Ectopic ACTH-producing neuroendocrine tumor occurring with large recurrent metastatic pheochromocytoma: a case report.

BACKGROUND: Ectopic ACTH-dependent Cushing syndrome is rarely caused by pheochromocytoma (PCC). Glucocorticoid-regulated positive feedback loops in ACTH and catecholamines were proposed in some similar cases. CASE PRESENTATION: We present here an 80-year-old man who had previously undergone surgery for a left adrenal PCC and newly developed severe hypertension, hypokalemia, and typical Cushingoid manifestations. Investigations revealed hyperglycemia, hypokalemia, and extremely high catecholamines and their metabolites, ACTH and cortisol. Imaging modalities showed a recurrent large left adrenal mass positively visualized with 123I-metaiodobenzylguanidine as well as somatostatin receptor scintigraphy. Surgical interventions were not indicated; thus, metyrapone, phentolamine, and doxazocin were initiated, which successfully controlled his symptoms and biochemical conditions. With the evidence that metyrapone administration decreased ACTH and catecholamine levels, the existence of positive feedback loops was speculated. During the terminal stages of the disease, additional metyrosine treatment successfully stabilized his physiological and biochemical conditions. Upon the patient's death, pathological autopsy was performed. Immunohistochemical analysis indicated that the tumor appeared to be co-positive with tyrosine hydroxylase (TH) as well as ACTH in most tumor cells in both PCC and liver metastasis. Most cells were clearly positive for somatostatin receptor 2 staining in the membrane compartment. The dense immunostaining of ACTH, TH, dopamine-ß-hydroxylase and the large tumor size with positive feedback loops may be correlated with high levels of ACTH and catecholamines in the circulation. CONCLUSIONS: We experienced a case of severe ectopic ACTH producing the largest reported recurrent malignant left PCC with liver metastases that presented positive feedback loops in the ACTH/cortisol and catecholamine/cortisol axes. Clinicians should be aware of the paradoxical response of ACTH on metyrapone treatment and possible steroid-induced catecholamine crisis.

Inhibition of inflammation-mediated DPP-4 expression by linagliptin increases M2 macrophages in atherosclerotic lesions.

BACKGROUND AND AIMS: Dipeptidyl peptidase-4 (DPP-4) inhibitors have been reported to suppress atherosclerosis progression in atherosclerotic mouse models through unclear mechanisms. In this study, we investigated the effect of the DPP-4 inhibitor, linagliptin, on macrophage polarization in vitro and in vivo. METHODS: Mouse bone marrow macrophages (BMMs) were used in in vitro assays. High fat diet (HFD)-fed Apoe-/- mice were treated orally with linagliptin (10 mg/kg-1•day-1) or a vehicle (water) control. RESULTS: In in vitro assays using BMMs, treatment with LPS and IFNγ decreased the mRNA-expression levels of alternatively activated macrophage (M2) markers, and linagliptin treatment prevented these reductions. The mRNA levels of M2 markers and the number of M2 macrophages in the aorta were higher in linagliptin groups than in control groups. Linagliptin decreased the size of atherosclerotic lesions in HFD-fed Apoe-/- mice. Interestingly, inflammatory stimulation increased DPP-4 expression, and linagliptin suppressed these effects in BMMs. Treatment with DPP-4 small-interfering RNA (siRNA) reproduced linagliptin-mediated alteration of M2 polarization. CONCLUSIONS: Linagliptin increased M2 macrophage polarization by inhibiting DPP-4 expression and activity. These findings may indicate the beneficial effects of DPP-4 inhibitors on the progression of diabetic macrovascular complications.

Inhibition of Local Macrophage Growth Ameliorates Focal Inflammation and Suppresses Atherosclerosis.

OBJECTIVE: Macrophages play a central role in various stages of atherosclerotic plaque formation and progression. The local macrophages reportedly proliferate during atherosclerosis, but the pathophysiological significance of macrophage proliferation in this context remains unclear. Here, we investigated the involvement of local macrophage proliferation during atherosclerosis formation and progression using transgenic mice, in which macrophage proliferation was specifically suppressed. APPROACH AND RESULTS: Inhibition of macrophage proliferation was achieved by inducing the expression of cyclin-dependent kinase inhibitor 1B, also known as p27kip, under the regulation of a scavenger receptor promoter/enhancer. The macrophage-specific human p27kip Tg mice were subsequently crossed with apolipoprotein E-deficient mice for the atherosclerotic plaque study. Results showed that a reduced number of local macrophages resulted in marked suppression of atherosclerotic plaque formation and inflammatory response in the plaque. Moreover, fewer local macrophages in macrophage-specific human p27kip Tg mice helped stabilize the plaque, as evidenced by a reduced necrotic core area, increased collagenous extracellular matrix, and thickened fibrous cap. CONCLUSIONS: These results provide direct evidence of the involvement of local macrophage proliferation in formation and progression of atherosclerotic plaques and plaque stability. Thus, control of macrophage proliferation might represent a therapeutic target for treating atherosclerotic diseases.

Autoimmune Polyglandular Syndrome Type 3 Complicated with IgG4-related Disease.

A 52-year-old Japanese woman developed type 1 diabetes mellitus (type 1 DM) at 41 years old. She became complicated with Hashimoto's disease and showed swelling of both submandibular glands, which was diagnosed as IgG4-related disease (IgG4-RD). This is a rare case of a Japanese patient with autoimmune polyglandular syndrome type 3A (APS-3A) coexisting with autoimmune thyroid disease (AITD) and type 1 DM complicated by IgG4-RD. Bilateral submandibular gland resection was successfully performed without steroid therapy. We discuss the possibility that the immunological pathogenic mechanisms of APS-3A and IgG4-RD are related.

Impact of tissue macrophage proliferation on peripheral and systemic insulin resistance in obese mice with diabetes.

INTRODUCTION: Obesity-related insulin resistance is a widely accepted pathophysiological feature in type 2 diabetes. Systemic metabolism and immunity are closely related, and obesity represents impaired immune function that predisposes individuals to systemic chronic inflammation. Increased macrophage infiltration and activation in peripheral insulin target tissues in obese subjects are strongly related to insulin resistance. Using a macrophage-specific proliferation inhibition mouse model (mac-p27Tg), we previously reported that suppressed plaque inflammation reduced atherosclerosis and improved plaque stabilization. However, the direct evidence that proliferating macrophages are responsible for inducing insulin resistance was not provided. RESEARCH DESIGN AND METHODS: The mac-p27Tg mice were fed a high-fat diet, and glucose metabolism, histological changes, macrophage polarization, and tissue functions were investigated to reveal the significance of tissue macrophage proliferation in insulin resistance and obesity. RESULTS: The mac-p27Tg mice showed improved glucose tolerance and insulin sensitivity, along with a decrease in the number and ratio of inflammatory macrophages. Obesity-induced inflammation and oxidative stress was attenuated in white adipose tissue, liver, and gastrocnemius. Histological changes related to insulin resistance, such as liver steatosis/fibrosis, adipocyte enlargement, and skeletal muscle fiber transformation to fast type, were ameliorated in mac-p27Tg mice. Serum tumor necrosis factor alpha and free fatty acid were decreased, which might partially impact improved insulin sensitivity and histological changes. CONCLUSIONS: Macrophage proliferation in adipose tissue, liver, and skeletal muscle was involved in promoting the development of systemic insulin resistance. Controlling the number of tissue macrophages by inhibiting macrophage proliferation could be a therapeutic target for insulin resistance and type 2 diabetes.

Pioglitazone suppresses macrophage proliferation in apolipoprotein-E deficient mice by activating PPARγ.

BACKGROUND AND AIMS: Local macrophage proliferation is linked to enhanced atherosclerosis progression. Our previous study found that troglitazone, a thiazolidinedione (TZD), suppressed oxidized low-density lipoprotein (Ox-LDL)-induced macrophage proliferation. However, its effects and mechanisms are unclear. Therefore, we investigated the effects of pioglitazone, another TZD, on macrophage proliferation. METHODS: Normal chow (NC)- or high-fat diet (HFD)-fed apolipoprotein E-deficient (Apoe-/-) mice were treated orally with pioglitazone (10 mg/kg/day) or vehicle (water) as a control. Mouse peritoneal macrophages were used in in vitro assays. RESULTS: Atherosclerosis progression was suppressed in aortic sinuses of pioglitazone-treated Apoe-/- mice, which showed fewer proliferating macrophages in plaques. Pioglitazone suppressed Ox-LDL-induced macrophage proliferation in a dose-dependent manner. However, treatment with peroxisome proliferator-activated receptor-γ (PPARγ) siRNA ameliorated pioglitazone-induced suppression of macrophage proliferation. Low concentrations (less than 100 µmol/L) of pioglitazone, which can suppress macrophage proliferation, activated PPARγ in macrophages, but did not induce macrophage apoptosis. Pioglitazone treatment did not induce TUNEL-positive cells in atherosclerotic plaques of aortic sinuses in Apoe-/- mice. CONCLUSIONS: Pioglitazone suppressed macrophage proliferation through PPARγ without inducing macrophage apoptosis. These findings imply that pioglitazone could prevent macrovascular complications in diabetic individuals.