Impact of Glucocorticoid Replacement Therapy on Nocturnal Hypoglycemia in Adrenal Insufficiency: An Analysis of Multiple Case Studies.

BACKGROUND AND AIM: Adrenal insufficiency (AI) is a hormonal disorder characterized by insufficient glucocorticoid production. Nocturnal hypoglycemia (NH) occurs in patients with AI. However, the effect of glucocorticoid replacement therapy (GCRT) on AI and NH remains unclear. This study aimed to investigate the relationship between AI and NH by evaluating the impact of GCRT on NH in patients newly diagnosed with AI. METHODS: The present study was conducted between October 2018 and December 2022 at the Department of Diabetes, Metabolism and Endocrinology of the Tokyo Rosai Hospital, Japan. In total, 15 patients aged ≥18 years with newly diagnosed AI or NH were included in this study. The NH frequency was measured using continuous glucose monitoring (CGM). The primary outcome was the change in NH frequency before and after the GCRT intervention. RESULTS: GCRT significantly decreased NH frequency. Severe NH frequency and minimum nocturnal glucose levels changed significantly while fasting blood glucose and glycated hemoglobin levels did not change significantly. GCRT intervention improved CGM profiles' time below range, time in range, and average daily risk range. CONCLUSIONS:  The present study suggests that GCRT can help newly diagnosed patients with AI manage NH. These findings show that CGM can detect NH in patients with newly diagnosed AI, determine the optimal GCRT dosage, and hence prevent an impaired quality of life and even serious adverse effects in these patients. Further large multicenter studies should validate these findings and delve deeper into the mechanistic link between AI and NH.

Clinical insights of pregnancy management, adrenal insufficiency as a possible cause of elevated TSH: a pilot study of case series.

BACKGROUND: The upper limit for thyroid-stimulating hormone has been strictly defined for pregnancy management, at which point levothyroxine replacement therapy will been initiated. However, it is essential to exclude adrenal insufficiency, including subclinical adrenal insufficiency, when initiating levothyroxine replacement therapy. However, in pregnancy management, it has rarely reported the incidence, clinical course, and characteristics of adrenal insufficiency as a possible cause of elevated thyroid-stimulating hormone. METHODS: This case series study included pregnant patients undergoing thyroid-stimulating hormone management in a single-center diabetes endocrinology department between 2017 and 2020. The primary study outcome was the incidence of newly diagnosed adrenal insufficiency. We reported the clinical course and assessed the adrenal insufficiency characteristics at baseline and delivery and compared them with those of hypothyroidism. RESULT: Fifteen pregnant women were included for thyroid-stimulating hormone management; and nine were below the basal serum cortisol level, and four were newly diagnosed as having adrenal insufficiency (26.7%) with the endocrinological stimulation test. Among them, two cases exhibited nausea and hypoglycemic symptoms after the start of levothyroxine replacement therapy. In cases of adrenal insufficiency, the patients were successfully treated with appropriate steroid coverage. CONCLUSIONS: In the management of elevated thyroid-stimulating hormone levels during pregnancy, the frequency of adrenal insufficiency suspecting hypothyroidism may be higher than expected; therefore, we must be careful about starting levothyroxine replacement therapy for hypothyroidism. These clinical insights can have a significant impact on the pregnancy outcomes.

Ceftriaxone-associated Biliary Pseudolithiasis with Elderly Type 1 Diabetes Mellitus: Two Case Reports.

Biliary pseudolithiasis is a ceftriaxone (CTRX)-induced complication, but the risk in cases of elderly type 1 diabetes mellitus (T1DM) is unclear. Case 1: A 78-year-old woman with T1DM complicated by diabetic autonomic neuropathy was admitted with pneumonia and treated with CTRX. On day 8, biliary pseudolithiasis and cholecystitis were observed. Case 2: an 80-year-old woman with T1DM was suspected of having a urinary tract infection and treated with CTRX. After a week, she developed asymptomatic biliary pseudolithiasis with gastroparesis. CTRX-associated biliary pseudolithiasis was thus noted in these cases of elderly T1DM. CTRX should be cautiously administered, especially in elderly T1DM patients with diabetic autonomic neuropathy.

A comprehensive risk assessment for nocturnal hypoglycemia in geriatric patients with type 2 diabetes: A single-center case-control study.

AIMS: To evaluate the overall association between clinically significant nocturnal hypoglycemia (CsNH) and risk factors in geriatric patients with type 2 diabetes. METHODS: Overall, 606 geriatric with type 2 diabetes were evaluated for CsNH using Freestyle Libre Pro® (Abbott Diabetes Care, Tokyo, Japan) during October 2018-February 2020. We defined CsNH as blood glucose level <54 mg/dL (3.0 mmol/L). We investigated clinical characteristics and efficacies of hypoglycemic agents and insulin and analyzed CsNH risk factors using univariate and multivariate logistic regression analyses. RESULTS: We enrolled 152 patients each for the CsNH and non-nocturnal hypoglycemia groups. Insulin use (OR = 3.77 [95 % CI: 1.92-7.67]; P = 0.0002), age (OR = 1.06 [95 % CI: 1.01-1.12]; P = 0.0492), estimated glomerular filtration rate (OR = 0.97 [95 % CI: 0.95-0.98]; P = 0.0492), and fasting blood glucose level (OR = 0.94 [95 % CI: 0.91-0.94]; P < 0.0001) were independent CsNH risk factors. The combined results demonstrated a higher predictability of CsNH than each of the individual risk factors. CONCLUSIONS: We identified risk factors that could help predict CsNH in geriatric patients with type 2 diabetes and demonstrated a comprehensive risk factor assessment.

Results of a phase I clinical study using dendritic cell vaccinations for thyroid cancer.

OBJECTIVE: We assessed the feasibility and efficacy of dendritic cell (DC) therapy for advanced thyroid papillary and follicular cancer. DESIGN: Six Japanese patients (2 men and 4 women; aged 46-72 years, mean 60 years), who were diagnosed as advanced thyroid cancer with refractory distant metastases (papillary, n=5; follicular, n=1), were enrolled. Patients were first vaccinated weekly for 4 weeks with 10(7) autologous tumor lysate-pulsed monocyte-derived mature DCs followed by fortnightly vaccinations for 8 weeks (total=8 vaccinations). Lowdose (350 KIU) interleukin-2 was also administered for 3 days at each vaccination. Clinical response, adverse effects, delayed-type hypersensitivity skin testing (DTH), and IFN-( ) production by peripheral CD3(+) lymphocytes were evaluated. MAIN OUTCOME: Of the 6 patients, disease was assessed as stable in 2 and as progressive in 4. No adverse events were observed. Results of DTH and IFN-( ) production in peripheral lymphocytes did not correlate to the clinical response. CONCLUSIONS: DC immunotherapy could be administered to patients with thyroid papillary or follicular cancer without substantial side effects.

A potential pro-angiogenic cell therapy with human placenta-derived mesenchymal cells.

Recently several strategies to treat ischemic diseases have been proposed but the ideal way has to be determined. We explored whether human placenta-derived mesenchymal cells (hPDMCs) can be used for this purpose because placenta is very rich in vessels. First, production of human vascular endothelial growth factor (hVEGF) from hPDMCs was examined. The amount of hVEGF secreted by hPDMCs was similar to the amount produced by HeLa cells. hVEGF was barely detected in human umbilical vein endothelial cells (hUVECs) or human peripheral blood mononuclear cells. hVEGF secreted from hPDMCs stimulated the proliferation of hUVECs, indicating its biological activity. Transplantation of hPDMCs to the ischemic limbs of NOD/Shi-scid mice significantly improved the blood flow of the affected limbs. Blood vessel formation was more prominently observed in the limbs of treated mice as compared to the control mice. Real-time RT-PCR revealed that hPDMCs produced hVEGF for at least 7 days after transplantation. Thus, transplantation of hPDMCs could potentially be a promising treatment for human ischemic diseases.

Differential regulation of cell migration and proliferation through proline-rich tyrosine kinase 2 in endothelial cells.

Proline-rich tyrosine kinase 2 (Pyk2), a member of the focal adhesion kinase family, is thought to act as a key component in vasculogenesis and angiogenesis. Therefore, we studied the effect of mutant Pyk2 expression on the migration and proliferation in endothelial cells (ECs). Two types of mutant Pyk2 were examined by adenovirus vectors AxCA-Pyk2K457A, expressing a kinase inactive mutant, and AxCA-Pyk2Y402F, expressing a tyrosine autophosphorylation site mutant, in addition to AxCA-Pyk2, expressing wild-type Pyk2. Migration of ECs infected with AxCA-Pyk2Y402F increased to a level similar to that of ECs infected with AxCA-Pyk2. The size of effect was dependent on the amount of applied adenoviruses within the range of 3-30 multiplicity of infection. In contrast, AxCA-Pyk2K457A infection did not show any significant effect on cell migration. Western blotting showed that both phosphorylation of Pyk2 Y(881) and association of p130(Cas) with Pyk2 were enhanced in ECs infected with AxCA-Pyk2Y402F as well as with AxCA-Pyk2, but not in ECs infected with AxCA-Pyk2K457A. Therefore, signaling mediated by Pyk2 Y(881) and p130(Cas) may be involved in the migration of ECs infected either with AxCA-Pyk2Y402F or with AxCA-Pyk2. In proliferation assay, AxCA-Pyk2 infection suppressed EC proliferation significantly; however, neither AxCA-Pyk2Y402F nor AxCA-Pyk2K457A showed such an inhibitory effect. Thus, the two Pyk2 mutants revealed that Pyk2 signaling differentially regulates cell migration and proliferation pathways.