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Background Postprandial hypoglycemia after bariatric surgery is an exigent disorder, often impacting the quality of life. Distinguishing clinically relevant hypoglycemic episodes from symptoms of other origin can be challenging. Diagnosis is demanding and often requires an extensive testing such as prolonged glucose tolerance or mixed-meal test. Therefore, we investigated whether baseline parameters of patients after gastric bypass with suspected hypoglycemia can predict the diagnosis. Methods We analyzed data from 35 patients after gastric bypass with suspected postprandial hypoglycemia and performed a standardized mixed-meal test. Hypoglycemia was defined by the appearance of typical symptoms, low plasma glucose, and relief of symptoms following glucose administration. Parameters that differed in patients with and without hypoglycemia during MMT were identified and evaluated for predictive precision using receiver operating characteristic (ROC) areas under the curve (AUC). Results Out of 35 patients, 19 (54%) developed symptomatic hypoglycemia as a result of exaggerated insulin and C-peptide release in response to the mixed-meal. Hypoglycemic patients exhibited lower glycosylated hemoglobin A1c (HbA1c) and higher absolute and relative weight loss from pre-surgery to study date. HbA1c and absolute weight loss alone could achieve acceptable AUCs in ROC analyses (0.76 and 0.72, respectively) but a combined score of absolute weight loss divided by HbA1c (0.78) achieved the best AUC. Conclusions HbA1c and weight loss differed in patients with and without symptomatic hypoglycemia during mixed-meal test. These baseline parameters could be used for screening of postprandial hypoglycemia in patients after gastric bypass and may facilitate the selection of patients requiring further evaluation. Graphical abstract

Introduction Despite expert consensus guidelines, data is scarce on how to switch patients with type 2 diabetes when treatment with glucagon-like peptide 1 (GLP-1) receptor agonists is not effective and whether a switch to semaglutide brings any benefit on glucose and weight control for patients with type 2 diabetes. Methods Retrospective cohort analysis of patients with type 2 diabetes who were switched from any GLP-1 agonist in a stable dose to subcutaneously administered semaglutide. Primary endpoint was change of glycated haemoglobin (HbA1c) at 6 months. Secondary endpoints were weight, body mass index (BMI), heart rate, blood pressure and adverse events. Results In total, 77 patients (median age 65 years) with long-standing type 2 diabetes (median 15 years, median HbA1c 8.4%/68 mmol/l, median BMI 33 kg/m2) were included. HbA1c was significantly lower 6 months after switching to semaglutide (7.3%; 56 mmol/l). Median body weight was significantly lower at 3 months (94 kg) and 6 months (93 kg) compared to baseline (98 kg). An equipotential dose switch of semaglutide was used in 61 patients (79%) and a stepwise initiation approach was used in 16 patients (21%). Both treatment regimens improved glucose control and weight. Side effects occurred in 28 patients (36%). Conclusion Switching to semaglutide from established GLP-1 analogue therapy improved HbA1c and body weight. Both equipotential and stepwise dosing initiation appear to be effective and well tolerated. Supplementary Information The online version contains supplementary material available at 10.1007/s13300-021-01016-y.

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.

The aim of the present survey was to analyze plasma vitamin B6 levels in post-bariatric patients and to elucidate the causal factors associated with elevated plasma vitamin B6 levels. This is a retrospective analysis of electronic patient data of all post-bariatric patients evaluated at the endocrine outpatient clinic of the University Hospital Basel in 2017, for which plasma vitamin B6 values were assessed during regular follow-up visits. In total, 205 patients were included in the study, whereof a minority of 43% had vitamin B6 levels in the normal range. 50% of the patients had vitamin B6 levels up to fourfold higher than the upper normal limit and 7% had levels more than fourfold above the upper normal limit. Vitamin B6 deficiency was not observed in any patient. While multivitamin supplementation in general was associated with elevated plasma vitamin B6 levels, the highest vitamin B6 levels were found after biliopancreatic diversion (BPD) and in patients who reported daily energy drink intake. Elevated plasma vitamin B6 levels up to fourfold above the upper normal limit are common in postbariatric patients and are associated with regular multivitamin supplementation, while highly elevated plasma vitamin B6 levels were seen primarily upon regular energy drink intake. Thus, a regular follow-up of vitamin B6 plasma levels and critical evaluation of vitamin B6 supplementation, either as part of the multivitamin preparation or related to regular energy drink intake, is highly warranted and should be an integral part of the routine post-bariatric follow-up.

Objective Ectopic Cushing's syndrome (ECS) induced by medullary thyroid cancer (MTC) is rare, and data on clinical characteristics, treatment and outcome are limited. Design Retrospective cohort study in three German and one Swiss referral centres. Patients Eleven patients with MTC and occurrence of ECS and 22 matched MTC patients without ECS were included. Measurements The primary endpoint of this study was the overall survival (OS) in MTC patients with ECS versus 1:2 matched MTC patients without ECS. Results The median age at diagnosis of ECS was 59 years (range: 35-81) and the median time between initial diagnosis of MTC and diagnosis of ECS was 29 months (range: 0-193). Median serum morning cortisol was 49 µg/dl (range: 17-141, normal range: 6.2-18). Eight (73%) patients received treatment for ECS. Treatment of ECS consisted of bilateral adrenalectomy (BADX) in four (36%) patients and adrenostatic treatment in eight (73%) patients. One patient received treatment with multityrosine kinase inhibitor (MKI) to control hypercortisolism. All patients experienced complete resolution of symptoms of Cushing's syndrome and biochemical control of hypercortisolism. Patients with ECS showed a shorter median OS of 87 months (95% confidence interval [95% CI]: 64-111) than matched controls (190 months, 95% CI: 95-285). Of the nine deaths, four were related to progressive disease (PD). Four patients showed PD as well as complications and comorbidities of hypercortisolism before death. Conclusion This study shows that ECS occurs in advanced stage MTC and is associated with a poor prognosis. Adrenostatic treatment and BADX were effective systemic treatment options in patients with MTC and ECS to control their hypercortisolism. MKI treatment achieved complete remission of hypercortisolism and sustained tumour control in one treated case.

Assessment of insulin secretion is key to diagnose postprandial hyperinsulinemic hypoglycemia (PHH), an increasingly recognized complication following bariatric surgery. To this end, the Oral C-peptide Minimal Model (OCMM) can be used. This usually requires fixing C-peptide (CP) kinetics to the ones derived from the Van Cauter population model (VCPM), which has never been validated in PHH individuals. The objective of this work was to test the validity of the OCMM coupled with the VCPM in PHH subjects and propose a method to overcome the observed limitations. Two cohorts of adults with PHH after gastric bypass (GB) underwent either a 75 g oral glucose (9F/3M; age=42±9 y; BMI=28.3±6.9 kg/m2) or a 60 g mixed-meal (7F/3M; age = 43 ± 11 y; BMI=27.5±4.2 kg/m2) tolerance test. The OCMM was identified on CP concentration data with CP kinetics fixed to VCPM (VC approach). In both groups, the VC approach underestimated CP-peak and overestimated CP-tail suggesting CP kinetics predicted by VCPM to be inaccurate in this population. Thus, the OCMM was identified using CP kinetics estimated from the data (DB approach) using a Bayesian Maximum a Posteriori estimator. CP data were well predicted in all the subjects using the DB approach, highlighting a significantly faster CP kinetics in patients with PHH compared to the one predicted by VCPM. Finally, a simulation study was used to validate the proposed approach. The present findings question the applicability of the VCPM in patients with PHH after GB and call for CP bolus experiments to develop a reliable CP kinetic model in this population.

Insulin secretion is key to understand postprandial hyperinsulinemic hypoglycemia (PHH), an increasingly recognized and potentially debilitating complication of gastric bypass (GB) surgery. To assess it noninvasively, the Oral C-peptide Minimal Model (OCMM) can be used. This requires to know C-peptide (CP) metabolic clearance rate (MCR) usually fixed to the values predicted by the Van Cauter (VC) population model, but this has never been assessed in PHH individuals. Here, the aim is to fill this gap. Two groups of post-GB adults with PHH underwent either a 75g oral glucose (11F/5M; age=43±8 y; BMI=28.2±7.1kg/m2) or a 60g mixed-meal (9F/3M; age=44±10y; BMI=27.4±3.9kg/m2) tolerance test with sampling for plasma glucose and CP over 3.5 and 3h, respectively. The OCMM was used to describe CP concentration with CP kinetics fixed to VC or estimated based on data (DB). Model performance was assessed by its ability to predict CP data. In both groups, the VC approach underestimated CP-peak and overestimated CP-tail, while the DB one well predicted CP data in all subjects (Figure 1A). As a consequence, MCR resulted significantly higher with DB than VC approach (Figure 1B). The present findings question the validity of the VC population model to predict CP kinetics in PHH patients and call for CP bolus experiments to develop a reliable kinetic model in this population. Disclosure M. Schiavon: None. D. Herzig: None. M. Hepprich: None. M.Y. Donath: Advisory Panel; Self; AstraZeneca, Bayer Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Lilly Diabetes, Merck Sharp & Dohme Corp., Novo Nordisk Inc., Roche Pharma, Sanofi-Aventis. C. Stettler: None. L. Bally: None. C. Dalla Man: Research Support; Self; Sanofi-Aventis Deutschland GmbH. Funding Italian Ministry of Education (232/2016); Swiss National Science Foundation (PCEGP3_186978); University of Padova

Severe cases of postprandial hypoglycaemia after bariatric surgery can be a diagnostic and therapeutic challenge. The diagnostic role of 68Ga-DOTA-Exendin-4 PET/CT in postbariatric hypoglycaemia for further treatment decisions is unclear. We present a case of a 50-year-old woman with frequent and severe postprandial hypoglycaemic (≤2.5 mmol/L) episodes starting three years after Roux-Y gastric bypass. Despite strict dietary adherence and several medical therapies, the patient remained severely affected, and 68Ga-DOTA-Exendin-4 PET/CT was performed to exclude atypical presentation of an insulinoma or nesidioblastosis. No pancreatic abnormalities were found, but intensive tracer accumulation in the first and second part of the duodenum was detected, which proved to be hyperplastic Brunner’s glands on histology and were strongly positive for the glucagon-like peptide-1 receptor. This case provides histopathological verification that duodenal 68Ga-DOTA-Exendin-4 uptake is caused by uptake in Brunner’s glands and points to a potential relationship between bariatric surgery and Brunner’s glands.

Objectives Cytokines such as IL-1 seems to play a role in the pathogenesis of fatigue associated with some chronic diseases and anti-inflammatory treatment has been shown to reduce these symptoms. Ingestion of a calorie rich meal leads to postprandial fatigue, and is associated with increased systemic concentrations of cytokines, which is more pronounced in obese than lean subjects. We investigated whether postprandial fatigue is regulated by IL-1, and therefore reduced by IL-1 antagonism, in lean and obese subjects. Methods In a double-blind, crossover study in 8 lean and 8 obese male subjects, randomized to receive either saline (placebo) or the IL-1 receptor antagonist anakinra, we investigated whether postprandial fatigue was regulated by IL-1. To promote postprandial fatigue, subjects ran 30 min prior to a high-fat, high-carbohydrate meal. Fatigue was determined using the Stanford Sleepiness Scale and blood samples were drawn at baseline and after the intervention. Results IL-1 antagonism led to a reduction in postprandial fatigue and this effect was more pronounced in obese than lean individuals. Conclusions We conclude that IL-1 is involved in the regulation of postprandial fatigue under physiologic conditions in lean and obese individuals. It remains to be shown whether this effect translates into clinical relevant effects., Graphical abstract, Highlights • Ingestion of a calorie rich meal leads to postprandial fatigue • IL-1 contributes to postprandial fatigue in lean and obese individuals. • IL-1 antagonism may decrease postprandial fatigue in humans.

Introduction The clinical picture of hypothyroidism, including neurological symptoms, can be multiform, which may delay or hamper the correct diagnosis. Case presentation We present an uncommon clinical presentation of a 38-year-old Caucasian man with mild facial palsy on the left side, uvular deviation to the left with preserved gag reflex, tongue deviation to the left, lingual dysarthria, and xerosis by severe hypothyroidism. Blood tests on admission showed elevated serum creatinine of 151 μmol/L (glomerular filtration rate 47 ml/min/1.7 CKD-EPI [Chronic Kidney Disease Epidemiology Collaboration equation]), increased creatinine phosphokinase activity (1243 U/L), markedly elevated thyroid-stimulating hormone (292.2 mIU/L), low free thyroxine level (1.1 pmol/L), and free triiodothyronine level below the limit of detection (

Background: Postprandial hypoglycemia (PPH) is a debilitating complication after bariatric surgery, due to an exaggerated hyperinsulinemic response after carbohydrate ingestion. Recent studies have shown that IL-1β contributes to the postprandial stimulation of insulin. Similarly, lowering hyperglycemic peak by SGLT2-inhibition may reduce insulin secretion. We investigated whether the IL-1 receptor antagonist anakinra or empagliflozin influence PPH in patients after gastric bypass. Methods: We included 12 subjects with PPH after gastric bypass in a placebo controlled, double-blind, randomized, cross-over proof-of-concept study. Subjects received on each of the 3 study days either empagliflozin, anakinra or the respective placebos followed by a mixed-meal-test (MMT) with assessment of hypoglycaemia. Results: Treatment with empagliflozin reduced glycaemia at 30 (11.2 vs. 10.1 mmol/l), 60 (9.1 vs. 6.9 mmol/l) and 90 (4.5 vs. 3.5 mmol/l) minutes of the MMT compared to placebo and was followed by a significant reduction of hypoglycemic events (n = 2, 16.6%) compared to placebo (n = 8, 61.5%). Treatment with anakinra showed a similar glucose curve as placebo, but was also followed by a significantly reduced rate of hypoglycemic events (n = 2, 16.6%). Both treatment interventions showed lowered insulin and c-peptide levels compared to placebo (p Conclusion: Empagliflozin as well as Anakinra significantly reduced hypoglycemic episodes in patients after gastric bypass by decreased insulin secretion. Therefore, empagliflozin and IL-1 antagonism, could be promising novel therapeutic options for patients with refractory PPH after gastric bypass. Disclosure M. Hepprich: None. B. Schelker: None. S.J. Wiedemann: None. B. Trinh: None. M. Böni-Schnetzler: None. M.Y. Donath: Consultant; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Lilly Diabetes, Merck & Co., Inc., Novartis AG, Novo Nordisk A/S, Sanofi. Funding University of Basel

Background: Primary aldosteronism, characterized by inappropriately high and relatively autonomous aldosterone production, is one of the most frequent causes of secondary hypertension. In most cases, primary aldosteronism results from unilateral or bilateral adrenal hyperplasia and aldosterone-producing adenoma. Depending on the subtype, patient characteristics and preference, treatment comprises unilateral adrenalectomy or mineralocorticoid receptor antagonists. However, these treatments are not always well tolerated or suitable. Histological studies have shown up-regulation of mTOR activity in the adrenal cortex of primary aldosteronism patients and mTORC1 inhibition decreases aldosterone production in adrenocortical cells. Consistently, we found that treatment of mice with the mTORC1 inhibitor rapamycin decreased plasma aldosterone levels without affecting other adrenal steroid hormones. Therefore, we aimed to evaluate the mTORC1-inhibitor everolimus as an aldosterone-lowering drug in patients with primary aldosteronism. Methods: In this open-label, proof-of-concept study, we measured plasma aldosterone levels after a standardized, recumbent saline infusion test in 12 primary aldosteronism patients at baseline, following a two-week everolimus treatment (0.75mg twice daily) and after a two-week washout period. To investigate whether everolimus affects other steroid hormone levels, we measured steroid hormone metabolites in a 24-hour urine collected before each saline infusion test. Results: Median post-infusion plasma aldosterone levels after treatment did not differ significantly from baseline (386 pmol/l, IQR 248-495 vs. 312 pmol/l, IQR 245-426; p = 0.677). However, a marked decrease in aldosterone levels after treatment was observed in four subjects. Their aldosterone levels returned to baseline values after the washout period. This pattern was mirrored by changes in urinary aldosterone/creatinine and tetrahydroaldosterone/creatinine ratios, suggesting that the observed effect was treatment-related. No consistent changes were detected for other steroid metabolites. Conclusion: This is a first in human study on the treatment of primary aldosteronism with the mTORC1 inhibitor everolimus. Overall, we observed a numerical reduction in aldosterone levels after a 2-week treatment which did not reach statistical significance. However, 4 patients appeared to respond to treatment. Further studies with a larger patient cohort are required to further elucidate the effects of mTORC1 inhibitors in primary aldosteronism and to characterize the differences between potential responders and non-responders.

Context Mammalian target of rapamycin complex 1 (mTORC1) activity is often increased in the adrenal cortex of patients with primary aldosteronism (PA), and mTORC1 inhibition decreases aldosterone production in adrenocortical cells, suggesting the mTORC1 pathway as a target for treatment of PA. Objective To investigate the effect of mTORC1 inhibition on adrenal steroid hormones and hemodynamic parameters in mice and in patients with PA. Design (i) Plasma aldosterone, corticosterone, and angiotensin II (Ang II) were measured in mice treated for 24 hours with vehicle or rapamycin. (ii) Plasma aldosterone levels after a saline infusion test, plasma renin, and 24-hour urine steroid hormone metabolome and hemodynamic parameters were measured during an open-label study in 12 patients with PA, before and after 2 weeks of treatment with everolimus and after a 2-week washout. Main Outcome Measures (i) Change in plasma aldosterone levels. (ii) Change in other steroid hormones, renin, Ang II, and hemodynamic parameters. Results Treatment of mice with rapamycin significantly decreased plasma aldosterone levels (P = 0.007). Overall, treatment of PA patients with everolimus significantly decreased blood pressure (P < 0.05) and increased renin levels (P = 0.001) but did not decrease aldosterone levels significantly. However, prominent reduction of aldosterone levels upon everolimus treatment was observed in four patients. Conclusion In mice, mTORC1 inhibition was associated with reduced plasma aldosterone levels. In patients with PA, mTORC1 inhibition was associated with improved blood pressure and renin suppression. In addition, mTORC1 inhibition appeared to reduce plasma aldosterone in a subset of patients.

Postprandial hypoglycemia is a disabling complication of the treatment of obesity by bariatric surgery. So far, no therapy exists, and the underlying mechanisms remain unclear. Here, we hypothesized that glucose-induced IL-1β leads to an exaggerated insulin response in this condition. Therefore, we conducted a placebo-controlled, randomized, double-blind, cross-over study with the SGLT2-inhibitor empagliflozin and the IL-1 receptor antagonist anakinra. Both drugs reduced postprandial insulin release and prevented hypoglycemia. Moreover, analysis of monocytes ex vivo revealed a hyper-reactive inflammatory state that resembles an exaggerated response to a meal. Our study proposes a role for glucose-induced IL-1β in postprandial hypoglycemia after bariatric surgery and suggests that SGLT2-inhibitors and IL-1 antagonism may improve this condition.

Importance: Convalescent plasma is a proposed treatment for COVID-19. Objective: To assess clinical outcomes with convalescent plasma treatment vs placebo or standard of care in peer-reviewed and preprint publications or press releases of randomized clinical trials (RCTs). Data Sources: PubMed, the Cochrane COVID-19 trial registry, and the Living Overview of Evidence platform were searched until January 29, 2021. Study Selection: The RCTs selected compared any type of convalescent plasma vs placebo or standard of care for patients with confirmed or suspected COVID-19 in any treatment setting. Data Extraction and Synthesis: Two reviewers independently extracted data on relevant clinical outcomes, trial characteristics, and patient characteristics and used the Cochrane Risk of Bias Assessment Tool. The primary analysis included peer-reviewed publications of RCTs only, whereas the secondary analysis included all publicly available RCT data (peer-reviewed publications, preprints, and press releases). Inverse variance-weighted meta-analyses were conducted to summarize the treatment effects. The certainty of the evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation. Main Outcomes and Measures: All-cause mortality, length of hospital stay, clinical improvement, clinical deterioration, mechanical ventilation use, and serious adverse events. Results: A total of 1060 patients from 4 peer-reviewed RCTs and 10 722 patients from 6 other publicly available RCTs were included. The summary risk ratio (RR) for all-cause mortality with convalescent plasma in the 4 peer-reviewed RCTs was 0.93 (95% CI, 0.63 to 1.38), the absolute risk difference was -1.21% (95% CI, -5.29% to 2.88%), and there was low certainty of the evidence due to imprecision. Across all 10 RCTs, the summary RR was 1.02 (95% CI, 0.92 to 1.12) and there was moderate certainty of the evidence due to inclusion of unpublished data. Among the peer-reviewed RCTs, the summary hazard ratio was 1.17 (95% CI, 0.07 to 20.34) for length of hospital stay, the summary RR was 0.76 (95% CI, 0.20 to 2.87) for mechanical ventilation use (the absolute risk difference for mechanical ventilation use was -2.56% [95% CI, -13.16% to 8.05%]), and there was low certainty of the evidence due to imprecision for both outcomes. Limited data on clinical improvement, clinical deterioration, and serious adverse events showed no significant differences. Conclusions and Relevance: Treatment with convalescent plasma compared with placebo or standard of care was not significantly associated with a decrease in all-cause mortality or with any benefit for other clinical outcomes. The certainty of the evidence was low to moderate for all-cause mortality and low for other outcomes.

Summary Postprandial hypoglycemia is a disabling complication of the treatment of obesity by gastric bypass surgery. So far, no therapy exists, and the underlying mechanisms remain unclear. Here, we hypothesized that glucose-induced IL-1β leads to an exaggerated insulin response in this condition. Therefore, we conducted a placebo-controlled, randomized, double-blind, crossover study with the SGLT2-inhibitor empagliflozin and the IL-1 receptor antagonist anakinra ( clinicaltrials.gov NCT03200782 ; n = 12). Both drugs reduced postprandial insulin release and prevented hypoglycemia (symptomatic events requiring rescue glucose: placebo = 7/12, empagliflozin = 2/12, and anakinra = 2/12, pvallikelihood ratio test (LRT) = 0.013; nadir blood glucose for placebo = 2.4 mmol/L, 95% CI 2.18–2.62, empagliflozin = 2.69 mmol/L, 95% CI 2.31–3.08, and anakinra = 2.99 mmol/L, 95% CI 2.43–3.55, pvalLRT = 0.048). Moreover, analysis of monocytes ex vivo revealed a hyper-reactive inflammatory state that has features of an exaggerated response to a meal. Our study proposes a role for glucose-induced IL-1β in postprandial hypoglycemia after gastric bypass surgery and suggests that SGLT2-inhibitors and IL-1 antagonism may improve this condition.

PURPOSE Physiological pancreaticoduodenal uptake of radiolabeled exendin-4 in Brunner glands of the proximal duodenum is the most common pitfall for false interpretation of glucagon-like peptide-1 receptor (GLP-1R) imaging. The aim of this study was to analyze the pancreaticoduodenal uptake in GLP-1R PET/CT and SPECT/CT images and to identify additional potential reading pitfalls in patients with suspected insulinoma. METHODS A post hoc analysis of a prospective study, including 52 consecutive patients, was performed. All patients underwent 1 Ga-exendin-4 PET/CT and 2 In-exendin-4 SPECT/CT scans (4 and 72 hours postinjection) in a randomized crossover order. Three board-certified nuclear medicine physicians read all scans independently. They were unaware of other results. Reference standard was surgery with histopathological confirmation of an insulinoma/nesidioblastosis and normalization of blood glucose levels after surgery. RESULTS There were no false-positive readings. However, there were a number of false-negative PET/CT and SPECT/CT readings, respectively: (1) due to false interpretation of uptake in the pancreaticoduodenal region (falsely interpreted as physiological uptake in Brunner glands instead of an insulinoma in 0.6% vs 9.0%), (2) due to ectopic insulinoma (0% vs 2.6%), (3) due to small insulinoma (1.9% vs 5.1%), (4) due to insulinoma overlap with kidneys (1.9% vs 4.5%), and (5) due to nesidioblastosis (0.6% and 1.9%). Pitfalls were identified in all GLP-1R PET/CT and SPECT/CT scans. CONCLUSIONS Peripancreatic uptake, small size of an insulinoma, insulinoma overlap with kidneys, and presence of nesidioblastosis are potential pitfalls in GLP-1R imaging, which can lead to false reading results.