Preserved seasonal variation in glycemic control in patients with type 2 diabetes mellitus during COVID-19: a 3-year-long retrospective cohort study in older adults in Japan.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has changed our lifestyle by imposing restrictions, such as physical distancing. The effect of COVID-19 prevalence on seasonal variations in glycemic control in patients with diabetes mellitus (DM) remains unknown. METHODS: This single-center retrospective cohort study evaluated glycemic control in patients with type 2 DM who visited Sugi Cardiovascular Hospital in December 2021. We evaluated the clinical findings of all patients treated regularly between March 1, 2019, and December 31, 2021, including the periods both before and after the COVID-19 pandemic. All the standard treatments were approved. Furthermore, seasonal changes in hemoglobin A1c (HbA1c) levels were evaluated using stratified analyses based on age. RESULTS: This study analyzed 86 patients (mean age, 69.6 ± 9.2 years; men, 57). Median HbA1c (National Glycohemoglobin Standardization Program [Union of Clinical Chemistry]) levels in spring (March) were 7.70% (interquartile range (IQR):7.23%-8.30%) [60.6 mmol/mol (IQR:55.4-67.2 mmol/mol)], 7.35% (IQR:6.90%-7.90%) [56.8 mmol/mol (IQR:51.9-62.8 mmol/mol)], and 7.50% (IQR:7.10%-8.00%) [58.5 mmol/mol (IQR:54.1-63.9 mmol/mol)] in 2019, 2020, and 2021, respectively. During these periods, HbA1c levels and body mass index (BMI) revealed significant seasonal variations "high in spring" and "low in autumn." Median HbA1c levels in spring (March) and autumn (September) were 7.86% [61.2 mmol/mol] and 7.48% [57.4 mmol/mol] in 2019 (P < 0.001), 7.50% [57.7 mmol/mol] and 7.17% [54.2 mmol/mol] in 2020 (P < 0.001), and 7.61% [58.3 mmol/mol] and 7.19% [53.8 mmol/mol] in 2021 (P < 0.001). Seasonal variations in HbA1c levels and BMI were maintained over the past 3 years, including the pandemic period. None of the patients in this study developed COVID-19 during the study period. CONCLUSIONS: Seasonal variations in glycemic control in patients with DM were not influenced by lifestyle modifications associated with COVID-19. Maintenance of physical activity is necessary to prevent the development of sarcopenia. Moreover, seasonal variations in glycemic metabolism should be considered an independent factor for DM management. Additional extensive multifacility investigations are necessary to corroborate our findings.

Metyrosine-associated endocrinological changes in pheochromocytoma and paraganglioma.

Objective: Metyrosine (alpha-methyl-para-tyrosine) effectively reduces catecholamine levels in patients with pheochromocytoma/paraganglioma. However, improvements in physiological and metabolic parameters and changes in endocrine function associated with metyrosine administration should be validated in comparison to surgery. This study was performed to confirm the effects of metyrosine on the physiological, metabolic, and endocrinological functions of patients with pheochromocytoma/paraganglioma in the perioperative period. Design: This retrospective cohort study was performed at a single university hospital. Methods: We included ten patients with pheochromocytoma/paraganglioma who received oral metyrosine after α-blocker therapy and consecutive surgeries. Urinary catecholamine metabolite levels and other clinical parameters were evaluated before and after metyrosine administration, and 1 week after surgery. Results: The mean age was 53.1 ± 16.1 years. Of the ten participants (four men and six women), nine had pheochromocytoma and one had paraganglioma. The median maximum metyrosine dose was 750 mg/day. Urinary catecholamine metabolite levels significantly decreased in a dose-dependent manner after metyrosine administration. Both systolic and diastolic blood pressure significantly decreased after metyrosine and surgical treatment. Metyrosine administration significantly improved insulin sensitivity, although surgery improved the the basal insulin secretion. Additionally, serum prolactin and thyroid-stimulatory hormone levels were significantly increased by metyrosine treatment, whereas plasma renin activity was decreased. Conclusions: Metyrosine significantly reduced catecholamines in patients with pheochromocytoma/paraganglioma and ensured the safety of the surgery. Adjustment of metyrosine administration may make surgical pretreatment more effective in achieving stabilized blood pressure and improving glucose metabolism. Endocrine parameters may manifest as the systemic effects of metyrosine administration.

IgG4-Related Membranous Nephropathy with Acute Nephrotic Syndrome During Successful Steroid Maintenance Treatment for Type 1 Autoimmune Pancreatitis.

BACKGROUND Immunoglobulin G4 (IgG4)-related diseases (IgG4-RD) are systemic fibroinflammatory diseases that can develop asynchronously in multiple organs. IgG4-related kidney disease (IgG4-RKD) is generally characterized by tubulointerstitial nephritis but can also manifest as membranous nephropathy without tubulointerstitial nephritis. IgG4-related membranous nephropathy can present as a phenotype of systemic disorders, including autoimmune pancreatitis-associated diabetes mellitus; however, its clinical features remain unclear. CASE REPORT A 56-year-old Japanese man presented to our university hospital with bilateral edema of his lower legs. He had received a diagnosis of type 1 autoimmune pancreatitis and associated diabetes mellitus 16 months prior. He was successfully treated with oral glucocorticoids 25 mg/day of prednisolone as an initial dose, followed by titration down to a maintenance dose (5 mg/day), without recurrence of autoimmune pancreatitis. The pancreas showed atrophy and required basal-bolus insulin therapy owing to insulin insufficiency. Massive proteinuria and hypoalbuminemia with nephrotic syndrome on examination led to a renal biopsy to investigate the etiology and diagnosis of IgG4-RKD. Methylprednisolone and cyclosporine A were successfully administered to ameliorate the proteinuria and control systemic IgG4-RD with IgG4-related membranous nephropathy. CONCLUSIONS Ig4-RKD occurred despite maintenance treatment with prednisolone monotherapy and was controlled with methylprednisolone and cyclosporine A. Measurement of clinical parameters, including proteinuria, was important, and a renal biopsy finally established the diagnosis of IgG4-RKD. IgG4-RKD can present with progressive glomerular lesions and can be latent in cases diagnosed with diabetic kidney disease, particularly in patients with insulin insufficiency.

Eruptive xanthomas as a marker for metabolic disorders: A specific form of xanthoma that reflects hypertriglyceridemia.

Eruptive xanthomas are skin manifestations associated with hypertriglyceridemia. Accordingly, the improvement of hypertriglyceridemia can ameliorate this condition. We report a case of a patient with type 2 diabetes mellitus who was diagnosed with this skin lesion. Clinicians should be aware that eruptive xanthomas could indicate metabolic disorders associated with atherosclerosis.

Thyroid-related ophthalmopathy development in concurrence with growth hormone administration.

BACKGROUND: Thyroid stimulating hormone (TSH) receptor and local infiltrate lymphocytes have been considered as major pathological factors for developing thyroid-related ophthalmopathy. Overexpression of insulin-like growth factor-I (IGF-I) receptor has emerged as a promising therapeutic target for refractory patients. However, the relationship between activation of growth hormone (GH)/IGF-I receptor signaling and development or exacerbation of thyroid ophthalmopathy has not been elucidated. Herein we describe a case that provides further clarification into the association between thyroid-related ophthalmopathy and GH/IGF-I receptor signaling. CASE PRESENTATION: A 62-year-old Japanese female diagnosed with thyroid-related ophthalmopathy was admitted to Kurume University Hospital. She had received daily administration of GH subcutaneously for severe GH deficiency; however, serum IGF-I levels were greater than + 2 standard deviation based on her age and sex. She exhibited mild thyrotoxicosis and elevation in levels of TSH-stimulating antibody. Discontinuation of GH administration attenuated the clinical activity scores of her thyroid-related ophthalmopathy. Additionally, concomitant use of glucocorticoid and radiation therapies resulted in further improvement of thyroid-related ophthalmopathy. The glucocorticoid administration was reduced sequentially, followed by successful termination. Thereafter, the patient did not undergo recurrence of thyroid-related ophthalmopathy and maintained serum IGF-I levels within normal physiological levels. CONCLUSIONS: We describe here a case in which development of thyroid-related ophthalmopathy occurred upon initiation of GH administration. GH/IGF-I signaling was highlighted as a risk factor of developing thyroid-related ophthalmopathy. Additionally, aberrant TSH receptor expression was suggested to be a primary pathophysiological mechanism within the development of thyroid-related ophthalmopathy. Physicians should be aware of the risks incurred via GH administration, especially for patients of advanced age, for induction of thyroid-related ophthalmopathy.

Case Report: Metreleptin and SGLT2 Inhibitor Combination Therapy Is Effective for Acquired Incomplete Lipodystrophy.

Childhood cancer survivors (CCSs) who have undergone bone marrow transplantation with systemic chemotherapy and whole-body irradiation often experience impaired glucose tolerance with marked insulin resistance. Incomplete acquired diabetic lipodystrophy should be considered as a late complication of bone marrow transplantation. A 24-year-old Japanese female patient with incomplete acquired lipodystrophy, a CCS of acute lymphocytic leukemia at the age of 3 years, was treated for diabetes mellitus and dyslipidemia at our hospital. Administration of multiple daily insulin injections (70 units/day), and oral administration of 500 mg/day metformin, 15 mg/day pioglitazone, and 200 mg/day bezafibrate had proven ineffective for her metabolic disorders. Subcutaneous administration of metreleptin improved her insulin resistance and hypertriglyceridemia within a month; however, it failed to maintain adequate plasma glucose levels in the long term. When oral administration of 10 mg/day empagliflozin was added to the metreleptin supplementation, her HbA1c value (National Glycohemoglobin Standardization Program) improved from 11% to 8%, which was maintained for an additional 18 months. This is the first case report of incomplete lipodystrophy that shows efficacy of a combination therapy with metreleptin and a sodium glucose cotransporter 2 (SGLT2) inhibitor for the treatment of diabetes and dyslipidemia. An SGLT2 inhibitor attenuates hyperglycemia through urinary glucose excretion and has been suggested to enhance lipid catabolism in the extra-adipose tissues, especially in the liver and skeletal muscles. Furthermore, metreleptin supplementation could enhance the action of the SGLT2 inhibitor by promoting satiety and lipolysis through the central nervous system. Combination therapy with metreleptin and an SGLT2 inhibitor was suggested to recover the volume of adipose tissue, possibly through improvement of insulin resistance in the adipose tissue. This report highlights the pathophysiological mechanism of an SGLT2 inhibitor in the improvement of glucose metabolism in non-healthy lean CCSs with insulin resistance. Administration of SGLT2 inhibitor, along with metreleptin supplementation, could be a good alternative therapy for diabetic lipodystrophy observed in CCSs.

Improvement of skeletal muscle insulin sensitivity by 1 week of SGLT2 inhibitor use.

BACKGROUND AND AIMS: It is currently unclear whether sodium-glucose co-transporter 2 (SGLT2) inhibitor administration can improve the insulin sensitivity as well as rapidly reduce plasma glucose concentrations in humans during the early phase of treatment initiation. This study aimed to investigate the effect of SGLT2 inhibitor on insulin sensitivity in the early phase of treatment initiation. METHODS AND RESULTS: This single-center, open label, and single-arm prospective study recruited 20 patients (14 men) with type 2 diabetes mellitus (T2DM). We examined the patients' metabolic parameters before and 1 week after SGLT2 inhibitor (10 mg/day of empagliflozin) administration. The glucose infusion rate (GIR) was evaluated using the euglycemic hyperinsulinemic glucose clamp technique. Changes in laboratory and anthropometric parameters before and after SGLT2 inhibitor administration were analyzed according to the change in the GIR. The BMI, body fat amount, skeletal muscle amount, systolic blood pressure, and triglyceride level significantly decreased along with the treatment, while urinary glucose level and log GIR value significantly increased. Notably, changes in the GIR after SGLT2 inhibitor administration, which indicated improvement in peripheral insulin sensitivity, were negatively correlated with T2DM duration and positively with reduction in fluctuation of daily plasma glucose profiles before and after treatment. CONCLUSION: SGLT2 inhibitor improved insulin sensitivity in the skeletal muscle independent of anthropometric changes. Patients with short duration of T2DM and insulin resistance can be good candidates for short-term SGLT2 inhibitor administration to improve insulin sensitivity in the skeletal muscle.

Metreleptin Supplementation for Improving Lipid and Glycemic Profiles in Acquired Diabetes Lipodystrophy: A Case Report.

Most childhood cancer survivors who undergo hematopoietic stem cell transplantation subsequently develop impaired glucose tolerance and hypertriglyceridemia. These conditions are presumably associated with total-body irradiation-related acquired lipodystrophy and may lead to cardiovascular disease. Metreleptin (recombinant leptin) may help improve the lipoprotein profile, insulin sensitivity, and quality of life of patients with total-body irradiation-related lipodystrophy. This report describes the safe and effective use of metreleptin supplementation for insulin resistance and dyslipidemia in acquired incomplete lipodystrophy. A 24-year-old Japanese woman with diabetes mellitus and hypertriglyceridemia was admitted to our hospital. She was diagnosed with acute lymphocytic leukemia at 3 years of age and had undergone systemic chemotherapy and total-body irradiation before allogeneic stem cell transplantation. She was also diagnosed with hypertriglyceridemia and diabetes mellitus at 11 years of age. She had a low adiponectin level, low-normal leptin level, and diabetes mellitus with marked insulin resistance. Thus, acquired incomplete lipodystrophy was diagnosed. Her serum triglyceride and lipoprotein profiles improved within 1 month of treatment initiation. Glycemic metabolism and insulin sensitivity in the skeletal muscles improved after 6 months. As previously reported, metreleptin therapy is effective in improving lipid and glycemic profiles in generalized lipodystrophy. In the present case, we considered that metreleptin supplementation could reduce the remnant VLDL cholesterol fraction and improve diabetes mellitus. We conclude that it may be an effective alternative therapy for improving the expected prognosis of patients with acquired incomplete lipodystrophy, including childhood cancer survivors.

Human Leukocyte Antigen (HLA) Subtype-Dependent Development of Myasthenia Gravis, Type-1 Diabetes Mellitus, and Hashimoto Disease: A Case Report of Autoimmune Polyendocrine Syndrome Type 3.

BACKGROUND Patients with type 1 diabetes mellitus, myasthenia gravis (MG), and Hashimoto disease are diagnosed as having autoimmune polyendocrine syndrome type 3 (APS3). APS3 is rare, and its pathogenesis is unclear. We describe a female patient with APS3 whose human leukocyte antigen (HLA) type could provide a clue to the pathogenesis of APS3. CASE REPORT A 40-year-old Japanese female patient who had been diagnosed with MG at 5 years of age, and which had been treated with cholinesterase inhibitors, was referred to our hospital with thirst, polydipsia, polyuria, weight loss, and hyperglycemia. She was found to have type 1 diabetes mellitus based on laboratory tests. She was also positive for anti-thyroid peroxidase antibody and was thus diagnosed with Hashimoto disease. This combination of type 1 diabetes mellitus, myasthenia gravis, and Hashimoto disease led to a diagnosis of APS3. Her HLA serotype was A24; B46/54; DR4/9; DQ8/9, and genotype was A*24: 02; B*46: 01: 01/54: 01: 01; C*01: 02; DRB1*04: 06/09: 01: 02; DQB1*03: 02: 01/03: 03: 02; and DQA1*03: 01/03: 02: 01. We subsequently reviewed 10 cases of APS3 combined with MG, including the present case and cases reported in Japanese. This review revealed that HLA-DR9/DQ9 might be a specific HLA subtype associated with APS3 with MG. Four of the 10 cases had MG diagnosed before diabetes mellitus and autoimmune thyroid disease. CONCLUSIONS The present case showed that, in people with HLA-B46 and -DR9, antibody-negative MG can precede the development of APS3 by many years. Physicians should consider the possibility of APS3 when evaluating patients with ocular-type myasthenia gravis, and screen them for type 1 diabetes.

[Early onset of anti- erythropoietin antibody-mediated pure red cell aplasia after commencement of subcutaneous administration of epoetin-ß].

We report a 73-year-old Japanese man with early onset pure red cell aplasia (PRCA) caused by subcutaneous administration of recombinant epoetin-ß. Two months after the start of epoetin therapy, he developed PRCA. Anti-erythropoietin (EPO) antibody, detected in the patient's serum by enzyme immunoassay and radioimmunoprecipitation method, inhibited EPO-dependent growth of AS-E2 cells in vitro. Treatment with prednisone (1 mg/kg) significantly reduced antibody levels 3 months later. It is important to have an awareness of antibody-mediated PRCA. Our case shows that subcutaneous epoetin administration produces this complication in the early period of therapy.

TNF superfamily member 13, APRIL, inhibits allergic lung inflammation.

The T-cell functions of a proliferation-inducing ligand (APRIL, also known as TNFSF13) remain largely undefined. We previously showed that APRIL suppressed Th2 cytokine production in cultured CD4(+) T cells and Th2 antibody responses. Here we show that APRIL suppresses allergic lung inflammation, which is associated with diminished expression of the transcription factor c-maf. Mice deficient in the April gene (April(-/-) mice) had significantly aggravated lung inflammation compared with WT mice in the ovalbumin-induced allergic lung inflammation model. Likewise, blockade of APRIL in WT mice by the APRIL-receptor fusion protein, transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI)-Ig, enhanced lung inflammation. Transfer of APRIL-sufficient, ovalbumin-specific, TCR-transgenic CD4(+) T (OT-II) cells to April(-/-) mice restored the suppressive effect of APRIL on lung inflammation. Mechanistically, the expression of the Th2 cytokine transcription factor c-maf, but not GATA-3, was markedly enhanced in April(-/-) CD4(+) T cells at the RNA and protein level and under non-polarizing (Th neutral, ThN) and Th2-polarizing conditions. Since c-maf transactivates the IL-4 gene, the increased c-maf expression in April(-/-) mice readily explains increased Th2 cytokine production. Independent of its effect on IL-4, APRIL suppressed IL-13 expression. APRIL thus may regulate lung inflammation in a dual way, by acting on c-maf expression and by directly controlling IL-13 production.

APRIL (TNFSF13) regulates collagen-induced arthritis, IL-17 production and Th2 response.

A proliferation-inducing ligand (APRIL or TNFSF13) shares receptors with B-cell activation factor of the TNF family (BAFF) on B and T cells. Although much is known about the function of APRIL in B cells, its role in T cells remains unclear. Blocking both BAFF and APRIL suggested that BAFF and/or APRIL contributed to collagen-induced arthritis (CIA); however, the role of APRIL alone in CIA remained unresolved. We show here that, in vitro, our newly generated APRIL(-/-) mice exhibited increased T-cell proliferation, enhanced Th2 cytokine production under non-polarizing conditions, and augmented IL-13 and IL-17 production under Th2 polarizing conditions. Upon immunization with OVA and aluminum potassium sulfate, APRIL(-/-) mice responded with an increased antigen-specific IgG1 response. We also show that in APRIL(-/-) mice, the incidence of CIA was significantly reduced compared with WT mice in parallel with diminished levels of antigen-specific IgG2a autoantibody and IL-17 production. Our data indicate that APRIL plays an important role in the regulation of cytokine production and that APRIL-triggered signals contribute to arthritis. Blockade of APRIL thus may be a valuable adjunct in the treatment of rheumatoid arthritis.

Long-term follow-up after nonmyeloablative allogeneic hematopoietic stem cell transplantation for systemic sclerosis.

Systemic sclerosis (SSc) characteristically consists of fibrotic changes in various organs, and immunological abnormality is the main cause of the disease. Although high-dose immunosuppressive therapies with autologous or allogeneic hematopoietic stem cell support can reverse the disease course, they have a high treatment-related mortality. We report the successful use of nonmyeloablative allogeneic hematopoietic stem cell transplantation (HSCT) for SSc. A 40-year-old woman with diffuse scleroderma and interstitial pneumonia underwent allogeneic peripheral blood stem cell transplantation from an HLA-identical sibling after conditioning with low-dose total-body irradiation and fludarabine. Prophylaxis for graft-versus-host disease (GVHD) consisted of cyclosporine and mycophenolate mofetil. No infection or acute GVHD developed. One year after transplantation, the patient developed membranous glomerulopathy caused by chronic GVHD that was successfully treated with prednisolone. The patient's skin score decreased dramatically, and her pulmonary function is stable 4 years after transplantation. Nonmyeloablative allogeneic HSCT may be more effective than conventional therapies for SSc.

p16(INK4a) induces differentiation and apoptosis in erythroid lineage cells.

OBJECTIVE: Hematopoiesis is regulated by proliferation, differentiation, and death. p16(INK4a) has been reported to regulate apoptosis and differentiation of diverse cells, as well as arresting the cell cycle at G1 phase. The aim of this study is to explore the properties of p16 in apoptosis and differentiation of erythroid cells. METHODS: We transfected the INK4a gene to K562 cells, which defect the INK4a gene, and compared the effect of enforced expression of p16(INK4a) with that of various additives, topoisomerase I inhibitor (SN 38), interferon-alpha, phosphatidyl-inositol-3 kinase inhibitor (LY294002), and serum deprivation, which arrest cell cycle at different phases. We also investigated the role of p16(INK4a) in normal day-6 human erythroid colony-forming cells by transfecting the INK4a gene. RESULTS: p16(INK4a) induced cell cycle arrest at the G0/G1 phase, and promoted erythroid differentiation in viable K562 cells, but induced apoptosis in K562 cells with incomplete differentiation. The apoptosis induced by p16 was accompanied with downregulation of bcl-x and nuclear NF-kappaB. These findings were not observed in K562 cells treated with various additives. p16(INK4a) decreased the cell viability and promoted apoptosis in day-9 ECFC. CONCLUSION: We propose that p16(INK4a) plays a role in maintaining homeostasis during erythroid differentiation, and that the mechanisms for this effect are not confined to those inducing cell cycle arrest.

Clinical significance of telomerase activity in multiple myeloma.

BACKGROUND: The clinical course of patients with multiple myeloma varies, and therefore it is important to evaluate the disease state. We studied the telomerase activity of myeloma cells as a possible prognostic factor in such patients. METHODS: Twenty five samples from patients with multiple myeloma were studied. We purified myeloma cells in bone marrow samples according to the expression of surface antigens, CD38 and CD45. CD38+/CD45- or dim cells had morphologic characteristics of myeloma cells, with a purity exceeding 95%. The telomerase activity of myeloma cells was determined by a polymerase chain reaction-based telomeric repeat amplification protocol assay. Ki-67 positivity of the purified cells was determined by flow cytometry using anti-Ki-67 antibody. The relationship between telomerase activity and prognostic factors was also examined. RESULTS: A significantly high degree of telomerase activity was detected in subjects with a serum beta2-microglobulin level > or = 6 mg/dL or at Stage III (P = 0.002). The serum C-reactive protein, lactate dehydrogenase, and creatinine levels did not correlate with the telomerase activity, but this activity did significantly correlate with Ki-67 positivity and the percentage of plasma cells in the bone marrow (r = 0.561, P = 0.004, and r = 0.397, P = 0.049, respectively). The patients with high levels of telomerase activity were thus found to have a significantly short survival time after sampling (P = 0.035). CONCLUSIONS: The measurement of the telomerase activity in myeloma cells was found to be a reliable marker for the proliferating capacity and tumor mass in myeloma patients. The telomerase activity of myeloma cells may therefore be useful as a prognostic factor.