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Objective Glucose-dependent insulinotropic polypeptide (GIP) is speculated to worsen growth hormone (GH) hypersecretion in acromegaly and to be a cause of paradoxical increases in GH (PI-GH) during 75-g oral glucose tolerance testing (75-g OGTT). Dipeptidyl peptidase-4 inhibitors (DPP4is), which increase the circulating concentration of active GIP, are frequently administered to diabetic patients, including those with acromegaly. We aimed to determine whether or not the administration of a DPP4i increases GH concentration, especially in patients demonstrating PI-GH during a DPP4i-OGTT, in which a DPP4i was administered immediately before 75-g OGTT. Methods This prospective cross-sectional study was carried out on acromegalic patients admitted to Hokkaido University hospital between June 2011 and May 2018. The participants underwent both 75-g OGTT and DPP4i-OGTT. For those who underwent surgery, immunohistochemical staining and quantitative polymerase chain reaction (PCR) for the GIP receptor (GIPR) were performed on the resected pituitary adenomas. Results Twenty-five percent of the participants had PI-GH confirmed (3 of 12 cases). Two of the three participants who demonstrated PI-GH exhibited higher circulating GH concentrations during DPP4i-OGTT than during OGTT. The increase in plasma glucose was reduced during DPP4i-OGTT compared to during 75-g OGTT, suggesting that the increase in GH during DPP4i-OGTT was due not to high glucose concentrations but instead increased GIP caused by the administration of DPP4i. The adenoma from one participant with PI-GH displayed positive immunostaining for GIPR and a higher GIPR messenger ribonucleic acid (mRNA) expression than the others. Conclusion DPP4i may enhance the GH secretion response during glucose loading, especially in individuals with PI-GH.

Objective We previously reported that Neuromedin B (NMB) is expressed in murine pituitary corticotrophs under adrenal insufficiency (1). Because NMB is also expressed in several cancer cells and stimulates ACTH secretion, we hypothesized that NMB is related to corticotroph adenoma cell proliferation and hormone secretion. To examine this hypothesis, we investigated the effects of a NMB receptor (NMBR) antagonist on AtT-20 cells, a tumor xenograft model and patient-derived corticotroph adenoma cells. Methods 1. NMB and NMBR expression in human pituitary adenoma: We performed real-time qPCR and immunostaining on human pathological specimens of corticotroph and non-functioning pituitary adenomas to investigate NMB and NMBR expression. 2. Experiments in AtT-20 cells: We extracted RNAs, proteins and mediums from AtT-20 cells after incubation with NMBR antagonist PD168368, and performed real-time qPCR, western blotting and ELISA analyses. We also performed WST-1 assay to investigate cell proliferation. 3. Experiments in a tumor xenograft model: AtT-20 cells in Matrigel were injected subcutaneously into BALB/c-nu mice. A week after inoculation, we administered 1.2 mg/kg PD168368 intraperitoneally once daily for 14 days. Upon completion of treatment, tumors were measured and cardiac blood was collected. 4. Experiments in patient-derived corticotroph adenoma cells: We isolated surgically resected human corticotroph adenoma cells from patients who underwent trans-sphenoidal surgery and investigated mRNA expression and medium ACTH secretion after incubation with PD168368. Statistical analysis: Comparisons between two groups were made by unpaired Student t test. Multiple groups were compared using one-way ANOVA followed by Dunnett's test for comparison with control group. Statistical significance was defined as p < 0. 05. Results 1. NMB and NMBR expression levels were significantly higher in human corticotroph adenomas (13 and 33 times higher, respectively) than in non-functioning adenomas in the qPCR analyses. Immunostaining confirmed higher expression of NMB and NMBR in corticotroph adenoma. 2. Treatment with 100 nM PD168368 significantly suppressed Pomc mRNA and protein expression in AtT-20 cells by 22% and 25% respectively compared control group. Medium ACTH secretion, mRNA and protein expression of cyclin E1 and cell proliferation were also suppressed by PD168368. 3. Mice treated with PD168368 had significantly lower tumor growth rate, plasma ACTH and corticosterone than control group (70 vs 161%, 97 vs 180 pg/ml, 813 vs 1045 ng/ml, respectively). 4. Treatment with PD168368 significantly suppressed POMC mRNA expression (12-31%) in 4 out of 6 patient-derived corticotroph adenoma cells. Medium ACTH secretion was also suppressed (14-53%) in 3 out of 4 cases which could be evaluated. Cyclin E mRNA expression were also suppressed in 3 out of 4 cases in which POMC mRNA expression were suppressed. Conclusions NMBR antagonist may represent a potential treatment for Cushing disease, which effect may be mediated by decreased cyclin E expression. Reference: (1) Kameda H et al., Endocrinology 2014;155(7): 2492–9. Presentation: No date and time listed

Dipeptidyl peptidase‐4 (DPP‐4), namely CD26, is expressed on the surface of immune cells, suggesting that inhibition of DPP‐4 might affect the immune system. The current multicenter observational case–control study was carried out to investigate the effects of DPP‐4 inhibitor (DPP‐4i) administration on Graves' disease (GD) activity. This study comprised patients with GD and type 2 diabetes, who were administered an oral hypoglycemic agent including DPP‐4i. Exacerbation of GD was defined as an increase of antithyroid drug dose by 6 months after oral hypoglycemic agent administration. A total of 80 patients were enrolled and divided into an exacerbation group or a non‐exacerbation group. The frequency of DPP‐4i administration was significantly higher in the exacerbation group (88%) than that in the non‐exacerbation group (31%). In multivariate logistic regression analysis, there was a significant association between DPP‐4i administration and GD exacerbation (odds ratio 7.39). The current study suggests that DPP‐4i administration is associated with GD exacerbation., The frequency of dipeptidyl peptidase‐4 inhibitor administration was significantly higher in the Graves' disease exacerbation group than that in the non‐exacerbation group. Multivariate logistic regression analysis also showed a significant association between dipeptidyl peptidase‐4 inhibitor administration and Graves' disease exacerbation. Our study has proven the potential association of dipeptidyl peptidase‐4 inhibitor administration with Graves' disease exacerbation.

Abstract: [Background] Dipeptidyl peptidase-4 (DPP-4) is expressed as CD26 on the surface of immune cells including T cells, suggesting that inhibition of DPP-4 may affect the immune system (1). Actually, DPP-4 inhibitor (DPP-4i)-induced polyarthritis and bullous pemphigoid have been reported (2, 3). It has also been reported that the prevalence of Hashimoto’s thyroiditis was significantly higher in patients on DPP-4i treatment (4). However, relationships between DPP-4i and Graves’ disease has been unclear. [Methods] To investigate the impact of DPP-4i administration on the activity of Graves’ disease, we conducted a multicenter observational trial that included patients with both Graves’ disease and type 2 diabetes mellitus who were administered an oral hypoglycemic agent (OHA) including DPP-4i from December in 2009 to April in 2018. Patients who had systemic diseases affecting thyroid function and those who underwent thyroidectomy or radioiodine treatment within 6 months before or after OHA administration were excluded. Exacerbation of Graves’ disease was defined as an increase in antithyroid drug dose within 6 months after OHA administration. The trial was approved by the institutional review board of Hokkaido University Hospital. [Results] Eighty-three patients were enrolled in the study, and they were divided into an exacerbation group (n = 18) and a non-exacerbation group (n = 65). Comparing baseline characteristics, the percentage of DPP-4i administration was higher in the exacerbation group (83.3%) than in the non-exacerbation group (32.3%) (p = 0.0001). Mean age was also significantly higher in the exacerbation group (p = 0.04), and the duration of Graves’ disease was significantly shorter (p = 0.01). Multivariate logistic regression analysis using factors extracted by comparing baseline characteristics demonstrated a significant association between DPP-4i administration and Graves’ disease exacerbation (odds ratio 5.62, 95% confidence interval 1.16–27.0, p = 0.02). [Conclusion] The current study suggests that DPP-4i administration is associated with exacerbation of Graves’ disease. Reference: (1) Morimoto C et al., Immunol Rev. 1998 Feb;161:55–70. (2) Yokota K et al., Intern Med. 2012;51(15):2041–4. (3) Yoshiji S et al. J Diabetes Investig. 2018 Mar;9(2):445–447. (4) Kridin K et al. Immunol Res. 2018 Jun;66(3):425–430.

Background: Patients with diabetes present hypercortisolemia, which may exacerbate not only glycemic control but also diabetic complications and fatty liver (1). Blood steroid hormone levels including corticosterone and aldosterone are high in db/db mice (2), although the mechanism is still unclear. Objective: To reveal the mechanism underlying the hypothalamic-pituitary-adrenal (HPA) axis hyperactivity in obese and diabetic condition. Method: Total RNA from hypothalamus, pituitary, and adrenal glands in ten-week-old db/db and db/+ mice were extracted and analyzed with DNA microarray and real-time PCR. Experiments were approved by the Institutional Animal Care and Use Committee. Results: Hypothalamic Crh mRNA expression was not changed in db/db mice, although Avp expression was 2.8-fold higher than db/+ mice. Pituitary Crhr1 and Pomc expression were higher (3.0- and 7.0-fold, respectively), and Nr3c1 expression was lower (0.7-fold) in db/db mice than db/+ mice. Adrenal Mc2r, Nr5a1, Cyp11b1, and Cyp11b2 were higher in db/db mice than db/+ mice (1.7-, 1.7-, 2.2-, 1.3-fold, respectively). Conclusion: Increased expression of tropic hormone receptors and abrogated negative feedback system may be responsible for HPA axis hyperactivity in db/db mice. Reference: (1) Chiodini I et al. Diabetes Care. 2007 Jan;30:83–8. (2) Hofmann A et al. Horm Metab Res. 2017 Jan;49:43–49.

Carcinoembryonic antigen (CEA), the level of which is known to increase in both patients with gastrointestinal cancers and those with non-neoplastic conditions, is one of the most widely-used tumor markers. Hypothyroidism is a common endocrinological disorder in which CEA levels can rise, and is sometimes overlooked as a diagnosis in the absence of typical symptoms or thyroid enlargement. We report the cases of two patients with non-goiterous severe hypothyroidism with markedly elevated CEA levels that effectively decreased with levothyroxine replacement therapy alone. Hypothyroidism should be considered as an important cause of unexplained high serum CEA levels in order to avoid unnecessary medical examination.

A 62-year-old man was referred to our department for elevation of plasma ACTH and cortisol levels during nivolumab administration for renal cell carcinoma. Although his ACTH and cortisol levels had been maintained within their reference ranges, they were elevated to 232.7 pg/mL and 21.9 μg/dL, respectively, after eight courses of nivolumab without any subjective symptoms or Cushing's sign. He was hospitalized for endocrinological investigation. ACTH and cortisol returned to their normal ranges (29.18 pg/mL and 11.4 μg/dL, respectively) in the early morning on day 1, but fell down sharply to 3.7 pg/mL and 1.6 μg/dL, respectively, in the early morning on day 2 without subjective symptoms or vital sign changes. Brain magnetic resonance imaging showed no abnormality in his pituitary gland. ACTH response to CRH was apparently normal, but cortisol did not respond to increased ACTH. A rapid ACTH stimulation test showed slightly reduced response of cortisol to exogenous ACTH (1-24). These findings and his clinical course suggested secondary adrenal insufficiency arising from nivolumab-induced hypophysitis. In previous reports, most cases of immune checkpoint inhibitor (ICI)-induced hypophysitis were diagnosed based on adrenal insufficiency symptoms or hyponatremia with low ACTH and cortisol. The ACTH elevation observed in the present case may reflect destruction of the pituitary gland, suggesting that this finding may be important for early detection of ICI-induced hypophysitis. Our case underlines the necessity of close monitoring for subsequent onset of adrenal insufficiency when ACTH elevation is observed during ICI administration.