Hypereosinophilia is a predictive biomarker of immune checkpoint inhibitor-induced hypopituitarism in patients with renal cell carcinoma.

BACKGROUND: This study aimed to evaluate whether hypereosinophilia is a clinical biomarker of immune checkpoint inhibitor-induced hypopituitarism in patients with renal cell carcinoma treated with nivolumab plus ipilimumab. METHODS: This was a retrospective cohort study conducted at Jichi Medical University Saitama Medical Center between January 2018 and December 2020. In total, 12 patients with renal cell carcinoma who presented with immune checkpoint inhibitor-induced hypopituitarism were enrolled in this study. The clinical parameters and symptoms at baseline, last visit, and onset of hypopituitarism were analyzed. RESULTS: The median period from the initial treatment with immune checkpoint inhibitors to the onset of hypopituitarism was 82.5 (range: 56-196) days. Most patients developed hypopituitarism within 6 months. One patient presented with hypophysitis and 11 patients presented with isolated adrenocorticotropic hormone deficiency. The major symptoms noted at onset were fatigue (66.7%) and loss of appetite (41.7%). None of the patients had symptoms during the last visit. However, four developed hypereosinophilia. Eosinophil fraction (%) and eosinophil count (/µL) increased during the last visit and at the onset of hypopituitarism, respectively. The serum sodium and plasma glucose levels were similar. CONCLUSIONS: The eosinophil count increased before the onset of hypopituitarism. Thus, hypereosinophilia can be an early predictor of hypopituitarism.

Daily variability in serum levels of calciprotein particles and their association with mineral metabolism parameters: A cross-sectional pilot study.

AIM: Calciprotein particles (CPPs), colloidal protein-mineral nanoparticles composed of solid-phase calcium phosphate and serum protein fetuin-A found in blood, are emerging as a novel component of chronic kidney disease-mineral and bone disorder (CKD-MBD). The relationship of CPPs with factors known to underlie the CKD-MBD pathophysiology is not well known.The aim of this study is to examine daily variations in CPPs as well as their association with mineral metabolism parameters in normal individuals and early-stage CKD patients. METHODS: Twenty subjects (10 healthy adults, 10 diabetic patients) were enrolled. Serum CPP Fetuin-A was measured and analyzed in relation to clinical parameters. RESULTS: Estimated glomerular filtration rates (eGFR) were 103 ± 11 and 75 ± 24 mL/min per 1.73 m2 in healthy adults and diabetic patients, respectively. Serum CPP Fetuin-A (g/L) were elevated at postprandial 2 h in diabetic patients. Furthermore, serum CPP Fetuin-A were inversely correlated with eGFR and serum 1,25-dihydroxyvitamin D3 and magnesium levels and were positively correlated with serum fibroblast growth factor-23. CONCLUSIONS: These findings indicated that serum CPP Fetuin-A were affected by food intake and may contribute to the pathophysiology of mineral metabolism in subjects with normal and moderately impaired renal function.

Glucose and GTP-binding protein-coupled receptor cooperatively regulate transient receptor potential-channels to stimulate insulin secretion [Review].

In pancreatic ß-cells, glucose-induced closure of the ATP-sensitive K+ (KATP) channel is an initial process triggering glucose-stimulated insulin secretion (GSIS). This KATP-channel dependent pathway has been believed to be a central mechanism for GSIS. However, since the resting membrane potential of cells is determined by the balance of the net result of current amplitudes in outward and inward directions, it must be taken into consideration that not only KATP channel inhibition but also inward current via the basal opening of non-selective cation channels (NSCCs) plays a crucial role in membrane potential regulation. The basal activity of NSCCs is essential to effectively evoke depolarization in concert with KATP channel closure that is dependent on glucose metabolism. The present study summarizes recent findings regarding the roles of NSCCs in GSIS and GTP-binding protein coupled receptor-(GPCR) operated potentiation of GSIS.

Retrospective Study of IDegLira, a New Fixed-Ratio Combination, in Japanese Patients With Type 2 Diabetes Mellitus: Analysis of Background Factors Affecting Effectiveness After 6 Months of Treatment.

Background: The aim of the study was to provide real-world data on the effectiveness and safety of a new fixed-ratio combination, insulin degludec/liraglutide (IDegLira) injection in Japanese patients with type 2 diabetes mellitus (T2DM). Methods: The primary endpoint was the change in glycated hemoglobin (HbA1c) level 6 months after the introduction of IDegLira. We also examined the rate of achievement of target HbA1c 7% and the individualized HbA1c targets set for each patient. Baseline characteristics associated with the change in HbA1c were also assessed. Seventy-five patients with T2DM were included in the analysis. Results: After the initiation of IDegLira, HbA1c decreased significantly from baseline with a change of -1.81% (baseline 9.61% and at 6 months 7.80%; P < 0.001). At baseline, the achievement rate of 7% HbA1c was 2.67% (n = 2), which increased to 36.0% (n = 27) after 6 months of IDegLira introduction (P < 0.05). The attainment rate of individualized HbA1c targets, which were set considering each patient's characteristics, improved from 2.67% (n = 2) to 49.3% (n = 37) (P < 0.001). Regardless of sex, body mass index, estimated glomerular filtration rate, duration of diabetes, or history of glucagon-like peptide-1 receptor agonist use, IDegLira significantly reduced HbA1c, but a higher C-peptide index was associated with a greater reduction in HbA1c. Conclusion: In this study, initiation of IDegLira in a real-world clinical setting was beneficial in lowering HbA1c in Japanese T2DM patients with inadequate glycemic control with existing therapy.

Retrospective Analysis of the Effectiveness of Oral Semaglutide in Type 2 Diabetes Mellitus and Its Effect on Cardiometabolic Parameters in Japanese Clinical Settings.

Glucagon-like peptide-1 receptor agonists (GLP-1RA) have a more potent glycated hemoglobin (HbA1c)-lowering effect than existing therapies and are widely used for treating type 2 diabetes mellitus (T2DM). Once-daily oral semaglutide is the world's first oral GLP-1RA. This study aimed to provide real-world data on oral semaglutide in Japanese patients with T2DM and its effects on cardiometabolic parameters. This was a single-center retrospective observational study. We examined changes in HbA1c and body weight (BW) and the rate of achieving HbA1c < 7% after 6 months of oral semaglutide treatment in Japanese patients with T2DM. Furthermore, we examined differences in the efficacy of oral semaglutide with multiple patient backgrounds. A total of 88 patients were included in this study. Overall, the mean (standard error of the mean) HbA1c at 6 months decreased by -1.24% (0.20%) from baseline, and BW at 6 months (n = 85) also decreased by -1.44 kg (0.26 kg) from baseline. The percentage of patients who achieved HbA1c < 7% changed significantly from 14% at baseline to 48%. HbA1c decreased from baseline regardless of age, sex, body mass index, chronic kidney disease, or diabetes duration. Additionally, alanine aminotransferase, total cholesterol, triglyceride, and non-high-density lipoprotein cholesterol were significantly reduced from baseline. Oral semaglutide may be an effective option for the intensification of therapy in Japanese patients with T2DM who have inadequate glycemic control with existing therapy. It may also reduce BW and improve cardiometabolic parameters.

Effectiveness and Safety of Once-Weekly Semaglutide in Japanese Patients with Type 2 Diabetes in Treatment Intensification: A Retrospective Observational Single-Center Study.

INTRODUCTION: Once-weekly (OW) glucagon-like peptide 1 receptor agonist (GLP-1RA) semaglutide has been shown to have a more potent glycated hemoglobin (HbA1c)-lowering effect than other oral hypoglycemic agents and existing GLP-1RAs in global randomized controlled trials. The study aim was to evaluate the safety and effectiveness of OW semaglutide in Japanese patients with type 2 diabetes mellitus (T2DM) in a real-world clinical setting and identify pre- and post-treatment predictors of good response. METHODS: We investigated the change in HbA1c, percentage of patients achieving < 7% HbA1c, and factors contributing to the effect 6 months after OW semaglutide use in Japanese patients with T2DM. We also examined differences in effectiveness between patients with different backgrounds. RESULTS: At baseline, the 77 patients had a mean baseline HbA1c of 8.1% ± 1.23%, 74% of the patients were injecting another GLP-1RA, and 42.9% of the patients were being treated with insulin. HbA1c decreased by 0.89% and by 0.66% in the other GLP-1RA users. The rate of achievement of < 7% HbA1c increased from 21% to 43%. There were no differences in effect by age, sex, or body mass index. Higher baseline HbA1c and shorter duration of diabetes were associated with greater HbA1c reduction. OW semaglutide was tolerable for the majority of our study population. CONCLUSION: This study provided real-world evidence showing that OW semaglutide significantly reduced HbA1c in Japanese patients with T2DM who had inadequate HbA1c control.

A novel mechanism of imeglimin-mediated insulin secretion via the cADPR-TRP channel pathway.

AIMS/INTRODUCTION: Imeglimin is a novel oral hypoglycemic agent that improves blood glucose levels through multiple mechanisms of action including the enhancement of glucose-stimulated insulin secretion (GSIS), however, the details of this mechanism have not been clarified. In the process of GSIS, activation of the transient receptor potential melastatin 2 (TRPM2) channel, a type of non-selective cation channel (NSCCs) in ß-cells, promotes plasma membrane depolarization. The present study aimed to examine whether imeglimin potentiates GSIS via the TRPM2 channel in ß-cells. MATERIALS AND METHODS: Pancreatic islets were isolated by collagenase digestion from male wild-type and TRPM2-knockout (KO) mice. Insulin release and nicotinamide adenine dinucleotide (NAD+ ) production in islets were measured under static incubation. NSCC currents in mouse single ß-cells were measured by patch-clamp experiments. RESULTS: Batch-incubation studies showed that imeglimin enhanced GSIS at stimulatory 16.6 mM glucose, whereas it did not affect basal insulin levels at 2.8 mM glucose. Imeglimin increased the glucose-induced production of NAD+ , a precursor of cADPR, in islets and the insulinotropic effects of imeglimin were attenuated by a cADPR inhibitor 8-Br-cADPR. Furthermore, imeglimin increased NSCC current in ß-cells, and abolished this current in TRPM2-KO mice. Imeglimin did not potentiate GSIS in the TRPM2-KO islets, suggesting that imeglimin's increase of NSCC currents through the TRPM2 channel is causally implicated in its insulin releasing effects. CONCLUSIONS: Imeglimin may activate TRPM2 channels in ß-cells via the production of NAD+ /cADPR, leading to the potentiation of GSIS. Developing approaches to stimulate cADPR-TRPM2 signaling provides a potential therapeutic tool to treat type 2 diabetes.

Spontaneous recovery of immune checkpoint inhibitor-induced thyroiditis with high free T4 level: A case report.

We describe a case of severe hyperthyroidism with high free thyroxine and C-reactive protein levels, wherein thyroid function rapidly improved without treatment. In a similar case, conservative management with imaging follow-up can be considered.

Sodium-glucose cotransporter 2 inhibitors improved time-in-range without increasing hypoglycemia in Japanese patients with type 1 diabetes: A retrospective, single-center, pilot study.

AIMS/INTRODUCTION: Studies have shown that sodium-glucose cotransporter 2 (SGLT2) inhibitors increased time-in-range (TIR; percentage of time glucose level remains between 3.9 and 10.0 mmol/L [70-180 mg/dL]) and decreased glycemic variability in patients with type 1 diabetes. The aim of this study was to investigate the effects of SGLT2 inhibitors on TIR, glycemic variability and glucose control in Japanese patients with type 1 diabetes in a real clinical setting. MATERIALS AND METHODS: We designed a single-arm, retrospective cohort study to analyze data from patients starting to use ipragliflozin or dapagliflozin and who used a sensor-based flash glucose monitoring system between February 2019 and August 2019. We measured TIR, time above range >180 mg/dL (percentage of time with glucose level of >180 mg/dL or >10.0 mmol/L), time below range <70 mg/dL (percentage of time with glucose level of <70 mg/dL or <3.9 mmol/L), mean glucose and standard deviation, and coefficient of variation for glycemic variability, and then compared the data before and after SGLT2 inhibitors treatments. RESULTS: We enrolled 15 patients in the study. The total dosages of basal insulin decreased significantly, but the total doses of bolus insulin did not change significantly. TIR increased significantly by approximately 11.6%; the time below range <70 mg/dL remained unchanged; and the mean glucose and standard deviation decreased significantly, whereas the coefficients of variation did not. CONCLUSIONS: SGLT2 inhibitors improved TIR and the mean glucose level and standard deviation without increasing the time below range <70 mg/dL in patients with type 1 diabetes.

Risk Factors of Hypoglycemic Encephalopathy and Prolonged Hypoglycemia in Patients With Severe Hypoglycemia.

BACKGROUND: The aim of the study was to investigate risk factors of hypoglycemic encephalopathy (HE) in patients with severe hypoglycemia. METHODS: We retrospectively enrolled patients with severe hypoglycemia who were transported to the emergency department in an ambulance. We defined severe hypoglycemia as plasma glucose level < 60 mg/dL (or capillary levels < 50 mg/dL). HE was defined as severe hypoglycemia with altered level of consciousness (Glasgow coma scale < 12) and prolonged HE as coma or stupor lasting > 24 h after glucose administration. We compared several parameters between patients with and without HE and between prolonged and recovered patients. RESULTS: Included were 173 patients with severe hypoglycemia; of them, 94 were diagnosed with HE, with 12 of them prolonged HE. Glucose level in HE patients was lower than that in those without HE (P < 0.001). Moreover, we noted a significant difference in glucose levels between the prolonged and recovered groups. Furthermore, body temperature was higher in prolonged versus recovered patients (P = 0.0017). CONCLUSION: Blood glucose level may be correlated with severity of altered level of consciousness. In addition, body temperature may be related to coma or prolonged stupor.

Background Factors Determining the Introduction and Dosage of Insulin in Women With Gestational Diabetes Mellitus.

BACKGROUND: Gestational diabetes mellitus (GDM) is a risk for perinatal complication, and appropriate diagnosis of and intervention in this condition are important. This study aimed to identify patient factors associated with introduction and dosage of insulin, which is the main drug for treatment of GDM. METHODS: In total, 114 patients who had been diagnosed with GDM at our hospital were included in this study. We retrospectively collected clinical parameters of GDM patients, including how many times positive glucose tolerance test results were obtained, whether insulin was introduced, dosage of insulin, body weight, and infant weight. Background factors differing between the insulin introduction and non-introduction groups of GDM patients and parameters associated with the insulin dosage were analyzed. RESULTS: Insulin was introduced in 51 GDM patients (45%). In the insulin introduction group, the six-divided diet was less common and the 75-g glucose tolerance test result was positive a significantly greater number of times compared with the non-introduction group. The factor associated with the insulin introduction status was the number of positive 75-g glucose tolerance test results (odds ratio (OR) 2.04, 95% confidence interval (CI): 1.09 - 3.81, P value = 0.025). In addition, the insulin dosage was found to positively correlate with body weight in the non-pregnant state (P value = 0.005). CONCLUSIONS: The six-divided diet was effective for blood glucose control in GDM women. A positive correlation found between the insulin dosage and body weight in the non-pregnant state suggests the importance of proper pre-pregnancy body weight control.

Spontaneous pregnancy after full recovery from hypopituitarism caused by lymphocytic hypophysitis.

Lymphocytic hypophysitis (LyH) has been known to be associated with pregnancy. We herein report the case of a 33-year-old woman who underwent vaginal delivery without massive bleeding at 40 weeks of gestation. Because of the presence of headache and terrible fatigue after childbirth, she visited our hospital. Severe hyponatremia (Na, 118 mEq/L) and visual field abnormality was noted upon examination. MRI revealed pituitary enlargement with a swollen pituitary stalk, albeit at low signal intensity. Basal pituitary hormone levels were all reduced and remained low after exogenous administration of hypothalamic-releasing hormones. She was diagnosed with LyH and was started on prednisolone 60 mg/day. A month later, her pituitary function had gradually improved together with a decrease in pituitary enlargement and recovery of her visual field. The dose of prednisolone was gradually reduced and finally withdrawn 27 months later. After prednisolone withdrawal, her pituitary function remained normal despite the absence of any hormonal replacement. A year later, she became pregnant without medication and delivered a second baby without LyH recurrence. Thereafter, her pituitary function has been normal for more than 5 years. Two valuable observations can be highlighted from the case. First, the patient completely recovered from LyH through prompt prednisolone therapy during its initial phase and had almost normal pituitary function. Second, after recovery from LyH, she was able to undergo spontaneous pregnancy and deliver a baby. We believe that reporting incidences of spontaneous pregnancy after complete normalization of pituitary function in patients with LyH is of great significance. LEARNING POINTS: Females are more affected by LyH than males given its strong association with pregnancy.LyH possesses characteristic findings on pituitary MRI.Glucocorticoid therapy for LyH has been recommended as an effective treatment.A history of previous pregnancies does not increase the risk of developing AH in subsequent pregnancies.Early induction of high-dose prednisolone was therapeutically effective in treating LyH.

Association between Urinary Calcium Excretion and Estimated Glomerular Filtration Rate Decline in Patients with Type 2 Diabetes Mellitus: A Retrospective Single-center Observational Study.

Urinary calcium excretion is not known to predict progression of renal dysfunction in patients with type 2 diabetes mellitus. This study aimed to investigate associations between urinary calcium excretion and progression of estimated glomerular filtration rate (eGFR) in type 2 diabetic patients. This study was a retrospective, single-center, observational cohort study. We enrolled a total of 89 patients with type 2 diabetes mellitus and the average follow-up period was 7.2 ± 1.0 years. We divided patients into two groups based on the median of annual decline in the slope of eGFR, then defined the over-median population as the progressed group and under-median population as the non-progressed group. Median of annual decline in the slope of eGFR was −1.1 mL/min/1.73 m²/year. Correlation coefficient analysis showed positive correlation of urinary calcium excretion with eGFR (r = 0.39, p < 0.001). Multivariate logistic analysis showed that baseline eGFR and urinary calcium excretion were independent variables for progression of eGFR decline. Urinary calcium excretion could be a useful metabolic parameter for predicting decline in slope of eGFR in patients with type 2 diabetes mellitus.

The Urinary Phosphate to Serum Fibroblast Growth Factor 23 Ratio, Deemed the Nephron Index, Is a Useful Clinical Index for Early Stage Chronic Kidney Disease in Patients with Type 2 Diabetes: An Observational Pilot Study.

Renal function decline is associated with progressive type 2 diabetes mellitus, which causes mineral and bone disorders. In the present study, we defined the ratio of urinary phosphate excretion (mg/day) to serum fibroblast growth factor 23 as the nephron index. We examined changes in the nephron index in type 2 diabetes patients with early stage chronic kidney disease (stages 1-3), enrolling 15 patients and retrospectively analysing the follow-up data. After follow-up at 5.4 years, we observed no significant changes in the estimated glomerular filtration rate; the nephron index, however, was significantly reduced between the baseline and the follow-up. We propose that the nephron index may be potentially useful as a biomarker for monitoring the decline of renal function in the early stages of diabetic chronic kidney disease patients.

Effect of Liraglutide on Type B Insulin Resistance Syndrome and Insulin Allergy in Type 2 Diabetes: A Case Report.

INTRODUCTION: The appearance of anti-insulin antibodies or an allergy to insulin occasionally causes clinical problems with glycemic control in insulin users. METHODS: In the present report, we describe a therapeutic approach that was employed for a man with type 2 diabetes who had insulin allergy, anti-insulin antibodies, and anti-insulin receptor antibodies that developed during his insulin treatment. RESULTS: We started the patient on liraglutide, a glucagon-like peptide-1 receptor agonist, and attained glycemic control without incurring any side effects. Two years after liraglutide induction, his blood glucose was being maintained at a healthy level by liraglutide monotherapy. CONCLUSION: Liraglutide may be a therapeutic option for patients with insulin allergy, anti-insulin antibodies, and type B insulin resistance syndrome, as it represents an alternative strategy to insulin.

Diabetic ketoacidosis producing extreme hyperkalemia in a patient with type 1 diabetes on hemodialysis.

Diabetic ketoacidosis (DKA) is a critical complication of type 1 diabetes associated with water and electrolyte disorders. Here, we report a case of DKA with extreme hyperkalemia (9.0 mEq/L) in a patient with type 1 diabetes on hemodialysis. He had a left frontal cerebral infarction resulting in inability to manage his continuous subcutaneous insulin infusion pump. Electrocardiography showed typical changes of hyperkalemia, including absent P waves, prolonged QRS interval and tented T waves. There was no evidence of total body water deficit. After starting insulin and rapid hemodialysis, the serum potassium level was normalized. Although DKA may present with hypokalemia, rapid hemodialysis may be necessary to resolve severe hyperkalemia in a patient with renal failure. LEARNING POINTS: Patients with type 1 diabetes on hemodialysis may develop ketoacidosis because of discontinuation of insulin treatment.Patients on hemodialysis who develop ketoacidosis may have hyperkalemia because of anuria.Absolute insulin deficit alters potassium distribution between the intracellular and extracellular space, and anuria abolishes urinary excretion of potassium.Rapid hemodialysis along with intensive insulin therapy can improve hyperkalemia, while fluid infusions may worsen heart failure in patients with ketoacidosis who routinely require hemodialysis.