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Objective: In glucose-sensing neurons, ATP-sensitive K(+) channels (K(ATP) channels) are thought to translate metabolic signals into an alteration in neuronal firing rates. Because these neurons express the Kir6.2/SUR-1 isoform of the K(ATP) channel, we sought to examine the therapeutic potential of the SUR-1-selective potassium channel opener (KCO), NN414, to amplify counterregulatory response to hypoglycemia.Research Design and Methods: In vivo dose-response studies with NN414 delivered intravenously to normal Sprague-Dawley rats before the induction of controlled hypoglycemia were performed. Based on these studies, the potential for NN414 to restore counterregulatory responses in chronically cannulated nondiabetic and diabetic BB rats was explored using the in vivo hyperinsulinemic-hypoglycemic clamp technique.Results: NN414 delivered systemically amplified epinephrine responses during acute hypoglycemia and showed a persisting effect to amplify the epinephrine response when given 24 h before the hypoglycemic study. Local delivery of a potassium-channel blocker to the ventromedial hypothalamus reversed the effects of systemic NN414. In addition, NN414 amplified the epinephrine response to hypoglycemia in both nondiabetic and diabetic BB rats with defective hormonal counterregulation.Conclusions: These studies demonstrate in a variety of rodent models that systemic delivery of Kir6.2/SUR-1-selective KCOs enhance the glucose counterregulatory response to insulin-induced hypoglycemia. Future studies in human subjects are now required to determine their potential as a therapy for hypoglycemia-associated autonomic failure in type 1 diabetes. [ABSTRACT FROM AUTHOR]

Objective: We have previously demonstrated that modulation of gamma-aminobutyric acid (GABA) inhibitory tone in the ventromedial hypothalamus (VMH), an important glucose-sensing region in the brain, modulates the magnitude of glucagon and sympathoadrenal responses to hypoglycemia. In the current study, we examined whether increased VMH GABAergic tone may contribute to suppression of counterregulatory responses after recurrent hypoglycemia.Research Design and Methods: To test this hypothesis, we quantified expression of the GABA synthetic enzyme, glutamic acid decarboxylase (GAD), in the VMH of control and recurrently hypoglycemic rats. Subsequently, we used microdialysis and microinjection techniques to assess changes in VMH GABA levels and the effects of GABA(A) receptor blockade on counterregulatory responses to a standardized hypoglycemic stimulus.Results: Quantitative RT-PCR and immunoblots in recurrently hypoglycemic animals revealed that GAD(65) mRNA and protein were increased 33 and 580%, respectively. Basal VMH GABA concentrations were more than threefold higher in recurrently hypoglycemic animals. Furthermore, whereas VMH GABA levels decreased in both control and recurrently hypoglycemic animals with the onset of hypoglycemia, the fall was not significant in recurrently hypoglycemic rats. During hypoglycemia, recurrently hypoglycemic rats exhibited a 49-63% reduction in glucagon and epinephrine release. These changes were reversed by delivery of a GABA(A) receptor antagonist to the VMH.Conclusions: Our data suggest that recurrent hypoglycemia increases GABAergic inhibitory tone in the VMH and that this, in turn, suppresses glucagon and sympathoadrenal responses to subsequent bouts of acute hypoglycemia. Thus, hypoglycemia-associated autonomic failure may be due in part to a relative excess of the inhibitory neurotransmitter, GABA, within the VMH. [ABSTRACT FROM AUTHOR]

Hypoglycemia provokes a multifaceted counterregulatory response involving the sympathoadrenal system, stimulation of glucagon secretion, and the hypothalamo-pituitary-adrenal axis that is commonly impaired in diabetes. We examined whether modulation of inhibitory input from gamma-aminobutyric acid (GABA) in the ventromedial hypothalamus (VMH), a major glucose-sensing region within the brain, plays a role in affecting counterregulatory responses to hypoglycemia. Normal Sprague-Dawley rats had carotid artery and jugular vein catheters chronically implanted, as well as bilateral steel microinjection guide cannulas inserted down to the level of the VMH. Seven to 10 days following surgery, the rats were microinjected with artificial extracellular fluid, the GABA(A) receptor agonist muscimol (1 nmol/side), or the GABA(A) receptor antagonist bicuculline methiodide (12.5 pmol/side) before being subjected to a hyperinsulinemic-hypoglycemic (2.5 mmol/l) glucose clamp for 90 min. Following VMH administration of bicuculline methiodide, glucose infusion rates were significantly suppressed, whereas muscimol raised glucose infusion rates significantly compared with controls. Glucagon and epinephrine responses were elevated with the antagonist and suppressed with the agonist compared with controls. Corticosterone responses, however, were unaffected by either administration of the agonist or antagonist into the VMH. These data demonstrate that modulation of the GABAergic system in the VMH alters both glucagon and sympathoadrenal, but not corticosterone, responses to hypoglycemia. Our findings are consistent with the hypothesis that GABAergic inhibitory tone within the VMH can modulate glucose counterregulatory responses. [ABSTRACT FROM AUTHOR]

Type 1 diabetes is associated with chronic hyperglycemia and exposure to intermittent severe hypoglycemia. The long-term cerebral effects of these consequences of diabetes are ill defined. In this study, the history of preceding severe hypoglycemia and the presence of background retinopathy were examined in relation to cognitive ability (neuropsychological test battery) and brain structure (magnetic resonance imaging) in a cross-sectional evaluation of 74 young people with type 1 diabetes. Participants differed by their severe hypoglycemia exposure and degree of diabetic retinopathy and none had previous neuropsychological pathology. Severe hypoglycemia did not influence cognitive ability or brain structure. Background diabetic retinopathy was associated with small focal white-matter hyperintensities in the basal ganglia (33.3 vs. 4.7%, after correction for age, P = 0.005) and significant cognitive disadvantage, affecting fluid intelligence (P = 0.008, Eta(2) = 0.14), information processing (P = 0.001, Eta(2) = 0.22), and attention and concentration ability (P = 0.03, Eta(2) = 0.09). In conclusion, recurrent exposure to severe hypoglycemia alone in young people with type 1 diabetes had no detrimental impact on brain structure or function over the duration of diabetes examined. Chronic hyperglycemia (inferred by the presence of background diabetic retinopathy) may affect brain structure and function. [ABSTRACT FROM AUTHOR]

Objective: The recent availability of cardiovascular risk-reducing type 2 diabetes (T2D) therapies makes it imperative to optimally identify individuals who could derive benefit. Current clinical risk prediction may misclassify individuals as low risk and could be improved. Our aim was to determine the incremental prognostic value of a coronary heart disease (CHD) genome-wide polygenic risk score (PRS) to a clinical risk score in prediction of major adverse cardiovascular events (MACE) in patients with T2D., Research Design and Methods: We evaluated 10,556 individuals with T2D aged 40-79 without a prior cardiovascular hospitalization. We calculated 10-year clinical cardiovascular risk at the date of recruitment using the Pooled Cohort Equation (PCE Risk) and constructed a CHD PRS. The primary outcome was time to first MACE incidence, and we assessed the additional incremental predictive value of the CHD PRS to the PCE risk., Results: At 10 years, there were 1,477 MACE. After adjustment for clinical risk, the CHD PRS was significantly associated with MACE (hazard ratio [HR] 1.69 per SD increase, 95% CI 1.60-1.79). Individuals with PCE Risk <7.5% but in the top quintile of CHD PRS had a significantly increased likelihood of MACE (HR 10.69, 95% CI 5.07-22.55) compared with those in the lowest. The addition of the PRS to the clinical risk score led to significant improvements in risk prediction, particularly in those at low clinical risk., Conclusions: The addition of a CHD PRS to clinical assessment improved MACE prediction in T2D individuals without prior cardiovascular disease, particularly in those at low clinical risk., (© 2024 by the American Diabetes Association.)

Objective: Use of continuous glucose monitoring (CGM) has led to greater detection of hypoglycemia; the clinical significance of this is not fully understood. The Hypoglycaemia-Measurement, Thresholds and Impacts (Hypo-METRICS) study was designed to investigate the rates and duration of sensor-detected hypoglycemia (SDH) and their relationship with person-reported hypoglycemia (PRH) in people living with type 1 diabetes (T1D) and insulin-treated type 2 diabetes (T2D) with prior experience of hypoglycemia., Research Design and Methods: We recruited 276 participants with T1D and 321 with T2D who wore a blinded CGM and recorded PRH in the Hypo-METRICS app over 10 weeks. Rates of SDH <70 mg/dL, SDH <54 mg/dL, and PRH were expressed as median episodes per week. Episodes of SDH were matched to episodes of PRH that occurred within 1 h., Results: Median [interquartile range] rates of hypoglycemia were significantly higher in T1D versus T2D; for SDH <70 mg/dL (6.5 [3.8-10.4] vs. 2.1 [0.8-4.0]), SDH <54 mg/dL (1.2 [0.4-2.5] vs. 0.2 [0.0-0.5]), and PRH (3.9 [2.4-5.9] vs. 1.1 [0.5-2.0]). Overall, 65% of SDH <70 mg/dL was not associated with PRH, and 43% of PRH had no associated SDH. The median proportion of SDH associated with PRH in T1D was higher for SDH <70 mg/dL (40% vs. 22%) and SDH <54 mg/dL (47% vs. 25%) than in T2D., Conclusions: The novel findings are that at least half of CGM hypoglycemia is asymptomatic, even below 54 mg/dL, and many reported symptomatic hypoglycemia episodes happen above 70 mg/dL. In the clinical and research setting, these episodes cannot be used interchangeably, and both need to be recorded and addressed., (© 2024 by the American Diabetes Association.)

Aims/hypothesis: The aim of this work was to examine the impact of hypoglycaemia on daily functioning among adults with type 1 diabetes or insulin-treated type 2 diabetes, using the novel Hypo-METRICS app., Methods: For 70 consecutive days, 594 adults (type 1 diabetes, n=274; type 2 diabetes, n=320) completed brief morning and evening Hypo-METRICS 'check-ins' about their experienced hypoglycaemia and daily functioning. Participants wore a blinded glucose sensor (i.e. data unavailable to the participants) for the study duration. Days and nights with or without person-reported hypoglycaemia (PRH) and/or sensor-detected hypoglycaemia (SDH) were compared using multilevel regression models., Results: Participants submitted a mean ± SD of 86.3±12.5% morning and 90.8±10.7% evening check-ins. For both types of diabetes, SDH alone had no significant associations with the changes in daily functioning scores. However, daytime and night-time PRH (with or without SDH) were significantly associated with worsening of energy levels, mood, cognitive functioning, negative affect and fear of hypoglycaemia later that day or while asleep. In addition, night-time PRH (with or without SDH) was significantly associated with worsening of sleep quality (type 1 and type 2 diabetes) and memory (type 2 diabetes). Further, daytime PRH (with or without SDH), was associated with worsening of fear of hyperglycaemia while asleep (type 1 diabetes), memory (type 1 and type 2 diabetes) and social functioning (type 2 diabetes)., Conclusions/interpretation: This prospective, real-world study reveals impact on several domains of daily functioning following PRH but not following SDH alone. These data suggest that the observed negative impact is mainly driven by subjective awareness of hypoglycaemia (i.e. PRH), through either symptoms or sensor alerts/readings and/or the need to take action to prevent or treat episodes., (© 2024. The Author(s).)

Aims/hypothesis: Few studies have examined the clinical characteristics associated with changes in weight before and after diagnosis of type 2 diabetes. Using a large real-world cohort, we derived trajectories of BMI before and after diabetes diagnosis, and examined the clinical characteristics associated with these trajectories, including assessing the impact of pre-diagnosis weight change on post-diagnosis weight change., Methods: We performed an observational cohort study using electronic medical records from individuals in the Scottish Care Information Diabetes Collaboration database. Two trajectories were calculated, based on observed BMI measurements between 3 years and 6 months before diagnosis and between 1 and 5 years after diagnosis. In the post-diagnosis trajectory, each BMI measurement was time-dependently adjusted for the effects of diabetes medications and HbA 1c change., Results: A total of 2736 individuals were included in the study. There was a pattern of pre-diagnosis weight gain, with 1944 individuals (71%) gaining weight overall, and 875 (32%) gaining more than 0.5 kg/m 2 per year. This was followed by a pattern of weight loss after diagnosis, with 1722 individuals (63%) losing weight. Younger age and greater social deprivation were associated with increased weight gain before diagnosis. Pre-diagnosis weight change was unrelated to post-diagnosis weight change, but post-diagnosis weight loss was associated with older age, female sex, higher BMI, higher HbA 1c and weight gain during the peri-diagnosis period. When considering the peri-diagnostic period (defined as from 6 months before to 12 months after diagnosis), we identified 986 (36%) individuals who had a high HbA 1c at diagnosis but who lost weight rapidly and were most aggressively treated at 1 year; this subgroup had the best glycaemic control at 5 years., Conclusions/interpretation: Average weight increases before diagnosis and decreases after diagnosis; however, there were significant differences across the population in terms of weight changes. Younger individuals gained weight pre-diagnosis, but, in older individuals, type 2 diabetes is less associated with weight gain, consistent with other drivers for diabetes aetiology in older adults. We have identified a substantial group of individuals who have a rapid deterioration in glycaemic control, together with weight loss, around the time of diagnosis, and who subsequently stabilise, suggesting that a high HbA 1c at diagnosis is not inevitably associated with a poor outcome and may be driven by reversible glucose toxicity., (© 2024. The Author(s).)

Aims/hypothesis: Whether hypoglycaemia increases the risk of other adverse outcomes in diabetes remains controversial, especially for hypoglycaemia episodes not requiring assistance from another person. An objective of the Hypoglycaemia REdefining SOLutions for better liVEs (Hypo-RESOLVE) project was to create and use a dataset of pooled clinical trials in people with type 1 or type 2 diabetes to examine the association of exposure to all hypoglycaemia episodes across the range of severity with incident event outcomes: death, CVD, neuropathy, kidney disease, retinal disorders and depression. We also examined the change in continuous outcomes that occurred following a hypoglycaemia episode: change in eGFR, HbA 1c , blood glucose, blood glucose variability and weight., Methods: Data from 84 trials with 39,373 participants were pooled. For event outcomes, time-updated Cox regression models adjusted for age, sex, diabetes duration and HbA 1c were fitted to assess association between: (1) outcome and cumulative exposure to hypoglycaemia episodes; and (2) outcomes where an acute effect might be expected (i.e. death, acute CVD, retinal disorders) and any hypoglycaemia exposure within the last 10 days. Exposures to any hypoglycaemia episode and to episodes of given severity (levels 1, 2 and 3) were examined. Further adjustment was then made for a wider set of potential confounders. The within-person change in continuous outcomes was also summarised (median of 40.4 weeks for type 1 diabetes and 26 weeks for type 2 diabetes). Analyses were conducted separately by type of diabetes., Results: The maximally adjusted association analysis for type 1 diabetes found that cumulative exposure to hypoglycaemia episodes of any level was associated with higher risks of neuropathy, kidney disease, retinal disorders and depression, with risk ratios ranging from 1.55 (p=0.002) to 2.81 (p=0.002). Associations of a similar direction were found when level 1 episodes were examined separately but were significant for depression only. For type 2 diabetes cumulative exposure to hypoglycaemia episodes of any level was associated with higher risks of death, acute CVD, kidney disease, retinal disorders and depression, with risk ratios ranging from 2.35 (p<0.0001) to 3.00 (p<0.0001). These associations remained significant when level 1 episodes were examined separately. There was evidence of an association between hypoglycaemia episodes of any kind in the previous 10 days and death, acute CVD and retinal disorders in both type 1 and type 2 diabetes, with rate ratios ranging from 1.32 (p=0.017) to 2.68 (p<0.0001). These associations varied in magnitude and significance when examined separately by hypoglycaemia level. Within the range of hypoglycaemia defined by levels 1, 2 and 3, we could not find any evidence of a threshold at which risk of these consequences suddenly became pronounced., Conclusions/interpretation: These data are consistent with hypoglycaemia being associated with an increased risk of adverse events across several body systems in diabetes. These associations are not confined to severe hypoglycaemia requiring assistance., (© 2024. The Author(s).)

Aims: To assess the impact of high-intensity interval training (HIIT) on hypoglycemia frequency and duration in people with type 1 diabetes (T1D) with impaired awareness of hypoglycemia (IAH)., Methods: Post hoc analysis of four weeks of continuous glucose monitoring (CGM) data from HIT4HYPOS; a parallel-group study comparing HIIT + CGM versus no exercise + CGM in 18 participants with T1D and IAH., Results: When compared with those participating individuals not exercising, HIIT did not increase total hypoglycemia frequency, T Hypo(L1) 1.44 [1.00-2.77]% versus 2.53 [1.46-4.23]%; P = .335, T Hypo(L2) 0.25 [0.09-0.37]% versus 0.45 [0.20-0.78]%; P = .146, HIIT + CGM versus CGM, respectively, rate ( EventPerWeek Hypo 5.30 [3.35-8.27] #/week vs 7.45 [3.54-10.81] #/week, P = .340) or duration ( Duration Hypo 33.33 [27.60-39.10] minutes vs 39.56 [31.00-48.38] minutes; P = .219, HIIT + CGM vs CGM, respectively). There was a reduction in nocturnal hypoglycemia in those who carried out HIIT, T Hypo (L1) 0.50 [0.13-0.97]% versus 2.45 [0.77-4.74]%; P = .076; T Hypo (L2) 0.00 [0.00-0.03]% versus 0.49 [0.13-0.74]%; P = .006, HIIT + CGM versus CGM, respectively., Conclusions/interpretation: Based on CGM data collected from a real-world study of four weeks of HIIT versus no exercise in individuals with T1D and IAH, we conclude that HIIT does not increase hypoglycemia, and in fact reduces exposure to nocturnal hypoglycemia., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Aim: To determine whether recent repeated exposure to real-life hypoglycaemia affects the pro-inflammatory response during a hypoglycemia episode., Materials and Methods: This was a post hoc analysis of a hyperinsulinaemic normoglycaemic-hypoglycaemic clamp study, involving 40 participants with type 1 diabetes. Glucose levels 1 week before the clamp were monitored using a Freestyle Libre 1. Blood was drawn during normoglycaemia and hypoglycaemia, and 24 hours after resolution of hypoglycaemia for measurements of inflammatory responses and counterregulatory hormone levels. We determined the relationship between the frequency and duration of spontaneous hypoglycaemia, and time below range (TBR) and the inflammatory response to experimental hypoglycaemia., Results: On average, participants experienced 0.79 (0.43, 1.14) hypoglycaemia episodes per day, with a duration of 78 (47, 110) minutes and TBR of 5.5% (2.8%, 8.5%). TBR and hypoglycaemia frequency were inversely associated with the increase in circulating granulocyte and lymphocyte counts during experimental hypoglycaemia (P < .05 for all). A protein network consisting of DNER, IF-R, uPA, Flt3L, FGF-5 and TWEAK was negatively associated with hypoglycaemia frequency (P < .05), but not with the adrenaline response. Neither other counterregulatory hormones, nor hypoglycaemia awareness status, was associated with any of the inflammatory parameters markers., Conclusions: Repeated exposure to spontaneous hypoglycaemia is associated with blunted effects of subsequent experimental hypoglycaemia on circulating immune cells and the number of inflammatory proteins., (© 2024 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Aim: Experimental hypoglycaemia blunts the counterregulatory hormone and symptom responses to a subsequent episode of hypoglycaemia. In this study, we aimed to assess the associations between antecedent exposure and continuous glucose monitoring (CGM)-recorded hypoglycaemia during a 1-week period and the counterregulatory responses to subsequent experimental hypoglycaemia in people with type 1 diabetes., Materials and Methods: Forty-two people with type 1 diabetes (20 females, mean ± SD glycated haemoglobin 7.8% ± 1.0%, diabetes duration median (interquartile range) 22.0 (10.5-34.9) years, 29 CGM users, and 19 with impaired awareness of hypoglycaemia) wore an open intermittently scanned CGM for 1 week to detect hypoglycaemic exposure before a standardized hyperinsulinaemic-hypoglycaemic [2.8 ± 0.1 mmol/L (50.2 ± 2.3 mg/dl)] glucose clamp. Symptom responses and counterregulatory hormones were measured during the clamp. The study is part of the HypoRESOLVE project., Results: CGM-recorded hypoglycaemia in the week before the clamp was negatively associated with adrenaline response [β -0.09, 95% CI (-0.16, -0.02) nmol/L, p = .014], after adjusting for CGM use, awareness of hypoglycaemia, glycated haemoglobin and total daily insulin dose. This was driven by level 2 hypoglycaemia [<3.0 mmol/L (54 mg/dl)] [β -0.21, 95% CI (-0.41, -0.01) nmol/L, p = .034]. CGM-recorded hypoglycaemia was negatively associated with total, autonomic, and neuroglycopenic symptom responses, but these associations were lost after adjusting for potential confounders., Conclusions: Recent exposure to CGM-detected hypoglycaemia was independently associated with an attenuated adrenaline response to experimental hypoglycaemia in people with type 1 diabetes., (© 2024 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Aims/hypothesis: Valid and reliable patient-reported outcome measures are vital for assessing disease impact, responsiveness to healthcare and the cost-effectiveness of interventions. A recent review has questioned the ability of existing measures to assess hypoglycaemia-related impacts on health-related quality of life for people with diabetes. This mixed-methods project was designed to produce a novel health-related quality of life patient-reported outcome measure in hypoglycaemia: the Hypo-RESOLVE QoL., Methods: Three studies were conducted with people with diabetes who experience hypoglycaemia. In Stage 1, a comprehensive health-related quality of life framework for hypoglycaemia was elicited from semi-structured interviews (N=31). In Stage 2, the content validity and acceptability of draft measure content were tested via three waves of cognitive debriefing interviews (N=70 people with diabetes; N=14 clinicians). In Stage 3, revised measure content was administered alongside existing generic and diabetes-related measures in a large cross-sectional observational survey to assess psychometric performance (N=1246). The final measure was developed using multiple evidence sources, incorporating stakeholder engagement., Results: A novel conceptual model of hypoglycaemia-related health-related quality of life was generated, featuring 19 themes, organised by physical, social and psychological aspects. From a draft version of 76 items, a final 14-item measure was produced with satisfactory structural (χ 2 =472.27, df=74, p<0.001; comparative fit index =0.943; root mean square error of approximation =0.069) and convergent validity with related constructs (r=0.46-0.59), internal consistency (α=0.91) and test-retest reliability (intraclass correlation coefficient =0.87)., Conclusions/interpretation: The Hypo-RESOLVE QoL is a rigorously developed patient-reported outcome measure assessing the health-related quality of life impacts of hypoglycaemia. The Hypo-RESOLVE QoL has demonstrable validity and reliability and has value for use in clinical decision-making and as a clinical trial endpoint., Data Availability: All data generated or analysed during this study are included in the published article and its online supplementary files ( https://doi.org/10.15131/shef., Data: 23295284.v2 )., (© 2024. The Author(s).)

Introduction: This study examined associations between hypoglycemia awareness status and hypoglycemia symptoms reported in real-time using the novel Hypoglycaemia-MEasurement, ThResholds and ImpaCtS (Hypo-METRICS) smartphone application (app) among adults with insulin-treated type 1 (T1D) or type 2 diabetes (T2D). Methods: Adults who experienced at least one hypoglycemic episode in the previous 3 months were recruited to the Hypo-METRICS study. They prospectively reported hypoglycemia episodes using the app for 10 weeks. Any of eight hypoglycemia symptoms were considered present if intensity was rated between "A little bit" to "Very much" and absent if rated "Not at all." Associations between hypoglycemia awareness (as defined by Gold score) and hypoglycemia symptoms were modeled using mixed-effects binary logistic regression, adjusting for glucose monitoring method and diabetes duration. Results: Of 531 participants (48% T1D, 52% T2D), 45% were women, 91% white, and 59% used Flash or continuous glucose monitoring. Impaired awareness of hypoglycemia (IAH) was associated with lower odds of reporting autonomic symptoms than normal awareness of hypoglycemia (NAH) (T1D odds ratio [OR] 0.43 [95% confidence interval {CI} 0.25-0.73], P  = 0.002); T2D OR 0.51 [95% CI 0.26-0.99], P  = 0.048), with no differences in neuroglycopenic symptoms. In T1D, relative to NAH, IAH was associated with higher odds of reporting autonomic symptoms at a glucose concentration <54 than >70 mg/dL (OR 2.18 [95% CI 1.21-3.94], P  = 0.010). Conclusion: The Hypo-METRICS app is sensitive to differences in hypoglycemia symptoms according to hypoglycemia awareness in both diabetes types. Given its high ecological validity and low recall bias, the app may be a useful tool in research and clinical settings. The clinical trial registration number is NCT04304963.

Aims/hypothesis: The objective of the Hypoglycaemia REdefining SOLutions for better liVES (Hypo-RESOLVE) project is to use a dataset of pooled clinical trials across pharmaceutical and device companies in people with type 1 or type 2 diabetes to examine factors associated with incident hypoglycaemia events and to quantify the prediction of these events., Methods: Data from 90 trials with 46,254 participants were pooled. Analyses were done for type 1 and type 2 diabetes separately. Poisson mixed models, adjusted for age, sex, diabetes duration and trial identifier were fitted to assess the association of clinical variables with hypoglycaemia event counts. Tree-based gradient-boosting algorithms (XGBoost) were fitted using training data and their predictive performance in terms of area under the receiver operating characteristic curve (AUC) evaluated on test data. Baseline models including age, sex and diabetes duration were compared with models that further included a score of hypoglycaemia in the first 6 weeks from study entry, and full models that included further clinical variables. The relative predictive importance of each covariate was assessed using XGBoost's importance procedure. Prediction across the entire trial duration for each trial (mean of 34.8 weeks for type 1 diabetes and 25.3 weeks for type 2 diabetes) was assessed., Results: For both type 1 and type 2 diabetes, variables associated with more frequent hypoglycaemia included female sex, white ethnicity, longer diabetes duration, treatment with human as opposed to analogue-only insulin, higher glucose variability, higher score for hypoglycaemia across the 6 week baseline period, lower BP, lower lipid levels and treatment with psychoactive drugs. Prediction of any hypoglycaemia event of any severity was greater than prediction of hypoglycaemia requiring assistance (level 3 hypoglycaemia), for which events were sparser. For prediction of level 1 or worse hypoglycaemia during the whole follow-up period, the AUC was 0.835 (95% CI 0.826, 0.844) in type 1 diabetes and 0.840 (95% CI 0.831, 0.848) in type 2 diabetes. For level 3 hypoglycaemia, the AUC was lower at 0.689 (95% CI 0.667, 0.712) for type 1 diabetes and 0.705 (95% CI 0.662, 0.748) for type 2 diabetes. Compared with the baseline models, almost all the improvement in prediction could be captured by the individual's hypoglycaemia history, glucose variability and blood glucose over a 6 week baseline period., Conclusions/interpretation: Although hypoglycaemia rates show large variation according to sociodemographic and clinical characteristics and treatment history, looking at a 6 week period of hypoglycaemia events and glucose measurements predicts future hypoglycaemia risk., (© 2024. The Author(s).)

Introduction: Reporting of hypoglycaemia and its impact in clinical studies is often retrospective and subject to recall bias. We developed the Hypo-METRICS app to measure the daily physical, psychological, and social impact of hypoglycaemia in adults with type 1 and insulin-treated type 2 diabetes in real-time using ecological momentary assessment (EMA). To help assess its utility, we aimed to determine Hypo-METRICS app completion rates and factors associated with completion., Methods: Adults with diabetes recruited into the Hypo-METRICS study were given validated patient-reported outcome measures (PROMs) at baseline. Over 10 weeks, they wore a blinded continuous glucose monitor (CGM), and were asked to complete three daily EMAs about hypoglycaemia and aspects of daily functioning, and two weekly sleep and productivity PROMs on the bespoke Hypo-METRICS app. We conducted linear regression to determine factors associated with app engagement, assessed by EMA and PROM completion rates and CGM metrics., Results: In 602 participants (55% men; 54% type 2 diabetes; median(IQR) age 56 (45-66) years; diabetes duration 19 (11-27) years; HbA1c 57 (51-65) mmol/mol), median(IQR) overall app completion rate was 91 (84-96)%, ranging from 90 (81-96)%, 89 (80-94)% and 94(87-97)% for morning, afternoon and evening check-ins, respectively. Older age, routine CGM use, greater time below 3.0 mmol/L, and active sensor time were positively associated with app completion., Discussion: High app completion across all app domains and participant characteristics indicates the Hypo-METRICS app is an acceptable research tool for collecting detailed data on hypoglycaemia frequency and impact in real-time., (© 2024 The Authors. Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK.)

Non-small cell lung cancer (NSCLC) constitutes one of the deadliest and most common malignancies. The LKB1/STK11 tumour suppressor is mutated in ∼ 30% of NSCLCs, typically lung adenocarcinomas (LUAD). We implemented zebrafish and human lung organoids as synergistic platforms to pre-clinically screen for metabolic compounds selectively targeting LKB1-deficient tumours. Interestingly, two kinase inhibitors, Piceatannol and Tyrphostin 23, appeared to exert synthetic lethality with LKB1 mutations. Although LKB1 loss alone accelerates energy expenditure, unexpectedly we find that it additionally alters regulation of the key energy homeostasis maintenance player leptin (LEP), further increasing the energetic burden and exposing a vulnerable point; acquired sensitivity to the identified compounds. We show that compound treatment stabilises Hypoxia-inducible factor 1-alpha (HIF1A) by antagonising Von Hippel-Lindau (VHL)-mediated HIF1A ubiquitination, driving LEP hyperactivation. Importantly, we demonstrate that sensitivity to piceatannol/tyrphostin 23 epistatically relies on a HIF1A-LEP-Uncoupling Protein 2 (UCP2) signaling axis lowering cellular energy beyond survival, in already challenged LKB1-deficient cells. Thus, we uncover a pivotal metabolic vulnerability of LKB1-deficient tumours, which may be therapeutically exploited using our identified compounds as mitochondrial uncouplers., (© 2024. The Author(s).)

Background and Aims: Sodium-glucose co-transporter 2 (SGLT2) inhibitors have beneficial effects in heart failure (HF), including reverse remodelling, but the mechanisms by which these benefits are conferred are unclear. Inflammation is implicated in the pathophysiology of heart failure (HF) and there are some pre-clinical data suggesting that SGLT2 inhibitors may reduce inflammation. There is however a lack of clinical data. The aim of our study was to investigate whether improvements in cardiac remodelling caused by dapagliflozin in individuals with type 2 diabetes (T2D) and left ventricular hypertrophy (LVH) were associated with its effects on inflammation., Methods: We measured C-reactive protein (CRP), tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), interleukin 6 (IL-6), and interleukin 10 (IL-10) and neutrophil-to-lymphocyte ratio (NLR) in plasma samples of 60 patients with T2D and left ventricular hypertrophy (LVH) but without symptomatic HF from the DAPA-LVH trial in which participants were randomised dapagliflozin 10 mg daily or placebo for 12 months and underwent cardiac magnetic resonance imaging (CMR) at baseline and end of treatment. The primary analysis was to investigate the effect of dapagliflozin on inflammation and to assess the relationships between changes in inflammatory markers and LV mass and global longitudinal strain (GLS) and whether the effect of dapagliflozin on LV mass and GLS was modulated by baseline levels of inflammation., Results: Following 12 months of treatment dapagliflozin significantly reduced CRP compared to placebo (mean difference of -1.96; 95% CI -3.68 to -0.24, p = 0.026). There were no significant statistical changes in other inflammatory markers. There were modest correlations between improvements in GLS and reduced inflammation (NLR (r = 0.311), IL-1β (r = 0.246), TNF-α (r = 0.230)) at 12 months., Conclusions: Dapagliflozin caused a significant reduction in CRP compared to placebo. There were correlations between reductions in inflammatory markers including IL-1β and improvements in global longitudinal strain (but not reduced LV mass). Reductions in systemic inflammation might play a contributory role in the cardiovascular benefits of dapagliflozin., Trial Registration: Clinicaltrials.gov NCT02956811 (06/11/2016)., (© 2024. The Author(s).)

Introduction: Nocturnal hypoglycemia is generally calculated between 00:00 and 06:00. However, those hours may not accurately reflect sleeping patterns and it is unknown whether this leads to bias. We therefore compared hypoglycemia rates while asleep with those of clock-based nocturnal hypoglycemia in adults with type 1 diabetes (T1D) or insulin-treated type 2 diabetes (T2D). Methods: Participants from the Hypo-METRICS study wore a blinded continuous glucose monitor and a Fitbit Charge 4 activity monitor for 10 weeks. They recorded details of episodes of hypoglycemia using a smartphone app. Sensor-detected hypoglycemia (SDH) and person-reported hypoglycemia (PRH) were categorized as nocturnal (00:00-06:00 h) versus diurnal and while asleep versus awake defined by Fitbit sleeping intervals. Paired-sample Wilcoxon tests were used to examine the differences in hypoglycemia rates. Results: A total of 574 participants [47% T1D, 45% women, 89% white, median (interquartile range) age 56 (45-66) years, and hemoglobin A1c 7.3% (6.8-8.0)] were included. Median sleep duration was 6.1 h (5.2-6.8), bedtime and waking time ∼23:30 and 07:30, respectively. There were higher median weekly rates of SDH and PRH while asleep than clock-based nocturnal SDH and PRH among people with T1D, especially for SDH <70 mg/dL (1.7 vs. 1.4, P  < 0.001). Higher weekly rates of SDH while asleep than nocturnal SDH were found among people with T2D, especially for SDH <70 mg/dL (0.8 vs. 0.7, P  < 0.001). Conclusion: Using 00:00 to 06:00 as a proxy for sleeping hours may underestimate hypoglycemia while asleep. Future hypoglycemia research should consider the use of sleep trackers to record sleep and reflect hypoglycemia while asleep more accurately. The trial registration number is NCT04304963.

Information on BMI and risk of developing hypertension in type 1 diabetes (T1D) is scarce, and it comes mostly from cross-sectional analyses. This study underscores a risk of developing hypertension in T1D individuals with high BMI, and this risk appears to be higher than in those with type 2 diabetes., Competing Interests: Declaration of competing interest The authors declare no potential conflict of interest relevant to this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Basal insulin continues to be a vital part of therapy for many people with diabetes. First attempts to prolong the duration of insulin formulations were through the development of suspensions that required homogenization prior to injection. These insulins, which required once- or twice-daily injections, introduced wide variations in insulin exposure contributing to unpredictable effects on glycemia. Advances over the last 2 decades have resulted in long-acting, soluble basal insulin analogues with prolonged and less variable pharmacokinetic exposure, improving their efficacy and safety, notably by reducing nocturnal hypoglycemia. However, adherence and persistence with once-daily basal insulin treatment remains low for many reasons including hypoglycemia concerns and treatment burden. A soluble basal insulin with a longer and flatter exposure profile could reduce pharmacodynamic variability, potentially reducing hypoglycemia, have similar efficacy to once-daily basal insulins, simplify dosing regimens, and improve treatment adherence. Insulin icodec (Novo Nordisk) and insulin efsitora alfa (basal insulin Fc [BIF], Eli Lilly and Company) are 2 such insulins designed for once-weekly administration, which have the potential to provide a further advance in basal insulin replacement. Icodec and efsitora phase 2 clinical trials, as well as data from the phase 3 icodec program indicate that once-weekly insulins provide comparable glycemic control to once-daily analogues, with a similar risk of hypoglycemia. This manuscript details the technology used in the development of once-weekly basal insulins. It highlights the clinical rationale and potential benefits of these weekly insulins while also discussing the limitations and challenges these molecules could pose in clinical practice., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Aim: The sympathetic nervous and hormonal counterregulatory responses to hypoglycaemia differ between people with type 1 and type 2 diabetes and may change along the course of diabetes, but have not been directly compared. We aimed to compare counterregulatory hormone and symptom responses to hypoglycaemia between people with type 1 diabetes, insulin-treated type 2 diabetes and controls without diabetes, using a standardised hyperinsulinaemic-hypoglycaemic clamp., Materials: We included 47 people with type 1 diabetes, 15 with insulin-treated type 2 diabetes, and 32 controls without diabetes. Controls were matched according to age and sex to the people with type 1 diabetes or with type 2 diabetes. All participants underwent a hyperinsulinaemic-euglycaemic-(5.2 ± 0.4 mmol/L)-hypoglycaemic-(2.8 ± 0.13 mmol/L)-clamp., Results: The glucagon response was lower in people with type 1 diabetes (9.4 ± 0.8 pmol/L, 8.0 [7.0-10.0]) compared to type 2 diabetes (23.7 ± 3.7 pmol/L, 18.0 [12.0-28.0], p < 0.001) and controls (30.6 ± 4.7, 25.5 [17.8-35.8] pmol/L, p < 0.001). The adrenaline response was lower in type 1 diabetes (1.7 ± 0.2, 1.6 [1.3-5.2] nmol/L) compared to type 2 diabetes (3.4 ± 0.7, 2.6 [1.3-5.2] nmol/L, p = 0.001) and controls (2.7 ± 0.4, 2.8 [1.4-3.9] nmol/L, p = 0.012). Growth hormone was lower in people with type 2 diabetes than in type 1 diabetes, at baseline (3.4 ± 1.6 vs 7.7 ± 1.3 mU/L, p = 0.042) and during hypoglycaemia (24.7 ± 7.1 vs 62.4 ± 5.8 mU/L, p = 0.001). People with 1 diabetes had lower overall symptom responses than people with type 2 diabetes (45.3 ± 2.7 vs 58.7 ± 6.4, p = 0.018), driven by a lower neuroglycopenic score (27.4 ± 1.8 vs 36.7 ± 4.2, p = 0.012)., Conclusion: Acute counterregulatory hormone and symptom responses to experimental hypoglycaemia are lower in people with type 1 diabetes than in those with long-standing insulin-treated type 2 diabetes and controls., (© 2024. The Author(s).)

Aims: We examined severe hospitalised hypoglycaemia (SHH) rates in people with type 1 and type 2 diabetes in Scotland during 2016-2022, stratifying by sociodemographics., Methods: Using the Scottish National diabetes register (SCI-Diabetes), we identified people with type 1 and type 2 diabetes alive anytime during 2016-2022. SHH events were determined through linkage to hospital admission and death registry data. We calculated annual SHH rates overall and by age, sex, and socioeconomic status. Summary estimates of time and stratum effects were obtained by fitting adjusted generalised additive models using R package mgcv., Results: Rates for those under 20 with type 1 diabetes reached their minimum at the 2020-2021 transition, 30% below the study period average. A gradual decline over time also occurred among 20-49-year-olds with type 1 diabetes. Overall, females had 15% higher rates than males with type 2 diabetes (rate ratio 1.15, 95% CI 1.08-1.22). People in the most versus least deprived quintile experienced 2.58 times higher rates (95% CI 2.27-2.93) in type 1 diabetes and 2.33 times higher (95% CI 2.08-2.62) in type 2 diabetes., Conclusions: Despite advances in care, SHH remains a significant problem in diabetes. Future efforts must address the large socioeconomic disparities in SHH risks., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: P.M.M. declares stock ownership in the following: Bayer and Roche Pharmaceuticals. H.M.C. declares grants from Juvenile Diabetes Research Foundation International, Diabetes UK, IQVIA, Chief Scientist Office, Medical Research Council (UK Research and Innovation), and European Union Commission, honoraria from Novo Nordisk, advisory board fees paid through her institution from Novo Nordisk and Bayer, and stock ownership in Bayer and Roche Pharmaceuticals. S.H. declares consulting fees paid through his institution from Vertex Pharma, Zucara Pharmaceuticals, and Zealand Pharma, honoraria from Medtronic and Novo Nordisk, and has served as Chair of DSMB for Eli Lilly development programme and as a Member of Novo Nordisk Independent Advisory Board. R.J.M. declares honoraria from Sanofi and Novo Nordisk for lectures and presentations, travel support from Sanofi, and is a non-executive member of NHS Tayside Health Board. F.W.G. declares advisory board fees from Abbott Diabetes and Insulet, speaker fees from Abbott Diabetes, Insulet, Novo Nordisk, and Lilly, and travel support from Abbott Diabetes and Novo Nordisk. S.P. declares grants from Novo Nordisk, Lilly, and Amgen, travel support from Novo Nordisk, and has participated on an Advisory board for Roche Pharmaceuticals. N.S. has consulted for and/or received speaker honoraria from Abbott Laboratories, Abbvie, Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Hanmi Pharmaceuticals, Janssen, Menarini-Ricerche, Novartis, Novo Nordisk, Pfizer, Roche Diagnostics, and Sanofi; and received grant support paid to his University from AstraZeneca, Boehringer Ingelheim, Novartis, and Roche Diagnostics outside the submitted work. No other potential conflicts of interest relevant to this article were reported., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Hypoglycaemia has been shown to induce a systemic pro-inflammatory response, which may be driven, in part, by the adrenaline response. Prior exposure to hypoglycaemia attenuates counterregulatory hormone responses to subsequent hypoglycaemia, but whether this effect can be extrapolated to the pro-inflammatory response is unclear. Therefore, we investigated the effect of antecedent hypoglycaemia on inflammatory responses to subsequent hypoglycaemia in humans., Methods: Healthy participants (n = 32) were recruited and randomised to two 2-h episodes of either hypoglycaemia or normoglycaemia on day 1, followed by a hyperinsulinaemic hypoglycaemic (2.8 ± 0.1 mmol/L) glucose clamp on day 2. During normoglycaemia and hypoglycaemia, and after 24 h, 72 h and 1 week, blood was drawn to determine circulating immune cell composition, phenotype and function, and 93 circulating inflammatory proteins including hs-CRP., Results: In the group undergoing antecedent hypoglycaemia, the adrenaline response to next-day hypoglycaemia was lower compared to the control group (1.45 ± 1.24 vs 2.68 ± 1.41 nmol/l). In both groups, day 2 hypoglycaemia increased absolute numbers of circulating immune cells, of which lymphocytes and monocytes remained elevated for the whole week. Also, the proportion of pro-inflammatory CD16 + -monocytes increased during hypoglycaemia. After ex vivo stimulation, monocytes released more TNF-α and IL-1β, and less IL-10 in response to hypoglycaemia, whereas levels of 19 circulating inflammatory proteins, including hs-CRP, increased for up to 1 week after the hypoglycaemic event. Most of the inflammatory responses were similar in the two groups, except the persistent pro-inflammatory protein changes were partly blunted in the group exposed to antecedent hypoglycaemia. We did not find a correlation between the adrenaline response and the inflammatory responses during hypoglycaemia., Conclusion: Hypoglycaemia induces an acute and persistent pro-inflammatory response at multiple levels that occurs largely, but not completely, independent of prior exposure to hypoglycaemia. Clinical Trial information Clinicaltrials.gov no. NCT03976271 (registered 5 June 2019)., (© 2024. The Author(s).)

Aims/hypothesis: Impaired awareness of hypoglycaemia (IAH) in type 1 diabetes may develop through a process referred to as habituation. Consistent with this, a single bout of high intensity interval exercise as a novel stress stimulus improves counterregulatory responses (CRR) to next-day hypoglycaemia, referred to as dishabituation. This longitudinal pilot study investigated whether 4 weeks of high intensity interval training (HIIT) has sustained effects on counterregulatory and symptom responses to hypoglycaemia in adults with type 1 diabetes and IAH., Methods: HIT4HYPOS was a single-centre, randomised, parallel-group study. Participants were identified using the Scottish Diabetes Research Network (SDRN) and from diabetes outpatient clinics in NHS Tayside, UK. The study took place at the Clinical Research Centre, Ninewells Hospital and Medical School, Dundee, UK. Participants were aged 18-55 years with type 1 diabetes of at least 5 years' duration and HbA 1c levels <75 mmol/mol (<9%). They had IAH confirmed by a Gold score ≥4, modified Clarke score ≥4 or Dose Adjustment For Normal Eating [DAFNE] hypoglycaemia awareness rating of 2 or 3, and/or evidence of recurrent hypoglycaemia on flash glucose monitoring. Participants were randomly allocated using a web-based system to either 4 weeks of real-time continuous glucose monitoring (RT-CGM) or RT-CGM+HIIT. Participants and investigators were not masked to group assignment. The HIIT programme was performed for 20 min on a stationary exercise bike three times a week. Hyperinsulinaemic-hypoglycaemic (2.5 mmol/l) clamp studies with assessment of symptoms, hormones and cognitive function were performed at baseline and after 4 weeks of the study intervention. The predefined primary outcome was the difference in hypoglycaemia-induced adrenaline (epinephrine) responses from baseline following RT-CGM or RT-CGM+HIIT., Results: Eighteen participants (nine men and nine women) with type 1 diabetes (median [IQR] duration 27 [18.75-32] years) and IAH were included, with nine participants randomised to each group. Data from all study participants were included in the analysis. During the 4 week intervention there were no significant mean (SEM) differences between RT-CGM and RT-CGM+HIIT in exposure to level 1 (28 [7] vs 22 [4] episodes, p=0.45) or level 2 (9 [3] vs 4 [1] episodes, p=0.29) hypoglycaemia. The CGM-derived mean glucose level, SD of glucose and glucose management indicator (GMI) did not differ between groups. During the hyperinsulinaemic-hypoglycaemic clamp studies, mean (SEM) change from baseline was greater for the noradrenergic responses (RT-CGM vs RT-CGM+HIIT: -988 [447] vs 514 [732] pmol/l, p=0.02) but not the adrenergic responses (-298 [687] vs 1130 [747] pmol/l, p=0.11) in those participants who had undergone RT-CGM+HIIT. There was a benefit of RT-CGM+HIIT for mean (SEM) change from baseline in the glucagon CRR to hypoglycaemia (RT-CGM vs RT-CGM+HIIT: 1 [4] vs 16 [6] ng/l, p=0.01). Consistent with the hormone response, the mean (SEM) symptomatic response to hypoglycaemia (adjusted for baseline) was greater following RT-CGM+HIIT (RT-CGM vs RT-CGM+HIIT: -4 [2] vs 0 [2], p<0.05)., Conclusions/interpretation: In this pilot clinical trial in people with type 1 diabetes and IAH, we found continuing benefits of HIIT for overall hormonal and symptomatic CRR to subsequent hypoglycaemia. Our findings also suggest that HIIT may improve the glucagon response to insulin-induced hypoglycaemia., Trial Registration: ISRCTN15373978., Funding: Sir George Alberti Fellowship from Diabetes UK (CMF) and the Juvenile Diabetes Research Foundation., (© 2023. The Author(s).)

Aims/hypothesis: Repeated exposures to insulin-induced hypoglycaemia in people with diabetes progressively impairs the counterregulatory response (CRR) that restores normoglycaemia. This defect is characterised by reduced secretion of glucagon and other counterregulatory hormones. Evidence indicates that glucose-responsive neurons located in the hypothalamus orchestrate the CRR. Here, we aimed to identify the changes in hypothalamic gene and protein expression that underlie impaired CRR in a mouse model of defective CRR., Methods: High-fat-diet fed and low-dose streptozocin-treated C57BL/6N mice were exposed to one (acute hypoglycaemia [AH]) or multiple (recurrent hypoglycaemia [RH]) insulin-induced hypoglycaemic episodes and plasma glucagon levels were measured. Single-nuclei RNA-seq (snRNA-seq) data were obtained from the hypothalamus and cortex of mice exposed to AH and RH. Proteomic data were obtained from hypothalamic synaptosomal fractions., Results: The final insulin injection resulted in similar plasma glucose levels in the RH group and AH groups, but glucagon secretion was significantly lower in the RH group (AH: 94.5±9.2 ng/l [n=33]; RH: 59.0±4.8 ng/l [n=37]; p<0.001). Analysis of snRNA-seq data revealed similar proportions of hypothalamic cell subpopulations in the AH- and RH-exposed mice. Changes in transcriptional profiles were found in all cell types analysed. In neurons from RH-exposed mice, we observed a significant decrease in expression of Avp, Pmch and Pcsk1n, and the most overexpressed gene was Kcnq1ot1, as compared with AH-exposed mice. Gene ontology analysis of differentially expressed genes (DEGs) indicated a coordinated decrease in many oxidative phosphorylation genes and reduced expression of vacuolar H + - and Na + /K + -ATPases; these observations were in large part confirmed in the proteomic analysis of synaptosomal fractions. Compared with AH-exposed mice, oligodendrocytes from RH-exposed mice had major changes in gene expression that suggested reduced myelin formation. In astrocytes from RH-exposed mice, DEGs indicated reduced capacity for neurotransmitters scavenging in tripartite synapses as compared with astrocytes from AH-exposed mice. In addition, in neurons and astrocytes, multiple changes in gene expression suggested increased amyloid beta (Aβ) production and stability. The snRNA-seq analysis of the cortex showed that the adaptation to RH involved different biological processes from those seen in the hypothalamus., Conclusions/interpretation: The present study provides a model of defective counterregulation in a mouse model of type 2 diabetes. It shows that repeated hypoglycaemic episodes induce multiple defects affecting all hypothalamic cell types and their interactions, indicative of impaired neuronal network signalling and dysegulated hypoglycaemia sensing, and displaying features of neurodegenerative diseases. It also shows that repeated hypoglycaemia leads to specific molecular adaptation in the hypothalamus when compared with the cortex., Data Availability: The transcriptomic dataset is available via the GEO ( http://www.ncbi.nlm.nih.gov/geo/ ), using the accession no. GSE226277. The proteomic dataset is available via the ProteomeXchange data repository ( http://www.proteomexchange.org ), using the accession no. PXD040183., (© 2023. The Author(s).)

The complement system constitutes an integral component of the innate immune system and plays a critical role in adaptive immunity. Activation of this system engenders the production of complement peptide fragments, including C5a, which engage G-protein coupled receptors predominantly expressed in immune-associated cells, such as neutrophils, initiating pro-inflammatory responses. Intriguingly, our investigation has unveiled the presence of C5a receptor 1 (C5aR1) expression within skeletal muscle, a key metabolic tissue and primary target of insulin. Herein, we demonstrate that C5aR1 activation by C5a in differentiated human skeletal muscle cells elicits acute suppression of insulin signalling. This suppression manifests as impaired insulin-dependent association between IRS1 and the p85 subunit of PI3-kinase, a 50% reduction in Akt phosphorylation, and a 60% decline in insulin-stimulated glucose uptake. This impairment in insulin signalling is associated with a three-fold elevation in intramyocellular diacylglycerol (DAG) levels and a two-fold increase in cytosolic calcium content, which promote PKC-mediated IRS1 inhibition via enhanced phosphorylation at IRS1 Ser1101. Significantly, our findings demonstrate that structurally diverse C5aR1 antagonists, along with genetic deletion or stable silencing of C5aR1 by 80% using short-hairpin RNA, effectively attenuate repression of insulin signalling by C5a in LHCN-M2 human skeletal myotubes. These results underscore the potential of heightened C5aR1 activation, characteristic of obesity and chronic inflammatory conditions, to detrimentally impact insulin function within skeletal muscle cells. Additionally, the study suggests that agents targeting the C5a-C5aR axis, originally devised for mitigating complement-dependent inflammatory conditions, may offer therapeutic avenues to ameliorate immune-driven insulin resistance in key peripheral metabolic tissues, including skeletal muscle., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest that pertain to this work., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Aims: Research on hypoglycaemia and quality of life (QoL) has focused mostly on severe hypoglycaemia and psychological outcomes, with less known about other aspects of hypoglycaemia (e.g., self-treated episodes) and impacts on other QoL domains (e.g., relationships). Therefore, we examined the impact of all aspects of hypoglycaemia on QoL in adults with type 1 diabetes (T1DM)., Methods: Participants completed an online survey, including assessment of hypoglycaemia-specific QoL (using the 12-item Hypoglycaemia Impact Profile). Mann-Whitney U tests examined differences in hypoglycaemia-specific QoL by hypoglycaemia frequency, severity, and awareness. Hierarchical linear regression examined associations with QoL., Results: Participants were 1028 adults with T1DM (M ± SD age: 47 ± 15 years; diabetes duration: 27 ± 16 years). Severe and self-treated hypoglycaemia and impaired awareness negatively impacted on overall QoL and several QoL domains, including leisure activities, physical health, ability to keep fit/be active, sleep, emotional well-being, spontaneity, independence, work/studies, and dietary freedom. Diabetes distress was most strongly associated with hypoglycaemia-specific QoL, followed by generic emotional well-being, fear of hypoglycaemia, and confidence in managing hypoglycaemia. Hypoglycaemia frequency and awareness were no longer significantly associated with QoL once psychological factors were considered., Conclusions: Hypoglycaemia negatively impacts on several QoL domains. Psychological factors supersede the effect of hypoglycaemia frequency and awareness in accounting for this negative impact., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: Metformin is the first line therapy recommended for type 2 diabetes. However, the precise mechanism of action remains unclear and up to a quarter of patients show some degree of intolerance to the drug, with a similar number showing poor response to treatment, limiting its effectiveness. A better understanding of the mechanism of action of metformin may improve its clinical use. SLC2A2 (GLUT2) is a transmembrane facilitated glucose transporter, with important roles in the liver, gut and pancreas. Our group previously identified single nucleotide polymorphisms in the human SLC2A2 gene, which were associated with reduced transporter expression and an improved response to metformin treatment. The aims of this study were to model Slc2a2 deficiency and measure the impact on glucose homoeostasis and metformin response in mice., Methods: We performed extensive metabolic phenotyping and 2-deoxy-2-[ 18 F]fluoro-d-glucose ([ 18 F]FDG)-positron emission tomography (PET) analysis of gut glucose uptake in high-fat diet-fed (HFD) mice with whole-body reduced Slc2a2 (Slc2a2 +/- ) and intestinal Slc2a2 KO, to assess the impact of metformin treatment., Results: Slc2a2 partial deficiency had no major impact on body weight and insulin sensitivity, however mice with whole-body reduced Slc2a2 expression (Slc2a2 +/- ) developed an age-related decline in glucose homoeostasis (as measured by glucose tolerance test) compared to wild-type (Slc2a2 +/+ ) littermates. Glucose uptake into the gut from the circulation was enhanced by metformin exposure in Slc2a2 +/+ animals fed HFD and this action of the drug was significantly higher in Slc2a2 +/- animals. However, there was no effect of specifically knocking-out Slc2a2 in the mouse intestinal epithelial cells., Conclusions: Overall, this work identifies a differential metformin response, dependent on expression of the SLC2A2 glucose transporter, and also adds to the growing evidence that metformin efficacy includes modifying glucose transport in the gut. We also describe a novel and important role for this transporter in maintaining efficient glucose homoeostasis during ageing., Competing Interests: Declaration of Competing Interest The authors report no conflict of interest., (Copyright © 2023 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

Aim: To determine the duration and the extension of the pro-inflammatory response to hypoglycaemia both in people with type 1 diabetes and healthy controls., Materials and Methods: Adults with type 1 diabetes (n = 47) and matched controls (n = 16) underwent a hyperinsulinaemic-euglycaemic hypoglycaemic (2.8 ± 0.1 mmoL/L [49.9 ± 2.3 mg/dL]) glucose clamp. During euglycaemia, hypoglycaemia, and 1, 3 and 7 days later, blood was drawn to determine immune cell phenotype, monocyte function and circulating inflammatory markers., Results: Hypoglycaemia increased lymphocyte and monocyte counts, which remained elevated for 1 week. The proportion of CD16 + monocytes increased and the proportion of CD14 + monocytes decreased. During hypoglycaemia, monocytes released more tumour necrosis factor-α and interleukin-1β, and less interleukin-10, after ex vivo stimulation. Hypoglycaemia increased the levels of 19 circulating inflammatory proteins, including high sensitive C-reactive protein, most of which remained elevated for 1 week. The epinephrine peak in response to hypoglycaemia was positively correlated with immune cell number and phenotype, but not with the proteomic response., Conclusions: Overall, despite differences in prior exposure to hypoglycaemia, the pattern of the inflammatory responses to hypoglycaemia did not differ between people with type 1 diabetes and healthy controls. In conclusion, hypoglycaemia induces a range of pro-inflammatory responses that are sustained for at least 1 week in people with type 1 diabetes and healthy controls., (© 2023 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Background: The Hypoglycaemia - MEasurement, ThResholds and ImpaCtS (Hypo-METRICS) smartphone app was developed to investigate the impact of hypoglycemia on daily functioning in adults with type 1 diabetes mellitus or insulin-treated type 2 diabetes mellitus. The app uses ecological momentary assessments, thereby minimizing recall bias and maximizing ecological validity. It was used in the Hypo-METRICS study, a European multicenter observational study wherein participants wore a blinded continuous glucose monitoring device and completed the app assessments 3 times daily for 70 days., Objective: The 3 aims of the study were to explore the content validity of the app, the acceptability and feasibility of using the app for the duration of the Hypo-METRICS study, and suggestions for future versions of the app., Methods: Participants who had completed the 70-day Hypo-METRICS study in the United Kingdom were invited to participate in a brief web-based survey and an interview (approximately 1h) to explore their experiences with the app during the Hypo-METRICS study. Thematic analysis of the qualitative data was conducted using both deductive and inductive methods., Results: A total of 18 adults with diabetes (type 1 diabetes: n=10, 56%; 5/10, 50% female; mean age 47, SD 16 years; type 2 diabetes: n=8, 44%; 2/8, 25% female; mean age 61, SD 9 years) filled out the survey and were interviewed. In exploring content validity, participants overall described the Hypo-METRICS app as relevant, understandable, and comprehensive. In total, 3 themes were derived: hypoglycemia symptoms and experiences are idiosyncratic; it was easy to select ratings on the app, but day-to-day changes were perceived as minimal; and instructions could be improved. Participants offered suggestions for changes or additional questions and functions that could increase engagement and improve content (such as providing more examples with the questions). In exploring acceptability and feasibility, 5 themes were derived: helping science and people with diabetes; easy to fit in, but more flexibility wanted; hypoglycemia delaying responses and increasing completion time; design, functionality, and customizability of the app; and limited change in awareness of symptoms and impact. Participants described using the app as a positive experience overall and as having a possible, although limited, intervention effect in terms of both hypoglycemia awareness and personal impact., Conclusions: The Hypo-METRICS app shows promise as a new research tool to assess the impact of hypoglycemia on an individual's daily functioning. Despite suggested improvements, participants' responses indicated that the app has satisfactory content validity, overall fits in with everyday life, and is suitable for a 10-week research study. Although developed for research purposes, real-time assessments may have clinical value for monitoring and reviewing hypoglycemia symptom awareness and personal impact., (©Uffe Søholm, Natalie Zaremba, Melanie Broadley, Johanne Lundager Axelsen, Patrick Divilly, Gilberte Martine-Edith, Stephanie A Amiel, Julia K Mader, Ulrik Pedersen-Bjergaard, Rory J McCrimmon, Eric Renard, Mark Evans, Bastiaan de Galan, Simon Heller, Christel Hendrieckx, Pratik Choudhary, Jane Speight, Frans Pouwer, Hypo-RESOLVE consortium Hypo-RESOLVE consortium. Originally published in JMIR Diabetes (https://diabetes.jmir.org), 29.09.2023.)

Aims/hypothesis: Chronic hyperglycaemia and recurrent hypoglycaemia are independently associated with accelerated cognitive decline in type 1 diabetes. Recurrent hypoglycaemia in rodent models of chemically induced (streptozotocin [STZ]) diabetes leads to cognitive impairment in memory-related tasks associated with hippocampal oxidative damage. This study examined the hypothesis that post-hypoglycaemic hyperglycaemia in STZ-diabetes exacerbates hippocampal oxidative stress and explored potential contributory mechanisms., Methods: The hyperinsulinaemic glucose clamp technique was used to induce equivalent hypoglycaemia and to control post-hypoglycaemic glucose levels in mice with and without STZ-diabetes and Nrf2 -/- mice (lacking Nrf2 [also known as Nfe2l2]). Subsequently, quantitative proteomics based on stable isotope labelling by amino acids in cell culture and biochemical approaches were used to assess oxidative damage and explore contributory pathways., Results: Evidence of hippocampal oxidative damage was most marked in mice with STZ-diabetes exposed to post-hypoglycaemic hyperglycaemia; these mice also showed induction of Nrf2 and the Nrf2 transcriptional targets Sod2 and Hmox-1. In this group, hypoglycaemia induced a significant upregulation of proteins involved in alternative fuel provision, reductive biosynthesis and degradation of damaged proteins, and a significant downregulation of proteins mediating the stress response. Key differences emerged between mice with and without STZ-diabetes following recovery from hypoglycaemia in proteins mediating the stress response and reductive biosynthesis., Conclusions/interpretation: There is a disruption of the cellular response to a hypoglycaemic challenge in mice with STZ-induced diabetes that is not seen in wild-type non-diabetic animals. The chronic hyperglycaemia of diabetes and post-hypoglycaemic hyperglycaemia act synergistically to induce oxidative stress and damage in the hippocampus, possibly leading to irreversible damage/modification to proteins or synapses between cells. In conclusion, recurrent hypoglycaemia in sub-optimally controlled diabetes may contribute, at least in part, to accelerated cognitive decline through amplifying oxidative damage in key brain regions, such as the hippocampus., Data Availability: The datasets generated during and/or analysed during the current study are available in ProteomeXchange, accession no. 1-20220824-173727 ( www.proteomexchange.org ). Additional datasets generated during and/or analysed during the present study are available from the corresponding author upon reasonable request., (© 2023. The Author(s).)

Competing Interests: RJM has served on advisory panels and speakers bureau for Sanofi and Novo Nordisk (related to once-weekly GLP1RAs and fixed ratio combination therapies); has received research support from the European Union, Medical Research Council, Chief Scientists Office, Diabetes UK, and the Juvenile Diabetes Research Foundation; and reports clinical trial fees paid to his institution from Novo Nordisk, Lilly, Pfizer, and Boehringer Ingelheim all related broadly to diabetes research but unrelated to once-weekly insulins. RJM is a non-executive member of NHS Tayside Health Board.

Objective: To assess the real-world cardiovascular (CV) safety for sulfonylureas (SU), in comparison with dipeptidyl peptidase 4 inhibitors (DPP4i) and thiazolidinediones (TZD), through development of robust methodology for causal inference in a whole nation study., Research Design and Methods: A cohort study was performed including people with type 2 diabetes diagnosed in Scotland before 31 December 2017, who failed to reach HbA1c 48 mmol/mol despite metformin monotherapy and initiated second-line pharmacotherapy (SU/DPP4i/TZD) on or after 1 January 2010. The primary outcome was composite major adverse cardiovascular events (MACE), including hospitalization for myocardial infarction, ischemic stroke, heart failure, and CV death. Secondary outcomes were each individual end point and all-cause death. Multivariable Cox proportional hazards regression and an instrumental variable (IV) approach were used to control confounding in a similar way to the randomization process in a randomized control trial., Results: Comparing SU to non-SU (DPP4i/TZD), the hazard ratio (HR) for MACE was 1.00 (95% CI: 0.91-1.09) from the multivariable Cox regression and 1.02 (0.91-1.13) and 1.03 (0.91-1.16) using two different IVs. For all-cause death, the HR from Cox regression and the two IV analyses was 1.03 (0.94-1.13), 1.04 (0.93-1.17), and 1.03 (0.90-1.17)., Conclusions: Our findings contribute to the understanding that second-line SU for glucose lowering are unlikely to increase CV risk or all-cause mortality. Given their potent efficacy, microvascular benefits, cost effectiveness, and widespread use, this study supports that SU should remain a part of the global diabetes treatment portfolio., (© 2023 by the American Diabetes Association.)

Introduction: The aim of this study was to determine the acceptability and psychometric properties of the Hypo-METRICS (Hypoglycemia MEasurement, ThResholds and ImpaCtS) application (app): a novel tool designed to assess the direct impact of symptomatic and asymptomatic hypoglycemia on daily functioning in people with insulin-treated diabetes., Materials and Methods: 100 adults with type 1 diabetes mellitus (T1DM, n = 64) or insulin-treated type 2 diabetes mellitus (T2DM, n = 36) completed three daily 'check-ins' (morning, afternoon and evening) via the Hypo-METRICs app across 10 weeks, to respond to 29 unique questions about their subjective daily functioning. Questions addressed sleep quality, energy level, mood, affect, cognitive functioning, fear of hypoglycemia and hyperglycemia, social functioning, and work/productivity. Completion rates, structural validity, internal consistency, and test-retest reliability were explored. App responses were correlated with validated person-reported outcome measures to investigate convergent (rs>±0.3) and divergent (rs<±0.3) validity., Results: Participants' mean±SD age was 54±16 years, diabetes duration was 23±13 years, and most recent HbA1c was 56.6±9.8 mmol/mol. Participants submitted mean±SD 191±16 out of 210 possible 'check-ins' (91%). Structural validity was confirmed with multi-level confirmatory factor analysis showing good model fit on the adjusted model (Comparative Fit Index >0.95, Root-Mean-Square Error of Approximation <0.06, Standardized Root-Mean-square Residual<0.08). Scales had satisfactory internal consistency (all ω≥0.5), and high test-retest reliability (rs≥0.7). Convergent and divergent validity were demonstrated for most scales., Conclusion: High completion rates and satisfactory psychometric properties demonstrated that the Hypo-METRICS app is acceptable to adults with T1DM and T2DM, and a reliable and valid tool to explore the daily impact of hypoglycemia., Competing Interests: US works for Novo Nordisk A/S (the work for this manuscript was undertaken prior to this employment). UPB has served on advisory boards and received lecture fees from for Novo Nordisk and Sanofi. BDG has received research support from Novo Nordisk. SAA has served on advisory boards for Novo Nordisk and Medtronic and have spoken at educational events sponsored by Novo Nordisk and Sanofi. JKM is a member on the advisory board of Abbott Diabetes Care, Boehringer Ingelheim, Becton-Dickinson, Eli Lilly, Medtronic, Novo Nordisk A/S, Prediktor A/S, Roche Diabetes Care, Sanofi-Aventis and received speaker honoraria from Abbott Diabetes Care, AstraZeneca, Becton-Dickinson, Dexcom, Eli Lilly, MSD, Novo Nordisk A/S, Roche Diabetes Care, Sanofi, and Servier. JKM is a shareholder of decide Clinical Software GmbH. FP has received unrestricted funding for research from Novo Nordisk, Eli Lilly and Sanofi. PC has received personal fees from Abbott, Insulet, Medtronic, Novo Nordisk, Eli Lilly, Sanofi and Dexcom. This does not alter our adherence to PLOS ONE policies on sharing data and materials. The data underlying the results presented in the study are available from the Hypo-RESOLVE data repository for researchers who meet the criteria for access. Please contact Hypo-RESOLVE (chair of the publication committee Professor Stephanie Amiel or principal investigator Professor Pratik Choudhary) for further details: https://hypo-resolve.eu/contact, (Copyright: © 2023 Søholm et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Assessment of patient-reported outcome measures (PROMs), including quality of life (QoL), is essential in diabetes research and care. However, a recent review concluded that current hypoglycaemia-specific PROMs have limited evidence of validity, reliability and responsiveness for assessing the impact of hypoglycaemia on QoL in people living with diabetes. None of the PROMs identified could be used directly to inform the cost-effectiveness of treatments and interventions. There is a need for a new hypoglycaemia-specific QoL PROM, which can be used directly to inform economic evaluations., Aims: This project has three aims: (a) To develop draft PROM content for measuring the impact of hypoglycaemia on QoL in adults with diabetes. (b) To refine the draft content using cognitive debriefing interviews and psychometrics. This will result in a condition-specific PROM that can be used to quantify the impact of hypoglycaemia upon QoL. (c) To generate a preference-based measure (PBM) that will enable utility values to be calculated for economic evaluation., Methods: A mixed-methods, three-stage design is used: (a) Qualitative interviews will inform the draft PROM content. (b) Cognitive debriefing interview data will be used to refine the draft PROM content. The PROM will be administered in a large-scale survey to enable psychometric validation. Final item selection for the PROM will be informed by psychometric performance, translatability assessment and input from stakeholder groups. (c) A classification system will be generated, comprising a reduced number of items from the PROM. A valuation survey will be conducted to derive a value set for the PBM., (© 2022 The Authors. Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK.)

Aim: To report prespecified and post hoc analyses of the SoliMix dataset exploring the impact of baseline participant characteristics on the original SoliMix study outcomes, to enable informed treatment choices for people with different biomedical characteristics., Methods: SoliMix (EudraCT 2017-003370-13) compared once-daily iGlarLixi (a fixed-ratio combination of insulin glargine 100 U/mL and the glucagon-like peptide-1 receptor agonist lixisenatide) with twice-daily BIAsp 30 (30% insulin aspart and 70% insulin aspart protamine). In this analysis, the original primary outcomes of noninferiority of iGlarLixi versus BIAsp 30 in terms of glycated haemoglobin (HbA1c) change and superiority in terms of body weight change, together with change in basal insulin dose and hypoglycaemia outcomes, were investigated by baseline age, duration of diabetes, insulin dose, HbA1c level, body mass index (BMI), and renal function., Results: No evidence of difference in comparative treatment effect was detected across baseline age, duration of diabetes, insulin dose, HbA1c level, BMI and renal function subgroups for any endpoint (all heterogeneity P > 0.05), except American Diabetes Association Level 2 hypoglycaemia event rate when stratified by insulin dose (P = 0.011), which may be a chance difference given multiple testing and the small numbers of Level 2 events., Conclusions: Treatment effects of iGlarLixi were consistent irrespective of baseline HbA1c, insulin dose, BMI, age, duration of diabetes and renal function, supporting the use of iGlarLixi as an efficacious and well-tolerated treatment option in people with type 2 diabetes with a wide range of biomedical characteristics., (© 2022 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Aim: For people with suboptimally controlled type 2 diabetes (T2D) on basal insulin (BI), guidelines recommend several treatment advancement options. This study compared the clinical effectiveness of once-daily iGlarLixi versus a multiple-injection BI + rapid acting insulin (RAI) regimen in adults with T2D advancing from BI therapy in real-world clinical practice., Materials and Methods: Electronic medical records from the Observational Medical Outcomes Partnership (OMOP) database were analysed retrospectively using propensity score matching to compare therapy advancement with iGlarLixi or BI + RAI in US adults ≥18 years with T2D on BI who had ≥1 valid glycated haemoglobin (HbA1c) value at baseline and at the 6-month follow-up. The primary objective was non-inferiority of iGlarLixi to BI + RAI in HbA1c change from baseline to 6 months (margin 0.3%)., Results: Propensity score matching generated cohorts with balanced baseline characteristics (N = 814 in each group). HbA1c reduction from baseline to 6 months with iGlarLixi was non-inferior to BI + RAI [mean difference (95% confidence interval): 0.1 (-0.1, 0.2)%; one-sided p = .0032]. At 6 months, weight gain was significantly lower with iGlarLixi than with BI + RAI [-0.8 (-1.3, -0.2) kg; two-sided p = .0069]. Achievement of HbA1c <7% without hypoglycaemia and weight gain were similar between groups [odds ratio (95% confidence interval): 1.15 (0.81, 1.63); p = .4280]. Hypoglycaemia was low in both groups, probably because of underreporting., Conclusions: In real-world clinical practice, glycaemic outcomes 6 months after treatment advancement from BI are similar for people with T2D using iGlarLixi versus BI + RAI, with iGlarLixi leading to less weight gain., (© 2022 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Aims: To explore details of the incidence and rates of daytime and nocturnal hypoglycaemia, levels of hypoglycaemia, and relationship to glycated haemoglobin (HbA1c), when comparing iGlarLixi versus premixed biphasic insulin aspart 30 (BIAsp 30) in the SoliMix randomized controlled trial., Materials and Methods: This exploratory analysis of SoliMix used logistic regression and negative binomial regression analyses to assess between-treatment differences in the incidence and rates of hypoglycaemia by time of day. A negative binomial model was used to derive estimated annualized hypoglycaemia rates as a function of HbA1c., Results: iGlarLixi was associated with lower incidence and rates of American Diabetes Association Level 2 (<54 mg/dL [<3.0 mmol/L]) hypoglycaemia during both night and day versus BIAsp 30. Incidence and rates of Level 1 (<70 to ≥54 mg/dL [<3.9 to ≥3.0 mmol/L]) hypoglycaemia were also mostly shown to be reduced with iGlarLixi versus BIAsp 30. Severe (Level 3) events were too few for analysis (n = 3). iGlarLixi was associated with lower modelled event rates of Level 2 and Level 1 hypoglycaemia over a wide range of HbA1c levels versus BIAsp 30., Conclusions: These results show that the lower HbA1c levels and weight benefit seen with iGlarLixi versus premixed BIAsp 30 in people with type 2 diabetes advancing their basal insulin therapy in the SoliMix trial are also accompanied by a lower risk of hypoglycaemia at any time of day and across a broad range of HbA1c levels., (© 2022 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Iatrogenic hypoglycemia activates the immune system and is associated with an increased risk for atherosclerotic disease. We determined acute and long-term effects of insulin-induced hypoglycemia on inflammatory markers in humans with or without type 2 diabetes. A total of 15 adults with type 2 diabetes and 16 matched control subjects (17 men and 14 women, age 59.6 ± 7.1 years, BMI 28.5 ± 4.3 kg/m2) underwent a hyperinsulinemic-euglycemic (5.31 ± 0.32 mmol/L) hypoglycemic (2.80 ± 0.12 mmol/L) glucose clamp. Blood was drawn during euglycemia and hypoglycemia and 1, 3, and 7 days later to determine circulating immune cell composition, function, and inflammatory proteins. In response to hypoglycemia, absolute numbers of circulating lymphocytes and monocytes significantly increased and remained elevated for 1 week. The proportion of CD16+ monocytes increased, and the proportion of CD14+ monocytes decreased, which was sustained for 1 week in people without diabetes. During hypoglycemia, ex vivo stimulated monocytes released more tumor necrosis factor-α and interleukin 1β, and less interleukin 10, particularly in people with diabetes. hs-CRP and 25 circulating inflammatory proteins increased, remaining significantly elevated 1 week after hypoglycemia. While levels at euglycemia differed, responses to hypoglycemia were broadly similar in people with or without type 2 diabetes. We conclude that hypoglycemia induces a proinflammatory response at the cellular and protein level that is sustained for 1 week in people with type 2 diabetes and control subjects., (© 2022 by the American Diabetes Association.)

Aims: People with type 1 and type 2 diabetes still frequently experience hypoglycaemia, which can be severe, leading to loss of consciousness. This review will examine the cellular consequences of recurrent hypoglycaemia., Methods: This review, based on the Dorothy Hodgkin Lecture given at the Diabetes UK 2022 annual symposium by the author, will discuss our current understanding of the mechanisms by which hypoglycaemia is detected and the consequences of recurrent exposure to hypoglycaemia., Results: Glucose-responsive cells found in the periphery as well as multiple areas of the brain are organised in a classical sensori-motor integrative network encompassing peripheral, hindbrain and hypothalamic components. The mechanism used by glucose-responsive neurons to detect hypoglycaemia parallel those of the classical glucose sensor the pancreatic ß-cell, namely in their use of glucokinase, K ATP channels and AMP-activated protein kinase. Recurrent exposure to hypoglycaemia results in a series of cellular adaptations that may be designed to increase the resilience of cells to future hypoglycaemia. This review also highlights how hypoglycaemia, as an oxidative stressor, may also exacerbate chronic hyperglycaemia-induced increases in oxidative stress and inflammation, leading to damage to vulnerable brain regions., Conclusions: Impaired awareness of hypoglycaemia follows the adaptation of central glucose-responsive neurons to repeated hypoglycaemia and may represent a form of memory called habituation. In diabetes, recurrent hypoglycaemia may have tissue consequences as a result of a profound disruption in the cellular response to a hypoglycaemic challenge that increases vulnerability to oxidative damage., (© 2022 The Author. Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK.)