A case of insulinoma misidentified as schizophrenia due to its manifestation in neuropsychiatric symptoms.

Insulinomas can present with neuroglycopenic symptoms suggesting neuropsychiatric disorders, delaying diagnosis and treatment. We recently treated a 65-year-old woman with insulinoma who was misdiagnosed at her nearby psychiatric clinic as having schizophrenia because of personality changes and memory impairment; she was treated with brexpiprazole, which was discontinued due to persistence of the symptoms. Despite her relatively low casual plasma glucose (70 mg/dL), the physician at the psychiatric clinic did not investigate the possibility of hypoglycemia, partly because her HbA1c level (5.2%) was within normal range. After skipping lunch one day, she was found by her family to be unable to communicate properly. She was transported to the emergency room of our hospital, where intermittently scanning continuous glucose monitoring (isCGM) use permitted detection of the hypoglycemia and led to a diagnosis of insulinoma and successful resection. A 72-h fasting test established hyperinsulinemic hypoglycemia. Contrast-enhanced computed-tomography and endoscopic ultrasonography together with selective arterial calcium stimulation test revealed an insulin-secreting tumor in the tail of the pancreas. Surgical resection of the tumor corrected her glucose and insulin levels as well as eliminated the insulinoma neuropsychiatric symptoms. Pathological examination showed that the tumor was positive for chromogranin A, synaptophysin and insulin. It is, therefore, important for physicians to be aware that insulinomas can manifest as neuroglycopenic symptoms and to consider the possibility of hypoglycemia by careful medical interview and isCGM, especially when patients suspected of psychiatric disorders do not show the expected response to antipsychotic drugs. Supplementary Information: The online version contains supplementary material available at 10.1007/s13340-024-00722-9.

A consensus statement from the Japan Diabetes Society (JDS): a proposed algorithm for pharmacotherapy in people with type 2 diabetes-2nd Edition (English version).

The Japan Diabetes Society (JDS) adopted a sweeping decision to release consensus statements on relevant issues in diabetes management that require updating from time to time and launched a "JDS Committee on Consensus Statement Development." In March 2020, the committee's first consensus statement on "Medical Nutrition Therapy and Dietary Counseling for People with Diabetes" was published. In September 2022, a second consensus "algorithm for pharmacotherapy in people with type 2 diabetes" was proposed. In developing an algorithm for diabetes pharmacotherapy in people with type 2 diabetes, the working concept was that priority should be given to selecting such medications as would appropriately address the diabetes pathology in each patient while simultaneously weighing the available evidence for these medications and the prescribing patterns in clinical practice in Japan. These consensus statements are intended to present the committee's take on diabetes management in Japan, based on the evidence currently available for each of the issues addressed. It is thus hoped that practicing diabetologists will not fail to consult these statements to provide the best available practice in their respective clinical settings. Given that the persistent dual GIP/GLP-1 receptor agonist tirzepatide was approved in April 2023, these consensus statements have been revised1). In this revision, specifically, tirzepatide was added to the end of [likely involving insulin resistance] of "Obese patients" in Step 1: "Select medications to address the diabetes pathology involved" in Fig. 2. While the sentence, "Insulin insufficiency and resistance can be assessed by referring to the various indices listed in the JDS 'Guide to Diabetes Management.' was mentioned in the previous edition as well, "While insulin resistance is analogized based on BMI, abdominal obesity, and visceral fat accumulation, an assessment of indicators (e.g., HOMA-IR) is desirable" was added as information in order to more accurately recognize the pathology. Regarding Step 2: "Give due consideration to safety," "For renal excretion" was added to the "Rule of thumb 2: Avoid glinides in patients with renal impairment." The order of the medications in "rule of thumb 3: Avoid thiazolidinediones and biguanides in patients with heart failure (in whom they are contraindicated)." to thiazolidinediones then biguanides. In the description of the lowest part of Fig. 2, for each patient failing to achieve his/her HbA1c control goal, "while reverting to step 1" was changed to "while reverting to the opening" and "including reassessment if the patient is indicated for insulin therapy" was added. In the separate table, the column for tirzepatides was added, while the two items, "Characteristic side effects" and "Persistence of effect" were added to the area of interest. The revision also carried additional descriptions of the figure and table such as tirzepatides and "Characteristic side effects" in the statement, and while not mentioned in the proposed algorithm figure, nonalcoholic fatty liver disease (NAFLD) is covered from this revision for patients with comorbidities calling for medical attention. Moreover, detailed information was added to the relative/absolute indication for insulin therapy, the Kumamoto Declaration 2013 for glycemic targets, and glycemic targets for older people with diabetes. Again, in this revision, it is hoped that the algorithm presented here will not only contribute to improved diabetes management in Japan, but will continue to evolve into a better algorithm over time, reflecting new evidence as it becomes available.

Safety and effectiveness of tofogliflozin in Japanese people with type 2 diabetes: A multicenter prospective observational study in routine clinical practice.

AIMS/INTRODUCTION: Sodium-glucose cotransporter 2 (SGLT2) inhibitors effectively and safely reduce fasting and postprandial hyperglycemia while promoting weight loss. However, their unique mechanism of action contributes to concerns regarding their safety. We therefore carried out a large-scale, non-commercial, investigator-initiated study on the safety and effectiveness of the SGLT2 inhibitor tofogliflozin. MATERIALS AND METHODS: This multicenter, open-label, uncontrolled, prospective observational study was carried out at hospitals and clinics across Japan in participants aged ≥20 years who were SGLT2 inhibitor-naïve and had an established diagnosis of type 2 diabetes. The primary endpoint was adverse drug reactions (ADRs) of special interest. Secondary endpoints included all other ADRs and adverse events, glycated hemoglobin (HbA1c), and weight loss. RESULTS: The study, carried out from June 2014 through February 2020, enrolled 11,480 participants from 1,103 medical institutions; 6,967 participants completed the 104-week follow up. The most common ADRs of special interest were urinary and genital tract infections (1.53%), followed by volume depletion (1.25%). Hypoglycemia occurred in 27 participants (0.24%), adverse events in 1,054 (9.18%) and ADRs in 645 (5.62%). HbA1c decreased by 0.85% (95% confidence interval 0.82%-0.88%) and bodyweight decreased by 3.05 kg (95% confidence interval 2.94-3.17 kg). The HbA1c target was achieved by 51.70% of participants for target HbA1c <7.0%, 85.3% for <8.0% and 5.4% for <6.0% at week 104. CONCLUSIONS: Tofogliflozin was associated with only mild or moderate ADRs characteristic of SGLT2 inhibitors, with no unpredictable, new, serious, or high-incidence adverse events or ADRs. This independent study confirmed the safety and effectiveness of tofogliflozin in adult type 2 diabetes patients.

A consensus statement from the Japan Diabetes Society: A proposed algorithm for pharmacotherapy in people with type 2 diabetes - 2nd edition (English version).

This algorithm was issued for the appropriate use of drugs for the treatment of type 2 diabetes mellitus in Japan. The revisions include safety considerations, fatty liver disease as a comorbidity to be taken into account and the position of tirzepatide.

Impaired Fat Absorption from Intestinal Tract in High-Fat Diet Fed Male Mice Deficient in Proglucagon-Derived Peptides.

(1) Background: Proglucagon-derived peptides (PDGPs) including glucagon (Gcg), GLP-1, and GLP-2 regulate lipid metabolism in the liver, adipocytes, and intestine. However, the mechanism by which PGDPs participate in alterations in lipid metabolism induced by high-fat diet (HFD) feeding has not been elucidated. (2) Methods: Mice deficient in PGDP (GCGKO) and control mice were fed HFD for 7 days and analyzed, and differences in lipid metabolism in the liver, adipose tissue, and duodenum were investigated. (3) Results: GCGKO mice under HFD showed lower expression levels of the genes involved in free fatty acid (FFA) oxidation such as Hsl, Atgl, Cpt1a, Acox1 (p < 0.05), and Pparα (p = 0.05) mRNA in the liver than in control mice, and both FFA and triglycerides content in liver and adipose tissue weight were lower in the GCGKO mice. On the other hand, phosphorylation of hormone-sensitive lipase (HSL) in white adipose tissue did not differ between the two groups. GCGKO mice under HFD exhibited lower expression levels of Pparα and Cd36 mRNA in the duodenum as well as increased fecal cholesterol contents compared to HFD-controls. (4) Conclusions: GCGKO mice fed HFD exhibit a lesser increase in hepatic FFA and triglyceride contents and adipose tissue weight, despite reduced ß-oxidation in the liver, than in control mice. Thus, the absence of PGDP prevents dietary-induced fatty liver development due to decreased lipid uptake in the intestinal tract.

Sporadic Parathyroid Carcinoma Treated With Lenvatinib, Exhibiting a Novel Somatic MEN1 Mutation.

Parathyroid carcinoma (PC) is extremely rare and is primarily treated surgically. Chemotherapy is an option for advanced stages, but no standard regimen exists. Emerging research suggests the efficacy of multitarget tyrosine kinase inhibitors (MTKIs) for PC, targeting vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR). A 61-year-old Japanese woman presented with a neck mass, diagnosed as PC with pleural and lumbar metastases. After parathyroidectomy and radiation for lumbar metastasis, immunohistochemistry showed VEGFR overexpression, leading to targeted therapy with MTKIs. Despite no actionable mutations on cancer genomic panel test, a novel MEN1 somatic mutation (NM_130801: exon2: c.332delG: p.G111fs*8) was identified, which may affect VEGFR2 expression and tumor epigenetics. Although severe hand-foot syndrome necessitated dose reductions and treatment interruptions, sorafenib treatment managed hypercalcemia with evocalcet and denosumab. Lenvatinib, as second-line therapy, was effective against pleural metastases but caused thrombocytopenia and hematuria, leading to discontinuation and uncontrolled recurrence and metastasis progression. Our case highlights the need for further research on genomic profiling, molecular targets, and therapy response in PC.

[18F]FB(ePEG12)12-exendin-4 noninvasive imaging of insulinoma negative for insulin immunostaining on specimen from endoscopic ultrasonography-guided fine needle aspiration: a case report with review of literature.

Insulinomas are the most common functional pancreatic neuroendocrine neoplasm; when treatment is delayed, they induce hyperinsulinemic hypoglycemia, which is life-threatening. As surgical resection is the only curative treatment for insulinoma, preoperative localization is crucial; however, localization based on conventional imaging modalities such as computed tomography (CT) and magnetic resonance imaging is often inconclusive. Somatostatin receptor-targeted imaging is another option for detecting pancreatic neuroendocrine neoplasms but has low sensitivity and is not specific for insulinoma. The clinical application of other localizing approaches such as selective arterial calcium stimulation and endoscopic ultrasonography-guided fine needle aspiration (EUS-FNA) is limited by their being invasive and/or technically complex. Moreover, an EUS-FNA specimen of an insulinoma may be negative on insulin immunostaining. Thus, a noninvasive and clinically practical insulinoma-specific diagnostic tool to discriminate insulinomas with high accuracy is anticipated. Glucagon-like peptide-1 receptor (GLP-1R)-targeted imaging has emerged in the effort to fulfill this need. We recently developed the novel fluorine-18-labeled exendin-4-based probe conjugated with polyethylene glycol, [18F]FB(ePEG12)12-exendin-4 (18F-exendin-4) for positron emission tomography (PET) imaging and reported its clinical benefit in a case of insulinoma in the pancreatic tail. We report here a case of insulinoma in the pancreatic head in which an EUS-FNA specimen was negative on insulin immunostaining while precise preoperative localization and conclusive evidence for curative enucleation was provided by 18F-exendin-4 PET/CT (Japan Registry of Clinical Trials; jRCTs051200156).

A Study on the Compatibility of a Food-Recording Application with Questionnaire-Based Methods in Healthy Japanese Individuals.

In Japan, nutritional guidance based on food-recording apps and food frequency questionnaires (FFQs) is becoming popular. However, it is not always recognized that different dietary assessment methods have different nutritional values. Here, we compared the compatibility of dietary intake data obtained from an app with those obtained from FFQs in 59 healthy individuals who recorded information regarding their diet for at least 7 days per month using an app developed by Asken (Tokyo, Japan). The diurnal coefficient of variation in total energy and protein intake was 20%, but those for vitamins B12 and D were >80%, reflecting the importance of 7 days of recording rather than a single day of recording for dietary intake analyses. Then, we compared the results of two FFQs-one based on food groups and one based on a brief self-administered diet history questionnaire-for 7 days, as recorded by the app. There was a correlation coefficient of >0.4 for all the items except salt. Regarding the compatibility between the app and FFQs, the percentage errors for total energy and nutrients were >40-50%, suggesting no agreement between the app and the two FFQs. In conclusion, careful attention should be paid to the impact of different dietary assessment methods on nutrient assessment.

PIONEER REAL Japan: Baseline characteristics of a multicenter, prospective, real-world study of oral semaglutide in adults with type 2 diabetes in clinical practice in Japan.

AIMS/INTRODUCTION: PIONEER REAL Japan was a non-interventional, multicenter, prospective study investigating oral semaglutide in adults with type 2 diabetes in routine clinical practice. We report baseline characteristics of participants enrolled in this study. MATERIALS AND METHODS: Adults aged ≥20 years with type 2 diabetes but no previous treatment with injectable glucose-lowering medication were enrolled. Participants initiated oral semaglutide at their treating physician's discretion and were followed for 34-44 weeks. Participants were stratified into <75-year-old and ≥75-year-old subgroups. RESULTS: A total of 624 participants initiated the study. The mean (standard deviation) age was 64.1 years (14.1), the mean (standard deviation) body weight was 72.4 kg (16.1), and the mean (standard deviation) body mass index was 27.5 kg/m2 (5.0). Participants had a median (interquartile range) type 2 diabetes duration of 9.3 years (4.2, 15.2) and mean (standard deviation) glycated hemoglobin 7.7% (1.1). Most (75.6%) participants were taking glucose-lowering medications at baseline; the most common was metformin (51.9%). The main reasons for initiating oral semaglutide were glycemic control and weight loss. Most (86.0%) participants had an individualized target for glycemic control of glycated hemoglobin ≤7%. The <75-year-old subgroup was heavier (mean [standard deviation] body mass index 28.6 kg/m2 [5.2] vs 25.1 kg/m2 [3.4]) but had comparable glycated hemoglobin levels (mean [standard deviation] 7.7% [1.2] vs 7.8% [1.0]) to the ≥75-year-old subgroup. CONCLUSIONS: PIONEER REAL Japan describes the characteristics of individuals with type 2 diabetes prescribed oral semaglutide. The baseline characteristics provide insights into Japanese individuals with type 2 diabetes prescribed oral semaglutide in clinical practice.

Japanese 17q12 Deletion Syndrome with Complex Clinical Manifestations.

17q12 deletion syndrome is a rare chromosomal anomaly with variable phenotypes, caused by the heterozygous deletion of chromosome 17q12. We herein report a 35-year-old Japanese patient with chromosomal 17q12 deletion syndrome identified by de novo deletion of the 1.46 Mb segment at the 17q12 band by genetic analyses. He exhibited a wide range of phenotypes, such as maturity-onset diabetes of the young (MODY) type 5, structural or functional abnormalities of the kidney, liver, and pancreas; facial dysmorphic features, electrolyte disorders; keratoconus, and acquired perforating dermatosis. This case report provides valuable resources concerning the clinical spectrum of rare 17q12 deletion syndrome.

Primary aldosteronism patients with previous cardiovascular and cerebrovascular events have high aldosterone responsiveness to ACTH stimulation.

Aldosterone secretion in primary aldosteronism (PA) is often regulated by adrenocorticotropic hormone (ACTH) in addition to its autonomous secretion. However, the clinical characteristics and risk of cardiovascular and cerebrovascular (CCV) events in PA patients with aldosterone responsiveness to ACTH stimulation remain unclear. This study aimed to investigate the prevalence of CCV events in PA patients with high aldosterone responsiveness to ACTH stimulation. A retrospective cross-sectional study was conducted as part of the Japan Primary Aldosteronism Study/Japan Rare Intractable Adrenal Disease project. PA patients with adrenal venous sampling (AVS) between January 2006 and March 2019 were enrolled. The ACTH-stimulated plasma aldosterone concentration (PAC) of the inferior vena cava during AVS was used to evaluate aldosterone responsiveness to ACTH. We analyzed the relationship between responsiveness and previous CCV events. Logistic regression analysis demonstrated that the ΔPAC (the difference between the PAC measurements before and after ACTH stimulation) significantly increased the odds of previous CCV events in PA patients after adjusting for classical CCV event risk factors, baseline PAC and duration of hypertension (relative PAC: odds ratio [OR], 2.896; 95% confidence interval [CI], 0.989-8.482; ΔPAC: OR, 2.344; 95% CI, 1.149-4.780; ACTH-stimulated PAC: OR, 2.098; 95% CI, 0.694-6.339). This study clearly demonstrated that aldosterone responsiveness to ACTH is closely related to previous CCV events. The responsiveness of the PAC to ACTH could be useful in predicting CCV event risk.Registration Number in UMIN-CTR is UMIN000032525.

Impact of Participant Characteristics on Clinical Outcomes with iGlarLixi in Type 2 Diabetes: Post Hoc Analysis of SPARTA Japan.

INTRODUCTION: The real-world SPARTA Japan study confirmed the effectiveness and safety of the fixed-ratio combination of insulin glargine 100 U/mL plus lixisenatide (iGlarLixi) once daily over 6 months in Japanese people with type 2 diabetes (T2D). This post hoc analysis examined the impact of participant characteristics on the achievement of age-defined glycaemic targets with iGlarLixi therapy. METHODS: The retrospective, observational SPARTA Japan study included adults with T2D who initiated iGlarLixi. In this analysis, data from insulin-naïve and insulin-experienced participants were separately assessed to compare glycated haemoglobin (HbA1c), body weight and safety outcomes between those who achieved ('achieved' group) and those who did not achieve ('not-achieved' group) age-defined glycaemic targets after 6 months of iGlarLixi. The not-achieved group was further stratified by whether or not their iGlarLixi dose was increased during treatment. RESULTS: In total, 418 participants were included in this analysis (138 insulin naïve and 280 insulin experienced). Among both insulin-naïve and insulin-experienced participants, those in the achieved group were older and had lower baseline HbA1c than those in the not-achieved group. Compared with the not-achieved group, the achieved group showed significantly greater HbA1c reductions from baseline (in both insulin-naïve and insulin-experienced participants) and significantly greater body weight reductions (in insulin-naïve participants), despite some participants in the not-achieved group receiving significantly higher insulin glargine doses than those in the achieved group. In both insulin-naïve and insulin-experienced participants, the incidence of hypoglycaemia and gastrointestinal-related adverse events was similar in the achieved and not-achieved groups. In a multivariate analysis, glycaemic target achievement was significantly more likely in older individuals and those who lost weight during iGlarLixi treatment. CONCLUSIONS: Achievement of age-defined glycaemic targets with iGlarLixi treatment for 6 months was significantly affected by increased age and body weight loss, regardless of prior insulin exposure. TRIAL REGISTRATION: UMIN-CTR Trials Registry, UMIN000044126; registered 10 May 2021.

iGlarLixi is an injectable product used to treat type 2 diabetes that contains a fixed combination of two drugs, insulin glargine (at a concentration of 100 U/mL) and lixisenatide. The SPARTA Japan study investigated the effectiveness of controlling blood glucose levels and the safety of iGlarLixi in Japanese people when taken once daily for over 6 months as part of their routine medical care. The analysis reported in this article looked back at data from SPARTA Japan to assess whether certain characteristics of the people who took part in the study affected how well blood glucose targets were met. People who had previously taken insulin and those who had not were identified, and their results were assessed separately. The people were divided into those who had met their blood glucose level target (with the target defined as the glycated haemoglobin level for each person based on their age) and those who had not met their target. It was found that people who achieved their blood glucose target while receiving iGlarLixi were more likely to be older, to have had a lower glycated haemoglobin level before starting iGlarLixi, and to have lost weight during treatment than those who did not achieve their target, whether or not they had previously been treated with insulin. Side effects of excessively low blood glucose levels or gastrointestinal upset with iGlarLixi treatment occurred in a similar number of people who achieved or did not achieve their blood glucose target.

Long-term safety and efficacy of SGLT2 inhibitor use in older east Asians with type 2 diabetes.

Sodium-glucose cotransporter 2 inhibitors (SGLT2is) have been shown in cardiovascular outcome trials to reduce the risk of heart failure and major adverse cardiovascular as well as renal events in individuals with type 2 diabetes. Moreover, clinical evidence indicates that SGLT2i use reduces heart failure and chronic kidney disease (CKD) in east Asian patients with type 2 diabetes. Thus, SGLT2is might seem to be the preferred treatment for older patients with type 2 diabetes even in the presence of multiple comorbidities. However, older patients with type 2 diabetes may well have impaired physiological function, making the risk of certain adverse events higher than that in the general population. While a randomized clinical trial has been conducted to evaluate changes in skeletal muscle mass and function as well as those in cognitive function with SGLT2i use in older Japanese individuals with type 2 diabetes who are otherwise healthy, the safety of SGLT2is remains to be established among older individuals with type 2 diabetes also having impaired activity of daily living and/or cognitive impairment. Even so, international and domestic consensus reports recommend SGLT2is for patients with type 2 diabetes and heart failure, CKD, and/or cardiovascular diseases, and SGLT2is are being widely prescribed by general practitioners to older individuals with type 2 diabetes with little regard to the patient's comorbidities. We maintain that SGLT2i use in older patients with type 2 diabetes should be prescribed cautiously in consideration of the pathophysiology of the disease and the presence of complications and comorbidities as well as the individual's lifestyle.

Lifestyle factors associated with a rapid decline in the estimated glomerular filtration rate over two years in older adults with type 2 diabetes-Evidence from a large national database in Japan.

BACKGROUND: The present study investigated lifestyle risk factors from metabolic syndrome-related lifestyles for a rapid decline in the estimated glomerular filtration rate (eGFR) among adults aged 40-74 years with treated and untreated type 2 diabetes. METHODS AND RESULTS: This study analyzed data from the National Database of Health Insurance Claims and Specific Health Checkups of Japan, encompassing the period from fiscal year (FY) 2017 to FY2020. We established FY2018 as our baseline year. The subjects of this study were adults aged 40-74 in FY2018(baseline) who had type 2 diabetes and underwent specific health checkups in FY2020. We excluded adults with a medical record of kidney dialysis between FY2017 and FY2018, records of suspected type 1 diabetes between FY2017 and FY2020, or a baseline eGFR >85 mL/min/1.73 m2 or missing eGFR data as of FY2020. Eventually we analyzed 573,860 individuals. The outcome variable was a rapid decline in eGFR (≥30%) during the follow-up. Exposure lifestyle factors included skipping breakfast, late-night dinners, regular smoking, a high alcohol intake, non-refreshing sleep, and a lack of habitual exercise. Logistic regression models were stratified by age (40-59 and 60-74 years) and baseline eGFR levels (60-85, 30-59, and <30 mL/min/1.73 m2). Covariates included sex, a history of heart disease, a history of stroke, a history of renal failure, anemia, low-density lipoprotein, systolic blood pressure, hemoglobin A1C, body mass index, antidiabetic medications, antihypertension drugs, lipid-lowering drugs, the oral adsorbent Kremezin, non-steroidal anti-inflammatory drugs, and drugs for the treatment of renal anemia. A rapid decline in eGFR was detected in approximately 1.3% of participants (7,683 cases). In the baseline eGFR >30 subgroups (60-85 or 30-59 mL/min/1.73 m2), skipping breakfast and regular smoking were associated with a rapid decline in eGFR in both age groups, while a lack of habitual exercise and late-night dinners in the 60-74 age group and non-refreshing sleep in the 40-59 age group were identified as risk factors. Additionally, skipping breakfast was a risk factor for a rapid decline in eGFR in the 60-74 age group regardless of baseline eGFR levels. In the baseline eGFR <30 mL/min/1.73 m2 subgroup, skipping breakfast and non-refreshed sleep were risk factors for a rapid decline in eGFR. CONCLUSIONS: We found specific lifestyle risk factors were associated with a rapid eGFR decline among people with type 2 diabetes from a nationwide database in Japan. The associations varied by baseline eGFR level, age, and sex. Lifestyle modifications may effectively prevent the aggravation of diabetic kidney disease.

Erdheim-Chester Disease With BRAF V600E Mutation and Central Diabetes Insipidus Successfully Treated With Glucocorticoid.

Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis characterized by xanthoma/xanthogranuloma infiltration in various organs and a broad spectrum of clinical presentations, including bone lesions, central diabetes insipidus and renal failure. BRAF V600E mutation is seen in almost half of the cases of ECD; the BRAF inhibitor vemurafenib is recommended treatment in the United States and the European Union. However, the indication for vemurafenib in Japan is limited to unresectable malignant melanoma with BRAF mutation. Although glucocorticoids, interferon, chemotherapy, and radiation therapy are treatment options, no standard therapy for ECD has yet been established in Japan. We describe here a patient with central diabetes insipidus and retroperitoneal lesions who was successfully treated with prednisolone. Glucocorticoid therapy is therefore a plausible alternative for ECD with BRAF V600E mutation when the BRAF inhibitor vemurafenib cannot be used.

Glucokinase Variant Proteins Are Resistant to Fasting-Induced Uridine Diphosphate Glucose-Dependent Degradation in Maturity-Onset Diabetes of the Young Type 2 Patients.

We previously reported that glucokinase undergoes ubiquitination and subsequent degradation, a process mediated by cereblon, particularly in the presence of uridine diphosphate glucose (UDP-glucose). In this context, we hereby present evidence showcasing the resilience of variant glucokinase proteins of maturity-onset diabetes of the young type 2 (MODY2) against degradation and, concomitantly, their influence on insulin secretion, both in cell lines and in the afflicted MODY2 patient. Hence, glucose-1-phodphate promotes UDP-glucose production by UDP-glucose pyrophosphorylase 2; consequently, UDP-glucose-dependent glucokinase degradation may occur during fasting. Next, we analyzed glucokinase variant proteins from MODY2 or persistent hyperinsulinemic hypoglycemia in infancy (PHHI). Among the eleven MODY2 glucokinase-mutated proteins tested, those with a lower glucose-binding affinity exhibited resistance to UDP-glucose-dependent degradation. Conversely, the glucokinaseA456V-mutated protein from PHHI had a higher glucose affinity and was sensitive to UDP-glucose-dependent degradation. Furthermore, in vitro studies involving UDP-glucose-dependent glucokinase variant proteins and insulin secretion during fasting in Japanese MODY2 patients revealed a strong correlation and a higher coefficient of determination. This suggests that UDP-glucose-dependent glucokinase degradation plays a significant role in the pathogenesis of glucose-homeostasis-related hereditary diseases, such as MODY2 and PHHI.

Gastric inhibitory polypeptide receptor antagonism suppresses intramuscular adipose tissue accumulation and ameliorates sarcopenia.

BACKGROUND: Intramuscular adipose tissue (IMAT) formation derived from muscle fibro-adipogenic progenitors (FAPs) has been recognized as a pathological feature of sarcopenia. This study aimed to explore whether genetic and pharmacological gastric inhibitory polypeptide (GIP) receptor antagonism suppresses IMAT accumulation and ameliorates sarcopenia in mice. METHODS: Whole body composition, grip strength, skeletal muscle weight, tibialis anterior (TA) muscle fibre cross-sectional area (CSA) and TA muscle IMAT area were measured in young and aged male C57BL/6 strain GIP receptor (Gipr)-knockout (Gipr-/- ) and wild-type (Gipr+/+ ) mice. FAPs isolated from lower limb muscles of 12-week-old Gipr+/+ mice were cultured with GIP, and their differentiation into mature adipocytes was examined. Furthermore, TA muscle IMAT area and fibre CSA were measured in untreated Gipr-/- mice and GIP receptor antagonist-treated Gipr+/+ mice after glycerol injection into the TA muscles. RESULTS: Body composition analysis revealed that 104-week-old Gipr-/- mice had a greater proportion of lean tissue mass (73.7 ± 1.2% vs. 66.5 ± 2.7%, P < 0.05 vs. 104-week-old Gipr+/+ mice) and less adipose tissue mass (13.1 ± 1.3% vs. 19.4 ± 2.6%, P < 0.05 vs. 104-week-old Gipr+/+ mice). Eighty-four-week-old Gipr-/- mice exhibited increases in grip strength (P < 0.05), weights of TA (P < 0.05), soleus (P < 0.01), gastrocnemius (P < 0.05) and quadriceps femoris (P < 0.01) muscles, and average TA muscle fibre CSA (P < 0.05) along with a reduction in TA muscle IMAT area assessed by the number of perilipin-positive cells (P < 0.0001) compared with 84-week-old Gipr+/+ mice. Oil Red O staining analysis revealed 1.6- and 1.7-fold increased adipogenesis in muscle FAPs cultured with 10 and 100 nM of GIP (P < 0.01 and P < 0.001 vs. 0 nM of GIP, respectively). Furthermore, both untreated Gipr-/- mice and GIP receptor antagonist-treated Gipr+/+ mice for 14 days after glycerol injection into the TA muscles at 12 weeks of age showed reduced TA muscle IMAT area (1.39 ± 0.38% and 2.65 ± 0.36% vs. 6.54 ± 1.30%, P < 0.001 and P < 0.01 vs. untreated Gipr+/+ mice, respectively) and increased average TA muscle fibre CSA (P < 0.01 and P < 0.05 vs. untreated Gipr+/+ mice, respectively). CONCLUSIONS: GIP promotes the differentiation of muscle FAPs into adipocytes and its receptor antagonism suppresses IMAT accumulation and promotes muscle regeneration. Pharmacological GIP receptor antagonism may serve as a novel therapeutic approach for sarcopenia.

Correction: A consensus statement from the Japan Diabetes Society (JDS): a proposed algorithm for pharmacotherapy in people with type 2 diabetes.

[This corrects the article DOI: 10.1007/s13340-022-00605-x.].