Daily Endocrinology Research Analysis

Hyperglycemia is a principal driver of β cell failure and multiple-organ complications in diabetes. Chronic exposure to hyperglycemia overstimulates mTORC1, disrupting glucose metabolism and promoting ER stress, oxidative stress, and inflammation; however, the upstream metabolic signal(s) linking glucose to mTORC1 activation remains unclear. Here, we identified glucosamine as a key metabolite connecting elevated glucose to mTORC1 signaling in pancreatic islets and kidney, both major targets of hyperglycemic damage. Using 13C6-glucose metabolic labeling in diabetic rodents treated with or without the SGLT2 inhibitor dapagliflozin or insulin, combined with targeted metabolomics and metabolic flux analysis, we found that tissue glucose concentrations strongly correlated with glucosamine. A similar correlation with plasma glucose was conserved in humans with or without type 2 diabetes, and inversely associated with β cell function. In vitro, low-dose glucosamine stimulated mTORC1 in islets and kidney proximal tubule cells in an O-GlcNAcylation-dependent manner. Broad phosphoproteomics and transcriptomics analyses in β cells showed that glucosamine activated mTORC1-regulating pathways, induced oxidative stress, ER stress, and dedifferentiation. Genetic inhibition of β cell mTORC1 via heterozygous Raptor knockout, as well as pharmacologic inhibition of the glucosamine/mTORC1 axis through SGLT2 inhibition, alleviated β cell stress, improved glycemic control, and restored β cell function. These findings identified the glucosamine/mTORC1 pathway as an important mediator of β cell and kidney dysfunction in diabetes.

AIMS/HYPOTHESIS: The aim of this study was to determine the effect of a novel somatostatin receptor 2 (SSTR2) antagonist, ZT-01, on impaired glucagon counterregulation in hypoglycaemia and its safety in adults with type 1 diabetes. METHODS: In a randomised crossover phase 1b single-site study, blinded to both participants and researchers, participants, aged 18-65 years with BMI 18.5-27 kg/m RESULTS: Twenty-four randomised participants (9 female and 15 male) received at least one administration of placebo or ZT-01 and were included for safety analysis. Twenty-two participants completed at least one glucose clamp and were included for pharmacodynamics analysis. Transient increases in plasma glucagon were observed with ZT-01 administration (by 25.7 ± 2.4 ng/l with 3 mg ZT-01 and by 28.4 ± 2.4 ng/l with 20 mg ZT-01), with levels declining to near the pre-dose values before the start of the level 1 hypoglycaemic period. Mean glucagon levels rose again over baseline in both ZT-01 treatment arms during level 1 (by 15.6 ± 2.3 pg/l with 3 mg ZT-01 and by 14.9 ± 2.4 pg/l with 20 mg ZT-01) and level 2 (by 22.8 ± 2.7 pg/l with 3.0 mg ZT-01 and by 29.6 ± 2.8 pg/l with 20 mg ZT-01) hypoglycaemia. With placebo, glucagon levels were unchanged following dosing and during level 1 hypoglycaemia but rose modestly during level 2 hypoglycaemia (by 8.9 ± 2.5 ng/l). Both frequency and amplitude of the increases in glucagon were higher with ZT-01 vs placebo during level 1 and level 2 hypoglycaemia. There were no drug treatment-related adverse events. CONCLUSIONS/INTERPRETATION: Administration of the SSTR2 antagonist ZT-01 increased glucagon responsiveness during insulin-induced hypoglycaemia in individuals with type 1 diabetes. TRIAL REGISTRATION: ClinicalTrials.gov NCT05007977.

CONTEXT: Insulinomas are the main cause of endogenous hyperinsulinemic hypoglycemia (EHH) in adults, with surgery as the only cure. Pancreas-preserving surgery is preferred, making precise preoperative localization crucial. GLP-1R-targeted imaging, such as [68Ga]Ga-DOTA-exendin-4 PET/CT, outperforms other imaging procedures for insulinoma localization. OBJECTIVE: To investigate the performance and clinical impact of [68Ga]Ga-DOTA-exendin-4 PET/CT for the detection of insulinomas in patients with EHH and prior negative or inconclusive conventional imaging. METHODS: In this retrospective, real-world, dual-center imaging study, 101 patients with biochemically proven EHH and/or a positive Whipple's triad underwent [68Ga]Ga-DOTA-exendin-4 PET/CT at two tertiary centers between April 2017 and March 2024. Among these, 58 patients with prior negative or inconclusive conventional imaging constituted the primary analysis cohort. Endpoints: Insulinoma detection rate and sensitivity by [68Ga]Ga-DOTA-exendin-4 PET/CT after negative or inconclusive conventional imaging and impact on clinical management. RESULTS: Among the 58 patients with prior negative or inconclusive conventional imaging, [68Ga]Ga-DOTA-exendin-4 PET/CT was positive in 42 patients, corresponding to a detection rate of 72% (95% CI, 59-83%). Thirty patients subsequently underwent PET/CT-guided surgery. Overall, 32 patients had histological verification (including two PET/CT-negative cases), corresponding to a sensitivity of 93.8% (95% CI, 79-99%). CONCLUSION: In real-world clinical practice, [68Ga]Ga-DOTA-exendin-4 PET/CT provides a high detection rate of 72% for localizing insulinomas, including one case of diffuse nesidioblastosis in patients with EHH and prior negative or inconclusive conventional imaging, thereby enabling PET/CT-guided surgical approaches. These findings underscore the substantial clinical impact of GLP-1R-targeted PET/CT on patient management and prognosis.GLP-1 receptor.