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OBJECTIVE: This study aimed to evaluate the long-term effects of spinal cord stimulation (SCS) in patients with painful diabetic polyneuropathy (PDPN).MATERIALS AND METHODS: This prospective cohort study was the eight-to-ten-year follow-up of a previously performed pilot and randomized controlled trial on the effects of SCS in PDPN, initiated by the multidisciplinary pain center of Maastricht University Medical Center+. The study population consisted of a subgroup of patients who still used SCS treatment ≥ eight years after implantation (n = 19). Pain intensity scores (numeric rating scale [NRS]) during the day and night and data on secondary outcomes (ie, quality of life, depression, sleep quality) were reported during yearly follow-up consultations. Long-term efficacy of SCS was analyzed by comparing the most recently obtained data eight to ten years after implantation with those obtained at baseline.RESULTS: Pain intensity, day and night, was significantly (p < 0.01) reduced by 2.3 (NRS 6.6-4.3) and 2.2 (NRS 6.8-4.6) points, respectively, when comparing the long-term data with baseline. Moreover, for > 50% of patients, the pain reduction was > 30%, which is considered clinically meaningful. No differences were found regarding the secondary outcomes.CONCLUSION: This eight-to-ten-year follow-up study indicates that SCS can remain an effective treatment in the long term to reduce pain intensity in a subcohort of patients with PDPN who still had an SCS device implanted after eight years.

Aims/hypothesis It is generally recommended to reduce basal insulin doses after exercise to reduce the risk of post-exercise nocturnal hypoglycaemia. Based on its long t½, it is unknown whether such adjustments are required or beneficial for insulin degludec. Methods The ADREM study (Adjustment of insulin Degludec to Reduce post-Exercise (nocturnal) hypoglycaeMia in people with diabetes) was a randomised controlled, crossover study in which we compared 40% dose reduction (D40), or postponement and 20% dose reduction (D20-P), with no dose adjustment (CON) in adults with type 1 diabetes at elevated risk of hypoglycaemia, who performed a 45 min aerobic exercise test in the afternoon. All participants wore blinded continuous glucose monitors for 6 days, measuring the incidence of (nocturnal) hypoglycaemia and subsequent glucose profiles. Results We recruited 18 participants (six women, age 38 ± 13 years, HbA1c 56 ± 8 mmol/mol [7.3 ± 0.8%], mean ± SD). Time below range (i.e. glucose p=0.043), without differences in the number of hypoglycaemic events. Time above range (i.e. glucose >10 mmol/l) was greater for D20-P vs CON (mean ± SEM, 584 ± 81 vs 364 ± 66 min, p=0.001) and D40 (385 ± 72 min, p=0.003). Conclusions/interpretation Post-exercise adjustment of degludec does not mitigate the risk of subsequent nocturnal hypoglycaemia in people with type 1 diabetes. Although reducing degludec reduced next-day time below range, this did not translate into fewer hypoglycaemic events, while postponing degludec should be avoided because of increased time above range. Altogether, these data do not support degludec dose adjustment after a single exercise bout. Trial registration EudraCT number 2019-004222-22 Funding The study was funded by an unrestricted grant from Novo Nordisk, Denmark. Graphical abstract

Background: People with impaired awareness of hypoglycemia (IAH) are at elevated risk of severe, potentially hazardous, hypoglycemia and would benefit from a device alerting to hypoglycemia. Heart rate variability (HRV) changes with hypoglycemia due to sympathetic activity. Since IAH is associated with suppressed sympathetic activity, we investigated whether hypoglycemia elicits a measurable change in HRV in patients with T1D and IAH. Method: Eligible participants underwent a modified hyperinsulinemic euglycemic hypoglycemic clamp (glucose nadir, 43.1 ± 0.90 mg/dl), while HRV was measured by a VitalConnect HealthPatch. Measurements of HRV included Root Mean Square of the Successive Differences (RMSSD) and low to high frequency (LF:HF) ratio. Wilcoxon rank-sum test was used for testing within-subject HRV changes. Results: We included 12 participants (8 female, mean age 57 ± 12 years, mean HbA1c 57 ± 5 mmol/mol (7.4 ± 0.4%)). Symptoms increased from 4.0 (1.5-7.0) at euglycemia to 7.5 (5.0-11.0) during hypoglycemia ( P = .003). In response to hypoglycemia, the LF:HF ratio and RMSSD increased when normalized for data obtained during euglycemia (both P < .01). The LF:HF ratio increased in 6 participants (50%) and declined in one other participant (8%). The RMSSD decreased in 3 (25%) and increased in 4 (33%) participants. In 2 patients, no change in HRV could be detected in response to hypoglycemia. Conclusions: This study reveals that hypoglycemia-induced changes in HRV are retained in the majority of people with T1D and IAH, and that these changes can be detected by a wearable device. Real-time HRV seems usable for detection of hypoglycemia in patients with IAH.

Contains fulltext : 290742.pdf (Publisher’s version ) (Open Access) AIMS: Impaired awareness of hypoglycaemia (IAH) has been reported to affect up to a third of people with type 1 diabetes. Whether the increased use of sensor technology has changed its prevalence remains unknown. The aim of this study was to investigate the current prevalence of IAH and its change over time in a cohort of individuals with type 1 diabetes. METHODS: IAH was assessed using the modified Clarke questionnaire in adults with type 1 diabetes. Participants were recruited from the diabetes outpatient clinic from February 2020 through April 2021. The scores were compared to similar data collected during previous assessments in 2006, 2010 and 2016 respectively. RESULTS: A total of 488 individuals (51.2% male) with a mean (±SD) age of 51.3 ± 15.9 years, median [Q1-Q3] diabetes duration of 30 [16-40] years and mean HbA(1c) of 60 ± 12 mmol/mol (7.7 ± 1.1%) were included. Sensors were used by 85% of the study population. IAH was present among 78 (16.0%) participants, whereas 86 (17.6%) participants had a history of severe hypoglycaemia. By comparison, the prevalence of IAH equalled 32.5% in 2006, 32.3% in 2010 and 30.1% in 2016 (p for trend

BACKGROUND: Endogenously formed advanced glycation end products (AGEs) may be important drivers of microvascular dysfunction and the microvascular complications of diabetes. AGEs are also formed in food products, especially during preparation methods involving dry heat.OBJECTIVES: We aimed to assess cross-sectional associations between dietary AGE intake and generalized microvascular function in a population-based cohort.METHODS: In 3144 participants of the Maastricht Study (mean ± SD age: 60 ± 8 y, 51% men) the dietary AGEs Nε-(carboxymethyl)lysine (CML), Nε-(1-carboxyethyl)lysine (CEL), and Nδ-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (MG-H1) were estimated using the combination of our ultra-performance LC-tandem MS dietary AGE database and an FFQ. Microvascular function was determined in the retina as flicker light-induced arteriolar and venular dilation and as central retinal arteriolar and venular equivalents, in plasma as a z score of endothelial dysfunction biomarkers (soluble vascular adhesion molecule 1 and soluble intracellular adhesion molecule 1, soluble E-selectin, and von Willebrand factor), in skin as the heat-induced skin hyperemic response, and in urine as 24-h albuminuria. Associations were evaluated using multiple linear regression adjusting for demographic, cardiovascular, lifestyle, and dietary factors.RESULTS: Overall, intakes of CML, CEL, and MG-H1 were not associated with the microvascular outcomes. Although higher intake of CEL was associated with higher flicker light-induced venular dilation (β percentage change over baseline: 0.14; 95% CI: 0.02, 0.26) and lower plasma biomarker z score (β: -0.04 SD; 95% CI: -0.08, -0.00 SD), the effect sizes were small and their biological relevance can be questioned.CONCLUSIONS: We did not show any strong association between habitual intake of dietary AGEs and generalized microvascular function. The contribution of dietary AGEs to generalized microvascular function should be further assessed in randomized controlled trials using specifically designed dietary interventions.

Traditionally, clinicians consider lactate as a waste product of anaerobic glycolysis. Interestingly, research has shown that lactate may serve as an alternative fuel for the brain to protect it against harm. The increasing scientific awareness of the potential beneficial side of lactate, however, is entering the clinic rather slowly. Following this, and realizing that the application of potential novel therapeutic strategies in pediatric populations often lags behind the development in adults, this review summarizes the key data on therapeutic use of intravenous infusion of sodium lactate in humans. PubMed and clinicaltrial.gov were searched up until November 2021 focusing on interventional studies in humans. Thirty-four articles were included in this review, with protocols of lactate infusion in adults with diabetes mellitus, traumatic brain injury, Alzheimer’s disease, and cardiac disease. One study on lactate infusion in children was also included. Results of our literature search show that sodium lactate can be safely administrated, without major side effects. Additionally, the present literature clearly shows the potential benefits of therapeutic lactate infusion under certain pathological circumstances, including rather common clinical conditions like traumatic brain injury.Conclusion: This review shows that lactate is a save, alternative energy source for the adult brain warranting studies on the potential therapeutic effects of sodium lactate infusion in children. What is Known:• Lactate is generally considered a waste product of anaerobic glycolysis. However, lactate also is an alternative fuel for different organs, including the brain.• Lactate infusion is not incorporated in standard care for any patient population. What is New:• Thirty-four studies investigated the therapeutic use of intravenous sodium lactate in different patient populations, all with different study protocols.• Literature shows that lactate infusion may have beneficial effects in case of hypoglycemia, traumatic brain injury, and cardiac failure without the risk of major side effects.

Data on hyperglycemia and glucose variability in relation to diabetes mellitus, either known or unknown in ICU-setting in COVID-19, are scarce. We prospectively studied daily glucose variables and mortality in strata of diabetes mellitus and glycosylated hemoglobin among mechanically ventilated COVID-19 patients. We used linear-mixed effect models in mechanically ventilated COVID-19 patients to investigate mean and maximum difference in glucose concentration per day over time. We compared ICU survivors and non-survivors and tested for effect-modification by pandemic wave 1 and 2, diabetes mellitus, and admission HbA1c. Among 232 mechanically ventilated COVID-19 patients, 21.1% had known diabetes mellitus, whereas 16.9% in wave 2 had unknown diabetes mellitus. Non-survivors had higher mean glucose concentrations (ß 0.62 mmol/l; 95%CI 0.20–1.06; P = 0.004) and higher maximum differences in glucose concentrations per day (ß 0.85 mmol/l; 95%CI 0.37–1.33; P = 0.001). Effect modification by wave, history of diabetes mellitus and admission HbA1c in associations between glucose and survival was not present. Effect of higher mean glucose concentrations was modified by pandemic wave (wave 1 (ß 0.74; 95% CI 0.24–1.23) mmol/l vs. wave 2 ß 0.37 (95%CI 0.25–0.98) mmol/l). Hyperglycemia and glucose variability are associated with mortality in mechanically ventilated COVID-19 patients irrespective of the presence of diabetes mellitus.

Aims/hypothesis The role of beta cell mass in the balance of glucose control and hypoglycaemic burden in people with type 1 diabetes is unclear. We applied positron emission tomography (PET) imaging with radiolabelled exendin to compare beta cell mass among people with type 1 diabetes and either low glucose variability (LGV) or high glucose variability (HGV). Methods All participants with either LGV (n=9) or HGV (n=7) underwent a mixed-meal tolerance test to determine beta cell function and wore a blinded continuous glucose monitor for a week. After an i.v. injection with [68Ga]Ga-NODAGA-exendin-4, PET images were acquired for the quantification of pancreatic uptake of radiolabelled exendin. The mean standardised uptake value (SUVmean) of the pancreas was used to determine the amount of beta cell mass. Results Participants with LGV had lower HbA1c (46.0 mmol/mol [44.5–52.5] [6.4% (6.3–7)] vs 80 mmol/mol [69.0–110] [9.5% (8.5–12.2)], p=0.001) and higher time in range (TIR) (75.6% [73.5–90.3] vs 38.7% [25.1–48.5], p=0.002) than those with HGV. The SUVmean of the pancreas was higher for the LGV than for the HGV group (5.1 [3.6–5.6] vs 2.9 [2.1–3.4], p=0.008). The AUCC-peptide:AUCglucose ratio was numerically, but not statistically, higher in the LGV compared with the HGV group (2.7×10−2 [6.2×10−4–5.3×10−2] vs 9.3×10−4 [4.7×10−4–5.2×10−3], p=0.21). SUVmean correlated with the AUCC-peptide:AUCglucose ratio (Pearson r=0.64, p=0.01), as well as with the TIR (r=0.64, p=0.01) and the SD of interstitial glucose levels (r=−0.66, p=0.007). Conclusion/interpretation Our data show higher beta cell mass in people with type 1 diabetes and LGV than in those with HGV, independent of beta cell function. Graphical abstract

Aims/hypothesis Recurrent hypoglycaemia in people with diabetes leads to progressive suppression of counterregulatory hormonal responses to subsequent hypoglycaemia. Recently it has been proposed that the mechanism underpinning this is a form of adaptive memory referred to as habituation. To test this hypothesis, we use two different durations of cold exposure to examine whether rodents exposed to recurrent hypoglycaemia exhibit two characteristic features of habituation, namely stimulus generalisation and dishabituation. Methods In the first study (stimulus generalisation study), hyperinsulinaemic–hypoglycaemic (2.8 mmol/l) glucose clamps were performed in non-diabetic rodents exposed to prior moderate-duration cold (4°C for 3 h) or control conditions. In the second study (dishabituation study), rodents exposed to prior recurrent hypoglycaemia or saline (154 mmol/l NaCl) injections over 4 weeks underwent a longer-duration cold (4°C for 4.5 h) exposure followed 24 h later by a hyperinsulinaemic–hypoglycaemic (2.8 mmol/l) glucose clamp. Output measures were counterregulatory hormone responses during experimental hypoglycaemia. Results Moderate-duration cold exposure blunted the adrenaline (epinephrine) response (15,266 ± 1920 vs 7981 ± 1258 pmol/l, Control vs Cold; p p Conclusions/interpretation Non-diabetic rodents exhibit two cardinal features of habituation, namely stimulus generalisation and dishabituation. These findings provide further support for the hypothesis that suppressed counterregulatory responses following exposure to recurrent hypoglycaemia in diabetes result from habituation. Graphical abstract

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OBJECTIVE Hypoglycemia poses an immediate threat for cognitive function. Due to its association with acute cognitive impairment, the International Hypoglycemia Study Group (IHSG) defines a blood glucose level RESEARCH DESIGN AND METHODS Adults with type 1 diabetes with normal (n = 26) or impaired (n = 21) hypoglycemic awareness or with insulin-treated type 2 diabetes (n = 15) and age-matched control subjects without diabetes (n = 32) underwent a hyperinsulinemic-euglycemic-hypoglycemic glucose clamp (2.80 ± 0.13 mmol/L [50.2 ± 2.3 mg/dL]). At baseline and during hypoglycemia, calculation ability, attention, working memory and cognitive flexibility were measured with the Paced Auditory Serial Addition Test (PASAT) and the Test of Attentional Performance (TAP). RESULTS For the whole group, hypoglycemia decreased the mean ± SD proportion of correct answers on the PASAT by 8.4 ± 12.8%, increased reaction time on the TAP Alertness task by 32.1 ± 66.6 ms, and increased the sum of errors and omissions on the TAP Working Memory task by 2.0 ± 5.5 (all P < 0.001). Hypoglycemia-induced cognitive declines were largely irrespective of the presence or type of diabetes, level of symptomatic awareness, diabetes duration, or HbA1c. CONCLUSIONS IHSG level 2 hypoglycemia impairs cognitive function in people with and without diabetes, irrespective of type of diabetes or hypoglycemia awareness status. These findings support the cutoff value of hypoglycemia

OBJECTIVE Hypoglycemia poses an immediate threat for cognitive function. Due to its association with acute cognitive impairment, the International Hypoglycemia Study Group (IHSG) defines a blood glucose level RESEARCH DESIGN AND METHODS Adults with type 1 diabetes with normal (n=26) or impaired (n=21) hypoglycemic awareness, or with insulin-treated type 2 diabetes (n=15) and age-matched controls without diabetes (n=32) underwent a hyperinsulinemic-euglycemic hypoglycemic glucose clamp (2.80 ± 0.13 mmol/L [50.2 ± 2.3 mg/dL]). At baseline and during hypoglycemia, calculation ability, attention, working memory and cognitive flexibility were measured with the Paced Auditory Serial Addition Test (PASAT) and the Test of Attentional Performance (TAP). RESULTS For the whole group, hypoglycemia decreased the proportion of correct answers on the PASAT by 8.4 ± 12.8%, increased the mean reaction time on the TAP Alertness task by 32.1 ± 66.6 ms, and increased the sum of errors and omissions on the TAP Working Memory task by 2.0 ± 5.5 (all p < 0.001). Hypoglycemia-induced cognitive declines were largely irrespective of the presence or type of diabetes, level of symptomatic awareness, diabetes duration or HbA1c. CONCLUSIONS IHSG level 2 hypoglycemia impairs cognitive function in people with and without diabetes, irrespective of type of diabetes or hypoglycemia awareness status. These findings support the cut-off value of hypoglycemia

N-acetylaspartate (NAA) is the second most abundant metabolite in the human brain; although it is assumed to be a proxy for a neuronal marker, its function is not fully elucidated. NAA is also detectable in plasma, but its relation to cerebral NAA levels, cognitive performance, or features of cerebral disease has not been investigated. To study whether circulating NAA tracks cerebral NAA levels, and whether circulating NAA correlates with cognitive function and features of cerebral small vessel disease (SVD). Two datasets were analyzed. In dataset 1, structural MRI was acquired in 533 subjects to assess four features of cerebral SVD. Cognitive function was evaluated with standardized test scores (N = 824). In dataset 2, brain 1H-MRS from the occipital region was acquired (N = 49). In all subjects, fasting circulating NAA was measured with mass spectrometry. Dataset 1: in univariate and adjusted for confounders models, we found no correlation between circulating NAA and the examined features of cerebral SVD. In univariate analysis, circulating NAA levels were associated inversely with the speed in information processing and the executive function score, however these associations were lost after accounting for confounders. In line with the negative findings of dataset 1, in dataset 2 there was no correlation between circulating and central NAA or total NAA levels. This study indicates that circulating NAA levels do not reflect central (occipital) NAA levels, cognitive function, or cerebral small vessel disease in man.

The role of beta cell mass in the balance of glucose control and hypoglycaemic burden in people with type 1 diabetes is unclear. We applied positron emission tomography (PET) imaging with radiolabelled exendin to compare beta cell mass among people with type 1 diabetes and either low glucose variability (LGV) or high glucose variability (HGV).All participants with either LGV (n=9) or HGV (n=7) underwent a mixed-meal tolerance test to determine beta cell function and wore a blinded continuous glucose monitor for a week. After an i.v. injection with [Participants with LGV had lower HbAOur data show higher beta cell mass in people with type 1 diabetes and LGV than in those with HGV, independent of beta cell function.

Background: Hypoglycemia and its impact on people with diabetes is typically reported retrospectively and is subject to recall bias. Ecological momentary assessment (EMA) uses repeated sampling to collect real time, granular data about patient experiences, typically over 3-5 days. We developed the Hypo-METRICS app to determine the physical, psychological, and economic impact in people with type 1 (T1D) and type 2 diabetes (T2D) over weeks using EMA. We tested user acceptability of the Hypo-METRICS app. Methods: We recruited 323 adults (T1D=186, T2D=137, 55% men, mean age 54±16 years, diabetes duration 22±13 years) using insulin with ≥1 episode of hypoglycemia in the last month. Participants were prompted to complete three daily EMA and two weekly questionnaires (the Work Productivity and Activity Impairment Questionnaire and PROMIS Sleep Disturbance scale) for weeks. EMA included 29 items over morning, afternoon and evening time points. EMA questions spanned seven categories including experience of hypoglycemia, sleep, and daily functioning. Participants recorded hypoglycemia episodes using a symptom tracker in real time. Results: The overall mean completion rate was 89±10% (T1D=87±11%, T2D=91±8%) , with 86,487 completed items. EMAs had a completion rate of 88±11% (T1D=87±11% T2D=90±9%) . Weekly questionnaires had a completion rate of 92±11% (T1D=91±12 T2D=95±8) . A total of 5,585 episodes of participant-reported hypoglycemia (T1D=4,118, T2D=1,467) were recorded in real time with a mean of 1.7±1.4 episodes reported per participant/week (T1D=2.2±1.4 T2D=1.1±1.0) . Conclusion: The Hypo-METRICS app is an acceptable tool to collect prospective detailed data on the frequency of hypoglycemia episodes and their impact on daily functioning over a prolonged period. Disclosure N.Zaremba: None. R.J.Mccrimmon: Advisory Panel; Novo Nordisk, Sanofi, Research Support; Diabetes UK, European Union, MedImmune. E.Renard: Consultant; Abbott, AstraZeneca, Boehringer Ingelheim International GmbH, Dexcom, Inc., Insulet Corporation, LifeScan, Lilly, Novo Nordisk, Roche Diabetes Care, Sanofi, Tandem Diabetes Care, Inc. S.R.Heller: Advisory Panel; Eli Lilly and Company, Medtronic, Mylan N.V., Zealand Pharma A/S, Zucara Therapeutics, Other Relationship; Eli Lilly and Company, Research Support; Dexcom, Inc., Speaker's Bureau; Novo Nordisk A/S. M.Evans: Advisory Panel; Pila Pharma, Zucara Therapeutics, Other Relationship; Abbott Diabetes, Dexcom, Inc., Medtronic, Novo Nordisk, Research Support; AstraZeneca, Sanofi, Speaker's Bureau; Lilly Diabetes. J.K.Mader: Advisory Panel; Abbott Diabetes, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Medtronic, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Roche Diabetes Care, Sanofi-Aventis Deutschland GmbH, Speaker's Bureau; Abbott Diabetes, Eli Lilly and Company, Medtronic, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Roche Diabetes Care, Sanofi-Aventis Deutschland GmbH, Servier Laboratories, Stock/Shareholder; decide Clinical Software GmbH. A.Seibold: Employee; Abbott Diabetes, Stock/Shareholder; Abbott. S.A.Amiel: Advisory Panel; Medtronic, Novo Nordisk, Other Relationship; Sanofi. P.Choudhary: Advisory Panel; Abbott Diabetes, Lilly Diabetes, Medtronic, Research Support; Novo Nordisk, Speaker's Bureau; Dexcom, Inc., Glooko, Inc., Insulet Corporation, Sanofi. Hypo-resolve consortium: n/a. G.Martine-edith: Other Relationship; Novo Nordisk. P.Divilly: None. Z.Mahmoudi: Employee; Novo Nordisk A/S. U.Soeholm: Research Support; Novo Nordisk A/S. M.M.Broadley: None. F.Pouwer: Research Support; Eli Lilly and Company, Novo Nordisk, Sanofi. B.E.De galan: Research Support; Novo Nordisk. U.Pedersen-bjergaard: Advisory Panel; Novo Nordisk A/S, Sanofi. Funding Innovative Medicines Initiative (777460)

Aim: To examine how hypoglycemia while asleep impacts self-reported daily functioning among adults with type 1 diabetes (T1D) . Methods: On 70 consecutive mornings, 250 people with T1D wearing a continuous glucose monitor reported sleep quality, mood, and alertness via the Hypo-METRICS smartphone app. Each night was categorized based on presence (+) or absence (-) of person-reported hypoglycemia (PRH) and sensor-detected hypoglycemia (SDH) into one of four types (see Figure 1, Type A-D) . Multilevel regression assessed associations between hypoglycemia and daily functioning (unstandardized coefficients (β) on original 0-scale) , adjusted for baseline demographic, clinical and psychological factors. Results: In the first 54 adults (52% women, age[M±SD]: 45±15 years) , nighttime PRH (Type C & D, Figure 1) was associated with reduced subjective sleep quality (C: β=-0.67; D: β=-0.58) , mood (C: β=-0.43; D: β=-0.58) and alertness (C: β=-0.34, p=0.015; D: β=-0.46) (all p0.05) . Conclusion: These novel data show the potentially pivotal role of the subjective experience of hypoglycemia for sleep quality, mood and alertness. Disclosure U.Soeholm: Research Support; Novo Nordisk A/S. E.Renard: Consultant; Abbott, AstraZeneca, Boehringer Ingelheim International GmbH, Dexcom, Inc., Insulet Corporation, LifeScan, Lilly, Novo Nordisk, Roche Diabetes Care, Sanofi, Tandem Diabetes Care, Inc. E.J.Abbink: None. P.M.Baumann: None. S.R.Heller: Advisory Panel; Eli Lilly and Company, Medtronic, Mylan N.V., Zealand Pharma A/S, Zucara Therapeutics, Other Relationship; Eli Lilly and Company, Research Support; Dexcom, Inc., Speaker's Bureau; Novo Nordisk A/S. B.E.De galan: Research Support; Novo Nordisk. U.Pedersen-bjergaard: Advisory Panel; Novo Nordisk A/S, Sanofi. M.Evans: Advisory Panel; Pila Pharma, Zucara Therapeutics, Other Relationship; Abbott Diabetes, Dexcom, Inc., Medtronic, Novo Nordisk, Research Support; AstraZeneca, Sanofi, Speaker's Bureau; Lilly Diabetes. D.Pollard: Other Relationship; Novo Nordisk. R.J.Mccrimmon: Advisory Panel; Novo Nordisk, Sanofi, Research Support; Diabetes UK, European Union, MedImmune. S.A.Amiel: Advisory Panel; Medtronic, Novo Nordisk, Other Relationship; Sanofi. M.M.Broadley: None. C.Hendrieckx: None. J.Speight: Advisory Panel; Insulet Corporation, Research Support; Novo Nordisk, Sanofi. P.Choudhary: Advisory Panel; Abbott Diabetes, Lilly Diabetes, Medtronic, Research Support; Novo Nordisk, Speaker's Bureau; Dexcom, Inc., Glooko, Inc., Insulet Corporation, Sanofi. F.Pouwer: Research Support; Eli Lilly and Company, Novo Nordisk, Sanofi. N.Zaremba: None. P.Divilly: None. G.Martine-edith: Other Relationship; Novo Nordisk. G.Nefs: None. Z.Mahmoudi: Employee; Novo Nordisk A/S. J.K.Mader: Advisory Panel; Abbott Diabetes, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Medtronic, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Roche Diabetes Care, Sanofi-Aventis Deutschland GmbH, Speaker's Bureau; Abbott Diabetes, Eli Lilly and Company, Medtronic, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Roche Diabetes Care, Sanofi-Aventis Deutschland GmbH, Servier Laboratories, Stock/Shareholder; decide Clinical Software GmbH. M.Cigler: None. Funding This work was supported by the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement 777460

Impaired awareness of hypoglycemia (IAH) is attributed to hypoglycemia exposure. Continuous glucose monitoring (CGM) detects more hypoglycemia particularly during sleep. We compared rates and duration of sensor detected hypoglycemia (SDH) and patient reported hypoglycemia (PRH) in people with type 1 diabetes (T1D) using CGM or flash monitoring.We recruited 92 participants with T1D using CGM/Flash reporting >1 hypoglycemic episode in the last month. Participants were defined as normal awareness of hypoglycemia (NAH) (Gold score 4; n=22) . All wore an additional blinded CGM and recorded episodes of PRH (symptomatic episodes that resolved on carbohydrate ingestion, or a measured glucose Disclosure P.Divilly: None. S.R.Heller: Advisory Panel; Eli Lilly and Company, Medtronic, Mylan N.V., Zealand Pharma A/S, Zucara Therapeutics, Other Relationship; Eli Lilly and Company, Research Support; Dexcom, Inc., Speaker’s Bureau; Novo Nordisk A/S. M.Evans: Advisory Panel; Pila Pharma, Zucara Therapeutics, Other Relationship; Abbott Diabetes, Dexcom, Inc., Medtronic, Novo Nordisk, Research Support; AstraZeneca, Sanofi, Speaker’s Bureau; Lilly Diabetes. J.K.Mader: Advisory Panel; Abbott Diabetes, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Medtronic, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Roche Diabetes Care, Sanofi-Aventis Deutschland GmbH, Speaker’s Bureau; Abbott Diabetes, Eli Lilly and Company, Medtronic, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Roche Diabetes Care, Sanofi-Aventis Deutschland GmbH, Servier Laboratories, Stock/Shareholder; decide Clinical Software GmbH. S.A.Amiel: Advisory Panel; Medtronic, Novo Nordisk, Other Relationship; Sanofi. P.Choudhary: Advisory Panel; Abbott Diabetes, Lilly Diabetes, Medtronic, Research Support; Novo Nordisk, Speaker’s Bureau; Dexcom, Inc., Glooko, Inc., Insulet Corporation, Sanofi. A.Seibold: Employee; Abbott Diabetes, Stock/Shareholder; Abbott. G.Martine-edith: Other Relationship; Novo Nordisk. Z.Mahmoudi: Employee; Novo Nordisk A/S. N.Zaremba: None. U.Soeholm: Research Support; Novo Nordisk A/S. U.Pedersen-bjergaard: Advisory Panel; Novo Nordisk A/S, Sanofi. R.J.Mccrimmon: Advisory Panel; Novo Nordisk, Sanofi, Research Support; Diabetes UK, European Union, MedImmune. B.E.De galan: Research Support; Novo Nordisk. E.Renard: Consultant; Abbott, AstraZeneca, Boehringer Ingelheim International GmbH, Dexcom, Inc., Insulet Corporation, LifeScan, Lilly, Novo Nordisk, Roche Diabetes Care, Sanofi, Tandem Diabetes Care, Inc. Funding Innovative Medicines Initiative (777460)

Hypoglycemia acutely activates the immune system and is associated with an increased risk for atherosclerotic disease. Since atherosclerosis is driven by inflammation, we set out to determine the duration of the pro-inflammatory response to a hypoglycemic event in people with and without diabetes. Adults with type 1 diabetes (n = 47) or insulin-treated type 2 diabetes (n = 15) , and age-matched controls without diabetes (n = 32) underwent a hyperinsulinemic-euglycemic (5.2 ± 0.4 mmol/L) -hypoglycemic (2.8 ± 0.1 mmol/L) glucose clamp. Before, during and up to a week thereafter, blood was drawn to determine circulating immune cell composition and function combined with measurements of and circulating hs-CRP concentrations. At baseline, participants with diabetes had higher counts of produced cytokines and hs-CRP compared to individuals without diabetes (all p < 0.01) . In response to hypoglycemia, absolute numbers of lymphocytes (1.57 ± 0.53 vs. 2.69 ± 0.95·103/µL) and monocytes (0.40 ± 0.14 vs. 0.62 ± 0.22·103/µL) increased acutely and remained elevated for one week in all subgroups (all p < 0.001) . During hypoglycemia, the proportion of pro-inflammatory CD16+-monocytes increased from 26.9 ± 13.3% to 38.1 ± 14.9% and the proportion of phagocytotic CD14+-monocytes decreased from 65.2 ± 14.4% to 54.5 ± 15.9% in all subgroups (all p < 0.01) . Stimulated monocytes released more TNF-α and IL-1β, and less IL-during hypoglycemia. Similarly, hs-CRP concentrations increased from 2.± 3.20 µg/mL to 2.71 ± 3.57 µg/mL 1 day after the clamp (p < 0.001) and remained elevated for one week (p < 0.001) thereafter to similar extent in all subgroups. In conclusion, a single hypoglycemic event induces a prolonged immune response in humans independent of the presence of diabetes. Disclosure C.E.Verhulst: None. J.Van heck: None. T.W.Fabricius: None. R.Stienstra: None. C.Tack: Advisory Panel; Bayer AG, Boehringer Ingelheim International GmbH, Lilly Diabetes, Novo Nordisk. U.Pedersen-bjergaard: Advisory Panel; Novo Nordisk A/S, Sanofi. B.E.De galan: Research Support; Novo Nordisk. Hypo-resolve consortium: n/a. Funding The Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement 777460. The JU receives support from the European Union’s Horizon 2020 research and innovation program and EFPIA and T1D Exchange, JDRF, International Diabetes Federation (IDF) , The Leona M. and Harry B. Helmsley Charitable Trust.

Continuous glucose monitoring (CGM) allows greater detection of hypoglycemia. We compared rates and duration of sensor detected hypoglycemia (SDH) and patient reported hypoglycemia (PRH) in people with type 1 diabetes (T1D) and normal awareness of hypoglycemia (NAH) (Gold score >4) using either flash or capillary blood glucose (CGB) monitoring. We included 91 participants (70 CGM vs. 21 CBG) with T1D with >1 hypoglycemic episode in the last month. They used blinded CGM in addition to their usual glucose monitoring and recorded PRH (symptomatic event that resolved on carbohydrate ingestion, or a self-measured glucose Disclosure P.Divilly: None. S.R.Heller: Advisory Panel; Eli Lilly and Company, Medtronic, Mylan N.V., Zealand Pharma A/S, Zucara Therapeutics, Other Relationship; Eli Lilly and Company, Research Support; Dexcom, Inc., Speaker’s Bureau; Novo Nordisk A/S. M.Evans: Advisory Panel; Pila Pharma, Zucara Therapeutics, Other Relationship; Abbott Diabetes, Dexcom, Inc., Medtronic, Novo Nordisk, Research Support; AstraZeneca, Sanofi, Speaker’s Bureau; Lilly Diabetes. S.A.Amiel: Advisory Panel; Medtronic, Novo Nordisk, Other Relationship; Sanofi. P.Choudhary: Advisory Panel; Abbott Diabetes, Lilly Diabetes, Medtronic, Research Support; Novo Nordisk, Speaker’s Bureau; Dexcom, Inc., Glooko, Inc., Insulet Corporation, Sanofi. A.Seibold: Employee; Abbott Diabetes, Stock/Shareholder; Abbott. G.Martine-edith: Other Relationship; Novo Nordisk. Z.Mahmoudi: Employee; Novo Nordisk A/S. N.Zaremba: None. U.Soeholm: Research Support; Novo Nordisk A/S. B.E.De galan: Research Support; Novo Nordisk. U.Pedersen-bjergaard: Advisory Panel; Novo Nordisk A/S, Sanofi. R.J.Mccrimmon: Advisory Panel; Novo Nordisk, Sanofi, Research Support; Diabetes UK, European Union, MedImmune. E.Renard: Consultant; Abbott, AstraZeneca, Boehringer Ingelheim International GmbH, Dexcom, Inc., Insulet Corporation, LifeScan, Lilly, Novo Nordisk, Roche Diabetes Care, Sanofi, Tandem Diabetes Care, Inc. Funding Innovative Medicines Initiative (777460)

Acute hypoglycemia impacts negatively on cognitive function. However, it remains unclear which specific domains of cognitive function are affected, and the extent to which level of hypoglycemia modifies this relationship. We conducted a systematic review and meta-analysis to investigate the impact of controlled hyperinsulinaemic hypoglycemia on cognitive function in adults with type 1 diabetes, following PRISMA guidelines. Experimental studies comparing cognitive function task performance during euglycemia and hypoglycemia were eligible for inclusion. Preliminary analyses were conducted on 38 studies, involving 54 cognitive task outcomes across three domains of cognitive function of varying complexity: attention/information processing speed (simplest) , working memory, and complex reasoning (most complex) . Three-level meta-analyses of the standardized mean differences (SMD) in performance during euglycemia and hypoglycemia, moderated by hypoglycemia level (Mdn=2.51; range=1.98-3.5 mmol/l) were conducted for each domain, with study and task as random effects to allow inclusion of multiple effect sizes per study. Hypoglycemia significantly impaired performance on all domains, with large effect sizes for attention/information processing speed (SMD=-1.17, 95% CI:-1.60 to -0.74) and working memory (SMD=-0.84, CI:-1.to -0.63) , and a medium effect size for complex reasoning (SMD=-0.61, CI:-0.99 to -0.23) . The degree of hypoglycemia significantly moderated this relationship for working memory only, such that for every 1mmol/l decrease in glucose level, performance was reduced by SMD=0.84 (CI:0.2 to 1.49) . These findings suggest that the impact of hypoglycemia on cognitive function is related to the cognitive domain complexity, with more impaired performance on simpler relative to more complex tasks. Further, degree of hypoglycemia may be differentially related to performance depending on the domain of cognitive function. Disclosure M.M.Broadley: None. C.Hendrieckx: None. R.J.Mccrimmon: Advisory Panel; Novo Nordisk, Sanofi, Research Support; Diabetes UK, European Union, MedImmune. G.Nefs: None. U.Pedersen-bjergaard: Advisory Panel; Novo Nordisk A/S, Sanofi. C.E.Verhulst: None. J.Speight: Advisory Panel; Insulet Corporation, Research Support; Novo Nordisk, Sanofi. F.Pouwer: Research Support; Eli Lilly and Company, Novo Nordisk, Sanofi. The hypo-resolve consortium: n/a. H.Chatwin: None. U.Soeholm: Research Support; Novo Nordisk A/S. J.Axelsen: None. S.A.Amiel: Advisory Panel; Medtronic, Novo Nordisk, Other Relationship; Sanofi. P.Choudhary: Advisory Panel; Abbott Diabetes, Lilly Diabetes, Medtronic, Research Support; Novo Nordisk, Speaker's Bureau; Dexcom, Inc., Glooko, Inc., Insulet Corporation, Sanofi. B.E.De galan: Research Support; Novo Nordisk. T.W.Fabricius: None. S.R.Heller: Advisory Panel; Eli Lilly and Company, Medtronic, Mylan N.V., Zealand Pharma A/S, Zucara Therapeutics, Other Relationship; Eli Lilly and Company, Research Support; Dexcom, Inc., Speaker's Bureau; Novo Nordisk A/S. Funding Innovative Medicines Initiative 2 Joint Undertaking (777460)

IntroductionImpaired awareness of hypoglycemia, clinically reflected by the inability to timely detect hypoglycemia, affects approximately 25% of the people with type 1 diabetes. Both altered brain lactate handling and increased cerebral blood flow (CBF) during hypoglycemia appear to be involved in the pathogenesis of impaired awareness of hypoglycemia. Here we examine the effect of lactate on CBF during hypoglycemia.Research design and methodsNine people with type 1 diabetes and normal awareness of hypoglycemia underwent two hyperinsulinemic euglycemic-hypoglycemic (3.0 mmol/L) glucose clamps in a 3T MR system, once with sodium lactate infusion and once with sodium chloride infusion. Global and regional changes in CBF were determined using pseudocontinuous arterial spin labeling.ResultsLactate (3.3±0.6 vs 0.9±0.2 mmol/L during lactate infusion vs placebo infusion, respectively) suppressed the counter-regulatory hormone responses to hypoglycemia. Global CBF increased considerably in response to intravenous lactate infusion but did not further increase during hypoglycemia. Lactate also blunted the hypoglycemia-induced regional redistribution of CBF towards the thalamus.ConclusionsElevated lactate levels enhance global CBF and blunt the thalamic CBF response during hypoglycemia in patients with type 1 diabetes, mimicking observations of impaired awareness of hypoglycemia. These findings suggest that alteration of CBF associated with lactate may play a role in some aspects of the development of impaired awareness of hypoglycemia.Trial registration numberNCT03730909.

Physical exercise has many health benefits, equally so for people with diabetes mellitus. The glycaemic responses to the various types of exercise differ and include an increased risk of late (nocturnal) hypoglycaemia, making physical exercise a challenge for some people with diabetes who are treated with insulin. Insulin treatment interferes with normal physiologic responses to exercise, which are necessary to maintain the blood glucose level within the normal range. During aerobic exercise, the blood glucose concentration usually drops, whereas anaerobic exercise generally causes a rise in glycaemia in people with diabetes using insulin. In people with insulin treated diabetes, a combination of frequent (continuous) blood glucose monitoring, adjustments in insulin dose and ingestion of carbohydrates ensures a safe management of glycaemia during and after physical activity.

Contains fulltext : 286897.pdf (Publisher’s version ) (Closed access) 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.

Contains fulltext : 286827.pdf (Publisher’s version ) (Open Access) AIM: To conduct a systematic review of published studies reporting on the longitudinal impacts of hypoglycaemia on quality of life (QoL) in adults with type 2 diabetes. METHOD: Database searches with no restrictions by language or date were conducted in MEDLINE, Cochrane Library, CINAHL and PsycINFO. Studies were included for review if they used a longitudinal design (e.g. cohort studies, randomised controlled trials) and reported on the association between hypoglycaemia and changes over time in patient-reported outcomes related to QoL. RESULTS: In all, 20 longitudinal studies published between 1998 and 2020, representing 50,429 adults with type 2 diabetes, were selected for review. A descriptive synthesis following Synthesis Without Meta-analysis guidelines indicated that self-treated symptomatic hypoglycaemia was followed by impairments in daily functioning along with elevated symptoms of generalised anxiety, diabetes distress and fear of hypoglycaemia. Severe hypoglycaemic events were associated with reduced confidence in diabetes self-management and lower ratings of perceived health over time. Frequent hypoglycaemia was followed by reduced energy levels and diminished emotional well-being. There was insufficient evidence, however, to conclude that hypoglycaemia impacted sleep quality, depressive symptoms, general mood, social support or overall diabetes-specific QoL. CONCLUSIONS: Longitudinal evidence in this review suggests hypoglycaemia is a common occurrence among adults with type 2 diabetes that impacts key facets in the physical and psychological domains of QoL. Nonetheless, additional longitudinal research is needed-in particular, studies targeting diverse forms of hypoglycaemia, more varied facets of QoL and outcomes assessed using hypoglycaemia-specific measures.

Contains fulltext : 286868.pdf (Publisher’s version ) (Open Access) OBJECTIVE: Hypoglycaemic episodes and fear of hypoglycaemia can be burdensome for adults with type 1 diabetes. This study explored support needs relating to hypoglycaemia among adults with type 1 diabetes living in Denmark, Germany, the Netherlands and the United Kingdom. RESEARCH DESIGN AND METHODS: Respondents participated in a web-based qualitative study involving four open-ended questions that asked what they wished other people understood about hypoglycaemia and what other people could do differently to support them with hypoglycaemia. Responses were analyzed using reflexive thematic analysis. RESULTS: Participants were 219 adults with type 1 diabetes (mean ± SD age 39 ± 13 years; mean ± SD diabetes duration 20 ± 14 years). They described unmet needs relating to: (1) Clinical support, involving access to new diabetes technologies, training on hypoglycaemia prevention, personalised care and psychological support; (2) Practical support, involving family and friends better supporting them with hypoglycaemia management and prevention; (3) Education for other people, involving others becoming more informed about hypoglycaemia; and (4) An appreciation of the burden, involving others recognizing the experience and impact of episodes, and the burden of living with the risk of hypoglycaemia. CONCLUSIONS: Adults with type 1 diabetes report several unmet support needs relating to hypoglycaemia. Service delivery should be person-centred and prioritise the individual's support needs. Clinical conversations are needed to identify the individual's support needs and develop tailored support plans. People with diabetes and their family members should be offered hypoglycaemia-specific education and training.

IntroductionAchieving glycemic targets and optimizing quality of life (QoL) are important goals of type 1 diabetes care. Hypoglycemia is a common barrier to achieving targets and can be associated with significant distress. However, the impact of hypoglycemia on QoL is not fully understood. The aim of this study was to explore how adults with type 1 diabetes are impacted by hypoglycemia in areas of life that are important to their overall QoL.Research design and methodsParticipants responded to a web-based qualitative survey involving a novel ‘Wheel of Life’ activity. Responses were analyzed using reflexive thematic analysis.ResultsThe final sample included 219 adults with type 1 diabetes from Denmark, Germany, the Netherlands, and the UK. They had a mean±SD age of 39±13 years and diabetes duration of 20±14 years. Participants identified eight areas of life important to their overall QoL, including relationships and social life, work and studies, leisure and physical activity, everyday life, sleep, sex life, physical health, and mental health. Participants reported emotional, behavioral, cognitive, and social impacts of hypoglycemia within domains. Across domains, participants described interruptions, limited participation in activities, exhaustion, fear of hypoglycemia, compensatory strategies to prevent hypoglycemia, and reduced spontaneity.ConclusionsThe findings emphasize the profound impact of hypoglycemia on QoL and diabetes self-care behaviors. Diabetes services should be aware of and address the burden of hypoglycemia to provide person-centered care. Clinicians could ask individuals how hypoglycemia affects important areas of their lives to better understand the personal impact and develop tailored management plans.

Background: Insulin-induced hypoglycemia, the most common adverse event in people with diabetes treated with insulin, is associated with increased risk of cardiovascular events. The effect of hypoglycemia on cardiac function has not yet been fully clarified. Our aim was to investigate the effect of hypoglycemia on left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS) in people with type 1 diabetes (T1DM) and in healthy controls (HC). Methods: We enrolled 15 adults with T1DM (M/F 9/6, age 47±19 years, HbA1c 7.9±2.9%, diabetes duration 22.5±12.6 years) and 14 HCs (M/F 7/7, age 39±17 years). All participants underwent a hyperinsulinemic normoglycemic (5.3±0.4 mmol/L, 30 min) hypoglycemic (2.8±0.5 mmol/L, 60 min) glucose clamp. At baseline and approximately 30 min into the hypoglycemic phase (steady-state), a cardiac ultrasound was performed (by the same person), for later analysis. Results: All participants had sinus rhythm at baseline and none developed arrhythmias during hypoglycemia. We found no difference between T1DM and HC for LVEF measured at baseline. In response to hypoglycemia, LVEF increased from 58.1±2.6% at baseline to 63.7±4.0% in the T1DM group (p Conclusion: An event of hypoglycemia increases the LVEF significantly in people with diabetes. Presumably due to the catecholamines chronotropic, inotropic and peripheral contracting effect. The result of this would be increased cardiac output, increased oxygen consumption and metabolism and thereby increased load on the heart. This may contribute to explain the link between hypoglycemia and cardiovascular disease. Disclosure T. W. Fabricius: None. C. E. Verhulst: None. M. Wienberg: None. A. L. Duijnhouwer: None. P. L. Kristensen: Speaker’s Bureau; Self; AstraZeneca, Eli Lilly and Company. B. E. De galan: Research Support; Self; Novo Nordisk. U. Pedersen-bjergaard: Advisory Panel; Self; Novo Nordisk A/S, Sanofi-Aventis, Consultant; Self; Abbott, Speaker’s Bureau; Self; Novo Nordisk A/S. Funding Innovative Medicines Initiative 2 Joint Undertaking (777460); European Union Horizon 2020 Research and Innovation Program; European Federation of Pharmaceutical Industries and Associations; T1D Exchange; JDRF; International Diabetes Federation; The Leona M. and Harry B. Helmsley Charitable Trust

Contains fulltext : 237990.pdf (Publisher’s version ) (Open Access) AIM: Impaired awareness of hypoglycaemia (IAH) affects about 25% of patients with type 1 diabetes (T1DM). IAH can be reversed by strict avoidance of hypoglycaemia for at least 3 weeks. Adjunctive treatment with sodium glucose cotransporter 2 inhibitors may reduce the risk of hypoglycaemia through reduction of glucose variability. We tested the hypothesis that short-term use of dapagliflozin may improve awareness of hypoglycaemia in people with T1DM and IAH. MATERIALS AND METHODS: Fifteen patients with T1DM and IAH were included in this randomized double-blind, placebo-controlled cross-over trial (age 49.7 ± 14.6 years, 40% men, disease duration 24.1 ± 14.2 years, glycated haemoglobin 7.5 ± 0.8% (58.6 ± 8.4 mmol/mol). They were treated with dapagliflozin 10 mg once daily or matching placebo, with a washout period of 2 weeks. At the end of each treatment period, participants underwent a modified hyperinsulinaemic normoglycaemic-hypoglycaemic glucose clamp (glucose nadir 2.5 mmol/L). Blinded continuous glucose monitors were used in the final treatment weeks. RESULTS: Treatment with dapagliflozin significantly improved glycated haemoglobin [-0.32 ± 0.10 vs. 0.22 ± 0.13% (-4.1 ± 0.9 vs. 2.3 ± 1.4 mmol/mol), dapagliflozin vs. placebo, p = .007] and glucose variability (standard deviation, 2.6 ± 0.2 vs. 3.1 ± 0.3 mmol/L, p = .029), but did not affect the frequency of hypoglycaemia. During the hypoglycaemic clamp, dapagliflozin did not affect symptom responses (8.0 ± 3.4 vs. 5.2 ± 1.6, p = .31), but significantly reduced the need for exogenous glucose to maintain hypoglycaemia (3.2 ± 0.3 vs. 4.1 ± 0.4 mg/kg/min, p = .022). CONCLUSIONS: Eight weeks of treatment with dapagliflozin did not restore hypoglycaemic awareness in people with T1DM and impaired awareness of hypoglycaemia, but ameliorated some clinical aspects.

Item does not contain fulltext AIM: To summarize and critically appraise the recent qualitative evidence regarding the impact of hypoglycaemia on the quality of life of family members of adults with type 1 or type 2 diabetes. METHODS: Four databases were searched systematically (MEDLINE, PsycINFO, CINAHL and Cochrane Library), and results were screened for eligibility. Article quality was assessed using the Joanna Briggs Institute Critical Appraisal Checklist for Qualitative Research. Data were extracted, coded and analysed using thematic analysis. The systematic review was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and Enhancing transparency in reporting of qualitative research (ENTREQ) guidelines. RESULTS: Eight qualitative studies were included in the final review. The majority of participants were partners or spouses of adults with type 1 diabetes. Thematic synthesis resulted in six analytical themes: 'Hypoglycaemia alters everyday life, reducing freedoms and increasing disruptions', 'Hypoglycaemia has an adverse impact on sleep', 'Hypoglycaemia negatively changes the relationship with the person with diabetes', 'Hypoglycaemia negatively impacts emotional well-being', 'The detection, prevention, and treatment of hypoglycaemia consumes time and energy' and 'Family members have unmet needs for informational and emotional support regarding hypoglycaemia'. Across the six analytical themes, family members described how hypoglycaemia has a severe negative impact on different aspects of their lives, including daily living, personal relationships and emotional well-being. CONCLUSIONS: Family members experience the impact of hypoglycaemia as a major recurrent challenge in their lives. The unmet needs of family members need further attention in research and clinical practice.

Aims/hypothesis The hyperinsulinaemic–hypoglycaemic glucose clamp technique has been developed and applied to assess effects of and responses to hypoglycaemia under standardised conditions. However, the degree to which the methodology of clamp studies is standardised is unclear. This systematic review examines how hyperinsulinaemic–hypoglycaemic clamps have been performed and elucidates potential important differences. Methods A literature search in PubMed and EMBASE was conducted. Articles in English published between 1980 and 2018, involving adults with or without diabetes, were included. Results A total of 383 articles were included. There was considerable variation in essential methodology of the hypoglycaemic clamp procedures, including the insulin dose used (49-fold difference between the lowest and the highest rate), the number of hypoglycaemic steps (range 1−6), the hypoglycaemic nadirs (range 2.0–4.3 mmol/l) and the duration (ranging from 5 to 660 min). Twenty-seven per cent of the articles reported whole blood glucose levels, most venous levels. In 70.8% of the studies, a dorsal hand vein was used for blood sampling, with some form of hand warming to arterialise venous blood in 78.8% of these. Key information was missing in 61.9% of the articles. Conclusions/interpretation Although the hyperinsulinaemic–hypoglycaemic clamp procedure is considered the gold standard to study experimental hypoglycaemia, a uniform standard with key elements on how to perform these experiments is lacking. Methodological differences should be considered when comparing results between hypoglycaemic clamp studies. PROSPERO registration This systematic review is registered in PROSPERO (CRD42019120083). Graphical abstract

Contains fulltext : 235355.pdf (Publisher’s version ) (Closed access) Hypoglycaemia is a common barrier to optimal glycaemic management and often feared among adults with type 1 diabetes. The aim of this systematic review was to summarize current evidence regarding the impact of hypoglycaemia on quality of life (QoL) and related outcomes. Electronic searches of MEDLINE, PsycINFO, CINAHL, Cochrane Database of Systematic Reviews, and Cochrane Central Register of Controlled Trials were conducted. Peer-reviewed empirical studies investigating the relationship between hypoglycaemia and QoL were eligible for inclusion. Thirty studies met the inclusion criteria. Extracted data was summarized in a narrative synthesis according to Synthesis Without Meta-Analysis guidelines. None of the studies examined the impact of hypoglycaemia on general QoL. There was no association between hypoglycaemia and diabetes-specific QoL in four of the 30 studies. Severe hypoglycaemia was associated with greater fear of hypoglycaemia and diabetes distress, and lower general emotional well-being, but not with depression, anxiety, or health status. Self-treated hypoglycaemia was associated with greater fear of hypoglycaemia. With the exception of fear of hypoglycaemia, this review shows mixed associations between hypoglycaemia and psychological outcomes. Further research is needed to investigate the impact of hypoglycaemia on other domains of QoL.

Background: Inhibition of the Na+/glucose co-transporter 2 is a new therapeutic strategy for diabetes. It is unclear how proximal loss of Na+ (and glucose) affects the subsequent Na+ transporters in the proximal tubule (PT), thick ascending limb of loop of Henle (TAL), distal convoluted tubule (DCT) and collecting duct (CD). Methods: Mice on a high fat diet were administered 3 doses streptozotocin 6 days prior to oral dapagliflozin administration or vehicle for 18 days. A control group of lean mice were also included. Body weight and glucose were recorded at regular intervals during treatment. Renal Na+ transporters expression in nephron segments were analyzed by RT-qPCR and Western blot. Results: Dapagliflozin treatment resulted in a significant reduction in body weight and blood glucose compared to vehicle-treated controls. mRNA results showed that Na+-hydrogen antiporter 3 (NHE3), Na+/phosphate cotransporter (NaPi-2a) and epithelial Na+ channel expression was increased, Ncx1, ENaCβ and ENaCγ expression declined (p all < 0.05), respectively, in dapagliflozin-treated mice when compared with saline vehicle mice. Na-K-2Cl cotransporters and Na-Cl cotransporter mRNA expression was not affected by dapagliflozin treatment. Na+/K+-ATPase (Atp1b1) expression was also increased significantly by dapagliflozin treatment, but it did not affect Atp1a1 and glucose transporter 2 expression. Western blot analysis showed that NaPi-2a, NHE3 and ATP1b1 expression was upregulated in dapagliflozin-treated diabetic mice when compared with saline vehicle mice (p < 0.05). Conclusion: Our findings suggest that dapagliflozin treatment augments compensatory changes in the renal PT in diabetic mice.

Aim To investigate whether a history of severe hypoglycaemia (SH) or the associated presence of impaired awareness of hypoglycaemia (IAH) is characterized by a pro‐inflammatory profile in people with type 1 diabetes. Research design and methods We measured circulating inflammatory markers and pro‐ and anti‐inflammatory cytokine production after ex vivo stimulation of peripheral blood mononuclear cells (PBMCs) in a well‐characterized cohort of individuals with type 1 diabetes (n = 239) and in people without diabetes (n = 56). Data were corrected for confounders by using multivariate linear regression models. Results People with type 1 diabetes had higher circulating concentrations of high‐sensitivity C‐reactive protein (hs‐CRP; 0.91 [0.36–2.25] vs. 0.52 [0.20–0.98] pg/mL, P < 0.001 and interleukin‐18‐binding protein (IL‐18BP; 1746 [1304–2112] vs. 1381 [1191–1807] pg/mL; P = 0.001) than those without diabetes. In multivariate analysis, only higher hs‐CRP concentrations persisted. Neither circulating immune cells nor ex vivo cytokine levels produced by PBMCs in response to an extensive panel of stimuli differed in groups defined by awareness state or a history of SH, apart from elevated IL‐18BP in people with, versus those without, history of SH (1524 [1227–1903] vs. 1913 [1459–2408] pg/mL; P < 0.001). Conclusions IAH or history of SH in people with type 1 diabetes was not associated with altered inflammatory profiles, arguing against chronically elevated inflammatory activity mediating the increased cardiovascular risk associated with hypoglycaemia. The finding of higher circulating concentrations of IL‐18BP in individuals with a history of SH requires further investigation.

BACKGROUND Checkpoint inhibitors are relatively new anti-cancer medicines that activate tumour cell immunity. CASE DESCRIPTION We describe two patients who presented to the emergency department due to severe ketoacidosis, this being the first symptom of diabetes in said patients. A few weeks prior to this, they each commenced treatment with the checkpoint inhibitor pembrolizumab. HbA1c level, assessed in one of the patients, was not elevated upon presentation. CONCLUSION Type 1 diabetes mellitus is a rare, but potentially life-threatening, complication of treatment with checkpoint inhibitors. However, routine measurement of glucose or HbA1c levels is not useful in patients who are treated with checkpoint inhibitors. Both patients and healthcare professionals should be (made) aware of the symptoms of hyperglycaemia, thereby ensuring immediate treatment with insulin in order to prevent severe ketoacidosis.