Clinical significance of amphiregulin in patients with chronic kidney disease.

BACKGROUND: Amphiregulin (AREG) is a ligand of epidermal growth factor receptor (EGFR), which plays an important role in injury-induced kidney fibrosis. However, the clinical significance of serum soluble AREG in chronic kidney disease (CKD) is unclear. In this study, we elucidated the clinical significance of serum soluble AREG in CKD by analyzing the association of serum soluble AREG levels with renal function and other clinical parameters in patients with CKD. METHODS: In total, 418 Japanese patients with CKD were enrolled, and serum samples were collected for the determination of soluble AREG and creatinine (Cr) levels, and other clinical parameters. Additionally, these parameters were evaluated after 2 and 3 years. Moreover, immunohistochemical assay was performed ate AREG expression in the kidney tissues of patients with CKD. RESULTS: Soluble AREG levels were positively correlated with serum Cr (p < 0.0001). Notably, initial AREG levels were positively correlated with changes in renal function (ΔCr) after 2 (p < 0.0001) and 3 years (P = 0.048). Additionally, soluble AREG levels were significantly higher (p < 0.05) in patients with diabetic nephropathy or primary hypertension. Moreover, AREG was highly expressed in renal tubular cells in patients with advanced CKD, but only weakly expressed in patients with preserved renal function. CONCLUSION: Serum soluble AREG levels were significantly correlated with renal function, and changes in renal function after 2 and 3 years, indicating that serum soluble AREG levels might serve as a biomarker of renal function and renal prognosis in CKD.

What is the optimal range of glycemic control for non-diabetic patients undergoing gastroenterological surgery? A single-center randomized controlled trial using an artificial pancreas.

BACKGROUND: This study aimed to determine the optimal target range of perioperative glycemic control for gastroenterological surgery. A closed-loop-type artificial pancreas (AP) was used to diminish the negative impact of hypoglycemia and glycemic variability during tight glycemic control. METHODS: In this single-center randomized trial, non-diabetic patients were assigned to tight (80-110 mg/dL) or moderate glycemic control (110-140 mg/dL) groups between August 2017 and May 2021. AP was used from the intraoperative period until discharge from the intensive care unit. The primary endpoint was the serum interleukin (IL)-6 level on the third postoperative day (3POD), and the secondary endpoints included clinical outcomes. RESULTS: Recruitment was closed before reaching the planned number of patients due to slow enrollment. Tight glycemic control (n = 62) resulted in lower mean glucose levels than moderate glycemic control (n = 66) (121.3 ± 10.8 mg/dL vs. 133.5 ± 12.0 mg/dL, p < 0.001). Insulin was administered at a 65% higher rate for tight glycemic control, achieving appropriate glucose control more than 70% of the treatment time. No hypoglycemia occurred during the AP treatment. No significant difference was observed in serum IL-6 levels on 3POD (23.4 ± 31.1 vs. 32.1 ± 131.0 pg/mL, p = 0.64), morbidity rate, surgical mortality rate, or length of hospital stay between the two groups. CONCLUSIONS: Clinically relevant short-term results did not differ, implying that 80-110 and 110-140 mg/dL are permissible glycemic control ranges when using AP in non-diabetic patients undergoing gastroenterological surgery. (Registered in UMIN; UMIN000028036).

Role of Reactive Oxygen Species in Glucose Metabolism Disorder in Diabetic Pancreatic ß-Cells.

The dysfunction of pancreatic ß-cells plays a central role in the onset and progression of type 2 diabetes mellitus (T2DM). Insulin secretory defects in ß-cells are characterized by a selective impairment of glucose stimulation, and a reduction in glucose-induced ATP production, which is essential for insulin secretion. High glucose metabolism for insulin secretion generates reactive oxygen species (ROS) in mitochondria. In addition, the expression of antioxidant enzymes is very low in ß-cells. Therefore, ß-cells are easily exposed to oxidative stress. In islet studies using a nonobese T2DM animal model that exhibits selective impairment of glucose-induced insulin secretion (GSIS), quenching ROS generated by glucose stimulation and accumulated under glucose toxicity can improve impaired GSIS. Acute ROS generation and toxicity cause glucose metabolism disorders through different molecular mechanisms. Nuclear factor erythroid 2-related factor 2 (Nrf2), a transcription factor, is a master regulator of antioxidant defense and a potential therapeutic target in oxidative stress-related diseases, suggesting the possible involvement of Nrf2 in ß-cell dysfunction caused by ROS. In this review, we describe the mechanisms of insulin secretory defects induced by oxidative stress in diabetic ß-cells.

Adult-onset Langerhans cell histiocytosis changing CNS lesion from pituitary to suprasellar extension.

Summary: Langerhans cell histiocytosis (LCH) is a rare disease characterized by the proliferation of abnormal Langerhans cells in various tissues and organs, including bone, skin, the lungs, and the pituitary gland. Hypothalamic-pituitary lesions in LCH often cause central diabetes insipidus (CDI), but the natural course of LCH in the CNS remains to be elucidated. In this study, we report an interesting case of altered LCH lesions in the CNS from the pituitary to the hypothalamus in a 45-year-old woman. She developed symptoms of polyuria and was diagnosed with CDI with lymphocytic hypophysitis due to an enlarged pituitary gland with stalk thickening shown on MRI. Short-term glucocorticoid therapy cured pituitary enlargement, but serum prolactin levels gradually increased. Six years later, the immunohistological findings of a skin biopsy revealed positive for leukocyte common antigen, S-100, and CD1a expression, indicating a diagnosis of LCH. MRI revealed a new lesion in the hypothalamus without pituitary involvement, likely due to LCH. Chemotherapy improved LCH lesions both in the skin and hypothalamus, but therapy was stopped on the patient's request. Although adult-onset LCH is rare, it should be considered as a differential diagnosis in cases of CDI as the primary disease. The clinical course in the present case indicated that LCH lesion was altered from pituitary to suprasellar extension; where such changes were observed, the possibility of LCH should be considered. Learning points: Diagnosing the primary disease of CDI is challenging; therefore, careful observation is necessary in pathologically unknown cases. Enhanced MRI should be performed in cases with suspected hypothalamic lesions, such as elevated serum prolactin. Although adult-onset LCH is rare, it should be considered a differential diagnosis in cases of CDI as the primary disease. The direction of changing CNS lesion from pituitary to suprasellar extension might be a unique MRI finding in LCH.

Knockout of Zeb2 ameliorates progression of renal tubulointerstitial fibrosis in a mouse model of renal ischemia-reperfusion injury.

BACKGROUND: Zeb2, a zinc finger E-box-binding homeobox transcription factor, regulates transforming growth factor (TGF)-ß signaling pathway. However, its role in the pathogenesis of acute kidney injury (AKI) and AKI-to-chronic kidney disease (CKD) transition is unclear. METHODS: We evaluated Zeb2 function in a bilateral renal ischemia-reperfusion injury (IRI)-induced AKI model using proximal tubule-specific Zeb2 conditional knockout (Zeb2-cKO) and wild-type (WT) mice, and in renal biopsy samples. RESULTS: In Zeb2-cKO mice, the levels of plasma creatinine and blood urea nitrogen post-IRI were significantly lower than that in WT mice. Immunohistological analysis revealed mild tubular injury, reduced neutrophil infiltration, fewer fibrotic changes and reduced expression of fibrotic proteins [collagen type IV, α-smooth muscle actin (α-SMA), fibronectin and connective tissue growth factor (CTGF)], at 3-14 days post-IRI. Zeb2 expression was upregulated in proximal tubular cells post-IRI in WT mice. Zeb2 siRNA transfection reduced TGF-ß-stimulated mRNA and protein expression of collagen type IV, α-SMA, fibronectin and CTGF in cultured renal tubular cells. Patients with AKI-to-CKD transition exhibited high Zeb2 expression in renal tubules, as revealed by renal biopsy. Hypoxia and CoCl2-treatment upregulated Zeb2 promoter activity and mRNA and protein expression in cultured renal tubular epithelial cells, suggesting a regulatory role for hypoxia. CONCLUSIONS: Zeb2 was upregulated in renal tissues in both mice and humans with AKI. Zeb2 regulates fibrotic pathways in the pathogenesis of AKI and AKI-to-CKD transition. Therefore, inhibition of Zeb2 could be a potential therapeutic strategy for AKI.

Unilateral adrenalectomy partially improved hyperglycemia in a patient with primary bilateral macronodular adrenal hyperplasia.

Primary bilateral macronodular adrenal hyperplasia (PBMAH) is characterized by bilateral multiple adrenal macro-nodules that often cause mild over-secretion of cortisol in the form of subclinical Cushing's syndrome. We herein describe a case, wherein unilateral adrenalectomy partially improved hyperglycemia in a patient with PBMAH and suggest the usefulness and limitations of this surgical strategy. A 64-year-old woman with type 2 diabetes had an incidental diagnosis of bilateral adrenal lesions. She had a family history of type 2 diabetes, and her HbA1c level was 8.9% under insulin therapy. She did not present with any symptoms associated with Cushing's syndrome. The basal cortisol level was in the normal range (12.0 µg/dL); however, the adrenocorticotropic hormone (ACTH) level was suppressed (2.1 pg/mL) and the serum cortisol level was not suppressed in the dexamethasone test. Computed tomography and magnetic resonance imaging showed bilateral adrenal macro-nodules and 131I-adosterol accumulated in the bilateral adrenal lesions. Collectively, she was diagnosed with subclinical Cushing's syndrome due to PBMAH complicated with diabetes mellitus, hypertension, and dyslipidemia. Laparoscopic left adrenalectomy was performed, and the pathologic findings were consistent with PBMAH. After unilateral adrenalectomy, serum cortisol levels decreased, and hypertension improved. Both HbA1c levels and insulin requirement also decreased, but insulin therapy was continuously needed. It should be noted that hyperglycemia may not be cured after successful surgery in a patient with PBMAH. Additional operation or medical therapy should be considered if unilateral adrenalectomy is unable to correct hypercortisolism in PBMAH patients.

Long-term safety and efficacy of alogliptin, a DPP-4 inhibitor, in patients with type 2 diabetes: a 3-year prospective, controlled, observational study (J-BRAND Registry).

INTRODUCTION: Given an increasing use of dipeptidyl peptidase-4 (DPP-4) inhibitors to treat patients with type 2 diabetes mellitus in the real-world setting, we conducted a prospective observational study (Japan-based Clinical Research Network for Diabetes Registry: J-BRAND Registry) to elucidate the safety and efficacy profile of long-term usage of alogliptin. RESEARCH DESIGN AND METHODS: We registered 5969 patients from April 2012 through September 2014, who started receiving alogliptin (group A) or other classes of oral hypoglycemic agents (OHAs; group B), and were followed for 3 years at 239 sites nationwide. Safety was the primary outcome. Symptomatic hypoglycemia, pancreatitis, skin disorders of non-extrinsic origin, severe infections, and cancer were collected as major adverse events (AEs). Efficacy assessment was the secondary outcome and included changes in hemoglobin A1c (HbA1c), fasting blood glucose, fasting insulin and urinary albumin. RESULTS: Of the registered, 5150 (group A: 3395 and group B: 1755) and 5096 (3358 and 1738) were included for safety and efficacy analysis, respectively. Group A patients mostly (>90%) continued to use alogliptin. In group B, biguanides were the primary agents, while DPP-4 inhibitors were added in up to ~36% of patients. The overall incidence of AEs was similar between the two groups (42.7% vs 42.2%). Kaplan-Meier analysis revealed the incidence of cancer was significantly higher in group A than in group B (7.4% vs 4.8%, p=0.040), while no significant incidence difference was observed in the individual cancer. Multivariate Cox regression analysis revealed that the imbalanced patient distribution (more elderly patients in group A than in group B), but not alogliptin usage per se, contributed to cancer development. The incidence of other major AE categories was with no between-group difference. Between-group difference was not detected, either, in the incidence of microvascular and macrovascular complications. HbA1c and fasting glucose decreased significantly at the 0.5-year visit and nearly plateaued thereafter in both groups. CONCLUSIONS: Alogliptin as a representative of DPP-4 inhibitors was safe and durably efficacious when used alone or with other OHAs for patients with type 2 diabetes in the real world setting.

Novel mechanism of impaired metabolism-secretion coupling in ß-cells: Loss of cytosolic adenosine triphosphate by leakage.

Zhang et al. recently proposed a new mechanism of metabolism-secretion coupling impairment in diabetic ß-cells involving the loss of cytosolic adenosine triphosphate by leakage through plasma membrane. Hyperglycemia increases mistargeting expression of the adenosine triphosphate-conducting mitochondrial outer membrane voltage-dependent anion channel-1 on the plasma membrane leading to adenosine triphosphate depletion. The interaction between reactive oxygen species overproduction and voltage-dependent anion channel-1 induction is an interesting issue to be resolved.

Dietary habits associated with reduced insulin resistance: The Nagahama study.

AIMS: To investigate the association between insulin resistance assessed by a homeostasis model and dietary habits. METHODS: Cross-sectional analysis using a community-based cohort, the Nagahama Prospective Cohort for Comprehensive Human Bioscience. Multiple linear regression analysis was performed with log HOMA-IR or log HOMA-ß as the dependent variable and 20 dietary habits, tobacco smoking, medical history, family medical history of diabetes, age and BMI as the simultaneous independent variables in each sex separately. RESULTS: Females (n = 2956) eating fish dishes every day had a HOMA-IR 0.90 times that of the reference group (P = 0.043). Females eating miso-soup every day had a HOMA-IR 0.95 times that of the reference group (P = 0.038). Males (n = 1371) eating vegetable dishes every day had a HOMA-IR 0.91 times that of the reference group (P = 0.003). Males eating egg dishes 4 to 5 times per week had a HOMA-IR 1.14 times that of the reference group (P = 0.011). Males eating fruits every day had a HOMA-IR 1.13 that of the reference group (P = 0.008). CONCLUSIONS: Dietary habits associated with lower insulin resistance were eating fish dishes, miso soup or vegetable dishes every day and eating staple foods for dinner, egg dishes or fruits less frequently.

Knockout of the interleukin-36 receptor protects against renal ischemia-reperfusion injury by reduction of proinflammatory cytokines.

IL-36, a newly named member of the IL-1 cytokine family, includes 3 isoforms, IL-36α, IL-36ß, and IL-36γ, all of which bind to a heterodimer containing the IL-36 receptor (IL-36R). Little is known about the role of the IL-36 axis in acute kidney injury (AKI) pathogenesis. Therefore, we evaluated IL-36 function in the bilateral renal ischemia-reperfusion injury model of AKI using IL-36R knockout and wild-type mice. IL-36R was found to be expressed in the kidney, mainly in proximal tubules. In IL-36R knockout mice, plasma creatinine, blood urea nitrogen, and IL-6 levels after ischemia-reperfusion injury were significantly lower than those in wild-type mice. Immunohistological analysis revealed mild tubular injury. IL-36α/ß/γ levels were increased after ischemia-reperfusion injury, and IL-36α was expressed in lymphocytes and proximal tubular cells, but post-ischemia-reperfusion injury mRNA levels of IL-6 and TNF-α were low in IL-36R knockout mice. In primary cultures of renal tubular epithelial cells, IL-36α treatment upregulated NF-κB activity and Erk phosphorylation. Notably, in patients with AKI, urine IL-36α levels were increased, and IL-36α staining in renal biopsy samples was enhanced. Thus, IL-36α/IL-36R blockage could serve as a potential therapeutic target in AKI.

Analysis of factors influencing glucose tolerance in Japanese patients with non-alcoholic fatty liver disease.

BACKGROUND: While the association of the prevalence of non-alcoholic fatty liver disease (NAFLD) with impaired glucose metabolism has been reported, the factors influencing glucose tolerance in NAFLD remain to be clarified. METHODS: Glucose tolerance of 131 Japanese patients diagnosed as NAFLD by histological findings of liver biopsy specimen was examined using 75 g-OGTT. According to Matteoni's classification, patients were divided to 4 groups [M1 ~ 4, M1, 2: non-alcoholic fatty liver (NAFL); and M3, 4: non-alcoholic steatohepatitis (NASH)]. Based on the OGTT data, insulinogenic index (IGI) and QUICKI were calculated as indices of insulin secretion and insulin sensitivity, respectively. Plasma glucose 120 min after glucose loading (G120) was used as the index for glucose intolerance. RESULTS: Stepwise multiple regression analysis using G120 as a dependent variable and loge-IGI, QUICKI, sex, BMI, age, NAFL/NASH as independent variables revealed that loge-IGI (ß = -0.595) and QUICKI (ß = -0.323) are significant factors predicting glucose intolerance (R2 = 0.403), indicating an important role of insulin secretion in glucose tolerance. These findings accord with glucose intolerance as high as 89.7% in patients with impaired insulin secretion defined by ≤43.2 pmol/mmol (40 µU/mg) IGI. Stepwise multiple regression analysis using QUICKI as a dependent variable and NAFL/NAFLD, sex, BMI, and age as independent variables revealed that BMI (ß = -0.469) and NAFL/NAFLD (ß = -0.204) are significant factors predicting insulin sensitivity (R2 = 0.248). CONCLUSION: Impairment of insulin secretion is the most important factor to predict glucose intolerance in NAFLD; severity of histological findings is associated with insulin sensitivity independent of adiposity in NAFLD.

Oral Administration of Apple Procyanidins Ameliorates Insulin Resistance via Suppression of Pro-Inflammatory Cytokine Expression in Liver of Diabetic ob/ob Mice.

Procyanidins, the main ingredient of apple polyphenols, are known to possess antioxidative and anti-inflammatory effects associated closely with the pathophysiology of insulin resistance and type 2 diabetes. We investigated the effects of orally administered apple procyanidins (APCs) on glucose metabolism using diabetic ob/ob mice. We found no difference in body weight or body composition between mice treated with APCs and untreated mice. A 4 week oral administration of APCs containing water [0.5% (w/v)] ameliorated glucose tolerance, insulin resistance, and hepatic gluconeogenesis in ob/ob mice. APCs also suppressed the increase in the level of the pancreatic ß-cell. Insulin-stimulated Akt phosphorylation was significantly enhanced; pro-inflammatory cytokine expression levels were significantly decreased, and c-Jun N-terminal kinase phosphorylation was downregulated in the liver of those mice treated with APCs. In conclusion, APCs ameliorate insulin resistance by improving hepatic insulin signaling through suppression of hepatic inflammation in ob/ob mice, which may be a mechanism with possible beneficial health effects of APCs in disturbed glucose metabolism.

Src regulates insulin secretion and glucose metabolism by influencing subcellular localization of glucokinase in pancreatic ß-cells.

AIMS/INTRODUCTION: Src, a non-receptor tyrosine kinase, regulates a wide range of cellular functions, and hyperactivity of Src is involved in impaired glucose metabolism in pancreatic ß-cells. However, the physiological role of Src in glucose metabolism in normal, unstressed ß-cells remains unclear. In the present study, we investigated the role of Src in insulin secretion and glucose metabolism. MATERIALS AND METHODS: Src was downregulated using small interfering ribonucleic acid in INS-1 cells, and glucose-induced insulin secretion, adenosine triphosphate content, intracellular calcium concentration, glucose utilization and glucokinase activity were measured. Expression levels of messenger ribonucleic acid and protein of glucokinase were examined by semiquantitative real-time polymerase chain reaction and immunoblotting, respectively. Cells were fractionated by digitonin treatment, and subcellular localization of glucokinase was examined by immunoblotting. Interaction between glucokinase and neuronal nitric oxide synthase was estimated by immunoprecipitation. RESULTS: In Src downregulated INS-1 cells, glucose-induced insulin secretion was impaired, whereas insulin secretion induced by high K(+) was not affected. Intracellular adenosine triphosphate content and elevation of intracellular calcium concentration by glucose stimulation were suppressed by Src downregulation. Src downregulation reduced glucose utilization in the presence of high glucose, which was accompanied by a reduction in glucokinase activity without affecting its expression. However, Src downregulation reduced glucokinase in soluble, cytoplasmic fraction, and increased it in pellet containing intaracellular organelles. In addition, interaction between glucokinase and neuronal nitric oxide synthase was facilitated by Src downregulation. CONCLUSIONS: Src plays an important role in glucose-induced insulin secretion in pancreatic ß-cells through maintaining subcellular localization and activity of glucokinase.

High-dose intravenous immunoglobulin therapy for rapidly progressive interstitial pneumonitis accompanied by anti-melanoma differentiation-associated gene 5 antibody-positive amyopathic dermatomyositis.

Anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive amyopathic dermatomyositis (ADM) associated with rapidly progressive interstitial pneumonitis (RPIP) frequently has a poor prognosis and optimal treatment is not well defined. Here, we report a 62-year-old Japanese man with anti-MDA5 antibody-positive ADM associated with RPIP presented with progressive shortness of breath, Heliotrope rash, Gottron's papules, arthralgia, and fatigue but no sign of muscle weakness. Laboratory investigation revealed serum levels of the following biomarkers: ferritin, 1393 ng/mL; Krebs von der Lungen-6, 1880 U/mL; and creatine kinase, 85 U/L. Computed tomography (CT) images showed diffuse ground-glass opacity in both lung fields. Because anti-MDA5 was positive, we made a diagnosis of ADM associated with RPIP and initiated treatment. Following five courses of combination therapy with prednisolone, cyclosporine A, and intravenous cyclophosphamide (IVCY), IVCY treatment was switched to high-dose intravenous immunoglobulin therapy (IVIg) because of the reactivation of interstitial pneumonia with an increased serum ferritin level. Additional treatment with IVIg improved RPIP, with normalization of anti-ADM antibody levels. Therefore, IVIg mayt be a new candidate treatment for anti-MDA5 antibody-positive ADM associated with RPIP.

IgG4-related tubulointerstitial nephritis accompanied with cystic formation.

BACKGROUND: An immunoglobulin G4 (IgG4)-related disease is important disease in differential diagnosis of tumors in kidney, pancreas, lung and other organs. The imaging findings of IgG4-related kidney diseases are usually expressed as defect contrast region, while cystic formation in kidney is extremely rare. Here, we report a case of IgG4-related tubulointerstitial nephritis with renal cystic change caused by the narrowing or obstruction of collecting duct in renal medulla. CASE PRESENTATION: Abdominal contrasted CT scan showed a 31 × 24 mm cystic tumor at the upper pole of the right kidney and multiple low-attenuation areas in the left kidney. 18 F-fluorodeoxyglucose (FDG)-PET/CT scan showed moderate FDG accumulation of cystic tumor in marginal lesion. In addition, FDG-PET/CT scan also showed moderate FDG accumulation in the pancreatic body. Laparoscopic right nephrectomy was performed. Histological examination was revealed lymphoplasmacytic infiltrate with focal fibrosis and severe narrowing or obstruction of lumen of collecting duct in renal medulla. Furthermore, the IgG4 positive plasma cells infiltrated exceeding 10 cells per one high-power field in renal medulla. The ratio of IgG4-plasma cells to IgG-positive plasma cells was about 50%. The serum level of IgG4 was also elevated (218 mg/dl). Based on these findings, we finally diagnosed IgG4-related tubulointerstitial nephritis with renal cystic change. CONCLUSION: IgG4-related kidney disease might cause cystic formation by severe narrowing and obstruction of collecting duct.

Spondylodiscitis and Achilles tendonitis due to gout.

The patient, a 62-year-old man with a 3-year history of hyperuricemia, presented with severe neck pain, Achilles enthesopathy and polyarthralgia. He consumed alcohol heavily. The biochemical profile was normal except for elevated levels of CRP (3.6 mg/dl; normal < 0.3), uric acid (UA) (10.9 mg/dl; normal 2.5-7.5) and creatinine (1.7 mg/dl; normal 0.5-1.0). Bone scintigraphy showed polyarthritis at the right elbow, wrist and bilateral first MTP joints. Notably, bone scintigraphy with computed tomography also revealed spondylodiscitis of C5-C6, which was confirmed by MRI, and left Achilles tendonitis. Moreover, left Achilles tendonitis was also confirmed by ultrasonography, indicating enthesitis with low-echoic lesion and calcification. Needle aspiration yielded a white viscous liquid, with numerous urate crystals identified on polarized light microscopy. He was diagnosed with gouty arthritis associated with spondylodiscitis and Achilles tendonitis. After the treatment with allopurinol, colchicine and predonisolone, his symptoms were improved, and serum CRP and UA levels were normalized. The cervical spine and Achilles tendon are rare and notable sites of involvements in gout, and differential diagnosis of gouty arthritis from spondyloarthritis, rheumatoid arthritis, tumor, pseudogout, and infection is necessary. When the patient was noted to have neck pain and Achilles enthesopathy, we should always recognize gouty arthritis.