lower than with glargine. CONCLUSION: Our results suggest that basal insulin with either degludec or glargine decreases the incidence of post-breakfast hyperglycemia accompanied by decreasing the post-breakfast PI/CPR ratio and fasting FFA levels in patients with type 2 diabetes.

Neurofibromatosis type 1 associated with hypophosphatemic osteomalacia due to hypersecretion of fibroblast growth factor 23: a case report.

BACKGROUND: Neurofibromatosis type 1 is characterized by multiple café au lait spots and cutaneous and plexiform neurofibromas, and is one of the most common autosomal dominant hereditary disorders caused by mutations of the neurofibromatosis type 1 tumor suppressor gene. Osteomalacia in neurofibromatosis type 1 is very rare and is characterized by later onset in adulthood. In humans, fibroblast growth factor 23, which is a causative factor of tumor-induced osteomalacia, is not only a paracrine and autocrine factor, but is also a physiological regulator of phosphate balance in normal serum. CASE PRESENTATION: Our patient was a 65-year-old Japanese woman whose neurofibromas began to appear when she was in elementary school. At age 28, she was diagnosed as having neurofibromatosis type 1. A spinal compression fracture and multiple rib fractures were identified in 2012 and 2017, respectively. Her laboratory findings revealed hypophosphatemia due to renal phosphate wasting and a high serum level of fibroblast growth factor 23. Neurofibromas located on the surface of her right forearm and left upper arm, in which a slight abnormal accumulation of tracers was observed on 111indium-pentetreotide scintigraphy, were surgically removed, but there was no improvement in hypophosphatemia or serum fibroblast growth factor 23 after surgery. Therefore, we administered eldecalcitol, which also failed to produce improvement in abnormal data. Subsequent combination with dibasic calcium phosphate hydrate led to improvement in some of the abnormalities, including hypophosphatemia. Immunohistochemical staining using anti-human fibroblast growth factor 23 antibody revealed slightly positive results, however, only one out of three amplifications of the fibroblast growth factor 23 gene was observed by real-time polymerase chain reaction, and no clear fibroblast growth factor 23 gene expression in the resected neurofibromas could be confirmed. CONCLUSIONS: We here describe a first rare case of a 65-year-old woman with neurofibromatosis type 1 associated with hypophosphatemic osteomalacia in which a high serum fibroblast growth factor 23 level was confirmed.

Performance of a 2-step insulin infusion protocol with adjustment of insulin doses for Asians in the medical intensive care unit following cardiothoracic surgery.

BACKGROUND: Most previous insulin infusion protocols are titrated for Westerners and are not simple to follow. In this study, we tested the efficacy and safety of our simple insulin infusion protocol utilizing lower insulin doses for Asians. METHODS: A total of 152 patients with type 2 diabetes undergoing cardiothoracic surgery were included. After surgery, blood glucose (BG) was initially managed according to our algorithm protocol, and subsequently by the post-algorithm protocol. Insulin infusion rates in the algorithm protocol were titrated in two steps according to (1) current BG levels and (2) the difference between current and previous BG levels. In the post-algorithm protocol, insulin lispro was injected subcutaneously in addition to intravenous insulin infusion according to BG levels. The efficacy was assessed as achievement rates of two target BG ranges (140-199 and 80-199 mg/dL), and safety was assessed as hypoglycemia (< 70 mg/dL) and protocol error rates. RESULTS: With the use of the algorithm protocol, 58.7% of 1749 BG measurements achieved a range of 140-199 mg/dL, and 95.9% achieved levels within the 80-199 mg/dL range. Hypoglycemia and protocol error rates were 0.47 and 0.51%, respectively. With the post-algorithm protocol, 48.7 and 98.3% of 898 BG measurements achieved each target range. Hypoglycemia and protocol error rates were 0.78 and 0.22%, respectively. Severe hypoglycemia (< 40 mg/dL) was not observed. CONCLUSIONS: Our insulin infusion protocol seems to be efficacious, safe, and widely feasible for Asian patients because of its simplicity and lower insulin dose.