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Hypoglycaemia (low plasma glucose) is a serious and potentially fatal complication of insulin-treated diabetes. In healthy individuals, hypoglycaemia triggers glucagon secretion, which restores normal plasma glucose levels by stimulation of hepatic glucose production. This counterregulatory mechanism is impaired in diabetes. Here we show in mice that therapeutic concentrations of insulin inhibit glucagon secretion by an indirect (paracrine) mechanism mediated by stimulation of intra-islet somatostatin release. Insulin’s capacity to inhibit glucagon secretion is lost following genetic ablation of insulin receptors in the somatostatin-secreting δ-cells, when insulin-induced somatostatin secretion is suppressed by dapagliflozin (an inhibitor of sodium-glucose co-tranporter-2; SGLT2) or when the action of secreted somatostatin is prevented by somatostatin receptor (SSTR) antagonists. Administration of these compounds in vivo antagonises insulin’s hypoglycaemic effect. We extend these data to isolated human islets. We propose that SSTR or SGLT2 antagonists should be considered as adjuncts to insulin in diabetes therapy. Impaired glucagon secretion in patients with diabetes causes hypoglycemia. Here the authors show that therapeutic concentrations of insulin inhibit alpha-cell glucagon secretion by stimulating delta-cell insulin receptor and the release of somatostatin. Blocking somatostatin secretion or action ameliorates this effect.

Diabetes is characterized by hyperglycaemia due to impaired insulin secretion and aberrant glucagon secretion resulting from changes in pancreatic islet cell function and/or mass. The extent to which hyperglycaemia per se underlies these alterations remains poorly understood. Here we show that β-cell-specific expression of a human activating K ATP channel mutation in adult mice leads to rapid diabetes and marked alterations in islet morphology, ultrastructure and gene expression. Chronic hyperglycaemia is associated with a dramatic reduction in insulin-positive cells and an increase in glucagon-positive cells in islets, without alterations in cell turnover. Furthermore, some β-cells begin expressing glucagon, whilst retaining many β-cell characteristics. Hyperglycaemia, rather than K ATP channel activation, underlies these changes, as they are prevented by insulin therapy and fully reversed by sulphonylureas. Our data suggest that many changes in islet structure and function associated with diabetes are attributable to hyperglycaemia alone and are reversed when blood glucose is normalized. In patients with diabetes, insulin release from pancreatic β-cells is reduced due to altered islet structure and function. Here, Brereton et al . show that elevated blood glucose underlies these changes and is sufficient to reversibly alter β-cell identity in a mouse model of β-cell dysfunction.

Glucagon secretion by pancreatic α-cells is triggered by hypoglycemia and suppressed by high glucose levels; impaired suppression of glucagon secretion is a hallmark of both type 1 and type 2 diabetes. Here, we show that α-cell glucokinase ( Gck ) plays a role in the control of glucagon secretion. Using mice with α-cell-specific inactivation of Gck ( αGckKO mice), we find that glucokinase is required for the glucose-dependent increase in intracellular ATP/ADP ratio and the closure of K ATP channels in α-cells and the suppression of glucagon secretion at euglycemic and hyperglycemic levels. αGckKO mice display hyperglucagonemia in the fed state, which is associated with increased hepatic gluconeogenic gene expression and hepatic glucose output capacity. In adult mice, fed hyperglucagonemia is further increased and glucose intolerance develops. Thus, glucokinase governs an α-cell metabolic pathway that suppresses secretion at or above normoglycemic levels; abnormal suppression of glucagon secretion deregulates hepatic glucose metabolism and, over time, induces a pre-diabetic phenotype. Glucagon secretion is promoted during hypoglycemia and inhibited by increased glucose levels. Here, Basco et al. show that glucokinase suppresses glucose-regulated glucagon secretion by modulating the intracellular ATP/ADP ratio and the closure of K ATP channels in α-cells.

International research highlights the potentially valuable contribution of outdoor education to the healthy development and proper holistic education of students. Among the various benefits that students gain from participating in outdoor activities are the mitigation of symptoms of Attention Deficit Hyperactivity Disorder (ADHD), improved respiration, memory improvement, skills development and others. Despite the well-documented contribution of such activities to children’s wellbeing, there is an increasing trend of younger children lacking contact with nature. The current study investigates to what extent teachers in Greece, at schools where students aged 6–18 attend, provide opportunities for outdoor activities to their students. Furthermore, it investigates the teacher’s perceptions of the benefits the students gain from such activities, based on their personal experience and the experience of other co-teachers in their school. The results presented in this study indicate that the percentage of teachers who choose outdoor activities during the educational process in Greece is rather low, although they identify that such activities provide significant benefits to students. Based on the perceptions of teachers regarding the mental, cognitive and physical benefits that students gain from outdoor activities a positive association was found between the participation of students in such activities and these benefits. Therefore, this study reveals that it is of significant importance to increase the number of opportunities for students’ participation in outdoor learning activities, by supporting teachers, creating learning communities with them and empowering them to provide more outdoor learning opportunities.

Background The prevention of type 2 diabetes (T2DM) is recognised as a health care priority in the UK. In people living with T2DM, lifestyle changes (e.g. increasing physical activity) have been shown to slow disease progression and protect from the development of associated comorbidities. The use of digital health technologies provides a strategy to increase physical activity in patients with chronic disease. Furthermore, behaviour economics suggests that financial incentives may be a useful strategy for increasing the maintenance and effectiveness of behaviour change intervention, including physical activity intervention using digital health technologies. The Milton Keynes Activity Rewards Programme (MKARP) is a 24-month intervention which combines the use of a mobile health app, smartwatch (Fitbit or Apple watch) and financial incentives to encourage people living with T2DM to increase physical activity to improve health. Therefore, this randomised controlled trial aims to examine the long-term acceptability, health effects and cost-effectiveness of the MKARP on HbA1c in patients living with T2DM versus a waitlist usual care comparator. Methods A two-arm, single-centre, randomised controlled trial aiming to recruit 1018 participants with follow-up at 12 and 24 months. The primary outcome is the change in HbA1c at 12 months. Secondary outcomes included changes in markers of metabolic, cardiovascular, anthropometric, and psychological health along with cost-effectiveness. Recruitment will be via annual diabetes review in general practices, retinal screening services and social media. Participants aged 18 or over, with a diagnosis of type 2 diabetes and a valid HbA1c measurement in the last 2 months are invited to take part in the trial. Participants will be individually randomised (1:1 ratio) to receive either the Milton Keynes Activity Rewards Programme or usual care. The intervention will last for 24 months with assessment for outcomes at baseline, 12 and 24 months. Discussion This study will provide new evidence of the long-term effectiveness of an activity rewards scheme focused on increasing physical activity conducted within routine care in patients living with type 2 diabetes in Milton Keynes, UK. It will also investigate the cost-effectiveness of the intervention. Trial registration ISRCTN 14925701. Registered on 30 October 2023.

A rare loss-of-function allele p.Arg138* in SLC30A8 encoding the zinc transporter 8 (ZnT8), which is enriched in Western Finland, protects against type 2 diabetes (T2D). We recruited relatives of the identified carriers and showed that protection was associated with better insulin secretion due to enhanced glucose responsiveness and proinsulin conversion, particularly when compared with individuals matched for the genotype of a common T2D-risk allele in SLC30A8 , p.Arg325. In genome-edited human induced pluripotent stem cell (iPSC)-derived β-like cells, we establish that the p.Arg138* allele results in reduced SLC30A8 expression due to haploinsufficiency. In human β cells, loss of SLC30A8 leads to increased glucose responsiveness and reduced K ATP channel function similar to isolated islets from carriers of the T2D-protective allele p.Trp325. These data position ZnT8 as an appealing target for treatment aimed at maintaining insulin secretion capacity in T2D. The rare loss-of-function allele p.Arg138* in SLC30A8 (encoding ZnT8) mediates protection against type 2 diabetes (T2D) through promoting better insulin secretion and enhanced glucose responsiveness, suggesting ZnT8 as a target for T2D treatment.

Abstract Introduction Hypercalcaemia is infrequent during pregnancy, but it is associated with foetal and maternal morbidity and mortality. Although primary hyperparathyroidism (pHPT) accounts for the majority of the cases, other aetiologies such as genetic causes in a young population should be considered. Clinical Case A 27-year-old female was diagnosed with pHPT during her 16th week of gestation after she presented with vomiting and was found to have raised adjusted calcium of 3.22 mmol/L, low phosphate of 0.6 mmol/L and Parathyroid Hormone of 10.6 pmol/L. The patient's hypercalcaemia dated back 2 years, she had a history of three previous miscarriages, and was not on any hypercalcaemia-inducing medications. Unbeknownst to her, her father was also being evaluated for hypercalcaemia. Her thyroid-stimulating hormone was fully suppressed with raised free thyroid hormones and negative TSH receptor antibodies; this was improved with Carbimazole therapy. Plasma and urine Metanephrines were normal, and neck ultrasound did not reveal any parathyroid lesions. She underwent parathyroidectomy three weeks later after a period of intravenous hydration. A 2 cm left superior parathyroid adenoma was excised, and the plasma calcium level promptly normalised. Genetic testing for familial hyperparathyroidism revealed an autosomal dominant heterozygous CDC73 variant, which is associated with Hyperparathyroidism-Jaw Tumour syndrome. The Clinical Genetics team is arranging genetic testing for her first-degree relatives. She delivered a live baby at 38 + 6 weeks of gestation via emergency caesarean section, performed for foetal hypoxia on cardiotocography, and genetic testing of the newborn child using umbilical cord blood was performed at the time of delivery. She will undergo regular screening for uterine, renal and jaw tumours (every 5 years), and is planned for 6-monthly calcium and parathyroid hormone tests. Conclusion Primary hyperparathyroidism is best treated with parathyroidectomy before pregnancy as the maternal and foetal complications increase according to the hypercalcaemia severity. During pregnancy, mild cases could be treated conservatively while parathyroidectomy is reserved for severe cases and is performed in the second trimester. Germline CDC73 analysis is recommended in young pHPT patients, and in this case revealed a pathological variant associated with Hyperparathyroidism-Jaw Tumour syndrome, familial isolated pHPT and parathyroid carcinoma.

Disclosure: I.I. Spiliotis: None. L. Anguelova: None. F. Kavvoura: None. K. Owen: None. Diabetes is a multi-hormone disorder involving both insufficient insulin secretion and aberrant glucagon secretion. MODY (Maturity Onset Diabetes of the Young) is a subgroup of diabetes which is caused by mutations in specific genes including HNF1A (MODY3) and HNF4A (MODY1). Most MODY3 or MODY1 patients are managed in the UK with the sulfonylurea gliclazide at a starting dose of around 20-40mg (vs. 80mg - 320mg daily for managing type 2 diabetes). It remains unclear clear why this population is particularly sensitive to gliclazide, and there is limited information on glucagon levels in these patients. The ”Glucagon in MODY” study was a non-randomized interventional pilot study (NCT03246828), aiming to investigate whether fasting and post-prandial glucagon levels are raised in MODY3 & MODY1 patients, and whether gliclazide treatment leads to more physiological glucose-induced glucagon suppression in this population. Methods: We recruited 10 patients from MODY clinics, whose diabetes was managed with gliclazide +/- metformin only at the time of the study. They each underwent a 2h 75g oral glucose tolerance test (OGTT) before and after omitting their gliclazide for 3 days. Blood samples were taken at 30min intervals for glucose, c-peptide and glucagon. Paired t-test was used to compare baseline fasting values on and off gliclazide, and two-way repeated measures ANOVA with post-hoc multiple comparisons was used to compare the OGTT timepoints versus baseline. Results: Study population characteristics were as follows (median ±CI): age 46±9.8, 6 females, BMI 23.9±1.1, HbA1c 52.5±13.6mmol/mol, gliclazide dose 60±29mg per day; 6 MODY3 and 4 MODY1. Fasting blood glucose values were significantly elevated off gliclazide (p<0.001) and rose by an average of 10mmol/L during the OGTT, as expected in this population; however two-way ANOVA did not show a significant difference on vs. off gliclazide. Neither fasting c-peptide nor glucagon values were significantly different on vs. off gliclazide, and while c-peptide rose in both groups, glucagon levels were only suppressed at 60min on gliclazide (p=0.035). When c-peptide and glucagon values were corrected for blood glucose levels during the OGTT, there was no significant change from baseline in c-peptide values on vs off gliclazide. However, glucagon values were significantly decreased on gliclazide from 60min onwards (p<0.01), and there was no correlation with corrected c-peptide values (p=0.2). Conclusion: In our limited study population of 6 MODY3 and 4 MODY1 patients, gliclazide appears to restore appropriate glucose-induced glucagon suppression during a 75g OGTT, which is not related to changes in c-peptide levels. This suggests that pancreatic alpha-cell regulation may be a previously unrecognized mechanism by which sulfonylurea treatment improves glycemic control in MODY. Presentation: Sunday, June 18, 2023

Limited access to human islets has prompted the development of human beta cell models. The human beta cell lines EndoC-βH1 and EndoC-βH2 are increasingly used by the research community. However, little is known of their electrophysiological and secretory properties. Here, we monitored parameters that constitute the glucose-triggering pathway of insulin release. Both cell lines respond to glucose (6 and 20 mM) with 2- to 3-fold stimulation of insulin secretion which correlated with an elevation of [Ca 2+ ] i , membrane depolarisation and increased action potential firing. Similar to human primary beta cells, K ATP channel activity is low at 1 mM glucose and is further reduced upon increasing glucose concentration; an effect that was mimicked by the K ATP channel blocker tolbutamide. The upstroke of the action potentials reflects the activation of Ca 2+ channels with some small contribution of TTX-sensitive Na + channels. The repolarisation involves activation of voltage-gated Kv2.2 channels and large-conductance Ca 2+ -activated K + channels. Exocytosis presented a similar kinetics to human primary beta cells. The ultrastructure of these cells shows insulin vesicles composed of an electron-dense core surrounded by a thin clear halo. We conclude that the EndoC-βH1 and -βH2 cells share many features of primary human β-cells and thus represent a useful experimental model.

Background: Diabetes is a multi-hormonal disorder characterised by insufficient insulin secretion and aberrant glucagon secretion with fasting hyperglucagonaemia leading to increased rates of hepatic glucose production, which further exacerbates hyperglycaemia. Sulfonylureas used at low concentrations have been shown to partially restore appropriate glucose-regulated glucagon secretion in isolated islets from donors with type 2 diabetes (T2DM). The main objective of this thesis was to investigate whether low doses of the sulfonylurea glibenclamide could reduce fasting hyperglucagonaemia in patients with T2DM. In addition, the effect of age and sex on islet hormone secretion was examined in human islets, as was the impact of low-dose gliclazide (another sulfonylurea) on glucagon secretion in MODY patients. Methods: I performed a pilot, dose-finding (0.3mg - 6mg/day) clinical trial (LEGEND-A) of a novel oral glibenclamide suspension in sixteen patients with T2DM (diet controlled or on metformin alone). Fasting plasma glucagon, glucose, insulin, C-peptide and glibenclamide were measured at each dose-change, and continuous glucose monitoring was used throughout. For the human islet hormone secretion study, a database analysis was performed which covered an 11-year period (2006-2017). Finally, a pilot clinical study (\"Glucagon in MODY\") involving an oral glucose tolerance test before and after the omission of gliclazide for 72h was performed in three patients diagnosed with HNF1-α MODY (study ongoing). Results: Glibenclamide at 0.3mg/day was able to reduce fasting glucagon levels by 30% in four T2DM patients who had hyperglucagonaemia, without causing insulin secretion and with no adverse effects. This effect was not observed at higher glibenclamide concentrations, nor in the twelve T2DM patient who had normal-range fasting glucagon levels. In addition, the islet hormone database analysis revealed the novel finding that islets from older donors (especially males) secreted twice as much insulin at euglycaemic conditions as those from younger donors, but only 40% as much glucagon when challenged with hypoglycaemic conditions. Finally, the preliminary results of the \"Glucagon in MODY\" study suggest that HNF1-α MODY patients may not display appropriate glucose-dependent glucagon suppression during an oral glucose tolerance test, and that this may be reinstated by using low doses of gliclazide. Conclusions: Using low-dose sulfonylureas it may be possible to normalise aberrant glucagon secretion patterns in patients with diabetes, perhaps by subtly altering the activity of the alpha-cell ATP-sensitive potassium channel. This novel approach has the potential to be used both as a standalone therapy and as an adjunct to other medications, such as SGLT2 inhibitors, in which a reduction in glucagon could increase overall efficiency. I have also demonstrated that age and sex can impact the secretion of insulin and glucagon in ex vivo human islets, and this may in part provide a mechanistic explanation for the vulnerability of older people to sulfonylurea-induced hypoglycaemia episodes.