The integrated incretin effect is reduced by both glucose intolerance and obesity in Japanese subjects.

Introduction: Incretin-based drugs are extensively utilized in the treatment of type 2 diabetes (T2D), with remarkable clinical efficacy. These drugs were developed based on findings that the incretin effect is reduced in T2D. The incretin effect in East Asians, whose pancreatic ß-cell function is more vulnerable than that in Caucasians, however, has not been fully examined. In this study, we investigated the effects of incretin in Japanese subjects. Methods: A total of 28 Japanese subjects (14 with normal glucose tolerance [NGT], 6 with impaired glucose tolerance, and 8 with T2D) were enrolled. Isoglycemic oral (75 g glucose tolerance test) and intravenous glucose were administered. The numerical incretin effect and gastrointestinally-mediated glucose disposal (GIGD) were calculated by measuring the plasma glucose and entero-pancreatic hormone concentrations. Results and discussion: The difference in the numerical incretin effect among the groups was relatively small. The numerical incretin effect significantly negatively correlated with the body mass index (BMI). GIGD was significantly lower in participants with T2D than in those with NGT, and significantly negatively correlated with the area under the curve (AUC)-glucose, BMI, and AUC-glucagon. Incretin concentrations did not differ significantly among the groups. We demonstrate that in Japanese subjects, obesity has a greater effect than glucose tolerance on the numerical incretin effect, whereas GIGD is diminished in individuals with both glucose intolerance and obesity. These findings indicate variances as well as commonalities between East Asians and Caucasians in the manifestation of incretin effects on pancreatic ß-cell function and the integrated capacity to handle glucose.

Gestational Ectopic Hyperparathyroidism: A Case Report of Perioperative and Perinatal Outcomes.

In the realm of obstetric care, discerning the subtle signs of primary hyperparathyroidism (PHPT) amidst common pregnancy symptoms remains a formidable challenge. Our exploration into a case of gestational hypercalcemia peels back the layers of this complexity, revealing the clinical conundrum posed by overlapping gastrointestinal manifestations. The journey from diagnosis through surgical intervention to the resolution of symptoms underscores the importance of vigilance for PHPT in pregnant patients. This case further prompts consideration of gamma-aminobutyric acid (GABA) as a potential piece in the puzzle of persistent symptoms post-calcium normalization, inviting a broader dialogue on the intricacies of parathyroid pathology in pregnancy.

Successful Treatment of Postprandial Hyperinsulinemic Hypoglycemia After Billroth-II Gastrojejunostomy Using Octreotide.

Postprandial hyperinsulinemic hypoglycemia, although rare, is a well-documented complication that can manifest after upper gastrointestinal surgery. Despite its potential for severe morbidity, the underlying pathogenesis and optimal treatment strategies for this condition remain insufficiently understood. This report presents a compelling case of postprandial hypoglycemia following Billroth-II gastrojejunostomy, characterized by a marked increase in postprandial insulin levels, accompanied by the exaggerated response of incretin hormones. The incretin effect in this patient was found to be exceptionally high, measuring at approximately 90%. While nutritional interventions proved ineffective in alleviating the patient's symptoms, the administration of octreotide significantly attenuated the exaggerated postprandial insulin and incretin response, substantially ameliorating both the symptoms and postprandial hypoglycemia. Monthly subcutaneous injections of long-acting repeatable octreotide were initiated, resulting in the complete resolution of symptomatic postprandial hypoglycemia. Although the patient developed acalculous cholecystitis and gallstone cholangitis 2 years after commencing octreotide therapy, she has remained free from symptomatic postprandial hypoglycemia for more than 4 years. Our case underscores the efficacy of somatostatin analogs in the management of postprandial hyperinsulinemia after gastrointestinal surgery, shedding light on the potential involvement of incretin hormones in the pathophysiology of this condition.

A Case of Lymphocytic Infundibulo-neurohypophysitis Exhibiting Spontaneous Regression.

Lymphocytic infundibulo-neurohypophysitis (LINH) is a rare autoimmune inflammatory process that selectively affects the neurohypophysis and the pituitary stalk, typically presenting with central diabetes insipidus (CDI). LINH is considered underdiagnosed because the definitive diagnosis requires invasive pituitary surgery with a high risk of complications. We present a case of CDI resulting from LINH, which was treated with conservative management, eschewing both glucocorticoid treatment and pituitary surgery. At presentation, the hormonal assessment indicated the presence of CDI without anterior pituitary dysfunction. Magnetic resonance imaging revealed stalk thickening without a posterior pituitary bright spot, and anti-rabphilin-3A antibodies were positive in serum. Collectively, we made a diagnosis of LINH. Considering that the patient did not exhibit any symptoms of mass effect, we chose conservative treatment with desmopressin acetate. One year later, the stalk thickening regressed spontaneously without surgical or glucocorticoid treatment, although the posterior pituitary bright spot remained absent, and CDI did not improve. The inflammatory process of LINH is mostly self-limited and recovers spontaneously, whereas life-long desmopressin treatment may be required because of pituitary stalk fibrosis and atrophy. Our case highlights the importance of noninvasive diagnosis and careful follow-up in preventing unnecessary interventions for patients with LINH.

Ovarian Hyperstimulation Syndrome Caused by Functional Gonadotroph Pituitary Adenoma.

Functional gonadotroph adenomas (FGAs) are rare, manifesting symptoms like menstrual irregularities or ovarian hyperstimulation syndrome (OHSS). We present a case of OHSS caused by an FGA during the follow-up of a pituitary tumor initially considered nonfunctioning. The patient presented with lower abdominal pain, abdominal swelling, and dyspnea. Magnetic resonance imaging (MRI) revealed 15 cm enlarged ovarian cysts and pleural effusion. Laboratory examination showed an elevated serum estradiol (E2) level (5741.4 pmol/L [1564.0 pg/mL]), suppressed luteinizing hormone, and nonsuppressed follicular-stimulating hormone (FSH). However, no pituitary hormone disorders were observed when a 19 mm pituitary tumor was discovered 11 months prior. Given the absence of human chorionic gonadotropin (hCG) administration, OHSS due to the FGA was suspected. Cabergoline, known for alleviating the severity of OHSS, was administered, but the ovarian cysts continued to enlarge. Subsequently, endoscopic transsphenoidal surgery was performed, and immunohistochemical analysis confirmed the diagnosis of the FSH-producing adenoma. Follow-up MRI scans showed reduced ovarian cysts and successful pituitary tumor resection with a reduced E2 level. This case highlights the importance of considering FGAs when encountering OHSS without hCG administration or following up on pituitary tumors in premenopausal female patients to take appropriate measures for accurate diagnosis and management.

Efficacy of antihyperglycemic therapies on cardiovascular and heart failure outcomes: an updated meta-analysis and meta-regression analysis of 35 randomized cardiovascular outcome trials.

BACKGROUND: Effects of antihyperglycemic therapies on cardiovascular and heart failure (HF) risks have varied widely across cardiovascular outcome trials (CVOTs), and underlying factors remain incompletely understood. We aimed to determine the relationships of glycated hemoglobin (HbA1c) or bodyweight changes with these outcomes in all CVOTs of antihyperglycemic therapies. METHODS: We searched PubMed and EMBASE up to 25 January 2023 for all randomized controlled CVOTs of antihyperglycemic therapies reporting both major adverse cardiovascular events (MACE) and HF outcomes in patients with type 2 diabetes or prediabetes. We performed meta-regression analyses following random-effects meta-analyses to evaluate the effects of HbA1c or bodyweight reductions on each outcome. RESULTS: Thirty-five trials comprising 256,524 patients were included. Overall, antihyperglycemic therapies reduced MACE by 9% [risk ratio (RR): 0.91; 95% confidence interval (CI) 0.88-0.94; P < 0.001; I2 = 36.5%]. In meta-regression, every 1% greater reduction in HbA1c was associated with a 14% reduction in the RR of MACE (95% CI 4-24; P = 0.010), whereas bodyweight change was not associated with the RR of MACE. The magnitude of the reduction in MACE risk associated with HbA1c reduction was greater in trials with a higher baseline prevalence of atherosclerotic cardiovascular disease. On the other hand, antihyperglycemic therapies showed no overall significant effect on HF (RR: 0.95; 95% CI 0.87-1.04; P = 0.28; I2 = 75.9%). In a subgroup analysis based on intervention type, sodium-glucose cotransporter-2 inhibitors (SGLT2i) conferred the greatest HF risk reduction (RR: 0.68; 95% CI 0.62-0.75; P < 0.001; I2 = 0.0%). In meta-regression, every 1 kg bodyweight reduction, but not HbA1c reduction, was found to reduce the RR of HF by 7% (95% CI 4-10; P < 0.001); however, significant residual heterogeneity (P < 0.001) was observed, and SGLT2i reduced HF more than could be explained by HbA1c or bodyweight reductions. CONCLUSIONS: Antihyperglycemic therapies reduce MACE in an HbA1c-dependent manner. These findings indicate that HbA1c can be a useful marker of MACE risk reduction across a wide range of antihyperglycemic therapies, including drugs with pleiotropic effects. In contrast, HF is reduced not in an HbA1c-dependent but in a bodyweight-dependent manner. Notably, SGLT2i have shown class-specific benefits for HF beyond HbA1c or bodyweight reductions.

Exploratory study on glycemic control improvement for patients with diabetes mellitus by appropriate re-education on insulin self-injection technique during COVID-19 pandemic.

AIMS: To conduct a study on glycemic control improvement by appropriate re-education on the self-injection technique (SIT) in patients with diabetes mellitus undergoing insulin therapy. METHODS: Patients who received appropriate SIT and were treated with insulin for more than a year were re-educated. For the observation period of six months, the subjects' SIT was checked, and hemoglobin A1c (HbA1c) levels were measured at each visit. HbA1c levels, insulin doses, and behavioral changes in SIT were investigated at baseline and at the end of the observation period. RESULTS: In the per-protocol set population, the HbA1c level decreased by 0.2 % (2.0 mmol/mol) on average, showing a significant difference (p = 0.009). No significant difference was observed in the proportion of subjects with decreased HbA1c levels, changes in total daily insulin doses, or blood glucose levels. Four of the six SIT items covered by re-education were improved. CONCLUSIONS: Providing re-education on insulin SIT was considered effective in reducing HbA1c levels and improving adherence to proper SIT.

Resolution of Visual Field Defect in Macroprolactinoma After Treatment With Cabergoline.

We report the case of a 49-year-old woman presenting with amenorrhea and progressive visual field defect for one month. Endocrinological workup revealed a high concentration of serum prolactin, and magnetic resonance imaging (MRI) showed pituitary macroadenoma with extrasellar extension as well as compression of optic nerves. Treatment with a dopamine agonist, cabergoline, for eight weeks led to the resolution of the visual field defect accompanied by a rapid decrease in the serum prolactin level. Follow-up MRI three months after the initial diagnosis revealed alleviation of visible mechanical compression of the optic chiasm by the tumor. We considered that the absence of retinal nerve damage and prompt initiation of cabergoline contributed to the rapid recovery of the visual acuity.

Plant sterol hyperabsorption caused by uncontrolled diabetes in a patient with a heterozygous ABCG5 variant.

Plant sterol intake is widely recommended for patients with cardiovascular risk factors based on the inhibitory effect on intestinal cholesterol absorption. Although plant sterols, once absorbed, can promote atherosclerosis, their intake is believed to be safe because of poor absorption, except in rare hyperabsorbers with homozygous ABCG5/8 mutations. We report a case of new-onset type 1 diabetes accompanied by hypercholesterolemia. At the initial presentation with diabetic ketoacidosis, the patient showed marked hypercholesterolemia. Whole-exome sequencing revealed a heterozygous pathogenic variant in ABCG5 (p.R419H). The initial serum plant sterol levels were markedly high (sitosterol 32.5 µg/mL, campesterol 66.0 µg/mL), close to the range observed in patients with homozygous ABCG5/8 mutations, which were largely reduced by insulin treatment without ezetimibe. The addition of ezetimibe normalized plant sterol levels. These findings provide the first evidence that uncontrolled diabetes plays a causal role in the pathogenesis of phytosterolemia.

Exploring a Suitable Marker of Glycemic Response to Dulaglutide in Patients with Type 2 Diabetes: A Retrospective Study.

INTRODUCTION: Previous studies suggested that ß-cell function markers such as fasting and postprandial serum C-peptide and C-peptide increment (FCPR, PCPR, and ΔCPR, respectively) may be useful in estimating glycemic response to glucagon-like peptide-1 receptor agonists. However, it remains elusive whether baseline glycemic control confounds these markers. Here we aimed to identify the least confounded ß-cell function markers and investigate whether these markers could predict glycemic response to dulaglutide. METHODS: We evaluated FCPR, PCPR, and ΔCPR levels in patients with type 2 diabetes who initiated dulaglutide treatment after a standardized meal tolerance test (MTT). We first investigated the confounding effects of baseline HbA1c on ß-cell function markers using Pearson's correlation test. Then, we evaluated the association between each ß-cell function marker and glycemic response (HbA1c change 0-6 months) to dulaglutide using generalized linear model and logistic regression analysis with adjustment for baseline HbA1c. RESULTS: In 141 patients, baseline HbA1c was significantly inversely correlated with PCPR and ΔCPR (P < 0.01 for both) but not with FCPR (r = 0.02; P = 0.853), suggesting that FCPR was the marker least confounded by baseline glycemic control. Of all patients, 59 continued dulaglutide for at least 6 months without initiating any additional glucose-lowering medications. Mean ± SE HbA1c change 0-6 months was - 1.16 ± 0.17% (P < 0.001 vs. baseline). The ß-cell function markers were significantly associated with HbA1c change 0-6 months in the generalized linear model. FCPR was also a significant predictor for achieving a reduction in HbA1c of at least 1% (P = 0.044) with an area under the receiver operating characteristic curve of 0.83 (sensitivity = 0.81 and specificity = 0.79). CONCLUSION: Fasting and meal-induced C-peptide levels are associated with glycemic response to dulaglutide, among which FCPR is least confounded by baseline glycemic control, suggesting its utility as a marker for glycemic response to dulaglutide.

First Japanese Family With PDX1-MODY (MODY4): A Novel PDX1 Frameshift Mutation, Clinical Characteristics, and Implications.

CONTEXT: The PDX1 gene encodes pancreatic and duodenal homeobox, a critical transcription factor for pancreatic ß-cell differentiation and maintenance of mature ß-cells. Heterozygous loss-of-function mutations cause PDX1-MODY (MODY4). CASE DESCRIPTION: Our patient is an 18-year-old lean man who developed diabetes at 16 years of age. Given his early-onset age and leanness, we performed genetic testing. Targeted next-generation sequencing and subsequent Sanger sequencing detected a novel heterozygous frameshift mutation (NM_00209.4:c.218delT. NP_000200.1: p.Leu73Profs*50) in the PDX1 transactivation domain that resulted in loss-of-function and was validated by an in vitro functional study. The proband and his 56-year-old father, who had the same mutation, both showed markedly reduced insulin and gastric inhibitory polypeptide (GIP) secretion compared with the dizygotic twin sister, who was negative for the mutation and had normal glucose tolerance. The proband responded well to sitagliptin, suggesting its utility as a treatment option. Notably, the proband and his father showed intriguing phenotypic differences: the proband had been lean for his entire life but developed early-onset diabetes requiring an antihyperglycemic agent. In contrast, his father was overweight, developed diabetes much later in life, and did not require medication, suggesting the oligogenic nature of PDX1-MODY. A review of all reported cases of PDX1-MODY also showed heterogeneous phenotypes regarding onset age, obesity, and treatment, even in the presence of the same mutation. CONCLUSIONS: We identified the first Japanese family with PDX1-MODY. The similarities and differences found among the cases highlight the wide phenotypic spectrum of PDX1-MODY.

Sporadic Pseudohypoparathyroidism Type 1B in Monozygotic Twins: Insights Into the Pathogenesis of Methylation Defects.

CONTEXT: Sporadic pseudohypoparathyroidism type 1B (sporPHP1B) is an imprinting disease without a defined genetic cause, characterized by broad methylation changes in differentially methylated regions (DMRs) of the GNAS gene. OBJECTIVE: This work aims to provide insights into the causative event leading to the GNAS methylation defects through comprehensive molecular genetic analyses of a pair of female monozygotic twins concordant for sporPHP1B who were conceived naturally, that is, without assisted reproductive techniques. METHODS: Using the leukocyte genome of the twins and family members, we performed targeted bisulfite sequencing, methylation-sensitive restriction enzyme (MSRE)-quantitative polymerase chain reaction (qPCR), whole-genome sequencing (WGS), high-density single-nucleotide polymorphism (SNP) array, and Sanger sequencing. RESULTS: Methylation analyses by targeted bisulfite sequencing and MSRE-qPCR revealed almost complete losses of methylation at the GNAS AS, XL, and A/B DMRs and a gain of methylation at the NESP55 DMR in the twins, but not in other family members. Except for the GNAS locus, we did not find apparent methylation defects at other imprinted genome loci of the twins. WGS, SNP array, and Sanger sequencing did not detect the previously described genetic defects associated with familial PHP1B. Sanger sequencing also ruled out any novel genetic alterations in the entire NESP55/AS region. However, the analysis of 28 consecutive SNPs could not exclude the possibility of paternal heterodisomy in a span of 22 kb comprising exon NESP55 and AS exon 5. CONCLUSION: Our comprehensive analysis of a pair of monozygotic twins with sporPHP1B ruled out all previously described genetic causes. Twin concordance indicates that the causative event was an imprinting error earlier than the timing of monozygotic twinning.

Metformin-associated lactic acidosis exacerbated by acute kidney injury in an overseas traveler.

We report the case of metformin-associated lactic acidosis (MALA) exacerbated by acute kidney injury (AKI) in a 65-year-old Asian American woman who was an overseas traveler. She had vomiting and diarrhea before arriving in Osaka, Japan, from the Philippines. She suffered from worsening respiratory distress, consciousness loss and anuria the day after coming to Japan. When she arrived at our emergency room via ambulance, she appeared to be in a state shock. Arterial blood gas analysis revealed severe lactic acidosis (pH 6.681, PO2 302 Torr under O2 supplementation, PCO2 15 Torr, HCO3-1.7 mmol/L, and lactate 17.00 mmol/L). She also had renal failure (BUN 108 mg/dL and serum creatinine 8.68 mg/dL) with hyperkalemia (6.1 mEq/L). We collected medical information from family members, and found her prescription medicines including metformin, diuretics and angiotensin-converting enzyme inhibitor (ACEI). We diagnosed her with MALA due to an unintended overdose of metformin resulting from acute kidney injury that can be induced by ACEI and diuretics in the volume-depleted condition. We immediately started hemodialysis therapy. Although she had a temporary cardiopulmonary arrest at the beginning of the treatment, her physical status was gradually improved and the severe acidemia resolved. On hospital day 4, she had urine and no longer needed hemodialysis therapy. On day 14, she was discharged and returned to the United States without noticeable sequelae. This is a case report of an overseas traveler who was successfully rescued through the collection of accurate medical information and understanding of the pathological condition.

Alu-Mediated MEN1 Gene Deletion and Loss of Heterozygosity in a Patient with Multiple Endocrine Neoplasia Type 1.

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder caused by mutations of the tumor suppressor gene MEN1. Most of the germline MEN1 gene mutations have been small mutations, and the whole gene deletion is rarely observed. In the present study, we revealed Alu retrotransposon-mediated de novo germline deletion of the whole MEN1 gene and somatic copy-neutral loss of heterozygosity (LOH) in a patient with MEN1. The patient is a 39-year-old woman who was referred to our department for the management of prolactinoma. She was also diagnosed with primary hyperparathyroidism and suspected of MEN1. Although nucleotide sequencing did not detect any MEN1 gene mutations, multiplex ligation-dependent probe amplification (MLPA) revealed a large germline deletion of the MEN1 gene. Subsequent quantitative polymerase chain reaction (qPCR)-based copy number mapping showed a monoallelic loss of approximately 18.5-kilobase region containing the whole MEN1 gene. Intriguingly, the 2 breakpoints were flanked by Alu repetitive elements, suggesting the contribution of Alu/Alu-mediated rearrangements (AAMR) to the whole MEN1 gene deletion. Furthermore, copy number mapping using MLPA and qPCR in combination with single nucleotide polymorphism analysis revealed copy-neutral LOH as a somatic event for parathyroid tumorigenesis. In conclusion, copy number mapping revealed a novel combination of Alu/Alu-mediated de novo germline deletion of the MEN1 gene and somatic copy-neutral LOH as a cytogenetic basis for the MEN1 pathogenesis. Moreover, subsequent in silico analysis highlighted the possible predisposition of the MEN1 gene to Alu retrotransposon-mediated genomic deletion.

Facilitating screening of Klinefelter syndrome among patients with diabetes.

Klinefelter syndrome (KS) is frequently complicated by diabetes. However, it is severely underdiagnosed due to a lack of reliable screening methods. We diagnosed two patients with KS at the Center for Diabetes and Endocrinology, Tazuke Kofukai Medical Research Institute Kitano Hospital, Osaka, Japan. By comparing the patients with 39 non-KS patients with diabetes, we propose a screening tool for KS in patients with diabetes.

"Switched" metabolic acidosis in mitochondrial diabetes mellitus.

A patient with mitochondrial diabetes mellitus developed diabetic ketoacidosis. During insulin treatment, although diabetic ketoacidosis improved, lactic acidosis unexpectedly worsened. This clinical course, named "switched metabolic acidosis," could reflect the unique pathophysiology of the mitochondrial disorder.

Solid-phase extraction treatment is required for measurement of active glucagon-like peptide-1 by enzyme-linked immunosorbent assay kit affected by heterophilic antibodies.

AIMS/INTRODUCTION: It is reported that interfering substances in the blood might influence the value for measurement of active glucagon-like peptide-1 (GLP-1) in human plasma. Solid phase extraction (SPE) pretreatment is recommended to reduce their influence, but it requires a lot of cost and time. However, there is little investigation about causative inhibitory substances and about methods that can replace solid phase extraction. In the present study, we aimed to seek the candidate of the substances that might interfere with an active GLP-1 enzyme-linked immunosorbent assay (ELISA). MATERIALS AND METHODS: Two kinds of active GLP-1 ELISA kits using different antibodies, plural extraction carriers and elution solutions were used to evaluate the SPE method. Active GLP-1 concentration was compared with or without SPE, and with or without a heterophilic blocking tube. RESULTS: Active GLP-1 values were often higher without SPE compared with those with SPE pretreatment. This difference was eliminated by pretreatment with a heterophilic blocking tube or ELISA kits that did not use a mouse monoclonal antibody, and was independent of SPE. CONCLUSIONS: Substances absorbed to a heterophilic blocking tube carrier might interfere with an active GLP-1 immunoassay. Solid-phase extraction treatment is required for measurement of active GLP-1 by an ELISA kit affected by heterophilic antibodies.

Medication Episode Construction Framework for Retrospective Database Analyses of Patients With Chronic Diseases.

OBJECTIVE: For chronic diseases, medical history reconstruction is essential for retrospective database analyses. One important aspect is determining which prescriptions belong to the same episode. However, a standard framework for this task is still lacking, particularly for multitherapy datasets. This paper presents a medication episode construction framework for the medical history of patients with chronic diseases. METHODS: Allen's relaxed temporal relations (i.e., temporal relations with time constraints relaxed by ) is used to define the consecutive prescription relations considering the patients' behavior. For example, patients occasionally arrive earlier or later than their appointment. RESULTS: influences the generation of stable periods (i.e., periods of time, at least three months, in which a medication is continuously taken by a patient). When using the lowest selected value (7 days), considerably fewer shorter stable periods (for durations less than 300 days) are produced and more longer stable periods are produced compared to cases without using . Furthermore, the results show that by using , regarding the number of events, where a stable period continues the previous stable period, decreases and the number of medication transition events available to be observed increases. CONCLUSION: Using in medication episode construction from multitherapy prescription datasets enables the longer expression of short-duration fragmented prescriptions and pruning repetitive prescriptions. SIGNIFICANCE: Our proposed framework is designed for multitherapy datasets, which has not been addressed by previous studies. The concept of relaxes the prescription relation against noise caused by the patient behavior and consequently provides a compact, but informative search space for observing medication transition events in a longitudinal analysis.