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).

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.

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.

Effects of linagliptin versus voglibose on treatment-related quality of life in patients with type 2 diabetes: sub-analysis of the L-STEP study.

Treatment-related quality of life (QOL) is an important aspect of diabetes management. However, no studies have compared the influence of dipeptidyl peptidase-4 inhibitors versus alpha-glucosidase inhibitors on treatment-related QOL. This prespecified sub-analysis of the Linagliptin Study of Effects on Postprandial blood glucose (L-STEP) compared the effects of linagliptin (5 mg once daily) and voglibose (0.2 mg/meal thrice daily) on treatment-related QOL in Japanese patients with type 2 diabetes (T2DM) inadequately controlled with diet and exercise therapy. Among 366 subjects in the original study, 182 in the linagliptin group and 173 in the voglibose group were included in this analysis. The outcome of this study was change in QOL as assessed by the Diabetes Therapy-Related Quality of Life 17 (DTR-QOL17) questionnaire from baseline to week 12. Compared with baseline data, total DTR-QOL17 scores were significantly higher after 12 weeks of linagliptin and voglibose treatment. The change in the total DTR-QOL17 score and the score of one domain, burden on social activities and daily activities, was significantly greater in the linagliptin group than in the voglibose group. In addition, only linagliptin treatment was identified as a factor associated with an increased total DTR-QOL17 score. Linagliptin is superior to voglibose in terms of improving treatment-related QOL in Japanese patients with T2DM.

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.

Hypopituitarism due to CNS Aspergillus Infection.

A 59-year-old man was admitted to our hospital with hyponatremia. An endocrine examination indicated panhypopituitarism, and magnetic resonance imaging revealed a mass-like lesion in the pituitary gland. Sinus endoscopy revealed a fungal mass in the sphenoid sinus, and the patient was diagnosed with hypopituitarism due to aspergillosis of the central nervous system (CNS). The patient's hyponatremia resolved with hydrocortisone replacement. Although the right internal carotid artery was eventually occluded, antifungal medications were administered for the aspergillosis, and the patient's general condition improved. The patient's CNS lesions have remained under control since discharge. This is the first case to suggest that ACTH secretion may be relatively preserved in Aspergillus-induced hypopituitarism.

Sestrin-2 and BNIP3 regulate autophagy and mitophagy in renal tubular cells in acute kidney injury.

Autophagy is a cellular recycling process induced in response to many types of stress. However, little is known of the signaling pathways that regulate autophagy during acute kidney injury (AKI). Bcl-2/adenovirus E1B 19 kDa-interacting protein (BNIP)3 and sestrin-2 are the target proteins of hypoxia-inducible factor (HIF)-1α and p53, respectively. The aim of this study was to investigate the roles of BNIP3 and sestrin-2 in oxidative stress-induced autophagy during AKI. We used rat ischemia-reperfusion injury and cultured renal tubular (NRK-52E) cells as in vivo and in vitro models of AKI, respectively. Renal ischemia-reperfusion injury upregulated the expression of BNIP3 and sestrin-2 in the proximal tubules, as measured by immunohistochemical staining and Western blot analysis. In vitro, NRK-52E cells exposed to hypoxia showed increased expression of BNIP3 mRNA and protein in a HIF-1α-dependent manner. In contrast, sestrin-2 mRNA and protein expression were upregulated in a p53-dependent manner after exposure to oxidative stress (exogenous H2O2). NRK-52E cells stably transfected with a fusion protein between green fluorescent protein and light chain 3 were used to investigate autophagy. Overexpression of BNIP3 or sestrin-2 in these cells induced light chain 3 expression and formation of autophagosomes. Interestingly, BNIP3-induced autophagosomes were mainly localized to the mitochondria, suggesting that this protein selectively induces mitophagy. These observations demonstrate that autophagy is induced in renal tubules by at least two independent pathways involving p53-sestrin-2 and HIF-1α-BNIP3, which may be activated by different types of stress to protect the renal tubules during AKI.

Self-monitoring of blood glucose (SMBG) improves glycaemic control in oral hypoglycaemic agent (OHA)-treated type 2 diabetes (SMBG-OHA study).

BACKGROUND: We conducted a clinical research study to determine the effect of self-monitoring of blood glucose (SMBG) on glycaemic control and the value of a putatively less painful blood sampling technique on SMBG in oral hypoglycaemic agent-treated type 2 diabetes patients; SMBG has not been broadly applied in non-insulin-treated patients in Japan. METHODS: One hundred thirty-seven subjects were recruited for the 24-week, prospective, comparison study and randomized into three groups: 46, no SMBG group; 46, fingertip group; and 45, palm group. The primary endpoint was change in HbA(1c). The secondary endpoints were SMBG compliance, dropout rate, treatment changes, and patient's and physician's satisfaction. RESULTS: Six subjects in the fingertip group (13.2%) and one subject in the palm group (2.2%) were dropped because of pain. A(1C) level of all subjects at 24-week was decreased more in the fingertip (-0.23%) and palm (-0.16%) groups than that in the no SMBG group (+0.31%) (p < 0.05). SMBG compliance was higher in the fingertip group (2.17 times/day) than that in the palm group (1.65 times/day) (p < 0.05). A(1C) level of treatment-unchanged subjects was decreased more in the fingertip (-0.25%) and palm (-0.21%) groups than that in the no SMBG group (+0.30%) (p < 0.05). SMBG compliance was higher in the fingertip group (2.24 times/day) than that in the palm group (1.65 times/day) (p < 0.05). Patient's questionnaire showed that 84.1% of the fingertip group and 90.2% of the palm group were satisfied with SMBG. Physician's satisfaction was higher in the palm group (94.0%) than that in the fingertip group (80.0%) (p < 0.05). CONCLUSION: SMBG is beneficial for glycaemic control, and palm blood sampling is a useful procedure for oral hypoglycaemic agent-treated type 2 diabetes.

Serum level of soluble (pro)renin receptor is modulated in chronic kidney disease.

BACKGROUND: Prorenin, the precursor of renin, binds to the (pro)renin receptor [(P)RR] and triggers intracellular signaling. The ligand binding sites of (P)RR are disconnected and are present in the soluble form of the receptor in serum. Given that the clinical significance of serum prorenin and soluble (P)RR in chronic kidney disease (CKD) is unclear, we investigated the relationship between serum prorenin, soluble (P)RR, and various clinical parameters in patients with CKD. METHODS: A total of 374 patients with CKD were enrolled. Serum samples were collected, and the levels of soluble (P)RR and prorenin were measured using ELISA kits. Serum creatinine (Cr), blood urea nitrogen (BUN), uric acid (UA), hemoglobin (Hb), soluble secreted α-Klotho, and the urine protein/Cr ratio were also measured. Similarly, clinical parameters were also evaluated using serum and urine sample collected after 1 year (n = 204). RESULTS: Soluble (P)RR levels were positively associated with serum Cr (P < 0.0001, r = 0.263), BUN (P < 0.0001, r = 0.267), UA (P < 0.005, r = 0.168) levels, CKD stage (P < 0.0001, r = 0.311) and urine protein/Cr ratio (P < 0.01, r = 0.157), and inversely with estimated glomerular infiltration rate (eGFR) (P < 0.0001, r = -0.275) and Hb (P < 0.005, r = -0.156). Soluble (P)RR levels were inversely associated with α-Klotho levels (P < 0.001, r = -0.174) but did not correlate with prorenin levels. With respect to antihypertensive drugs, soluble (P)RR levels were significantly lower in patients treated with an angiotensin II receptor blocker (ARB) than in those without ARB therapy (P < 0.005). Soluble (P)RR levels were significantly lower in CKD patients with diabetes mellitus or primary hypertension than in those without these conditions (P < 0.05). In contrast, serum levels of prorenin did not correlate with parameters related to renal function. Serum prorenin levels were significantly higher in CKD patients with diabetes mellitus than in nondiabetic patients (P < 0.05), but not in CKD patients with hypertension (P = 0.09). Finally, with respect to the relationship between basal soluble (P)RR levels and the progression rates of renal function, soluble (P)RR levels were positively associated with ΔCr (P < 0.05, r = 0.159) and inversely associated with ΔeGFR (P < 0.05, r = -0.148). CONCLUSION: Serum levels of soluble (P)RR correlated with the stage of CKD. Our findings suggest that soluble (P)RR may be involved in renal injury and influence the progression of CKD.

[Metabolic syndrome].

Metabolic syndrome (Mets) is a combination of disorders including abdominal obesity, impaired glucose tolerance, dyslipidemia and hypertension, which increases risk for cardiovascular disease (CVD) and type 2 diabetes when occurring together. In Japan, diagnosis criteria of Mets consists of an increased waist circumference and 2 or more of CVD risk factors. Annual health checkups and health guidance using Mets criteria were established in 2008 for the prevention of life-style related diseases in Japan. In this issue, history and diagnostic criteria of Mets and concerns for Mets concept were described.

Upregulation of HNF-1ß during experimental acute kidney injury plays a crucial role in renal tubule regeneration.

Hepatocyte nuclear factor-1ß (HNF-1ß) is a transcription factor expressed in the kidney, liver, pancreas, and other organs. Mutations of HNF-1ß cause maturity-onset diabetes of the young type 5 (MODY5). The aims of this study were to investigate the functional roles of the HNF-1ß/suppressor of cytokine signaling-3 (SOCS-3) pathway in tubule damage after acute kidney injury (AKI) both in vivo and in vitro and to examine the effect of HNF-1ß on renal tubule formation. To clarify the significance of the HNF-1ß/SOCS-3 pathway in AKI, we used a rat ischemia/reperfusion (I/R) AKI model and cultured renal tubular cells (NRK-52E cells). Western blot analysis showed that HNF-1ß and polycystic kidney disease 2 (PKD2) expressions were increased at 3-12 h and 12-24 h after I/R, respectively. The expression level of SOCS-3 was decreased at 3-48 h. Immunohistological examination revealed that expression of HNF-1ß was increased in proximal tubules. Overexpression of HNF-1ß resulted in decreased SOCS-3 expression, activation of signal transducer and activator of transcription 3 (STAT3) and Erk, and increased [(3)H]thymidine uptake in the presence of hepatocyte growth factor. Furthermore, tubule formation in three-dimensional gels was inhibited by dominant-negative HNF-1ß. Our study shows that HNF-1ß is upregulated after AKI in proximal tubular cells and that HNF-1ß controls cellular proliferation and tubule formation by regulating SOCS-3 expression and STAT3/Erk activation. Therefore, the current study unravels the physiological and pathological significance of the HNF-1ß pathway in AKI.

Serum levels of soluble secreted α-Klotho are decreased in the early stages of chronic kidney disease, making it a probable novel biomarker for early diagnosis.

BACKGROUND: α-Klotho was first identified as an aging gene and was later shown to be a regulator of phosphate metabolism. Fibroblast growth factor 23 (FGF23) is the key regulator of phosphate metabolism. Serum levels of soluble α-Klotho in chronic kidney disease (CKD) patients have not previously been determined, especially in relation with FGF23 and creatinine levels. This study was designed to investigate whether serum soluble α-Klotho levels are modulated by renal function, age, and FGF23 level in CKD patients. This study is the first report on the utility of measuring soluble α-Klotho levels in human CKD. METHODS: A total of 292 CKD patients were enrolled. Serum samples were collected, and FGF23 and soluble α-Klotho levels were measured using enzyme-linked immunosorbent assay kits. In addition, serum creatinine, hemoglobin, albumin, calcium, and phosphate levels were measured. RESULTS: Serum soluble α-Klotho levels were associated positively with estimated glomerular filtration rate (eGFR) (P < 0.0001) and inversely with serum creatinine level (P < 0.01). Interestingly, α-Klotho levels were significantly decreased in stage 2 CKD compared with stage 1 (P = 0.0001). Serum FGF23 levels were associated positively with serum creatinine and negatively with eGFR. FGF23 levels were significantly increased in stage 5 compared with stage 1 CKD. Soluble α-Klotho was associated inversely with log-transformed FGF23 level (P < 0.01). CONCLUSION: Our data indicate that soluble α-Klotho levels are significantly decreased in stage 2 CKD compared to stage 1, and not only in the advanced stages of the disease. Soluble α-Klotho may thus represent a new biomarker for the diagnosis of CKD, especially in the early stage.

Role of mitochondrial phosphate carrier in metabolism-secretion coupling in rat insulinoma cell line INS-1.

In pancreatic ß-cells, glucose-induced mitochondrial ATP production plays an important role in insulin secretion. The mitochondrial phosphate carrier PiC is a member of the SLC25 (solute carrier family 25) family and transports Pi from the cytosol into the mitochondrial matrix. Since intramitochondrial Pi is an essential substrate for mitochondrial ATP production by complex V (ATP synthase) and affects the activity of the respiratory chain, Pi transport via PiC may be a rate-limiting step for ATP production. We evaluated the role of PiC in metabolism-secretion coupling in pancreatic ß-cells using INS-1 cells manipulated to reduce PiC expression by siRNA (small interfering RNA). Consequent reduction of the PiC protein level decreased glucose (10 mM)-stimulated insulin secretion, the ATP:ADP ratio in the presence of 10 mM glucose and elevation of intracellular calcium concentration in response to 10 mM glucose without affecting the mitochondrial membrane potential (Δψm) in INS-1 cells. In experiments using the mitochondrial fraction of INS-1 cells in the presence of 1 mM succinate, PiC down-regulation decreased ATP production at various Pi concentrations ranging from 0.001 to 10 mM, but did not affect Δψm at 3 mM Pi. In conclusion, the Pi supply to mitochondria via PiC plays a critical role in ATP production and metabolism-secretion coupling in INS-1 cells.

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.

Tissue-specific regulation of 11ß hydroxysteroid dehydrogenase type-1 mRNA expressions in Cushing's syndrome mouse model.

The 11ß hydroxysteroid dehydrogenase type-1 (11ßHSD-1) is a predominant 11ß-reductase regenerating bioactive glucocorticoids (cortisol, corticosterone) from inactive 11-keto forms (cortisone, dehydrocorticosterone), expressed mainly in the brain, liver and adipose tissue. Although the expression levels of 11ß HSD-1 mRNA are known to be influenced by glucocorticoids, its tissue-specific regulation is not completely elucidated. In this study, we examined the effect of persistent glucocorticoid excess on the expression of 11ß HSD-1 mRNA in the hippocampus, liver, and abdominal adipose tissue in vivo using quantitative real-time PCR. We found that, in C57BL/6J mice treated with corticosterone (CORT) pellet for 2 weeks, 11ß HSD-1 mRNA decreased in the hippocampus (HIPP) and liver, whereas it increased in the abdominal fat (FAT), compared with placebo treatment [HIPP: placebo 1.00 ± 0.14, CORT 0.63 ± 0.04; liver: placebo 1.00 ± 0.08, CORT 0.73 ± 0.06; FAT: placebo 1.00 ± 0.16, CORT 2.26 ± 0.39]. Moreover, in CRH transgenic mice, an animal model of Cushing's syndrome with high plasma CORT level, 11ß HSD-1 mRNA was also decreased in the hippocampus and liver, and increased in the abdominal adipose tissue compared to that in wild-type mice. These changes were reversed after adrenalectomy in CRH-Tg mice. Altogether, these results reveal the differential regulation of 11ß HSD-1 mRNA by glucocorticoid among the tissues examined.

Systems analysis of GLP-1 receptor signaling in pancreatic ß-cells.

Glucagon-like peptide-1 (GLP-1) elevates intracellular concentration of cAMP ([cAMP]) and facilitates glucose-dependent insulin secretion in pancreatic ß-cells. There has been much evidence to suggest that multiple key players such as the GLP-1 receptor, G(s) protein, adenylate cyclase (AC), phosphodiesterase (PDE), and intracellular Ca(2+) concentration ([Ca(2+)]) are involved in the regulation of [cAMP]. However, because of complex interactions among these signaling factors, the kinetics of the reaction cascade as well as the activities of ACs and PDEs have not been determined in pancreatic ß-cells. We have constructed a minimal mathematical model of GLP-1 receptor signal transduction based on experimental findings obtained mostly in ß-cells and insulinoma cell lines. By fitting this theoretical reaction scheme to key experimental records of the GLP-1 response, the parameters determining individual reaction steps were estimated. The model reconstructed satisfactorily the dynamic changes in [cAMP] and predicted the activities of cAMP effectors, protein kinase A (PKA), and cAMP-regulated guanine nucleotide exchange factor [cAMP-GEF or exchange protein directly activated by cAMP (Epac)] during GLP-1 stimulation. The simulations also predicted the presence of two sequential desensitization steps of the GLP1 receptor that occur with fast and very slow reaction rates. The cross talk between glucose- and GLP-1-dependent signal cascades for cAMP synthesis was well reconstructed by integrating the direct regulation of AC and PDE by [Ca(2+)]. To examine robustness of the signaling system in controlling [cAMP], magnitudes of AC and PDE activities were compared in the presence or absence of GLP-1 and/or the PDE inhibitor IBMX.(1).