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.

[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).

Heterogeneous Effects of Intensive Glycemic and Blood Pressure on Cardiovascular Events Among Diabetes by Living Arrangements.

BACKGROUND: Although living alone versus with others is a key social element for cardiovascular prevention in diabetes, evidence is lacking about whether the benefit of intensive glycemic and blood pressure (BP) control differs by living arrangements. We thus aim to investigate heterogeneity in the joint effect of intensive glycemic and BP control on cardiovascular events by living arrangements among participants with diabetes. METHODS AND RESULTS: This study included 4731 participants with diabetes in the ACCORD-BP (Action to Control Cardiovascular Risk in Diabetes-Blood Pressure) trial. They were randomized into 4 study arms, each with glycated hemoglobin target (intensive, <6.0% versus standard, 7.0-7.9%) and systolic BP target (intensive, <120 mm Hg versus standard <140 mm Hg). Cox proportional hazard models were used to estimate the joint effect of intensive glycemic and BP control on the composite cardiovascular outcome according to living arrangements. At a mean follow-up of 4.7 years, the cardiovascular outcome was observed in 445 (9.4%) participants. Among participants living with others, intensive treatment for both glycemia and BP showed decreased risk of cardiovascular events compared with standard treatment (hazard ratio [HR], 0.68 [95% CI, 0.51-0.92]). However, this association was not found among participants living alone (HR, 0.96 [95% CI, 0.58-1.59]). P for interaction between intensive glycemic and BP control was 0.53 among participants living with others and 0.009 among those living alone (P value for 3-way interaction including living arrangements was 0.049). CONCLUSIONS: We found benefits of combining intensive glycemic and BP control for cardiovascular outcomes among participants living with others but not among those living alone. Our study highlights the critical role of living arrangements in intensive care among patients with diabetes.

Neprilysin Inhibition Promotes Skeletal Growth via the CNP/NPR-B Pathway.

C-type natriuretic peptide (CNP) plays a crucial role in enhancing endochondral bone growth and holds promise as a therapeutic agent for impaired skeletal growth. To overcome CNP's short half-life, we explored the potential of dampening its clearance system. Neprilysin (NEP) is an endopeptidase responsible for catalyzing the degradation of CNP. Thus, we investigated the effects of NEP inhibition on skeletal growth by administering sacubitril, a NEP inhibitor, to C57BL/6 mice. Remarkably, we observed a dose-dependent skeletal overgrowth phenotype in mice treated with sacubitril. Histological analysis of the growth plate revealed a thickening of the hypertrophic and proliferative zones, mirroring the changes induced by CNP administration. The promotion of skeletal growth observed in wild-type mice treated with sacubitril was nullified by the knockout of cartilage-specific natriuretic peptide receptor B (NPR-B). Notably, sacubitril promoted skeletal growth in mice only at 3 to 4 weeks of age, a period when endogenous CNP and NEP expression was higher in the lumbar vertebrae. Additionally, sacubitril facilitated endochondral bone growth in organ culture experiments using tibial explants from fetal mice. These findings suggest that NEP inhibition significantly promotes skeletal growth via the CNP/NPR-B pathway, warranting further investigations for potential applications in people with short stature.

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.

An exploratory study of factors in disordered eating behavior in diabetes self-management in Japan.

AIMS/INTRODUCTION: Diet directly affects glucose metabolism, and eating behavior is influenced by various daily life stressors. This study was conducted to investigate the relationship between common psychosomatic stressors on endocrine hormones and eating behavior in patients with type 2 diabetes. MATERIALS AND METHODS: This cross-sectional study was performed in 40 patients with type 2 diabetes. Resting hormone blood sampling and four self-reported questionnaires were employed. RESULTS: Patients who scored higher on the 'anger/hostility' (AH) subcategory of the profile of mood state (POMS) questionnaire had significantly higher serum cortisol (ß = 0.40, P = 0.01 by least squares adjusted for age and sex). In the eating behavior questionnaire, the subcategories of 'feeling of hunger/satiation' (ß = 0.49, P < 0.01) and 'eating as diversion' (ß = 0.39, P = 0.03) were associated with higher serum cortisol. Resting morning cortisol levels were higher in participants who rated high on the POMS-AH and in those who reported 'irritated when hungry' and 'tend to eat when irritated or anxious'. Sleep quality showed no association with eating behavior. CONCLUSIONS: Mood state is associated with eating behavior. Anger increases cortisol levels and may lead to compulsive eating. Various forms of hostility are important factors in appetite control and increased cortisol secretion, and can be an impediment to successful dietary self-management in patients with type 2 diabetes. Thus, assessment of mood state and control of negative mood are important therapeutic targets in diabetes management.

Effects of dipeptidyl peptidase-4 inhibition in vivo: Dipeptidyl peptidase-4 inhibitor/gut microbiome crosstalk suggests novel therapeutic options for diabetes management.

Wang et al. report that clinical dipeptidyl peptidase-4 (DPP-4) inhibitors show little effect on microbial DPP-4 produced by Bacteroides genus. Furthermore, oral administration of microbial DPP-4 to high-fat diet-fed mice was found to reduce plasma active glucagon-like peptide-1 levels through an increase in extraluminal intestinal tissular DPP-4 activity, resulting in reduced glucose-induced insulin levels and exacerbated glucose tolerance.

A Case Report of Diabetes in a Patient with Glycogen Storage Disease Type 1a.

Glycogen storage disease type 1a (GSD-1a) is a rare congenital disease. Recently, life expectancy with GSD-1a has been improved by its early diagnosis and management. Complications of diabetes with GSD-1a are extremely rare. The optimal treatment for glucose control using this disease combination remains unclear. The existence of GSD-1a and diabetes can cause both hypoglycemia and hyperglycemia, making glucose control especially problematic. In the present report, α-glucosidase inhibitor (α-GI) and dipeptidyl peptidase-4 (DPP-4) inhibitors improved hyperglycemia without symptoms of hypoglycemia in a patient with diabetes and GSD-1a using intermittent continuous glucose monitoring (isCGM).

Intestinal Morphology and Glucose Transporter Gene Expression under a Chronic Intake of High Sucrose.

Sucrose is a disaccharide that is degraded into fructose and glucose in the small intestine. High-sucrose and high-fructose diets have been reported, using two-dimensional imaging, to alter the intestinal morphology and the expression of genes associated with sugar transport, such as sodium glucose co-transporter 1 (SGLT1), glucose transporter 2 (GLUT2), and glucose transporter 5 (GLUT5). However, it remains unclear how high-fructose and high-sucrose diets affect the expression of sugar transporters and the intestinal morphology in the whole intestine. We investigate the influence of a chronic high-sucrose diet on the expression of the genes associated with sugar transport as well as its effects on the intestinal morphology using 3D imaging. High sucrose was found to increase GLUT2 and GLUT5 mRNA levels without significant changes in the intestinal morphology using 3D imaging. On the other hand, the delay in sucrose absorption by an α-glucosidase inhibitor significantly improved the intestinal morphology and the expression levels of SGLT1, GLUT2, and GLUT5 mRNA in the distal small intestine to levels similar to those in the proximal small intestine, thereby improving glycemic control after both glucose and sucrose loading. These results reveal the effects of chronic high-sugar exposure on glucose absorption and changes in the intestinal morphology.

Human RFX6 regulates endoderm patterning at the primitive gut tube stage.

Transcriptional factor RFX6 is known to be a causal gene of Mitchell-Riley syndrome (MRS), an autosomal recessive neonatal diabetes associated with pancreatic hypoplasia and intestinal atresia/malformation. The morphological defects are limited to posterior foregut and mid-hindgut endodermal lineages and do not occur in the anterior foregut lineage; the mechanism remains to be fully elucidated. In this study, we generated RFX6+/eGFP heterozygous knockin and RFX6eGFP/eGFP homozygous knockin/knockout human-induced pluripotent stem cell (hiPSC) lines and performed in vitro endoderm differentiation to clarify the role of RFX6 in early endoderm development. RFX6 expression was found to surge at the primitive gut tube (PGT) stage in comparison with that in the undifferentiated or definitive endoderm stage. At the PGT stage, the expression of PDX1 and CDX2, posterior foregut and mid-hindgut master regulators, respectively, was decreased by the RFX6 deficit. PDX1+ and CDX2+ cells were mostly green fluorescent protein (GFP)+ in RFX6+/eGFP hiPSCs, but their cell number was markedly decreased in RFX6eGFP/eGFP hiPSCs. The expression of SOX2, an anterior foregut marker, was not affected by the RFX6 deficit. In addition, we found a putative RFX6-binding X-box motif using cap analysis of gene expression-seq and the motif-containing sequences in the enhancer regions of PDX1 and CDX2 bound to RFX6 in vitro. Thus, RFX6 regulates the ParaHox genes PDX1 and CDX2 but does not affect SOX2 in early endodermal differentiation, suggesting that defects in early stage endoderm patterning account for the morphological pathology of MRS.

18F-labeled PEGylated exendin-4 imaging noninvasively differentiates insulinoma from an accessory spleen: the first case report of [18F]FB(ePEG12)12-exendin-4 positron emission tomography/computed tomography for insulinoma.

Background: Insulinomas are the most common functioning pancreatic neuroendocrine neoplasms, and these tumors induce hypoglycemia due to hyperinsulinemia. Hypoglycemia caused by insulinomas can cause seizures, coma or death due to the delayed diagnosis. The only curative treatment is surgical resection. To perform curative surgical resection of insulinomas, preoperative localization is crucial. However, localization of insulinomas is often challenging using conventional imaging methods such as computed tomography (CT) and magnetic resonance imaging. Although endoscopic ultrasound (EUS) fine-needle aspiration and selective arterial calcium stimulation test, which can reflect the endocrine character of the tumor, are performed in such cases, these modalities are invasive and require operator-dependent techniques. Additionally, somatostatin receptor (SSTR)-targeted imaging has a relatively low sensitivity for detecting insulinomas due to its low SSTR type 2 expression. Thus, there is an urgent need for developing a noninvasive diagnostic technique which is specific for detecting insulinomas. Consequently, glucagon-like peptide-1 receptor-targeted imaging has recently emerged and gained a wide interest. Recently, we have developed a novel 18F-labeled exendin-4-based probe conjugated with polyethylene glycol, [18F]FB(ePEG12)12-exendin-4 (18F-exendin-4), for positron emission tomography (PET) imaging. Here we report a case of insulinoma in which 18F-exendin-4 PET/CT noninvasively provided critical information for localization. Case description: This is a case of a 58-year-old male with symptomatic hypoglycemia for 10 years; however, a preoperative diagnosis of insulinoma was not established due to the difficulty in differentiating it from an accessory spleen using conventional imaging. Moreover, the patient requested to avoid invasive diagnostic procedures including EUS. 18F-exendin-4 PET/CT revealed significant uptakes in the pancreatic tail whereas no apparent uptakes were observed in the spleen; thus, curative laparoscopic enucleation of the pancreatic tail was performed. The diagnosis of insulinoma was confirmed via histopathological examination. This is the first case report of insulinoma diagnosed using 18F-exendin-4 PET/CT. Conclusion: In this case, PET information led to curative resection through enucleation of the pancreas. 18F-exendin-4 PET/CT may serve as a useful noninvasive clinical tool for insulinoma localization.

Augmentation of Growth Hormone by Chewing in Females.

Sarcopenia is an age-related condition characterized by progressive loss of muscle mass and strength. Age-related decline in the secretion of growth hormone (GH), a condition called somatopause, is thought to play a role in sarcopenia. As pharmacological GH has adverse effects, we attempted to increase physiological GH. While the relationship between chewing and ghrelin levels has been studied, there are no reports on the relationship between chewing and GH. The aim of this study was to clarify the effects of chewing on the muscle anabolic hormones serum GH and plasma ghrelin. Thirteen healthy adults ingested a chewy nutrition bar containing 5.56 g of protein, 12.71 g of carbohydrate, and 0.09 g of fat on two different days, chewing before swallowing in one trial and swallowing without chewing in the other. Blood samples were taken before and after ingestion (0, 15, 30, and 60 min); GH, acylated ghrelin, glucose, insulin, amino acids, and lactate were measured. Two-way repeated ANOVA revealed a significant difference in the GH concentrations between the "Chew trial" and "Swallow trial" in females (p = 0.0054). However, post-hoc analyses found no statistically significant difference at each time point. The area under the curve of the percentage increase in GH was significantly increased in the "Chew trial" compared with the "Swallow trial" in females (12,203 ± 15,402% min vs. 3735 ± 988% min, p = 0.0488). Chewing had no effect on glucose, insulin, amino acids, or lactate concentrations. Thus, we found that chewing a protein supplement rather than swallowing it without chewing elevates the blood GH concentration. These results serve as a rationale for larger research and longitudinal studies to confirm the impacts of chewing on GH secretion.

Psychological Factors Motivating Male Japanese Workers With Type 2 Diabetes to Engage in Dietary Modifications: A Qualitative Descriptive Study.

Introduction: Japanese men with type 2 diabetes mellitus (T2DM) usually encounter work-related difficulties when engaging in dietary modifications. Hence, healthcare providers must understand the psychological factors, such as the needs and goals, that motivate them to engage in dietary modifications. Objective: We aimed to describe the psychological factors motivating male Japanese workers with T2DM to engage in dietary modifications. Methods: Using a qualitative descriptive design, we conducted semi-structured interviews with 11 male Japanese workers with T2DM and identified categories based on semantic differences using qualitative content analysis. Results: The following eight categories emerged: (I want to) demonstrate my skills at work, be able to engage in dietary modifications on my own, avoid unpleasant symptoms caused by eating, avoid burdensome treatment, maintain my healthy life, get positive results in medical examinations, maintain my relationships with others, and enjoy healthy food. Conclusion: The factors motivating the participants to engage in dietary modifications were realistic and sincere desires rooted in their ideal lives. Their desire to prioritize work emerged as an important factor. Healthcare providers should identify an individual's ideal daily life, including work aspects, and encourage individuals to set realistic and valuable goals.

Prediction-based prompt levothyroxine replacement to prevent a hypothyroid state after immune-related adverse events involving the thyroid gland.

Immune checkpoint inhibitors (ICIs) are used for various malignancies, although they frequently cause immune-related adverse events involving the thyroid gland (thyroid irAEs). We conducted a retrospective cohort study to elucidate thyroid function outcomes. Fifty of 639 patients who received PD-1 blockade therapy met criteria and were divided into the following groups: thyrotoxicosis with subsequent hypothyroidism (Toxic-Hypo, n = 21); thyrotoxicosis without subsequent hypothyroidism (Toxic, n = 9); and hypothyroidism without prior thyrotoxicosis (Hypo, n = 20). The Toxic-Hypo group developed thyroid irAEs earlier than the Toxic group (26 vs. 91 days; p < 0.001), and had higher serum free T4 levels (3.210 vs. 1.880 ng/dL; p = 0.011). In addition, positive anti-thyroglobulin antibodies (TgAbs) at thyroid irAE onset were more common in the Toxic-Hypo group (93.3%) than in the Toxic group (0.0%; p = 0.005) and Hypo group (44.4%; p = 0.007). The Toxic-Hypo group developed severe hypothyroidism and required larger levothyroxine (LT4) doses than the Hypo group (75 vs. 25 µg/day; p = 0.007). We predicted that patients with positive TgAbs who developed severe thyrotoxicosis within 4 weeks after the first ICI administration would develop subsequent hypothyroidism. We treated 4 such patients with prompt LT4 replacement, characterized by LT4 initiation after thyrotoxicosis improvement and quick dose titration. Their euthyroid state was successfully maintained, in contrast with patients receiving conventional replacement. In conclusion, rapid-onset severe thyrotoxicosis in patients with TgAbs correlated with a high likelihood of subsequent hypothyroidism. Accordingly, prompt LT4 replacement is suggested to prevent a severely hypothyroid state.

TRIAC disrupts cerebral thyroid hormone action via negative feedback and heterogenous distribution among organs.

As 3,3',5-triiodothyroacetic acid (TRIAC), a metabolite of thyroid hormones (THs), was previously detected in sewage effluent, we aimed to investigate exogenous TRIAC's potential for endocrine disruption. We administered either TRIAC or 3,3',5-triiodo-L-thyronine (LT3) to euthyroid mice and 6-propyl-2-thiouracil-induced hypothyroid mice. In hypothyroid mice, TRIAC administration suppressed the hypothalamus-pituitary-thyroid (HPT) axis and upregulated TH-responsive genes in the pituitary gland, the liver, and the heart. We observed that, unlike LT3, TRIAC administration did not upregulate cerebral TH-responsive genes. Measurement of TRIAC contents suggested that TRIAC was not efficiently trafficked into the cerebrum. By analyzing euthyroid mice, we found that cerebral TRIAC content did not increase despite TRIAC administration at higher concentrations, whereas serum levels and cerebral contents of THs were substantially decreased. Disruption by TRIAC is due to the additive effects of circulating endogenous THs being depleted via a negative feedback loop involving the HPT axis and heterogeneous distribution of TRIAC among different organs.

Total gastrectomy as a risk factor for postoperative loss of skeletal muscle in minimally invasive surgery for patients with gastric cancer.

PURPOSE: Loss of skeletal muscle mass after gastrectomy for gastric cancer leads to decreased quality of life and poor postoperative survival. However, few studies have examined the postoperative loss of skeletal muscle mass following minimally invasive gastrectomy. This study investigated the impact of minimally invasive total gastrectomy (MI-TG) on changes in skeletal muscle mass during the early postoperative period. METHODS: Patients who underwent MI-TG or minimally invasive distal or proximal gastrectomy (MI-nonTG) for cStage I-III gastric cancer were retrospectively analyzed (n = 58 vs. 182). Their body composition was measured before surgery and 2 months after surgery. Multivariable linear regression analysis was performed to clarify the impact of the surgical procedure on skeletal muscle index changes using clinically relevant covariates. RESULTS: Skeletal muscle mass decreased more in the MI-TG group than in the MI-nonTG group (median [interquartile range]; -5.9% [-10.6, -3.7] vs -4.5% [-7.3, -1.9], P = 0.004). In multivariable linear regression analysis using clinically relevant covariates, MI-TG was an independent risk factor for postoperative loss of skeletal muscle mass (coefficient - 2.6%, 95% CI -4.5 to -0.68, P = 0.008). CONCLUSIONS: Total gastrectomy was a risk factor for loss of skeletal muscle mass during the early postoperative period. If oncologically feasible, proximal or distal gastrectomy with a small remnant stomach should be considered.

Noninvasive evaluation of donor and native pancreases following simultaneous pancreas-kidney transplantation using positron emission tomography/computed tomography.

It is crucial to develop practical and noninvasive methods to assess the functional beta-cell mass in a donor pancreas, in which monitoring and precise evaluation is challenging. A patient with type 1 diabetes underwent noninvasive imaging following simultaneous kidney-pancreas transplantation with positron emission tomography/computed tomography (PET/CT) using an exendin-based probe, [18 F]FB(ePEG12)12-exendin-4. Following transplantation, PET imaging with [18 F]FB(ePEG12)12-exendin-4 revealed simultaneous and distinct accumulations in the donor and native pancreases. The pancreases were outlined at a reasonable distance from the surrounding organs using [18 F]FB(ePEG12)12-exendin-4 whole-body maximum intensity projection and axial PET images. At 1 and 2 h after [18 F]FB(ePEG12)12-exendin-4 administration, the mean standardized uptake values were 2.96 and 3.08, respectively, in the donor pancreas and 1.97 and 2.25, respectively, in the native pancreas. [18 F]FB(ePEG12)12-exendin-4 positron emission tomography imaging allowed repeatable and quantitative assessment of beta-cell mass following simultaneous kidney-pancreas transplantation.

Hypothalamic and brainstem glucose-dependent insulinotropic polypeptide receptor neurons employ distinct mechanisms to affect feeding.

Central glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) signaling is critical in GIP-based therapeutics' ability to lower body weight, but pathways leveraged by GIPR pharmacology in the brain remain incompletely understood. We explored the role of Gipr neurons in the hypothalamus and dorsal vagal complex (DVC) - brain regions critical to the control of energy balance. Hypothalamic Gipr expression was not necessary for the synergistic effect of GIPR/GLP-1R coagonism on body weight. While chemogenetic stimulation of both hypothalamic and DVC Gipr neurons suppressed food intake, activation of DVC Gipr neurons reduced ambulatory activity and induced conditioned taste avoidance, while there was no effect of a short-acting GIPR agonist (GIPRA). Within the DVC, Gipr neurons of the nucleus tractus solitarius (NTS), but not the area postrema (AP), projected to distal brain regions and were transcriptomically distinct. Peripherally dosed fluorescent GIPRAs revealed that access was restricted to circumventricular organs in the CNS. These data demonstrate that Gipr neurons in the hypothalamus, AP, and NTS differ in their connectivity, transcriptomic profile, peripheral accessibility, and appetite-controlling mechanisms. These results highlight the heterogeneity of the central GIPR signaling axis and suggest that studies into the effects of GIP pharmacology on feeding behavior should consider the interplay of multiple regulatory pathways.

Stabilization of kidney function and reduction in heart failure events with sodium-glucose co-transporter 2 inhibitors: A meta-analysis and meta-regression analysis.

AIMS: Sodium-glucose co-transporter 2 (SGLT2) inhibitors reduce the risk of heart failure (HF) events regardless of diabetes status. However, factors associated with their efficacy in HF reduction remain unknown. This study aims to identify clinically relevant markers for the efficacy of SGLT2 inhibitors in HF risk reduction. MATERIALS AND METHODS: We searched PubMed/MEDLINE and EMBASE for randomized placebo-controlled trials of SGLT2 inhibitors reporting a composite of HF hospitalization or cardiovascular death in participants with or without type 2 diabetes published until 28 February 2023. Random-effects meta-analysis and mixed-effects meta-regression were conducted to evaluate the association between the outcomes and clinical variables, including changes in glycated haemoglobin, body weight, systolic blood pressure, haematocrit and overall/chronic estimated glomerular filtration rate (eGFR) slope. RESULTS: Thirteen trials with 90 413 participants were included. SGLT2 inhibitors reduced the hazard ratio of the composite of HF hospitalization or cardiovascular death (hazard ratio 0.77; 95% confidence interval, 0.74-0.81; p < .0001). In meta-regression analysis, chronic eGFR slope (eGFR change after the initial dip) was significantly associated with the composite outcome (p = .017), and each 1 ml/min/1.73 m2 /year improvement in chronic eGFR slope led to a 14% reduction in the composite outcome. By contrast, changes in the other parameters showed no significant associations. CONCLUSIONS: Improvement in chronic eGFR slope, which reflects the stabilization of kidney function, is significantly associated with the efficacy of the SGLT2 inhibitor in HF, highlighting the cardiorenal axis role in the beneficial effects on HF. The chronic eGFR slope can be a surrogate marker of the effects of SGLT2 inhibitors on HF reduction.

Elucidation of HHEX in pancreatic endoderm differentiation using a human iPSC differentiation model.

For pluripotent stem cell (PSC)-based regenerative therapy against diabetes, the differentiation efficiency to pancreatic lineage cells needs to be improved based on the mechanistic understanding of pancreatic differentiation. Here, we aimed to elucidate the molecular mechanisms underlying pancreatic endoderm differentiation by searching for factors that regulate a crucial pancreatic endoderm marker gene, NKX6.1. Unbiasedly screening an siRNA knockdown library, we identified a candidate transcription factor, HHEX. HHEX knockdown suppressed the expression of another pancreatic endoderm marker gene, PTF1A, as well as NKX6.1, independently of PDX1, a known regulator of NKX6.1 expression. In contrast, the overexpression of HHEX upregulated the expressions of NKX6.1 and PTF1A. RNA-seq analysis showed decreased expressions of several genes related to pancreatic development, such as NKX6.1, PTF1A, ONECUT1 and ONECUT3, in HHEX knockdown pancreatic endoderm. These results suggest that HHEX plays a key role in pancreatic endoderm differentiation.