Bilateral Adrenocortical Adenomas along with Virilization and Cushing's Syndrome.

We herein present the case of a 27-year-old woman with clinical and biochemical features of virilism. Imaging studies revealed the presence of a bilateral adrenal tumor. Although the secretion of androgens was remarkable, the autonomous production of cortisol was also evident because of a loss of circadian rhythm and the absence of cortisol suppression by dexamethasone. The surgical excision of both adrenal tumors was performed, and the histological examination showed no malignancy. We also report the successful pregnancy and delivery of the patient who showed evolving adrenocortical insufficiency along with virilization and Cushing's syndrome and who continued to receive glucocorticoid replacement therapy during pregnancy.

Selective peroxisome proliferator-activated receptor-α modulator K-877 regulates the expression of ATP-binding cassette transporter A1 in pancreatic beta cells.

ATP-binding cassette transporter A1 (ABCA1) protein is a pivotal regulator of cholesterol and phospholipid efflux from cells to high-density lipoprotein (HDL) particles. Pancreatic ABCA1 functions in beta cell cholesterol homeostasis and affects insulin secretion. We investigated the effect of pemafibrate (K-877), a novel selective PPARα modulator (SPPARMα), on pancreatic ABCA1 expression. In vivo experiment, mice were divided into four treatment groups, namely, normal food plus placebo, high fat diet (HFD) plus placebo, normal food plus K-877 (0.3 mg/kg/day), or HFD plus K-877 (0.3 mg/kg/day), and treated for eight weeks. The results in vitro experiment indicate that K-877 treatment increased levels of ABCA1 mRNA, as well as protein, subsequently reduced the cellular cholesterol content in INS-1 cells. PPARα specific antagonist GW6471 attenuate K-877 induced ABCA1 expression in INS-1 cells. ABCA1 promoter activity increased with K-877 treatment at concentration 1 µM and 10 µM. Glucose-stimulated insulin secretion was ameliorated by K-877 treatment in INS-1 cells and isolated mouse islets. Although the expression of ABCA1 was reduced in mice with HFD treatment, both ABCA1 protein and mRNA levels were increased in mice with K-877 treatment. K-877 treatment improved glucose intolerance induced by HFD in mice. These findings raise the possibility that K-877 may affect insulin secretion by controlling ABCA1 expression in pancreatic beta cells.

Angiotensin II induces cholesterol accumulation and impairs insulin secretion by regulating ABCA1 in beta cells.

In pancreatic ß cells, ABCA1, a 254 kDa membrane protein, affects cholesterol homeostasis and insulin secretion. Angiotensin II, as the main effector of the renin-angiotensin system, decreases glucose-stimulated insulin secretion (GSIS). We examined the effect of angiotensin II on ABCA1 expression in primary pancreatic islets and INS-1 cells. Angiotensin II decreased ABCA1 protein and mRNA; angiotensin II type 1 receptor (AT1R) blockade rescued this ABCA1 repression. In parallel, angiotensin II suppressed the promoter activity of ABCA1, an effect that was abrogated by PD98095, a specific inhibitor of MAPK kinase (MEK). LXR enhanced ABCA1 promoter activity, and angiotensin II decreased the nuclear abundance of LXR protein. On a chromatin immunoprecipitation assay, LXR mediated the transcription of ABCA1 by directly binding to its promoter. Mutation of the LXR binding site on the ABCA1 promoter cancelled the effect of angiotensin II. Furthermore, angiotensin II induced cholesterol accumulation and impaired GSIS; inhibition of AT1R or MEK pathway reversed these effects. In summary, our study showed that angiotensin II suppressed ABCA1 expression in pancreatic islets and INS-1 cells, indicating that angiotensin II may influence GSIS by regulating ABCA1 expression. Additional research may address therapeutic needs in diseases such as diabetes mellitus.

Effect of TNF-α on the expression of ABCA1 in pancreatic ß-cells.

ATP-binding cassette transporter A1 (ABCA1), a 254-kD membrane protein, is a key regulator of lipid efflux from cells to apolipoproteins. ABCA1 in pancreatic ß-cells influences insulin secretion and cholesterol homeostasis. Tumor necrosis factor (TNF)-α is a pleiotropic cytokine that elicits a wide spectrum of physiological events, including cell proliferation, differentiation, and apoptosis, and is also known to decrease glucose-dependent insulin secretion in pancreatic islets. In the present study, we examined the role of TNF-α on ABCA1 expression in rat pancreatic islets and INS-1 cells. ABCA1 protein levels decreased in response to rising concentrations of TNF-α in pancreatic islets. Real-time polymerase chain reaction analysis showed a significant decrease in ABCA1 mRNA expression. In parallel with its effect on endogenous ABCA1 mRNA levels, TNF-α suppressed the activity of a reporter construct containing the ABCA1 promoter. This effect was abrogated by BIRB796, but not by SB203580 or PD98095. The constitutively active form of p38 mitogen-activated protein kinase (MAPK) γ suppressed ABCA1 promoter activity but not p38-MAPK (α, ß), while a dominant-negative mutant of p38-MAPK γ blocked the effect of TNF-α on ABCA1 promoter activity. BIRB796 inhibited the increased cholesterol ester content induced by TNF-α. However, BIRB796 had no effect on the decreased insulin content nor ABCA1 suppression caused by TNF-α in INS-1 cells. In summary, TNF-α suppressed the expression of endogenous ABCA1 in pancreatic islets and INS-1 cells. These findings raise the possibility that TNF-α may affect insulin secretion by controlling ABCA1 expression.

IGF1 suppresses cholesterol accumulation in the liver of growth hormone-deficient mice via the activation of ABCA1.

Recently, several clinical studies have suggested that adult growth hormone (GH) deficiency that also has low concentration of IGF1 is associated with an increased prevalence of fatty liver (FL). ATP-binding cassette transporter A1 (ABCA1) is a pivotal regulator of lipid efflux from cells to apolipoproteins and plays an important role on formation of FL. In this study, we determined the effects of IGF1 on ABCA1 expression in GH-deficient mice to clarify its effects on FL. Western blotting, real-time PCR, and a luciferase assay were employed to examine the effect of IGF1. The binding of FoxO1 to the ABCA1 promoter was assessed by chromatin immunoprecipitation (ChIP) assay. Cholesterol accumulation was analyzed by Oil Red O stain and cholesterol content measurement. We confirmed that IGF1 upregulated the ABCA1 expression. The activity of a reporter construct containing the ABCA1 promoter was induced by IGF1, and this effect was blocked by LY294002, a specific inhibitor of phosphatidylinositol 3-kinase (PI3K). Constitutively active Akt stimulated the ABCA1 promoter activity, and a dominant-negative mutant of Akt or mutagenesis of the FoxO1 response element abolished the effect of IGF1. A ChIP assay indicated that FoxO1 mediated IGF1 transcriptional activity by directly binding to the ABCA1 promoter region. For in vivo experiments, we used an inhibitor for the GH receptor (Pegvisomant) to reduce the IGF1 level. A high-fat diet induced FL in mice (C57BL/6J) given Pegvisomant treatment. IGF1 treatment stimulated ABCA1 expression to improve cholesterol accumulation in these mice. These results show that the PI3K/Akt/FoxO1 pathway contributes to the regulation of ABCA1 expression in response to IGF1 stimulation that suppressed FL in GH-deficient mice.

Combination therapy of ipilimumab and nivolumab induced thyroid storm in a patient with Hashimoto's disease and diabetes mellitus: a case report.

BACKGROUND: Recently, immune checkpoint inhibitors have widely been used for the management of advanced melanoma. However, high-grade immune-related adverse events can occur, particularly with combination immunotherapy. We report a case of a patient with melanoma who developed thyroid storm following treatment with ipilimumab and nivolumab. CASE PRESENTATION: An 85-year-old Japanese man with a history of malignant melanoma presented to our department with severe thyrotoxicosis and poor blood glucose control. He was already being treated for Hashimoto's disease and type 2 diabetes mellitus before the treatment for the melanoma. During admission, laboratory investigations revealed the following thyroid functions: thyroid-stimulating hormone below sensitivity, free triiodothyronine 31.7 pg/ml, and thyroglobulin 48,000 IU/ml. Thyroid-stimulating hormone receptor antibody was negative, and a 99mTc-labeled thyroid scan revealed a markedly decreased uptake. He was treated with beta-blocker, orally administered potassium iodine, a relatively low dose of prednisolone, and insulin injection therapy to control his blood glucose, resulting in an improvement in thyroid function and his symptoms. CONCLUSION: It might be important to be aware of the possibility of thyroid storm induced by immune checkpoint inhibitors.

Thyroid stimulating hormone stimulates the expression of glucose transporter 2 via its receptor in pancreatic ß cell line, INS-1 cells.

Thyroid stimulating hormone (TSH) stimulates the secretion of thyroid hormones by binding the TSH receptor (TSHR). TSHR is well-known to be expressed in thyroid tissue, excepting it, TSHR has also been expressed in many other tissues. In this study, we have examined the expression of TSHR in rat pancreatic islets and evaluated the role of TSH in regulating pancreas-specific gene expression. TSHR was confirmed to be expressed in rodent pancreatic islets and its cell line, INS-1 cells. TSH directly affected the glucose uptake in INS cells by up-regulating the expression of GLUT2, and furthermore this process was blocked by SB203580, the specific inhibitor of the p38 MAPK signaling pathway. Similarly, TSH stimulated GLUT2 promoter activity, while both a dominant-negative p38MAPK α isoform (p38MAPK α-DN) and the specific inhibitor for p38MAPK α abolished the stimulatory effect of TSH on GLUT2 promoter activity. Finally, INS-1 cells treated with TSH showed increased protein level of glucokinase and enhanced glucose-stimulated insulin secretion. Together, these results confirm that TSHR is expressed in INS-1 cells and rat pancreatic islets, and suggest that activation of the p38MAPK α might be required for TSH-induced GLUT2 gene transcription in pancreatic ß cells.