Hypoglycemia induces vascular endothelial dysfunction in subjects with normal glucose tolerance.

This prospective study determined the effects of hypoglycemic stimulation on vascular endothelial function in non-diabetic patients using reactive hyperemia peripheral arterial tonometry (RH-PAT). The study included non-diabetic patients who were hospitalized for an insulin tolerance test (ITT) for the diagnosis of hypoadrenocorticism or hypopituitarism. Vascular endothelial function was assessed using the reactive hyperemia index (RHI) measured by the RH-PAT. We also measured the levels of anterior pituitary hormone, adrenaline, noradrenaline, and dopamine at the time of hypoglycemia. The primary endpoint was a change in the RHI at 120 min after insulin administration. The study included 27 patients. ITT was associated with significant increases in systolic blood pressure, pulse rate, and the blood levels of adrenocorticotropic hormone, cortisol, growth hormone, adrenaline, noradrenaline, and dopamine. RHI significantly decreased after ITT from 2.24 ± 0.51 to 1.71 ± 0.42. A significant inverse correlation was observed between the change in RHI and change in adrenaline (r = - 0.670, p = 0.012). We concluded that hypoglycemic stimulation altered vascular endothelial function, as measured by RH-PAT, even in patients free of glucose intolerance. The observed deterioration in vascular endothelial function correlated with increases in catecholamine levels during hypoglycemia.Trial registration: UMIN000033244.

An enhanced mitochondrial function through glutamine metabolism in plasmablast differentiation in systemic lupus erythematosus.

OBJECTIVE: To evaluate the dysfunction of B-cell metabolism and its involvement in SLE pathology. METHODS: We assessed the expression of metabolic markers of B cells in the peripheral blood of healthy controls (HCs) and SLE patients by using flow cytometry. In vitro, peripheral B cells were isolated from HCs and SLE patients to investigate the metabolic regulation mechanisms involved in their differentiation. RESULTS: The expression level of DiOc6 (mitochondrial membrane hyperpolarization) was higher in B cells from SLE patients than in HCs, and correlated to the percentage of plasmablasts in CD19+ cells and with SLEDAI, a disease activity score. Stimulation of CD19+ cells with the Toll-like receptor 9 (TLR9) ligand CpG and IFN-α enhanced glycolysis, oxidative phosphorylation (OXPHOS), DiOc6 expression, and plasmablast differentiation in vitro. In the absence of glutamine, both glycolysis and OXPHOS were reduced, and plasmablast differentiation was suppressed, whereas there was no change in the absence of glucose. As glutamine is an important nutrient for protein synthesis, we further investigated the effect of the glutaminase inhibitor BPTES, which inhibits glutamine degradation, on metabolic regulation. BPTES reduced DiOc6 expression, OXPHOS, reactive oxygen species (ROS) production, adenosine triphosphate (ATP) production, plasmablast differentiation without affecting glycolysis. Metformin inhibited CpG- and IFN-α-induced glutamine uptake, mitochondrial functions and suppressed plasmablast differentiation. CONCLUSIONS: Mitochondrial dysfunction in B cells is associated with plasmablast differentiation and disease activity in SLE. Enhanced mitochondrial functions mediated by glutamine metabolism are important for plasmablast differentiation, which may be a potential therapeutic target for SLE.

Pathological role of activated mTOR in CXCR3+ memory B cells of rheumatoid arthritis.

OBJECTIVES: B cells play an important pathological role in RA. In this study, we investigated the role of metabolic regulator mTOR in B cells and its relevance to the pathology of RA. METHODS: Peripheral blood mononuclear cells were isolated from 31 normal subjects and 86 RA patients and the gated B cells were assessed for mTOR phosphorylation and chemokine receptor expression. In vitro studies on peripheral blood B cells isolated from the control and RA patients investigated the molecular mechanisms. RESULTS: Higher concentrations of CXCL10 (CXCR3 ligands) and lower percentages of CXCR3+ memory B cells were present in the peripheral blood of RA patients relative to the control. RA patients with high CXCL10 concentrations had smaller percentage of CXCR3+ memory B cells and high disease activity. One-year treatment with TNF inhibitors increased the percentage of CXCR3+ memory B cells and reduced serum CXCL10 concentrations. mTOR phosphorylation in B cells was further enhanced in RA patients, compared with the control, and was selectively enhanced in CXCR3+ memory B cells. mTOR phosphorylation in CXCR3+ memory B cells correlated with disease activity. In vitro, mTOR phosphorylation in B cells enhanced IL-6 production and increased RANKL expression. CONCLUSION: mTOR activation in CXCR3+ memory B cells of RA patients is associated with disease activity, mediated through IL-6 production and RANKL expression. The obtained results also suggest that TNF inhibitors mediate an impact on the association between CXCL10 and mTOR activated CXCR3+ memory B cells.

Effect of tofogliflozin on arterial stiffness in patients with type 2 diabetes: prespecified sub-analysis of the prospective, randomized, open-label, parallel-group comparative UTOPIA trial.

BACKGROUND: Tofogliflozin, an SGLT2 inhibitor, is associated with favorable metabolic effects, including improved glycemic control and serum lipid profile and decreased body weight, visceral adipose tissue, and blood pressure (BP). This study evaluated the effects of tofogliflozin on the brachial-ankle pulse wave velocity (baPWV) in patients with type 2 diabetes (T2DM) without a history of apparent cardiovascular disease. METHODS: The using tofogliflozin for possible better intervention against atherosclerosis for type 2 diabetes patients (UTOPIA) trial is a prospective, randomized, open-label, multicenter, parallel-group, comparative study. As one of the prespecified secondary outcomes, changes in baPWV over 104 weeks were evaluated in 154 individuals (80 in the tofogliflozin group and 74 in the conventional treatment group) who completed baPWV measurement at baseline. RESULTS: In a mixed-effects model, the progression in the right, left, and mean baPWV over 104 weeks was significantly attenuated with tofogliflozin compared to that with conventional treatment (- 109.3 [- 184.3, - 34.3] (mean change [95% CI] cm/s, p = 0.005; - 98.3 [- 172.6, - 24.1] cm/s, p = 0.010; - 104.7 [- 177.0, - 32.4] cm/s, p = 0.005, respectively). Similar findings were obtained even after adjusting the mixed-effects models for traditional cardiovascular risk factors, including body mass index (BMI), glycated hemoglobin (HbA1c), total cholesterol, high-density lipoprotein (HDL)-cholesterol, triglyceride, systolic blood pressure (SBP), hypertension, smoking, and/or administration of drugs, including hypoglycemic agents, antihypertensive agents, statins, and anti-platelets, at baseline. The findings of the analysis of covariance (ANCOVA) models, which included the treatment group, baseline baPWV, and traditional cardiovascular risk factors, resembled those generated by the mixed-effects models. CONCLUSIONS: Tofogliflozin significantly inhibited the increased baPWV in patients with T2DM without a history of apparent cardiovascular disease, suggesting that tofogliflozin suppressed the progression of arterial stiffness. Trial Registration UMIN000017607. Registered 18 May 2015. ( https://www.umin.ac.jp/icdr/index.html ).

Hyperparathyroidism Which Developed after Resection of a Fibroblast Growth Factor 23-producing Tumor.

A 53-year-old woman presented with bone pain and was diagnosed with osteomalacia because of hypophosphatemia, hyperphosphatasemia, bone pain, and radiographic findings. Because her intact-fibroblast growth factor 23 (FGF23) levels were high and contrast-enhanced computed tomography revealed a mass in the anterior ethmoid sinus, FGF23-related osteomalacia was diagnosed. The tumor was resected, but she developed hypercalcemia and elevated blood parathyroid hormone (PTH) levels. Primary hyperparathyroidism (PHPT) was diagnosed, and surgical resection was performed. To our knowledge, this is the first case of a FGF23-producing tumor complicated by PHPT. Because PHPT manifested after resecting the FGF23-producing tumor, FGF23 is thus considered to suppress PTH secretion in humans.

Rationale and design of an investigator-initiated, multicenter, prospective open-label, randomized trial to evaluate the effect of ipragliflozin on endothelial dysfunction in type 2 diabetes and chronic kidney disease: the PROCEED trial.

BACKGROUND: Type 2 diabetes (T2D) is associated with renal impairment and vascular endothelial dysfunction. Therefore, this pathological connection is an important therapeutic target. Recent cardiovascular and renal outcome trials demonstrated that sodium glucose cotransporter 2 inhibitors (SGLT2is) consistently reduced the risks of cardiovascular and renal events and mortality in patients with T2D and various other background risks including chronic kidney disease (CKD). However, the precise mechanisms by which SGLT2is accords these therapeutic benefits remain uncertain. It is also unknown whether these SGLT2is-associated benefits are associated with the amelioration of endothelial dysfunction in patients with T2D and CKD. METHODS: The PROCEED trial is an investigator-initiated, prospective, multicenter, open-label, randomized-controlled trial. The target sample size is 110 subjects. After they furnish informed consent and their endothelial dysfunction is confirmed from their decreased reactive hyperemia indices (RHI), eligible participants with T2D (HbA1c, 6.0-9.0%) and established CKD (30 mL/min/1.73 m2 ≤ estimated glomerular filtration ratio [eGFR] < 60 and/or ≥ urine albumin-to-creatinine ratio 30 mg/g Cr) will be randomized (1:1) to receive either 50 mg ipragliflozin daily or continuation of background treatment (non-SGLT2i). The primary endpoint is the change in RHI from baseline after 24 weeks. To compare the treatment effects between groups, the baseline-adjusted means and their 95% confidence intervals will be estimated by analysis of covariance adjusted for HbA1c (< 7.0% or ≥ 7.0%), age (< 70 y or ≥ 70 y), RHI (< 1.67 or ≥ 1.67), eGFR (< 45 mL/min/1.73 m2 or ≥ 45 mL/min/1.73 m2), and smoking status. Prespecified responder analyses will be also conducted to determine the proportions of patients with clinically meaningful changes in RHI at 24 weeks. DISCUSSION: PROCEED is the first trial to examine the effects of ipragliflozin on endothelial dysfunction in patients with T2D and CKD. This ongoing trial will establish whether endothelial dysfunction is a therapeutic target of SGLT2is in this population. It will also provide deep insights into the potential mechanisms by which SGLT2is reduced the risks of cardiovascular and renal events in recent outcome trials. Trial registration Unique Trial Number, jRCTs071190054 (https://jrct.niph.go.jp/en-latest-detail/jRCTs071190054).

Response of thyrotropin-secreting pituitary tumors to preoperative lanreotide therapy. Report of two cases.

Case 1 was a 51-year-old man diagnosed with thyrotropin (TSH)-secreting pituitary tumor. The octreotide loading test showed suppression of TSH secretion. Treatment with lanreotide preoperatively at 90 mg/month resulted in normalization of thyroid function. Three months after treatment initiation, tumor shrinkage was observed, and pituitary tumor resection was performed through transsphenoidal surgery. Case 2 was a 47-year-old woman in whom the octreotide loading test showed suppressed TSH secretion. Treatment with lanreotide preoperatively at 90 mg/month resulted in normalization of thyroid function. After six months of treatment, tumor reduction was observed, and transsphenoidal surgery was performed. In both cases, lanreotide administration before TSH-secreting pituitary tumor resection achieved normalization of thyroid function and tumor shrinkage. Treatment with lanreotide seems effective in patients who show TSH secretion suppression in the octreotide loading test.

Usefulness of the index calculated as the product of levels of fasting plasma glucose and hemoglobin A1c for insulinoma screening.

Hypoglycemia is the major symptom of insulinoma. Chronic and recurrent hypoglycemia leads to the disappearance of autonomic symptoms and persistence of non-specific symptoms alone, possibly contributing to the delayed diagnosis of insulinoma and accounting for several undiagnosed cases. We previously reported the usefulness of hemoglobin A1c (HbA1c) and glycated albumin as markers for early insulinoma screening; however, their diagnostic prediction performance and diagnostic performance were not satisfactory. We hypothesized that the product of fasting plasma glucose (FPG) and HbA1c levels (FPG × HbA1c index) is low in insulinoma, and this index may be a useful marker for screening. This cross-sectional multicenter study compared 82 insulinoma patients with 100 age-, sex-, and body mass index-matched controls with normal glucose tolerance based on 75-g oral glucose tolerance test. The FPG × HbA1c index was significantly lower in the insulinoma group than in the control group. Receiver operating curve analysis showed that the optimal cutoff point of the FPG × HbA1c index to diagnose insulinoma was 447.1, and the area under the curves (AUCs) of the FPG × HbA1c index and HbA1c were 0.998 and 0.966, respectively. The AUC of the index was significantly higher than that of HbA1c (p = 0.010). Conversely, no significant difference existed between the AUC of the FPG × HbA1c index and that of the FPG/fasting immunoreactive insulin index. Thus, in apparently healthy population, the product of FPG and HbA1c yields a useful index for insulinoma screening in terms of accuracy and versatility.

A Case of Marine-Lenhart Syndrome with Predominance of Plummer Disease.

A 74-year-old woman with a left neck mass and thyrotoxicosis was referred to our hospital, and was later diagnosed with Marine-Lenhart syndrome based on positivity for thyroid autoantibodies, ultrasonographically evident left lobe thyroid nodule with increased blood flow, and scintigraphically identified not only increased tumor-like accumulation but also diffused uptake. Disease control was difficult despite administration of antithyroid drugs, so subtotal thyroidectomy was performed. No hyperplastic changes or histopathological findings characteristic of Graves disease were evident on histopathology, so Plummer disease was considered to be dominant. In case of hot in low type which showed higher uptake in the nodule and lower uptake in the extranodular part on scintigraphy, there is a possibility of relapse in drug treatment.

Usefulness of hemoglobin A1c and glycated albumin measurements for insulinoma screening: an observational case-control study.

BACKGROUND: Insulinoma represents hypoglycemia as a predominant symptom; the autonomic symptoms may be resolved by chronically recurrent hypoglycemia resulting in the persistence of non-specific symptoms alone. Therefore, it has been estimated that there are many patients in whom the disease takes longer to diagnose and has remained undiagnosed. Although some parameters exist for the definitive diagnosis of the disease, there are currently no indices for early screening. Indices of glycemic control, hemoglobin A1c (HbA1c), and glycated albumin (GA) may be useful for the screening of patients with insulinoma having chronic hypoglycemia because the values become low in such a condition. Because there are no articles that have reported the point, we examine the effective cutoff values of HbA1c and GA for the diagnosis of insulinoma in the present study. METHODS: In a multicenter cross-sectional study, 31 patients with insulinoma were included for comparison with 120 control subjects with normal glucose tolerance based on 75 g oral glucose tolerance tests whose characteristics were matched to the patients. The primary outcomes were optimal cutoff values of HbA1c and GA for the screening of insulinoma. RESULTS: HbA1c was significantly lower in the insulinoma group at 4.7 ± 0.4% compared to the healthy control group at 5.7 ± 0.3% (p < 0.001), and GA was significantly lower in the insulinoma group at 11.6 ± 1.8% compared to the healthy control group at 14.5 ± 1.0% (p < 0.001). According to a receiver operating characteristic (ROC) analysis, optimal cutoff values of HbA1c and GA for the diagnosis of insulinoma were 5.0 and 12.4%, respectively. Area under the curve values of HbA1c and GA were 0.970 and 0.929, respectively, showing no significant difference (p = 0.399). CONCLUSIONS: In the present study, HbA1c and GA values in patients with insulinoma were significantly lower compared to the healthy controls, and effective cutoff values for screening were shown in the diagnosis of insulinoma for the first time. HbA1c and GA can be useful indices for insulinoma screening. Because malignant insulinoma have a similar diagnostic process to that of benign insulinoma, these could be useful for malignant insulinoma.

Prednisolone Dosing Regimen for Treatment of Subacute Thyroiditis.

The rate of recurrence of subacute thyroiditis (SAT) during prednisolone (PSL) therapy is approximately 10 to 20%. However, there is little or no information on the time period to relapse following administration of a tapered dose of PSL and the factors associated with such relapse. The aim of this study was to determine the correlation between SAT recurrence and PSL tapering regimen used in the treatment of SAT. This study was a medical record-based retrospective study and involved 26 patients (3 men, 23 women) who received PSL therapy for SAT. The primary endpoint was the association between recurrence and number of days required to taper daily PSL dose to 5 mg. The secondary endpoint was the relationship between recurrence and several variables including age, clinical score, free thyroxine, inflammatory reaction, thyroglobulin, total treatment time, total dose of PSL and presence or absence of creeping thyroiditis. The SAT recurrence rate was 15.3%. There was no significant difference in the initial PSL dose between the non-recurrence and recurrence groups (27.5 mg vs 24.5 mg, P = 0.302). However, for the primary endpoint, significant differences were found between the two groups in time required for tapering PSL to 5 mg/day (non-recurrence: 44.3 ± 15.3 days, recurrence: 19.0 ± 11.9 days, P = 0.012). None of the clinical variables evaluated correlated significantly with SAT relapse. In conclusion, to prevent recurrence of SAT, consideration should be given to the period required for PSL tapering to 5 mg/day.

Effects of exenatide on postprandial vascular endothelial dysfunction in type 2 diabetes mellitus.

BACKGROUND: Basic studies have shown that glucagon-like peptide-1 (GLP-1) analogs exert a direct protective effect on the vascular endothelium in addition to their indirect effects on postprandial glucose and lipid metabolism. GLP-1 analogs are also reported to inhibit postprandial vascular endothelial dysfunction. This study examined whether the GLP-1 analog exenatide inhibits postprandial vascular endothelial dysfunction in patients with type 2 diabetes mellitus (T2DM). METHODS: Seventeen patients with T2DM underwent a meal tolerance test to examine changes in postprandial vascular endothelial function and in glucose and lipid metabolism, both without exenatide (baseline) and after a single subcutaneous injection of 10 µg exenatide. Vascular endothelial function was determined using reactive hyperemia index (RHI) measured by peripheral arterial tonometry before and 120 min after the meal loading test. The primary endpoint was the difference in changes in postprandial vascular endothelial function between the baseline and exenatide tests. RESULTS: The natural logarithmically-scaled RHI (L_RHI) was significantly lower after the baseline meal test but not in the exenatide test. The use of exenatide resulted in a significant decrease in triglycerides (TG) area under the curve and coefficient of variation (CV). The change in L_RHI correlated with changes in CV of triglycerides and HDL-cholesterol. Multivariate analysis identified changes in triglyceride CV as the only determinant of changes in L_RHI, contributing to 41% of the observed change. CONCLUSIONS: Exenatide inhibited postprandial vascular endothelial dysfunction after the meal loading test, suggesting that exenatide has a multiphasic anti-atherogenic action involving not only glucose but also lipid metabolism. TRIAL REGISTRATION: ClinicalTrials.gov: UMIN000015699.

Iatrogenic osteomalacia: report of two cases.

UNLABELLED: CASE 1: An 80-year-old man presented at our hospital with pain in both knees.He had received continuous intravenous administration of saccharated ferric oxide (SFO) over a period of five years following a diagnosis of iron-deficiency anemia.Blood tests revealed hypophosphatemia (1.4 mg/dl) and high circulating levels of fibroblast growth factor 23 (FGF23) at 248.8 mg/dl.These findings led to the diagnosis of FGF23-related osteomalacia due to SFO administration.Accordingly, the treatment plan was first to discontinue SFO, which led to a decrease in pain and normalization of phosphorus and FGF23 after 1 month.CASE 2: A 63-year-old woman presented at our hospital with leg pain.She had undergone total gastrectomy for gastric cancer at 36 years of age.Blood tests revealed hypocalcemia (8.3 mg/dl) and hypophosphatemia (2.2 mg/dl), and 25(OH)D at no more than 5 pg/ml.Bone X-rays showed significantly diminished bone shadowing.These findings led to a diagnosis of vitamin D-deficient osteomalacia due to impaired absorption following total gastrectomy.For therapy, she was treated with 1 µg/day oral alfacalcidol.Two months after initiating treatment, the pain improved. CONCLUSION: When a patient is diagnosed with unexplained pain, it is important to pay attention to the possibility of an iatrogenic etiology.

A case of zoledronate-induced tubulointerstitial nephritis with Fanconi syndrome.

A 54-year-old female underwent mastectomy in 1992 for breast cancer, but later developed liver metastasis in 2004, which was treated with docetaxel for a short period, and then discontinued due to nausea. Bone metastasis diagnosed in 2005 was treated with the combination of trastuzumab and zoledronate (4 mg/month) as well as radiotherapy. Progressive hypokalemia and renal dysfunction were observed since 2006 and the patient was admitted to our department in 2009 for further management of hypokalemia (serum potassium 2.2 mEq/L) and renal dysfunction (serum creatinine: 2.0 mg/dL). Accelerated potassium excretion and metabolic acidosis of the normal anion gap were observed and the patient was diagnosed with hypokalemia associated with renal tubular acidosis. Moreover, development of glucosuria, hypophosphatemia, hyperphosphaturia, hyponatremia, hypouricemia, and high ß2-microglobulin/NAG, together with histopathological findings compatible with renal tubular injury/interstitial nephritis on renal biopsy, allowed the diagnosis of Fanconi syndrome. Because the syndrome was considered to be induced by zoledronate based on the onset and clinical course, we stopped zoledronate. However, she continued the ambulatory chemotherapy with trastuzumab. This resulted in immediate and sustained improvement in renal function. To our knowledge, this is the first report of zoledronate-induced interstitial nephritis-Fanconi syndrome and indicates the close monitoring of renal function to avoid potential nephrotoxicity of zoledronate.