Daily Endocrinology Research Analysis

BACKGROUND: Multiple endocrine neoplasia type 1 (MEN1) is a rare hereditary disorder characterised by the combined occurrence of parathyroid, pancreatic, and pituitary tumours. Current treatments are based on very low-quality evidence. Our aims were to determine treatment outcomes in patients with MEN1 for: subtotal parathyroidectomy versus less than subtotal parathyroidectomy for primary hyperparathyroidism (Q1); surgery versus active surveillance for non-functioning pancreatic neuroendocrine tumours sized 2 cm or less (Q2); and dopamine agonist responses of prolactinomas in patients with MEN1 versus patients without MEN1 (Q3). METHODS: We conducted three systematic reviews and one meta-analysis. Four electronic databases (MEDLINE Ovid, Embase Ovid, The Cochrane Library, and Web of Science) were searched from Dec 1, 2001, to Feb 13, 2023, with no language restrictions. Study designs included randomised controlled trials, prospective and retrospective cohort studies, and case-controlled and case series. Adults and children with MEN1-associated tumours were included in all three systematic reviews. For each clinical question, three pairs of authors independently screened abstracts and assessed the full text for final inclusion, discordant views were resolved by senior authors. Dichotomous outcomes were calculated using risk ratios or hazard ratios for time-to-event analyses, with 95% CIs. Continuous outcomes were ascertained using mean difference with 95% CIs. Where feasible, outcomes from individual studies were analysed through meta-analysis, using a random-effects model. The systematic reviews were prospectively registered (PROSPERO reference numbers CRD42023409912, CRD42023409936, and CRD42023409949). FINDINGS: For primary hyperparathyroidism (Q1), 990 non-duplicate records were screened for title and abstract, of which 23 studies with 1073 patients were eligible for meta-analysis. These studies showed that subtotal parathyroidectomy had a significantly lower risk of persistent primary hyperparathyroidism (RR 0·32, 95% CI 0·20-0·52; I INTERPRETATION: In patients with MEN1, subtotal parathyroidectomy achieved greater reductions in persistence and recurrence of primary hyperparathyroidism than less than subtotal parathyroidectomy; for non-functioning pancreatic neuroendocrine tumours sized 2 cm or less, the few available studies suggest that active surveillance might be comparable to surgical resection; and for prolactinomas, dopamine agonist therapy appears to have comparable efficacy as in patients without MEN1. FUNDING: None.

The diabetic heart has reduced ketone utilization due to impaired ketolytic enzyme activity. In a randomized controlled crossover trial, we investigated whether the cardiac response to 3-hydroxybutyrate infusion is impaired in type 1 diabetes. The response on cardiac output was blunted by 80% in type 1 diabetes, with no improvement in systolic function and left ventricular work efficiency was reduced. These findings suggest impaired cardiac ketone metabolism may have clinical significance and could contribute to diabetic cardiomyopathy.

The incretin peptides glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors coordinate β cell secretion that is proportional to nutrient intake. This effect permits consistent and restricted glucose excursions across a range of carbohydrate intake. The canonical signaling downstream of ligand-activated incretin receptors involves coupling to Gαs protein and generation of intracellular cAMP. However, recent reports have highlighted the importance of additional signaling nodes engaged by incretin receptors, including other G proteins and β-arrestin proteins. Here, the importance of Gαs signaling was tested in mice with conditional, postdevelopmental β cell deletion of Gnas (encoding Gαs) under physiological and pharmacological conditions. Deletion of Gαs/cAMP signaling induced immediate and profound hyperglycemia that responded minimally to incretin receptor agonists, a sulfonylurea, or bethanechol. While islet area and insulin content were not affected in Gnasβcell-/-, perifusion of isolated islets demonstrated impaired responses to glucose, incretins, acetylcholine, and IBMX In the absence of Gαs, incretin-stimulated insulin secretion was impaired but not absent, with some contribution from Gαq signaling. Collectively, these findings validate a central role for cAMP in mediating incretin signaling, but also demonstrate broad impairment of insulin secretion in the absence of Gαs that causes both fasting hyperglycemia and glucose intolerance.