Frontiers in Endocrinology

Background/AimsPrandial hyperinsulinemia after Roux-en Y gastric bypass surgery (GB), and to lesser degree after sleeve gastrectomy (SG), has been attributed to rapid glucose flux from the gut and increased insulinotropic gut hormones. However, {beta}-cell sensitivity to exogenous incretin is markedly reduced after GB. This study examines the effect of GB versus SG on prandial glycemia and {beta}-cell response to increasing concentrations of endogenous incretins. MethodsGlucose kinetics, insulin secretion rate (ISR), and incretin responses to 50-gram oral glucose ingestion were compared between 10 non-diabetic subjects with GB versus 9 matched individuals with SG and 7 non-operated normal glucose tolerant controls (CN) on two days with and without administration of 200 mg sitagliptin. ResultsFasting glucose and hormonal levels were similar among 3 groups. Increasing plasma concentrations of endogenous incretins by 2-3-fold diminished post-OGTT glycemia and increased {beta}-cell secretion in all 3 groups (p<0.05), but insulin secretion per insulin sensitivity (i.e., disposition index) was increased only in GB (p<0.05 for interaction). As a result, sitagliptin administration led to hypoglycemia in 3 of 10 GB. Yet, plot of the slope of ISR versus the increase in endogenous incretin concentration was smaller after GB compared to both SG and CN. ConclusionAugmented glycemic-induced {beta}-cell response caused by enhanced incretin activity is unique to GB and not shared with SG. However, the {beta}-cell sensitivity to increasing concentrations of endogenous incretin is smaller after bariatric surgery, particularly after GB, compared to non-operated controls, indicating a long-term adaptation of gut-pancreas axis after these procedures. HIGHLIGHTSO_ST_ABSWhat is known?C_ST_ABSGlycemic effects of gastric bypass (GB) and sleeve gastrectomy (SG) is attributed to rapid nutrient flux and enhanced insulinotropic effects of gut hormones but {beta}-cell sensitivity to exogenous GLP-1 or GIP is diminished after GB. What the present findings add?Post-OGTT {beta}-cell sensitivity to enhanced endogenous incretins by DPP4i is markedly reduced in bariatric subjects versus non-operated controls, and yet insulin secretory response (disposition index) is increased leading to hypoglycemia in GB and not SG. Significance?Blunted sensitivity to GLP-1 may represent {beta}-cell adaptation to massive elevation in GLP-1 secretion following bariatric surgery to protect against hypoglycemia. The differential effect of enhanced concentrations of incretins on post-OGTT insulin response (disposition index) among GB versus SG highlights a distinct adaptive process among the two procedures. Augmented insulinotropic effects of gut hormones on postprandial insulin secretory response after GB despite a reduced beta-cell sensitivity to plasma concentrations of GLP-1 makes a case for non-hormonal mechanisms of GLP-1 action after GB. Better understanding of long-term effects of bariatric surgery on gut-pancreas axis activity is critical in development of GLP-1-based strategies to address glucose abnormalities (both hyperglycemia and hypoglycemia) in these settings.

BackgroundPET-CT scans of radioactive exendin-4, a ligand of the GLP-1 receptor, are claimed to provide a biomarker of pancreatic beta cell mass (BCM), although the GLP-1 receptor is expressed also in the exocrine pancreas (PX). Parotid glands may be a reference tissue for GLP-1 receptor expression in exocrine cells of the GI system. Our aims were 1. To assess biomarker(s) of BCM derived from 68Ga-NODAGA-exendin-4 PET-CT scans in participants with long-standing type 1 diabetes (T1DM) or in subjects with obesity (OBESE); 2. To investigate the relationship between biomarker(s) of BCM and a biomarker of beta cell functional mass (BCFxM) in OBESE. MethodsT1DM (n=8, Age: 50.4{+/-}3.8 yrs; T1DM duration: 34.2{+/-}3.0 yrs; BMI: 26.6{+/-}1.1 kg/m2; HbA1c: 7.5{+/-}0.36%) and OBESE (n=9; Age:48.2{+/-}2.2 yrs; BMI: 37.4{+/-}1.1 kg/m2; HbA1c: 5.4{+/-}0.17%) underwent two studies: 1) 68Ga-NODAGA-exendin-4 PET-CT scan of both PX and parotid glands 45-60 after i.v. injection and with CT-assessment of PX volume to compute biomarkers of BCM based on SUV (BCMSUV) or clearance (CLEAR; BCMCLEAR); 2) Mixed meal test (MMT), with measurement of plasma glucose, C-peptide, GLP-1 and GIP curves to assess BCFxM with state-of-art mathematical modeling. ResultsThe C-peptide response to the MMT in T1DM participants was absent or negligible, whereas the OBESE displayed a robust BCFxM. The PX volume was smaller in T1DM than in OBESE (51.7{+/-}6.6 vs 92.9{+/-}10.9 cc; p=0.007). The biomarkers of BCM, as assessed by 68Ga-NODAGA-exendin-4 SUV or CLEAR, were 6.6-fold (p=0.003) and 5.0-fold (p=0.002) lower, respectively, in T1DM than in OBESE. BCFxM was correlated in OBESE to both biomarkers of BCM (r=0.91 p<0.001, and r=0.82 p=0.006, respectively). Conclusion/interpretation68Ga-NODAGA-exendin-4 derived biomarkers of BCM can discriminate T1DM from OBESE. In OBESE 68Ga-NODAGA-exendin-4 derived BCM appears to be a pivotal determinant of the beta cell response to MMT and may be valuable to compare and monitor BCM both in research and in clinical settings. Research in contextO_ST_ABSWhat is already known about this subject?C_ST_ABSO_LIChanges in pancreatic beta cell functional mass are at the heart of alterations in glucose regulation, including diabetes mellitus. Beta cell functional mass can be assessed by mathematical modeling of the in vivo beta cell response to intravenous or oral challenges. C_LIO_LIBeta cell functional mass is the product of beta cell mass times beta cell function per mass unit, i.e. the result of two distinct entities, mass and function. No in vivo methods can dissect out beta cell mass and function. C_LIO_LIPancreatic 68Ga-exendin-4 uptake, as measured by PET-CT, has been proposed as a non-invasive biomarker of beta cell mass. However, the ratio of 3.6:1 between endocrine and exocrine pancreas 68Ga-exendin 4 uptake suggests that there is room for improvement. C_LI What are the key questions?O_LIDoes an improved 68Ga-exendin4 method provide a better separation between participants with type 1 diabetes and expected zero/nil beta cell mass vs people with nondiabetic obesity? C_LIO_LIWhat is the role of beta cell mass in determining beta cell functional mass in people living with obesity? C_LI What are the new findings?O_LIThe improvement in the quantitation of beta cell 68Ga-exendin-4 binding to beta cells resulted in a clearcut separation of participants with type 1 diabetes and expected zero/nil beta cell mass from people living with obesity C_LIO_LIIn people living with obesity, beta cell mass, as assessed by 68Ga-exendin-4 PET-CT scan, is a pivotal determinant of beta cell functional mass, as assessed by mathematical modeling of a frequently sampled mixed meal test C_LI How might this impact on clinical practice in the foreseeable future?O_LIThis method has the potential to track changes in beta cell mass both between-subjects and within-subjects over time C_LIO_LINatural history of glucose (in)tolerance and the impact of disease modifier candidates in diabetes mellitus can be assessed with the present method C_LI

IntroductionPostbariatric hypoglycaemia (PBH) is an increasingly recognized late metabolic complication of Roux-en-Y gastric bypass (GB) surgery. PBH typically manifests with a fact occurring post-meal hyperglycaemic peak, followed by a disproportionately exaggerated insulin response leading to low glucose levels. On this basis, we evaluated the effect of a single dose of empagliflozin 10mg vs. placebo on parameters of insulin kinetics. Materials and methodsInsulin secretion, hepatic insulin extraction and total insulin clearance were evaluated after a single of empagliflozin 10mg vs. placebo followed by a standardized liquid mixed meal were evaluated in 11 subjects with confirmed PBH after GB over 3h. Parameters of interest were calculated using established mathematical models. Indices were compared between the groups using the Wilcoxon signed-rank test. ResultsTotal beta-cell responsiveness tends to be lower with empagliflozin vs. placebo (24.83{+/-}11.00 vs. 27.15{+/-}9.68 [10-9 min-1], p=0.150). Total first-pass hepatic insulin extraction increased after empagliflozin compared to placebo (49.6{+/-}14.2 vs. 39.7{+/-}12.1 %, p=0.006), while no significant effect of empaglizflozin on basal first-pass hepatic insulin extraction was observed (79.7{+/-}7.1 vs. 81.1{+/-}6.6 %, p=0.521). Total insulin clearance resulted to be significantly lower after empagliflozin compared to placebo (3.91{+/-}1.58 vs. 3.00{+/-}1.27 l/min, p=0.002). ConclusionThe present analysis suggests that the hypoglycaemia-attenuating effect of SGLT2-inhibition in patients with PBH is mainly mediated by an increment in insulin clearance, with also a tendency to a reduction in insulin secretion.

BackgroundDespite bariatric surgerys success for most patients, up to 30% do not experience optimal weight loss outcomes. Reasons remain incompletely understood. Thyroid hormones, due to their role in energy expenditure, have received study. Yet research to date is inconclusive regarding the impact of standard thyroid markers (e.g., thyroid stimulating hormone, or TSH) on weight regulation after bariatric surgery. This prospective observational study investigates whether the early development of euthyroid sick syndrome (ESS) predicts reduced longer-term post-bariatric weight loss. ESS develops during periods of stress (e.g., critical illness, severe infection, famine) and is thought to serve a protective function by suppressing metabolism and conserving weight. Levels of metabolically active free triiodothyronine (FT3) drop, levels of non-catabolic reverse 3,3,5-triiodothyronine (rT3) rise, and TSH levels remain euthyroid. Reductions in the ratio of FT3 to rT3 significantly predict outcomes in critically ill patients with ESS yet have been unexamined in intentional weight loss among post-bariatric patients. Hence this hypothesis-generating preliminary study investigated whether early changes in the FT3:rT3 ratio predict weight changes at 1-2 years post-bariatric surgery MethodsTwenty-three adult patients undergoing Roux-en-Y gastric bypass (n=12) or sleeve gastrectomy (n=11) were recruited from a bariatric surgery clinic. The TSH, FT4, FT3, rT3, and self-reported hypothyroid symptoms were collected 2-weeks pre-surgery and between 2 weeks to 3 months post-surgery. Body mass index was measured pre-surgery and 1-2 years post-surgery. ResultsReductions in the FT3:rT3 ratio from pre- to early post-surgery significantly predicted reduced weight loss at 1 (p= 0.03) and 2 years (p= 0.02) post-surgery. No other thyroid-related markers nor hypothyroid symptoms were predictive. ConclusionsAlthough replication with larger samples is needed due to sizeable study attrition, this small exploratory study provides provocative support that early changes in the FT3:rT3 ratio associated with ESS predict longer-term reductions in post-bariatric surgery weight loss. Clinical implications are discussed.

This study investigates the individual and combined effects of Roux-en-Y gastric bypass (RYGB), sleeve gastrectomy (SG), and metformin on glucose regulation in a non-obese, insulin-deficient model of type 2 diabetes. Female Goto-Kakizaki (GK) rats underwent RYGB, SG, or sham surgery. Three weeks postoperatively, animals received metformin (50 mg/kg/day, 5 days/week) or vehicle for three additional weeks. Glucose tolerance was assessed using a standardized meal test, and insulin sensitivity was evaluated by insulin tolerance test. Plasma levels of GLP-1, GIP, insulin, and leptin were measured. RYGB and SG reduced body weight, food intake, and leptin levels, and improved fasting glucose, glucose tolerance, insulin sensitivity, and postprandial incretin and insulin secretion. Metformin alone improved glucose tolerance and insulin sensitivity independently of incretin or insulin changes. When combined with surgery, metformin further reduced postprandial glycemic excursions and advanced the glycemic peak but did not enhance insulin sensitivity or hormone secretion beyond surgery alone. In conclusion, bariatric surgery and metformin independently improve glucose regulation in non-obese diabetic GK rats. Their combination provides additional benefits on postprandial glucose control, despite no additive effects on insulin sensitivity or hormone levels. These findings support the use of metformin as an adjunct to bariatric surgery in insulin-deficient diabetes and highlight the need for longer-term, sex-inclusive studies to enhance translational relevance. NEW & NOTEWORTHYBariatric surgery and metformin each improved glucose regulation in non-obese, insulin-deficient female GK rats. Their combination yielded an additional reduction in postprandial glycemic excursions without further enhancing insulin sensitivity or incretin/insulin secretion. These findings reveal that postprandial glucose dynamics can be modulated independently of hormonal or insulin-sensitivity pathways, highlighting distinct and dissociable mechanisms governing glucose homeostasis in an insulin-deficient model.

In vertebrates, pituitary gonadotropins (follicle-stimulating and luteinizing hormones: FSH and LH) regulate gonadal development and maturation, therefore playing an essential role in reproduction. The seasonal regulation of gonadotropins has been widely studied in mammals and birds, and in these taxa thyroid-stimulating hormone (TSH) was found to play a critical role. By contrast, the seasonal regulation of gonadotropins remains unclear in teleost fish. In addition, the seasonal regulation of gonadotrope (gonadotropin-producing cell) proliferation has not been elucidated in any vertebrate group. Using the teleost fish medaka as a model, we show for the first time that long photoperiod enables reproduction by stimulating gonadotropin mRNA synthesis and gonadotrope cell proliferation. In female medaka, this proliferation is achieved by gonadotrope mitosis. We then demonstrate that in female medaka, photoperiod stimulates gonadotropin mRNA production and mitosis via an indirect intra-pituitary pathway, involving pituitary Tsh cells. We show that non-endocrine folliculostellate cells in the pituitary mediate the Tsh signal regulating gonadotrope activity and proliferation, as they are the only pituitary cells to express Tsh receptors and send projections to gonadotropes. Finally, we show that melatonin suppresses pituitary tshba expression in fish exposed to long photoperiod, suggesting that short photoperiod inhibits gonadotropin synthesis via melatonin in both fish and mammals. This study therefore demonstrates that in fish, photoperiod regulates gonadotrope cell activity and mitosis via a melatonin-Tsh pathway. It also reveals the existence of a novel intra-pituitary pathway for seasonal regulation of gonadotropes, involving folliculostellate cells, which we propose might also exist in other vertebrates. SIGNIFICANCEIn seasonally breeding mammals and birds, the production of the hormones that regulate reproduction (gonadotropins) by gonadotropes is controlled by the pituitary thyroid-stimulating hormone (TSH) through an indirect pathway via the brain. However, in fish, how seasonal environmental signals influence gonadotropins remains unclear. Here, we show that in a long day seasonally breeding fish, medaka, photoperiod not only regulates the activity (hormone production) of the gonadotropes but also their proliferation. We also reveal a novel intra-pituitary pathway that regulates gonadotrope cell activity and number. This pathway involves melatonin, Tsh, and folliculostellate cells. Interestingly, as all these components are also found in the mammalian pituitary, this study suggests the existence of an alternative regulatory mechanism of seasonal gonadotropin production across vertebrates.

BackgroundThe glycemic-independent actions of glucagon-like peptide 1 (GLP-1) in the prandial state in humans are largely unknown. Protein ingestion stimulates beta-cell secretion without changing plasma glucose concentration. We examined the contribution of endogenous GLP-1 to glucose metabolism and beta-cell response to protein ingestion under basal glucose concentrations, and whether these responses are affected by rerouted gut after gastric bypass (GB) or sleeve gastrectomy (SG). MethodsInsulin secretion rate (ISR) and glucose fluxes during a 50-gram oral protein load were compared between 10 non-diabetic individuals with GB, 9 matched subjects with SG and 7 non-operated controls (CN) with and without intravenous infusion of exendin-(9-39) [Ex-9], a specific GLP-1 receptor (GLP-1R) antagonist. ResultsBlocking GLP-1R increased plasma glucose concentration before and after protein ingestion and decreased beta-cell sensitivity to glucose in the first 30 minutes of protein ingestion (p<0.05) in all 3 groups. However, reduction in the premeal ISR by Ex-9 infusion only was observed in CN (p<0.05 for interaction), whereas diminished prandial ISR3h by GLP-1R blockade was observed in GB and SG and not in controls (p<0.05 for interaction). Also, GLP-1R blockade enhanced post-protein insulin action in GB and SG, but not in CN. Endogenous glucose production (EGP) during the first hour after protein ingestion was increased in all 3 groups but EGP3h was accentuated by Ex-9 infusion only in GB (p<0.05 for interaction). ConclusionThese findings are consistent with both a glucose-independent pancreatic and extra-pancreatic role for GLP-1 during protein ingestion in humans that are exaggerated by bariatric surgery. Trial registrationThis study was registered at Clinical Trials.Gov: NCT02823665

Uric acid (UA) is traditionally regarded as a metabolic risk marker; however, its dynamic behavior during glucose-lowering therapy remains incompletely understood. We compared UA responses to a modified traditional Japanese diet (MJDD) and the DPP-4 inhibitor alogliptin in patients with early-stage type 2 diabetes mellitus (T2DM). In this prospective observational study, drug-naive patients received MJDD (n=58) or alogliptin (n=52) monotherapy for 3 months. Changes ({Delta}) in serum UA were analyzed in relation to glycemic control, insulin resistance, adipose tissue insulin resistance (adipo-IR), and beta-cell function. Both interventions significantly reduced fasting blood glucose and HbA1c while paradoxically increasing serum UA and HOMA-B. Baseline UA was the primary determinant of {Delta}UA in both cohorts. MJDD significantly reduced body mass index, insulin, free fatty acids, HOMA-R, and adipo-IR, with effects most pronounced in subjects with baseline BMI >25. In contrast, alogliptin selectively reduced adipo-IR in leaner subjects (BMI <25). Across both treatments, {Delta}UA correlated positively with {Delta}HOMA-B and inversely with {Delta}HbA1c. Notably, during MJDD, {Delta}UA showed a paradoxical negative correlation with {Delta}BMI and {Delta}FBG, and a positive correlation with {Delta}FFA. Patients exhibiting the greatest UA increases demonstrated the most marked improvements in beta-cell function and, with MJDD, the greatest weight loss. These findings indicate that MJDD and alogliptin exert distinct metabolic effects in early T2DM, yet both link rising UA to enhanced beta-cell function, suggesting that UA may serve as a dynamic pharmacometabolic biomarker reflecting therapy-specific metabolic adaptation rather than metabolic deterioration.

Leptin receptor (LepRb)-expressing neurons are known to link body growth and reproduction, but whether these functions are mediated via insulin-like growth factor 1 receptor (IGF1R) signaling is unknown. IGF-1 and insulin can bind to each others receptors, permitting IGF-1 signaling in the absence of IGF1R. Therefore, we created mice lacking IGF1R exclusively in LepRb neurons (IGF1RLepRb mice) and simultaneously lacking IGF1R and insulin receptor (IR) in LepRb neurons (IGF1R/IRLepRb mice) and then characterized their body growth, bone morphology, reproductive and metabolic functions. We found that IGF1R and IR in LepRb neurons were required for normal timing of pubertal onset, while IGF1R in LepRb neurons played a predominant role in regulating adult fertility and exerted protective effects against reproductive aging. Accompanying these reproductive deficits, IGF1RLepRb mice and IGF1R/IRLepRb mice had transient growth retardation. Notably, IGF1R in LepRb neurons was indispensable for normal trabecular and cortical bone mass accrual in both sexes. These findings suggest that IGF1R in LepRb neurons is involved in the interaction among body growth, bone development, and reproduction. Though only mild changes in body weight were detected, simultaneous deletion of IGF1R and IR in LepRb neurons caused dramatically increased fat mass composition, decreased lean mass composition, lower energy expenditure, and locomotor activity in both sexes. Male IGF1R/IRLepRb mice exhibited impaired insulin sensitivity. These findings suggest that IGF1R and IR in LepRb neurons jointly regulated body composition, energy balance, and glucose homeostasis. Taken together, our studies identified the sex-dependent complex roles of IGF1R and IR in LepRb neurons in regulating body growth, reproduction, and metabolism.

Objective: Patients and physicians frequently focus on HbA1c and weight alone. We hypothesized that individuals with similar HbA1c and BMI may present markedly distinct metabolic backgrounds. We investigated whether the adipo-B index- composite of adipose insulin resistance (adipo-IR) and beta-cell function (HOMA-B)-can uncover hidden heterogeneity in this clinically homogeneous population. Methods: A total of 399 newly diagnosed, drug-naive Japanese subjects with T2DM were analyzed. Histograms of HbA1c and BMI demonstrated peak distributions within HbA1c 8-10% and BMI 24-26. Based on these distributions, a clinically homogeneous subgroup was defined to minimize confounding by glycemic severity and adiposity. Metabolic parameters including FBG, insulin, FFA, HOMA-R, HOMA-B, adipo-IR, adipo-B, T-C, TG, HDL-C and non-HDL-C were analyzed. Simple regression, multivariable linear regression, and subgroup stratification analyses were performed. Results: Despite comparable HbA1c and BMI by design, adipo-B stratification revealed significant differences in HOMA-B, FFA, non-HDL-C, and TG, whereas HOMA-R stratification identified only higher insulin and adipo-IR without differences in lipids or HOMA-B. Thus, adipo-B-but not HOMA-R-identified a lipotoxic, beta-cell-stressed phenotype invisible to conventional markers. Simple regression showed significant positive correlations between adipo-B and HbA1c, FBG, FFA, T-C, TG, and non-HDL-C, and negative correlations with insulin and HOMA-B. Multivariable linear regression confirmed that adipo-B was independently associated with non-HDL cholesterol, TG, and FFA after adjustment for HbA1c and BMI. Conclusion: Even among patients with identical HbA1c and BMI, the adipo-B index uncovers clinically relevant metabolic heterogeneity, supporting its role as a functional marker of the adipose-pancreas axis and a potential tool for precision phenotyping in early T2DM.

AMP-activated protein kinase (AMPK) is a critical cellular and whole body energy sensor activated by energy stress, including hypoglycemia, which is frequently experienced by people with diabetes. Previous studies using direct delivery of an AMPK activator to the ventromedial hypothalamus (VMH) in rodents increased hepatic glucose production. Moreover, recurrent glucoprivation in the hypothalamus leads to blunted AMPK activation and defective hormonal responses to subsequent hypoglycemia. These data suggest that amplifying AMPK activation may prevent or reduce frequency hypoglycemia in diabetes. We used a novel brain-permeable AMPK activator, R481, which potently increased AMPK phosphorylation in vitro. R481 significantly increased peak glucose levels during glucose tolerance tests in rats, which were attenuated by treatment with AMPK inhibitor SBI-0206965 and completely abolished by blockade of the autonomic nervous system. This occurred without altering insulin sensitivity measured by hyperinsulinemic-euglycemic clamps. Endogenous insulin secretion was not altered by R481 treatment. During hyperinsulinemic-hypoglycemic clamp studies, R481 treatment reduced exogenous glucose requirements and amplified peak glucagon levels during hypoglycemia. These data demonstrate that peripheral administration of the brain permeable AMPK activator R481 amplifies the counterregulatory response to hypoglycemia in rats, which could have clinical relevance for prevention of hypoglycemia.

The existence of sodium-glucose cotransporter 2 (SGLT2) in pancreatic alpha cells and its potential roles in glucagon secretion remain controversial, despite its well-established function in renal glucose reabsorption. While some studies suggest SGLT2 presence and its involvement in glucagon regulation, others deny its expression in alpha cells. To clarify this dispute, we investigated the functional effects of highly selective SGLT2 inhibitors, dapagliflozin and empagliflozin, on glucose uptake, intracellular ATP levels, and glucagon secretion in alpha-TC1 cells, a widely used model for glucagon-secreting cells in culture. The SGLT2 inhibitors significantly suppressed basal glucose uptake in alpha-TC1 cells, indicating functional SGLT2 presence. However, the inhibitors did not affect glucagon secretion. Neither the SGLT2 inhibitors nor the more potent glucose transport inhibitor, cytochalasin B, altered intracellular ATP levels or glucagon secretion. In contrast, pharmacological inhibition of K/ATP channels increased glucagon secretion without affecting glucose uptake or ATP levels. These results suggest that while SGLT2 is functionally present at low levels and mediates basal glucose uptake in alpha-TC1 cells, its inhibition has insufficient influence on intracellular ATP levels, and therefore glucagon secretion remains stable. Furthermore, our observations support predominant involvement of K/ATP channels in regulating glucagon secretion. Further studies in human purified pancreatic alpha cells in addition to islets are warranted to fully elucidate SGLT2s role in alpha-cell physiology.

BackgroundDifferentiating parathyroid adenoma from hyperplasia is critical for surgical planning, but conventional imaging often cannot reliably distinguish these lesions. Ultrasound elastography offers quantitative assessment of tissue stiffness and may improve preoperative characterization. PurposeTo evaluate the diagnostic accuracy of ultrasound elastography in differentiating parathyroid adenoma from hyperplasia. MethodsA systematic review and meta-analysis was conducted in accordance with PRISMA guidelines. PubMed, Scopus, and Embase were searched through July 2025, for studies assessing elastography for parathyroid lesion differentiation. Data on sensitivity, specificity, and other diagnostic metrics were extracted and pooled using a bivariate random-effects model in R software. ResultsFive studies comprising 579 parathyroid lesions were included, of which four studies with 352 adenomas and 202 hyperplasias were eligible for pooled analysis. Pooled sensitivity and specificity of elastography were 83.3% (95% CI: 74.3-89.6%) and 79.1% (95% CI: 65.5-88.3%), respectively, with an area under the SROC curve of 0.88 (95% CI: 0.79-0.92). Pooled likelihood ratios were 4.14 for a positive test and 0.216 for a negative test. Fagan nomogram analysis showed that, for a patient with a 50% pre-test probability of adenoma, a positive result increased post-test probability to 81%, while a negative result decreased it to 18%. ConclusionUltrasound elastography demonstrates good diagnostic performance in distinguishing parathyroid adenomas from hyperplasia and may help inform preoperative planning.

BackgroundCentral serous chorioretinopathy (CSCR) predominantly affects middle-aged men, in which systemic glucocorticoid exposure is a well-established risk factor. Genetic studies have implicated copy number variation (CNV) in complement component 4 (C4), located within the RCCX module alongside the steroid 21-hydroxylase gene (CYP21A2), in modifying disease susceptibility. However, the relationship between adrenal steroid metabolism and C4 CNV in CSCR has not been investigated. MethodsWe analyzed the serum steroidome of 45 male CSCR patients and 49 age-matched healthy male controls using liquid chromatography-tandem mass spectrometry. In a subset of 20 patients with chronic CSCR, genomic C4A and C4B copy numbers were quantified by qPCR and correlated with circulating steroid metabolites, including indices of CYP21A2 activity. ResultsCSCR patients exhibited significant alterations in steroid metabolism compared with controls. In the glucocorticoid pathway, 17-hydroxyprogesterone (17-OHP) was elevated, cortisone was reduced, and the 11-deoxycortisol/17-OHP ratio, reflecting CYP21A2 activity, was significantly lower. In the mineralocorticoid pathway, 11-deoxycorticosterone, dehydrocorticosterone, and aldosterone were decreased, while in the androgen pathway dehydroepiandrosterone (DHEA) was increased. In the subgroup with genomic analysis, patients carrying only one C4B copy displayed reduced CYP21A2 activity, as reflected by a lower S/17-OHP ratio, and correlations were observed between C4 copy number, 17-OHP levels, and the S/17-OHP ratio. ConclusionMen with CSCR present systemic dysregulation of glucocorticoid, mineralocorticoid and androgen pathways, linked to impaired CYP21A2 activity. The correlation between low C4B copy number and altered steroid metabolism suggests a role of the RCCX module in CSCR susceptibility, warranting further genetic and functional investigations

ObjectivesGlucocorticoids, mediated by the activation of the HPA axis, affect metabolic responses, insulin resistance, lipolysis and body fat distribution. Dehydroepiandrosterone-sulfate (DHEA-S) is a hormone produced by the adrenal glands and a precursor of sex hormones. The balance and interaction between cortisol and DHEA-S can significantly affect body composition. This study aimed to investigate the relationship between cortisol and DHEA-S levels, cortisol/DHEA-S ratio, and body composition in Korean men and women. MethodsIn total, 802 adults participated in this study between January 2018 and March 2023. Socio-demographic data and lifestyle factors were assessed using questionnaires. Body composition, clinical blood pressure, and metabolic variables, including cortisol and DHEA-S levels, were assessed. Cortisol and DHEA-S scores were analyzed in relation to height, body weight(BW), body mass index(BMI) and waist circumference(WC) according to age and sex. ResultsParticipants had a mean age of 52.6{+/-}11.7 years. Cortisol levels adjusted for age and gender were negatively correlated with BW, WC and BMI. This result was more significant in women than in men. DHEA-S levels were positively correlated with height, BW and WC after adjusting for age. The cortisol/DHEA-S ratio was associated with lower height and BW after adjusting for gender. Logistic regression for cortisol, DHEA-S and the cortisol/DHEA-S ratio in the prediction of central obesity was significant for men after adjusting for age and BMI. ConclusionsElevated cortisol concentrations are associated with lower adiposity. DHEA-S levels were positively correlated with height and body mass. The prediction of central obesity was associated with cortisol and the cortisol/DHEA-S ratio in men and negatively associated with DHEA-S.

The association of thyroid disease and diabetes has been classically described. However, the comorbidity of thyroid disparities and insulin resistance is not frequently assessed, especially the sequence of the occurrence of these markers. We performed a retrospective analysis to evaluate the association between thyroid disease and diabetes markers. We further investigated the sequence of occurrence of thyroid and diabetes markers to identify any predictive capabilities of these markers. We evaluated 32787 subjects who were classified based on their serum thyroid hormones and autoantibody levels. Our general prevalence results showed that HOMA-IR was elevated in overt hypothyroid subjects (43.7%) and overt hyperthyroid subjects (42.2%). HbA1C was elevated in subclinical hypothyroid subjects (19.2%), overt hypothyroid subjects (22.3%) and overt hyperthyroid subjects (21.2%). Glucose was significantly elevated in subclinical hypothyroid subjects (24.2%) and overt hyperthyroid subjects (31.0%). Insulin was only significantly elevated in overt hypothyroid subjects (15.1%). Interestingly, we found that 70.3% of subjects who had their HOMA-IR score escalated from negative (HOMA-IR<2.7) to positive (HOMA-IR>2.7) during their multiple visits had anti-TPO 369 ({+/-}242) days prior to the onset of this change. Our comprehensive study provided evidence that the presence of anti-TPO may suggest a predictive role in developing insulin resistance later in life. Strengths and limitations of the studyO_LIThe strength of our study is the large population size including a larger set of markers from both thyroid disease and diabetes. C_LIO_LIThe limitation in our study is the distorted male and female ratio. C_LI

In the context of type 2 diabetes mellitus (T2DM), the concept of organ-specific insulin resistance (IR) as a localized manifestation has garnered increasing attention. A scoping review was conducted to investigate the clinical relevance of IR confined to individual organs without systemic metabolic implications. Utilizing a methodological framework adapted from Arksey and OMalley, a comprehensive search of PubMed was performed, focusing on the period between January 1990 and October 2024. The search strategy combined Medical Subject Headings terms and keywords related to IR and specific organs. Notably, while "insulin resistance" yielded a substantial number of results, the subset of "organ-specific insulin resistance" returned a more limited dataset, highlighting a gap in current literature. The systematic selection process encompassed identification, screening, eligibility, and inclusion stages to ensure robust inclusion criteria. This scoping review underscores the importance of exploring organ-specific IR in the diabetic milieu and sets the stage for further research to elucidate its role in the pathogenesis of T2DM. Conclusion: The findings suggest that investigating organ-specific IR in the context of T2DM is a promising avenue for future research to deepen our understanding of disease pathophysiology. Thus, this scoping review answers the following question "In Situ Resistance Insulin - Localized Type 2 Diabetes Mellitus or Type 6 Diabetes Mellitus?", emphasizing the need for targeted investigations into localized manifestations of IR and their implications for DM management strategies.

Bariatric surgery enhances glucose metabolism, yet the detailed postprandial joint glucose and insulin responses, variability in individual outcomes, and differences in surgical approaches remain poorly understood. To address this, we used hierarchical multi-output Gaussian process (HMOGP) regression to reveal clinically relevant patterns between persons undergoing two types of bariatric surgery by modeling the individual postprandial glucose and insulin responses and estimating the average response curves from individual data. 44 participants with obesity underwent either Roux-en-Y gastric bypass (RYGB; n=24) or One-Anastomosis gastric bypass (OAGB; n=20) surgery. The participants were followed up at the 6th and 12th months after the operation, during which they underwent an oral glucose tolerance test (OGTT) and a mixed meal test (MMT). A marked reduction in glycemia, an earlier glucose peak, and an increase and sharpening in the postprandial glucose and insulin responses were evident in both metabolic tests post-operation. MMT resulted in higher postprandial glucose and insulin peaks compared with OGTT. Higher glucose and insulin responses were observed after RYGB compared with OAGB, suggesting differences between the procedures that may influence the clinical practice. Computational modeling with HMOGP regression can thus be used to, in detail, predict the combined responses of patient cohorts to ingested glucose or a mixed meal and help in assessing individual metabolic improvement after weight loss. This can lead to new knowledge in personalized metabolic interventions.

We have previously shown that prandial endogenous glucose production (EGP) during insulin-induced hypoglycemia is smaller in non-diabetic subjects with gastric bypass (GB), where prandial glucagon-like peptide 1 (GLP-1) concentrations are 5-10 times higher than those in non-operated controls. Here, we sought to determine the effect of endogenous GLP-1 on prandial counterregulatory response to hypoglycemia after GB. Glucose fluxes, and islet-cell and gut hormone responses before and after mixed-meal ingestion were compared during a hyperinsulinemic hypoglycemic ({bsim}3.2 mmol/l) clamp with and without a GLP-1 receptor (GLP-1R) antagonist exendin-(9-39) (Ex-9) in non-diabetic subjects with prior GB compared to matched subjects with SG and non-surgical controls. In this setting, GLP-1R blockade had no effect on insulin secretion or insulin action, whereas prandial glucagon was enhanced in all 3 groups. Ex-9 infusion raised prandial EGP response to hypoglycemia in every GB subject but had no consistent effects on EGP among subjects with SG or non-operated controls (P < 0.05 for interaction). These results indicate that impaired post-meal glucose counterregulatory response to hypoglycemia after GB is partly mediated by endogenous GLP-1, highlighting a novel mechanism of action of GLP-1R antagonists for the treatment of prandial hypoglycemia in this population.

Pregnancy induces or represses hepatic drug metabolism. Whether pregnancy affects hepatic drug transport is unexplored. We previously showed that a cocktail of pregnancy-related hormones (PRHC) induces mRNA expression and activity of sodium/taurocholate cotransporting polypeptide (NTCP), organic anion transporter 2 (OAT2), and organic cation transporter 1 (OCT1, mRNA only) in differentiated HepaRG cells. Here, using HepaRG cells, we identified cortisol as the hormone primarily responsible for this induction and explored the underlying mechanisms. Clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9-mediated knockdown studies in HepaRG cells showed that the glucocorticoid receptor (GR) is the primary mediator of this response. GR knockdown markedly attenuated cortisol-induced NTCP, OAT2, and OCT1 mRNA expression and activity. Cortisol also induced the mRNA expression of regulatory factors, including pregnane X receptor (PXR), constitutive androstane receptor (CAR), and hepatocyte nuclear factor (HNF) 4 alpha (HNF4). HNF4 knockdown selectively attenuated OAT2 and OCT1 induction, whereas HNF1 knockdown enhanced NTCP induction, attenuated OCT1 induction, and reduced basal organic anion transporting polypeptide 1B1 (OATP1B1) expression. In contrast, knockdown of CAR or PXR did not significantly alter cortisol-mediated transporter regulation. These data identify cortisol as the principal PRH driving regulation of the hepatic OAT2, NTCP, and OCT1 in HepaRG cells and indicate that this response is mediated primarily by GR, with selective downstream contributions from HNF4 and HNF1. These findings provide mechanistic insights into pregnancy-associated changes in hepatic transporter-mediated drug disposition, including when antenatal corticosteroids are administered to pregnant women to prevent respiratory distress syndrome in their prematurely born infants. Significance StatementThe extent and mechanisms by which pregnancy-related hormones regulate hepatic uptake transporters remain poorly defined. This study identifies cortisol as the principal pregnancy-related hormone driving NTCP, OAT2, and OCT1 induction in HepaRG cells and shows that this response is mediated primarily through GR, with transporter-specific contributions from HNF4 and HNF1.