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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.

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

INTRODUCTION: Several studies have recently pointed out the role of many inflammatory mediators in the progression of diabetes complications. We had previously demonstrated that mRNA expression of platelet-activating factor receptor (PAFR) in peripheral blood mononuclear cells (PBMCs) was associated with urinary albumin to creatinine ratio (ACR) and forearm flow-mediated dilatation in patients with type 2 diabetes. In an attempt to elucidate this association, patients were followed up for 1 year. MATERIALS AND METHODS: We recruited 95 patients from the hospital outpatient clinic, among whom 86 were followed up for 1 year (normoalbuminuria: 40 patients, microalbuminuria: 25 patients, macroalbuminuria: 21 patients). We then measured their baseline and 12 month characteristics and collected blood samples to extract PBMCs and measure gene expressions. RESULTS: Despite higher mRNA expression of PAFR in PBMCs among patients with macroalbuminuria, the rise in its value was not associated with biomarkers of nephropathy, while baseline values were not associated with progression of nephropathy. Moreover, changes in mRNA expression of PAFR were correlated with changes in ACR in all patients (r = 0.225, p = 0.037) and estimated glomerular filtration rate in patients with macroalbuminuria (r = − 0.438, p = 0.047) during the follow-up period. CONCLUSION: Our findings indicate that even though no causal relationship exists between diabetic nephropathy and elevated expression of PAFR in PBMCs, their close association signifies the presence of another common mechanism that could induce both events. Given these findings, the PAF/PAFR interaction could clarify corresponding mechanisms involved in diabetic complications. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s13340-019-00394-w) contains supplementary material, which is available to authorized users.

Background Central pontine myelinolysis (CPM) is a non-inflammatory demyelinating lesion of the pons. CPM and extrapontine demyelination (EPM) are together termed osmotic demyelination syndrome (ODS), a known and serious complication of acute correction of hyponatremia. Conversely, hyperglycemic hyperosmolarity syndrome (HHS) develops in patients with type 2 diabetes who still have some insulin secretory ability due to infection, non-compliance with treatment, drugs, and coexisting diseases, and is often accompanied by ketosis. HHS represents a life-threatening endocrine emergency (mortality rate, 10–50%) associated with marked hyperglycemia and severe dehydration. HHS may develop ODS, and some cases have been associated with hypernatremia. Case presentation The patient was an 87-year-old woman with hyperglycemia, dehydration, malnutrition, and potential thrombus formation during long-term bed rest. HHS was suspected to have developed due to progression of hyperglycemia and dehydration caused by pneumonia. Furthermore, ketoacidosis developed from ketosis and prerenal renal failure associated with circulating hypovolemia shock, which was also associated with disseminated intravascular coagulation. Treatment was started with continuous intravenous injection of fast-acting insulin and low-sodium replacement fluid. In addition, ceftriaxone sodium hydrate, heparin sodium, thrombomodulin α, human serum albumin, and dopamine hydrochloride were administered. Blood glucose, serum sodium, serum osmolality, and general condition (including vital, infection/inflammatory findings, and disseminated intravascular coagulation) improved promptly, but improvements in disturbance of consciousness were poor. Diffusion-weighted imaging of the brain 72 h after starting treatment showed no obvious abnormalities, but high-intensity signals in the midline of the pons became apparent 30 days later, leading to definitive diagnosis of CPM. Conclusions Fluctuation of osmotic pressure by treatment from hyperosmolarity due to hyperglycemia and hypernatremia in the presence of risk factors such as malnutrition, severe illness, and metabolic disorders may be a cause of CPM onset. When treating HHS with risk factors, the possibility of progression to ODS needs to be kept in mind.

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.

BackgroundThe 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 presentationThis 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 CO2narcosis at 65 years of age, and noninvasive positive pressure ventilation was started.ConclusionsThe 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.

The importance of sleep disturbance and depression in patients with type 2 diabetes is unclear. Our objective was to evaluate their effects on the quality of life (QOL) of patients with type 2 diabetes. For the study, 270 patients were recruited from the Shiga Prospective Observational Follow-up Study for Diabetic Complications. Depressive symptoms, sleep disturbance, and QOL were assessed by use of the Zung Self-Rating Depression Scale (SDS), the Pittsburgh Sleep Quality Index (PSQI), and SF-8, respectively, after evaluation of their metabolic control and complications. Furthermore, 141 patients were recruited to repeat the same study after 6–12 (mean 7.3) months. Significant correlations were found among sleep disturbance, depression, and QOL in patients with type 2 diabetes. Patients undergoing insulin therapy had significantly higher SDS scores, meaning more depressive symptoms, than those not undergoing insulin therapy. Patients with painful neuropathy had higher PSQI and SDS scores and lower physical component of the QOL score than patients without painful neuropathy. In the follow-up observation it was found that the presence of neuropathy and elevated HbA1c level were predictors of increasing PSQI score and SDS score, respectively. It was found that the presence of painful neuropathy was a risk factor for sleep disturbance for type 2 diabetic patients. Sleep disturbance and depressive symptoms correlated significantly with the QOL scores of patients with type 2 diabetes, suggesting the importance of these indices for better management of diabetic patients.

To examine the effect of laparoscopic sleeve gastrectomy (LSG) on glucose metabolism. LSG was performed in two patients with diabetes and one with impaired glucose tolerance. An oral glucose tolerance test (OGTT) was performed preoperatively and 3 months postoperatively. Plasma glucose, insulin, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) levels were measured during the OGTT. Fasting ghrelin levels were also measured. Two diabetic patients discontinued oral hypoglycemic agents or insulin immediately post-surgery, and the HbA1c level was improved. The area under the curve for insulin and GLP-1 was increased after surgery. In contrast, GIP secretion did not change significantly. Fasting ghrelin levels were decreased in all patients. LSG can lead to a rapid improvement of glucose tolerance with enhanced insulin secretion. Increased GLP-1 secretion and decreased ghrelin levels may play a role in improvement of glucose tolerance and insulin secretion after LSG.

Many in vitro studies have suggested that oxidative stress induced by hyperglycemic conditions has a pivotal role in the pathogenesis of vascular complications in diabetics. This study intended to evaluate the oxidative stress and antioxidant potential in patients with type 2 diabetes mellitus (DM), and to clarify the relation between oxidative stress and metabolic derangements including chronic hyperglycemia. We measured the levels of derivatives of reactive oxidative metabolites (ROM) and biological antioxidant potential (BAP) in 59 patients with type 2 DM and 10 healthy controls. Diabetic patients showed a significant increase in ROM levels and a decrease in adjusted BAP/ROM ratios compared with those of control. But no differences were found in BAP levels between the two groups. ROM levels were found to positively correlate with HbA1c, plasma glucose, and waist size, and adjusted BAP/ROM ratios negatively correlated with HbA1c, plasma glucose, waist size, and serum triglycerides. Stepwise multiple regression analysis indicated that HbA1c and waist size were independent factors contributing to the elevated ROM levels. The ROM level in patients with type 2 DM with metabolic syndrome was significantly higher than that in patients without metabolic syndrome. Glycemic control with glimepiride or miglitol for 3 months reduced ROM levels significantly by 9%. These results clearly demonstrate that glycemic control and visceral obesity are independently associated with an increasing oxidative stress in patients with type 2 DM.

We have previously reported an association between the activator protein-2beta (AP-2beta) transcription factor gene and type 2 diabetes. This gene is preferentially expressed in adipose tissue, and subjects with a disease-susceptible allele of AP-2beta showed stronger AP-2beta expression in adipose tissue than those without the susceptible allele. Furthermore, overexpression of AP-2beta led to lipid accumulation and induced insulin resistance in 3T3-L1 adipocytes.We found that overexpression of AP-2beta in 3T3-L1 adipocytes decreased the promoter activity of leptin, and subsequently decreased both messenger RNA (mRNA) and protein expression and secretion. Furthermore, knockdown of endogenous AP-2beta by RNA-interference increased mRNA and protein expression of leptin. Electrophoretic mobility shift and chromatin immunoprecipitation assays revealed specific binding of AP-2beta to leptin promoter regions in vitro and in vivo. In addition, site-directed mutagenesis of the AP-2-binding site located between position +34 and +42 relative to the transcription start site abolished the inhibitory effect of AP-2beta. Our results clearly showed that AP-2beta directly inhibited insulin-sensitizing hormone leptin expression by binding to its promoter.AP-2beta modulated the expression of leptin through direct interaction with its promoter region.

Aims/hypothesis. We studied 76 patients with Type II (non-insulin-dependent) diabetes mellitus and 16 age-matched non-diabetic subjects (control group) to clarify qualitative and quantitative abnormalities of waveform and flow volume of the popliteal artery. Methods. The 76 diabetic patients comprised 16 patients with occlusive arterial disease in the lower extremities [arteriosclerosis obliterans (ASO) group] and 60 patients free from this disease (non-ASO group). We flow analysed the popliteal artery and measured the phosphocreatine to inorganic phosphate ratio of resting plantar muscles to identify risk factors for foot lesions using gated magnetic resonance two-dimensional cine-mode phase-contrast imaging and 31P spectroscopy. Results. The control and non-ASO groups had a triphasic waveform with systolic, early and late diastolic components. All ASO patients had an abnormal monophasic waveform and a lower ankle brachial index than that of the control and non-ASO groups. To clarify the mechanism of reduced flow volume of lower extremities, we assigned the 60 patients of the non-ASO group to the three subgroups based on their levels of total flow volume of the popliteal artery. The lowest group showed an abnormal triphasic waveform with lower amplitudes of systolic and late diastolic components and flow velocities in foot arteries than those of the highest group although ABI was similar. From stepwise multiple regression analysis, late diastolic flow volume was identified as an independent determinant for the phosphocreatine to inorganic phosphate ratio (r 2 = 0.484, p < 0.001). Conclusion/interpretation. Waveform analysis of popliteal artery provides a powerful tool for identifying impaired peripheral circulation caused by either occlusive arterial disease or increased arterial resistance in diabetic patients. [Diabetologia (2000) 43: 1031–1038]

Aims/hypothesis. We studied 36 Type II (non-insulin-dependent) diabetic patients without occlusive arterial diseases in the lower extremities and 12 age-matched and sex-matched non-diabetic subjects to clarify the association between diabetic polyneuropathy and foot ulcers using 1H- and 31P-magnetic resonance spectroscopy and imaging.¶Methods. The 36 diabetic patients consisted of 12 patients with superficial foot ulcers and 24 patients free from this disease. We measured fat to water and phosphocreatine to inorganic phosphate (PCr:Pi) ratios and calculated the intracellular pH of resting plantar muscles by depth-resolved surface-coil spectroscopy using an 1H-31P double tuned coil. Furthermore, foot vasculature, fat and PCr contents of plantar muscles were visualised by phase-contrast angiography, T1-weighted spin-echo imaging and 31P-chemical shift imaging.¶Results. The 12 foot ulcer patients showed a reduced PCr to Pi ratio (p < 0.001) and peripheral nerve functions (p < 0.01–0.001) but an increased fat to water ratio (p < 0.001) and intracellular pH (p < 0.001) compared with the 24 patients without ulcers. From stepwise multiple regression analyses, motor nerve function as well as severity of nephropathy was associated with both fat to water and PCr to Pi ratios. When these patients were categorised into three groups based on their level of motor nerve function, the frequency of foot ulcers of the lowest group was higher than that of the highest group.¶Conclusion/interpretation. Our findings indicated that motor nerve dysfunction in diabetic patients was closely associated with impaired energy metabolism, fatty infiltration and increased intracellular pH of plantar muscles and high frequency of foot ulcers. These new techniques could contribute to help clarify the predisposing factors for foot ulcers. [Diabetologia (2000) 43: 165–172]

To the editor, Immunosuppressive therapy, including high-dose corticosteroids and other immunosuppressive agents, has markedly improved systemic lupus erythematosus (SLE) patient survival. However, these patients are deemed at increased risk for opportunistic infection because of impaired immunity due to immunosuppressive therapy. We encountered a patient with diVuse lupus nephritis complicated with severe thrombocytopenia and haemolytic anaemia, whose haematological manifestations might have been related to cytomegalovirus (CMV) reactivation. A 23-year-old Japanese man was hospitalized because of urinary abnormalities. Two months prior to admission, proteinuria and haematuria had been detected on a routine health examination. On admission, physical Wndings were unremarkable; however, laboratory testing revealed active nephritic urinary sediments with marked urinary protein excretion (2.6 g per day), low serum complement [C3 (24 mg/dl) and C4 (6 mg/dl)] values, and high titre of antidouble-stranded DNA (ds-DNA) antibody (63.1 IU/ml; reference range < 20). Renal biopsy revealed diVuse mesangial proliferation and capillary wall thickening on light microscopy, “full-house” pattern on immunoXuorescence microscopy, and mesangial/subendothelial electron-dense deposits on electron microscopy. During hospitalization, constitutional manifestations (i.e., fever and general myalgia), arthritis, and lymphopenia developed; thus, we diagnosed him to have SLE associated with diVuse lupus nephritis [International Society of Nephrology (ISN), Class IV]. Intravenous methyl prednisolone (0.5 g, three consecutive days) once every 2 weeks and oral corticosteroid (prednisolone, 55 mg per day) was started. This treatment improved his immunological abnormalities (i.e., hypocomplementaemia and elevated anti-ds-DNA antibody levels); however, his renal function deteriorated and serum creatinine levels were elevated to around 3.0 mg/dl with nephrotic-range proteinuria. On the 60th hospital day, gross haematuria, systemic petechia, melena, and epistaxis suddenly developed. He was afebrile, and physical examination was unremarkable except the bleeding tendency; however, laboratory data revealed marked thrombocytopenia (9,000/ l). Peripheral blood smear showed no morphological abnormalities. Coagulation screening results and serum transaminases were normal, but a haptoglobin level was undetectable. Bone marrow aspiration test showed a normal level and morphology of megakaryocytes, an active erythroid system, and no signs of haemophagocytosis. Abdominal computed tomography revealed no remarkable abnormalities. Platelet-associated IgG (157 ng/10 cells; reference range 5.0–25.0 ng/10 cells) was positive, but direct Coombs’ test, anti-granulocyte antibody, anti-cardiolipin-IgM/IgG antibodies, anti2 glycoprotein I antibody, cryoglobulin, and plasma activity of von Willebrand factorcleaving protease (69.5%) showed negative or normal results. Evaluation for bacterial infection, including blood and urine cultures, yielded negative results. Anti-parvovirus B 19 IgM antibody and Epstein–Barr (EB) virus plasma viremia were also negative, but peripheral blood CMV antigenaemia assay showed an equivocal result (5/34,000 peripheral blood leukocytes) [1]. Platelets transfusion for the marked bleeding symptoms was initiated. Intravenous methyl prednisolone (1.0 g per day, three consecutive days) followed by oral corticosteroid (prednisolone, 55 mg per T. Sugimoto (&) · M. Aoyama · N. Takeda · M. Sakaguchi · Y. Nishio · T. Uzu · A. Kashiwagi Department of Internal Medicine, Shiga University of Medical Science, Seta, Otsu, Shiga 520-2192, Japan e-mail: toshiro@belle.shiga-med.ac.jp

Microscopic polyangiitis, deWned as a necrotizing vasculitis aVecting small vessels (i.e., capillaries, venules, or arterioles), commonly manifests as rapidly progressive glomerulonephritis with necrotizing glomerular tuft, or alveolar hemorrhage or interstitial pneumonia with pulmonary capillaritis. Anti-neutrophil cytoplasmic antibodies (ANCA) are positive in 50–80% of patients with microscopic polyangiitis [1]. Here we describe a patient with myeloperoxidase (MPO)ANCA-related microscopic polyangiitis whose dominant manifestation was sensorineural hearing loss. A 77-year-old Japanese woman was admitted because of progression of renal dysfunction. At age 74 she had developed dyspnea on eVort, and a chest computed tomography (CT) scan revealed bilateral pulmonary Wbrosis in a local hospital. As no marked clinical and laboratory abnormalities (i.e., constitutional symptoms, renal dysfunction, urinary abnormalities, inXammatory signs, or auto-antibodies) had been identiWed, she was diagnosed as having idiopathic interstitial pneumonia and was closely observed without any medication. One month prior to the admission she had started to report constitutional manifestations (i.e., fever, general myalgia, and weight loss). Moreover, a marked increment of serum creatinine levels with active urinary abnormalities, from 0.66 to 1.03 mg/dl during the last 1 month, had been found. As a test for MPO-ANCA was positive (101 EU; normal value

To determine whether increased oxidative stress in diabetes mellitus is due to an impaired freeradical scavenger function in endothelial cells, GSH-dependent H2O2 degradation in human umbilical vein endothelial cells was studied. The GSH-dependent, NaN3-uninhibitable H2O2-degradation in endothelial cells was reduced by 48% (p