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.

Dietary obesity and glycemic excursions cause a parallel increase in STEAP4 and pro-inflammatory gene expression in murine PBMCs.

Background: The balance between pro-atherogenic and anti-atherogenic factors is very crucial in the development of atherosclerotic lesions. Although the expression of the six-transmembrane epithelial antigen of the prostate 4 (STEAP4) in myeloid cells is known to be atheroprotective, there is not a single study reporting on the status of STEAP4 expression in circulating monocytes in the early stages of diet-induced obesity or in events of glycemic excursions. Methods: We induced glycemic spikes twice daily for a 1-week duration to rats fed on regular chow and western diet, and analyzed gene expression changes in the peripheral blood mononuclear cells (PBMCs). We also conducted experiments on RAW 264.7 cells to gain insight into some of our in vivo findings. Results: Diet-induced obesity and glycemic excursions independently caused a significant increase in STEAP4 mRNA expression in PBMCs. This was also accompanied by an induction of a substantial number of pro-inflammatory cytokines, chemokines, and chemokine receptors. However, the combined effect of western diet and hyperglycemic spikes was subtle and non-additive. In the in vitro setting, either glucose spikes, persistent hyperglycemia, or a combination of palmitic acid and insulin resulted in a parallel increase in expression of STEAP4 and pro-inflammatory genes. This was, however, significantly abrogated with 4-octyl itaconate or attenuated by inhibitors of p38MAPK and NF-kB. Conclusions: STEAP4 expression in mononuclear cells is induced by increasing inflammation or oxidative stress. The observed increase in STEAP4 expression in circulating monocytes due to visceral obesity or glycemic excursions is a compensatory response. Supplementary Information: The online version contains supplementary material available at 10.1007/s13340-021-00542-1.

Correction to: Dietary obesity and glycemic excursions cause a parallel increase in STEAP4 and pro-inflammatory gene expression in murine PBMCs.

[This corrects the article DOI: 10.1007/s13340-021-00542-1.].

Repeated glucose spikes and insulin resistance synergistically deteriorate endothelial function and bardoxolone methyl ameliorates endothelial dysfunction.

BACKGROUND: Both insulin resistance and postprandial glucose spikes are known for their potential to induce vascular endothelial dysfunction in individuals with metabolic syndrome. However, these factors are inextricable, and therefore, their relative contributions to inducing endothelial dysfunction remain elusive. In this study, we aimed to disentangle the effects of these factors and clarify whether bardoxolone methyl (CDDO-Me), a novel nuclear factor erythroid 2-related factor 2 (Nrf2) activator, protects against glucose spike-induced endothelial dysfunction. METHODS: We induced glucose spikes twice daily for a duration of 1 week to rats fed a standard/control diet (CD) and Western-type diet (WTD). Endothelium-dependent relaxation (EDR) was evaluated using isolated thoracic aortas. Gene expression and dihydroethidium (DHE)-fluorescence studies were carried out; the effect of CDDO-Me on aortic endothelial dysfunction in vivo was also evaluated. RESULTS: Neither WTD-induced insulin resistance nor pure glucose spikes significantly deteriorated EDR. However, under high-glucose (20 mM) conditions, the EDR of thoracic aortas of WTD-fed rats subjected to glucose spikes was significantly impaired. In this group of rats, we observed significantly enhanced DHE fluorescence as a marker of reactive oxygen species, upregulation of an oxidative stress-related gene (NOX2), and downregulation of an antioxidant gene (SOD2) in the thoracic aortas. As expected, treatment of the thoracic aorta of this group of rats with antioxidant agents significantly improved EDR. We also noted that pretreatment of aortas from the same group with CDDO-Me attenuated endothelial dysfunction, accompanied by a correction of the redox imbalance, as observed in gene expression and DHE fluorescence studies. CONCLUSIONS: For the first time, we showed that insulin resistance and glucose spikes exert a synergistic effect on aortic endothelial dysfunction. Furthermore, our study reveals that CDDO-Me ameliorates endothelial dysfunction caused by glucose spikes in a rat model of metabolic syndrome.

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.

Growth hormone deficiency with late-onset hypothalamic hypoadrenocorticism associated with respiratory and renal dysfunction: a case report.

BACKGROUND: The prevalence of childhood-onset growth hormone (GH) deficiency (GHD) is estimated to be approximately 1 in 5000 or more, with the cause unknown in most cases (idiopathic isolated GHD). However, additional disorders of secretion of other pituitary hormones reportedly develop over time, with a frequency of 2-94% (median, 16%). Furthermore, median times to development of other anterior pituitary hormone deficiencies have been reported to be 6.4-9.4 years. On the other hand, adult patients affected by childhood-onset GHD reportedly develop impaired ventilation function due to reduced lung volumes and respiratory pressures, probably due to reductions in respiratory muscle strength. In addition, GH is known to play a role in stimulating the glomerular filtration rate (GFR), and the estimated GFR (eGFR) is decreased in patients with GHD. CASE PRESENTATION: This case involved a 65-year-old woman. Her short stature had been identified at around 3 years of age, but no effective treatments had been provided. The patient was mostly amenorrheic, and hair loss became apparent in her late 30s. She developed hyperuricemia, dyslipidemia, and hypertension at 45 years of age. In addition, the patient was diagnosed with hypothyroidism at 50 years of age. At 58 years of age, endocrinological examination showed impaired secretion of thyroid-stimulating hormone, luteinizing hormone/follicle-stimulating hormone, and growth hormone, and magnetic resonance imaging showed an empty sella turcica. However, secretion ability of adrenocorticotropic hormone was retained. At 63 years of age, respiratory function tests confirmed a markedly restricted ventilation disorder (vital capacity, 0.54 L; percentage predicted vital capacity, 26.9%). Renal function had also decreased (eGFR, 25.0 mL/min/1.73 m2). Furthermore, she was diagnosed with hypothalamic secondary hypoadrenocorticism. The patient developed CO2 narcosis at 65 years of age, and noninvasive positive pressure ventilation was started. CONCLUSIONS: The rare case of a 65-year-old woman with childhood-onset GHD with panhypopituitarism, including late-onset secondary hypoadrenocorticism in her 60s, associated with severely impaired respiratory function and renal dysfunction, was reported. In GHD patients with risk factors for progression from isolated GHD to combined pituitary hormone deficiency, such as empty sella turcica, lifelong endocrinological monitoring may be important.

Strategies to ameliorate endothelial dysfunction associated with metabolic syndrome, where are we?

There is a paucity of aggregated clinical trials on strategies of ameliorating endothelial dysfunction associated with Metabolic Syndrome (MS). We reviewed clinical trials conducted between 2008 and 2017, reporting on strategies of improving endothelial function in patients with MS. A comprehensive search of published articles by the Google Scholar and PubMed were carried out. Only studies involving non-invasive, objective measurement of endothelial function were included. Thirty (30) studies were selected for analysis, in which physical exercise training, diet modification, calcium channel blockers + alpha-lipoic acid, bezafibrate, allopurinol, mesoglycan, and l-arginine supplementation significantly improved Endothelial-Dependent Vasodilation (EDV) in patients with MS but without cardiovascular diseases. Large multicenter clinical trials are required to address the question of generalizability of these findings.

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.

Type 1 diabetes complicated with uncontrollable adult cyclic vomiting syndrome: a case report.

We herein describe the case of a 29-year-old woman with type 1 diabetes from 10 years of age who developed adult cyclic vomiting syndrome. Beginning at 25 years of age, she was frequently hospitalized for stress-induced vomiting. Her vomiting episodes developed acutely and remitted after severe vomiting of more than 30 times a day for a few days. The vomiting periods were accompanied by leukocytosis with a predominance of neutrophils, high blood pressure and fever. In addition, it was noted that her levels of both adrenocorticotropic hormone and antidiuretic hormone during the vomiting attacks increased and subsequently dramatically decreased immediately after symptom improvement; therefore, she was diagnosed with adult-type cyclic vomiting syndrome in accordance with the diagnostic criteria of Rome III, a system developed to classify functional gastrointestinal disorders. Though glycemic control had improved with continuous subcutaneous insulin infusion therapy, the vomiting frequency increased due to the failure of drug treatments and general psychotherapy to terminate the vomiting attacks, making discharge difficult and greatly interfering with everyday life. Eventually, hypnotherapy and miniature garden therapy were prescribed, which significantly reduced the vomiting frequency, making it possible to discharge her from inpatient medical care. In the treatment of this patient with type 1 diabetes and adult-type cyclic vomiting syndrome, continuous subcutaneous insulin infusion therapy and comprehensive psychotherapy were effective.

The role of adiponectin multimers in anorexia nervosa.

OBJECTIVE: Anorexia nervosa (AN) continues to be a refractory disease because of its unknown pathogenesis. The role of adiponectin in AN has not been clarified. Moreover, few reports have described the relations between adiponectin isoforms and AN in the physical and psychological states. Therefore, we measured plasma adiponectin and its isoforms levels in patients with AN to examine their roles in AN. METHODS: Eighteen women participated in this study: nine patients with AN and nine age-matched healthy controls. We examined plasma adiponectin and its isoforms levels in all subjects and administered three types of psychological test to patients with AN: the Eating Disorders Inventory-2, the Maudsley Obsessional-Compulsive Inventory, and the Beck Depression Inventory-2. RESULTS: We found that the percentage of high-molecular-weight (HMW) to total adiponectin (%HMW) was significantly low and the percentage of low-molecular-weight (LMW) to total adiponectin (%LMW) was significantly high in the AN group compared with the control group. The %HMW positively and the %LMW negatively correlated with body mass index in the entire study population. The %HMW was also positively correlated with psychological symptoms such as social insecurity or cleaning evaluated with the Eating Disorders Inventory-2 or the Maudsley Obsessional-Compulsive Inventory. CONCLUSIONS: Our study indicates that all adiponectin isoforms should be evaluated in patients with AN in addition to total adiponectin. The decreased %HMW and the increased %LMW that were correlated with the body mass index and some components of psychopathology in our patients may indicate a complex role of adiponectin isoforms in maintaining energy homeostasis and emotion during extreme malnourishment.

A case of anorexia nervosa with disseminated intravascular coagulation syndrome.

A 36-year-old Japanese woman with anorexia nervosa (AN) was admitted to our department because of severe emaciation. Although we were thorough in her clinical management and were careful to avoid precipitating refeeding syndrome, disseminated intravascular coagulation (DIC) developed 3 weeks after hospitalization. We treated her for DIC with sepsis using anticoagulants, protease inhibitors, antithrombin, and platelet concentrate transfusion. To treat her bacterial infection, we administered antimicrobial drugs and immunoglobulin. We began probiotic and prebiotic (synbiotics) treatment for bacterial translocation. We think that the prevention of sepsis via bacterial translocation is an important aspect of care for patients with severe AN in addition to the prevention of refeeding syndrome.

Ghrelin and anorexia nervosa: a psychosomatic perspective.

Anorexia nervosa (AN) is a serious medical illness associated with gastrointestinal, metabolic, and psychological complications, and there are no effective pharmacologic treatments for the condition. Recent studies have suggested that the regulatory peptides, including ghrelin, are involved in the pathologic feeding behavior of AN. Previous studies have indicated that plasma total ghrelin and acyl ghrelin levels in patients with AN are higher than in controls, and the ratio of des-acyl ghrelin to acyl ghrelin in AN tend to be higher than in controls. In addition, ghrelin has been reported to stimulate appetite and food intake in various diseases, including chronic heart failure, chronic obstructive pulmonary disease, and cancer. Because it is speculated that difficulties in resolving the underlying psychological condition preclude reversal of the pathologic feeding behavior in AN, ghrelin is expected to be applied in a clinical setting as a new treatment. In this review, we describe the role of ghrelin in the pathophysiology and potential treatment of AN along the gut-brain axis.

Ghrelin: a gut hormonal basis of motility regulation and functional dyspepsia.

Functional dyspepsia (FD) is a functional gastrointestinal disorder (FGID). Several pathophysiological mechanisms have been indicated as possible etiological factors, such as delayed gastric emptying, impaired proximal gastric accommodation and visceral hypersensitivity. Ghrelin is an important gut hormone. It is a motilin-related peptide that was discovered in the stomach, and it acts as an endogenous ligand of growth hormone secretagogue receptor. Ghrelin plays an important role in the stimulation of food intake and gut motility. Acyl ghrelin stimulates the percentage motor index (%MI) in the antrum and induces fasted motor activity in the duodenum. Des-acyl ghrelin decreases food intake and decrease gastric emptying. Although some studies have demonstrated that plasma acyl ghrelin levels tend to be lower in FD patients than in controls, the association between plasma ghrelin levels and FD remains controversial. Previous reports have demonstrated that hunger sensation was elevated through the administration of ghrelin to patients with FD. However, there have been few clinical reports relating to the administration of ghrelin. Altered gut-brain interactions may underlie the symptoms of FD. Ghrelin may be associated with FD through its effect on the regulation of gut motility. Further studies are needed to examine the effects of ghrelin in FD.

Plasma nesfatin-1 concentrations in restricting-type anorexia nervosa.

Restricting-type anorexia nervosa (AN-R) is characterized by chronic food restriction and severe emaciation due to various cognitive biases such as a distorted self-image. In spite of several treatments, AN-R continues to be a refractory disease because of its unknown pathogenesis. Although previous studies have shown that changes in feeding regulatory peptides such as ghrelin are involved in anorexia, few reports have described the relationship between AN-R and nesfatin-1, a recently identified satiety peptide. Therefore, we examined the plasma nesfatin-1 levels in AN-R patients to determine its role in AN-R. A total of 15 women participated in the study; 7 patients with AN-R and 8 age-matched healthy controls (average BMI, 13.02 ± 0.30 vs. 21.57 ± 0.48, respectively). Our results showed that plasma nesfatin-1 levels were significantly lower in AN-R group than in control group (6.23 ± 0.70 ng/ml vs. 8.91 ± 0.85 ng/ml, respectively, P<0.05). Plasma acyl ghrelin and des-acyl ghrelin levels were significantly higher in AN-R group than in control group (acyl ghrelin: 62.4 ± 10.15 fmol/ml vs. 27.20 ± 5.60 fmol/ml, P<0.01 and des-acyl ghrelin: 300.17 ± 55.95 fmol/ml vs. 107.34 ± 40.63 fmol/ml, P<0.05). Although AN-R is associated with emaciation for a prolonged period, our result suggested that nesfatin-1 levels may be regulated by nutrition status and response to starvation.