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Type 1 diabetes is characterized by insulin deficiency, and treatment is to supply insulin mimicking the physiological endogenous insulin secretion. Since its discovery, insulin therapy has evolved, and since the 1990s, an increasing number of insulin analogs with various pharmacokinetic and pharmacodynamic profiles have become available. Despite the improvement of insulin therapy, hypoglycemia remains the main side effect and is a daily concern for many people with diabetes and their families. A proportion of people with type 1 diabetes are at increased risk of hypoglycemia and experience recurring episodes. When designing insulin trials, this group of people is most often excluded in order to reduce the risk of adverse study outcomes, even though it may be the group that may benefit the most from treatment with new insulins. The results of the phase III trials, therefore, underestimate the clinical impact and pharmacoeconomic effect of the implementation of new insulins in the broader type 1 diabetes population. This paper reviews the four insulin trials that include people at increased risk of hypoglycemia. In general, the studies confirm the results from phase III trials in terms of similar reduction and maintenance of HbA1c, as well as relative rate reductions of hypoglycemia. However, the absolute treatment differences in the reduction of hypoglycemia are even greater in the trials, including people at high risk of hypoglycemia. This emphasizes the importance of including people at high risk of hypoglycemia to assess the full clinical and pharmacoeconomic benefit of new insulins., Competing Interests: PLK has received speakers fee from Sanofi-Aventis A/S, Boeringer Ingelheim A/S, Novo Nordisk A/S, and AstraZeneca A/S. UPB has served on advisory boards for Sanofi-Aventis A/S, Novo Nordisk A/S and Vertex A/S, and has received lecture fees from Abbott A/S, Sanofi-Aventis A/S and Novo Nordisk A/S. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Broeng-Mikkelgaard, Brøsen, Kristensen, Thorsteinsson and Pedersen-Bjergaard.)

Aim: Comparing continuous glucose monitoring (CGM)-recorded metrics during treatment with insulin degludec (IDeg) versus insulin glargine U100 (IGlar-100) in people with type 1 diabetes (T1D) and recurrent nocturnal severe hypoglycemia., Materials and Methods: This is a multicenter, two-year, randomized, crossover trial, including 149 adults with T1D and minimum one episode of nocturnal severe hypoglycemia within the last two years. Participants were randomized 1:1 to treatment with IDeg or IGlar-100 and given the option of six days of blinded CGM twice during each treatment. CGM traces were reviewed for the percentage of time-within-target glucose range (TIR), time-below-range (TBR), time-above-range (TAR), and coefficient of variation (CV)., Results: Seventy-four participants were included in the analysis. Differences between treatments were greatest during the night (23:00-06:59). Treatment with IGlar-100 resulted in 54.0% vs 49.0% with IDeg TIR (70-180 mg/dL) (estimated treatment difference [ETD]: -4.6%, 95% confidence interval [CI]: -9.1, -0.0, P = .049). TBR was lower with IDeg at level 1 (54-69 mg/dL) (ETD: -1.7% [95% CI: -2.9, -0.5], P < .05) and level 2 (<54 mg/dL) (ETD: -1.3% [95% CI: -2.1, -0.5], P = .001). TAR was higher with IDeg compared with IGlar-100 at level 1 (181-250 mg/dL) (ETD: 4.0% [95% CI: 0.8, 7.3], P < .05) and level 2 (> 250 mg/dL) (ETD: 4.0% [95% CI: 0.8, 7.2], P < .05). The mean CV was lower with IDeg than that with IGlar-100 (ETD: -3.4% [95% CI: -5.6, -1.2], P < .05)., Conclusion: For people with T1D suffering from recurrent nocturnal severe hypoglycemia, treatment with IDeg, compared with IGlar-100, results in a lower TBR and CV during the night at the expense of more TAR., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: J.M.B.B., H.B.-N., T.K.H., C.H., T.J.J., C.R.S., S.S.L., H.-H.P., L.T., and B.T. have no competing financial interests. U.P.-B. has served on advisory boards for Novo Nordisk and Sanofi and has received lecture fees from Abbott, Sanofi, and Novo Nordisk. A.C.A. and R.M.A. have been employed by Novo Nordisk A/S since September 2019 (after the finalization of the study). H.U.A. is on advisory boards for Abbott Laboratories, Astra Zeneca, and Novo Nordisk; has received lecture fees from Nordic Infucare; and owns stock in Novo Nordisk. P.G. has served on advisory boards for Abbott Laboratories, Astra Zeneca, Boehringer Ingelheim, Novo Nordisk, and Sanofi. C.B.J. serves on advisory boards for Novo Nordisk. K.N. serves as an advisor to Abbott Laboratories, Medtronic, and Novo Nordisk; has received fees for speaking from Bayer, Medtronic, Novo Nordisk, Roche Diabetes Care, Rubin Medical, Sanofi, and Zealand Pharma; and owns stock in Novo Nordisk.

Aim: To compare nocturnal glucose profiles according to hourly plasma glucose measurements during treatment with insulin degludec and insulin glargine U100 in a cohort of people with type 1 diabetes prone to nocturnal severe hypoglycaemia., Materials and Methods: The HypoDeg trial is a 2-year investigator-initiated, randomized, controlled crossover trial in 149 participants randomized to treatment with insulin degludec and insulin glargine U100 for 12 months each. The 51 participants in this predefined substudy stayed at least one night in hospital during each treatment arm for plasma glucose samples to be taken. Endpoints were glucose profiles, including mean plasma glucose, glycaemic variability and risk of hypoglycaemia., Results: There were no differences between treatments regarding mean plasma glucose. We saw a flatter glucose profile during insulin degludec compared with insulin glargine U100 treatment, which had a nadir at 4:00 AM, with a subsequent rise. During treatment with insulin degludec, the participants had lower glycaemic variability, with an estimated treatment difference of -4.3% (95% confidence interval [CI] -8.1 to -0.5; P < 0.05). Participants treated with insulin degludec were less likely to experience nocturnal hypoglycaemia below 3.0 mmol/L (hazard ratio 0.36 [95% CI 0.17-0.73; P < 0.05])., Conclusion: Based on nocturnal plasma glucose measurements, treatment with insulin degludec compared with insulin glargine U100 administered in the evening results in lower glycaemic variability and lower risk of nocturnal hypoglycaemia without differences in mean plasma glucose., (© 2023 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

The β2-receptor mediates the metabolic response to epinephrine. This study investigates the impact of the β2-receptor gene (ADRB2) polymorphism Gly16Arg on the metabolic response to epinephrine before and after repetitive hypoglycemia. Twenty-five healthy men selected according to ADRB2 genotype being homozygous for either Gly16 (GG) (n = 12) or Arg16 (AA) (n = 13) participated in 4 trial days (D1-4): D1pre and D4post with epinephrine 0.06 μg kg-1 ⋅ min-1 infusion and D2hypo1-2 and D3hypo3 with three periods of hypoglycemia by an insulin-glucose clamp. At D1pre, the insulin (mean ± SEM of area under the curve 44 ± 8 vs. 93 ± 13 pmol ⋅ L-1 h; P = 0.0051), glycerol (79 ± 12 vs. 115 ± 14 μmol ⋅ L-1 h; P = 0.041), and free fatty acid (724 ± 96 vs. 1,113 ± 140 μmol ⋅ L-1 h; P = 0.033) responses to epinephrine were decreased in AA participants compared with GG participants but without a difference in glucose response. There were no differences in response to epinephrine between genotype groups after repetitive hypoglycemia at D4post. The metabolic substrate response to epinephrine was decreased in AA participants compared with GG participants but without a difference between genotype groups after repetitive hypoglycemia., Article Highlights: This study investigates the impact of the β2-receptor gene (ADRB2) polymorphism Gly16Arg on the metabolic response to epinephrine before and after repetitive hypoglycemia. Healthy men homozygous for either Gly16 (n = 12) or Arg16 (n = 13) participated in the study. Healthy people with the Gly16 genotype have increased metabolic response to epinephrine compared with the Arg16 genotype but without a difference between genotypes after repetitive hypoglycemia., (© 2023 by the American Diabetes Association.)

Background and Aims: Nocturnal hypoglycemia is mainly a consequence of inappropriate basal insulin therapy in type 1 diabetes (T1D) and may compromise optimal glycemic control. Insulin degludec is associated with a lower risk of nocturnal hypoglycemia in T1D. As nocturnal hypoglycemia is often asymptomatic, we applied continuous glucose monitoring (CGM) to detect a more precise occurrence of nocturnal hypoglycemia in the HypoDeg trial, comparing insulin degludec with insulin glargine U100 in people with T1D and previous nocturnal severe hypoglycemia. Materials and Methods: In the HypoDeg trial, 149 people with T1D were included in an open-label randomized cross-over trial. Sixty-seven participants accepted optional participation in the predefined substudy of 4 × 6 days of blinded CGM requiring completion of at least one CGM period in each treatment arm. CGM data were reviewed for hypoglycemic events. Results: Treatment with insulin degludec resulted in a relative rate reduction (RRR) of 36% (95% confidence interval [CI]: 10%-54%; P  < 0.05) in nocturnal CGM-recorded hypoglycemia (≤3.9 mmol/L), corresponding to an absolute rate reduction (ARR) of 0.85 events per person-week. In nocturnal CGM-recorded hypoglycemia (≤3.0 mmol/L), we found an RRR of 53% (95% CI: 36%-65%; P  < 0.001), corresponding to an ARR of 0.75 events per person-week. At the lower detection limit of the CGM (≤2.2 mmol/L), treatment with insulin degludec resulted in a significant RRR of 58% (95% CI: 23%-77%; P  = 0.005). The reductions were primarily due to significant RRRs in asymptomatic hypoglycemia. Conclusion: In people with T1D, prone to nocturnal severe hypoglycemia, insulin degludec compared with insulin glargine U100 significantly reduces nocturnal CGM-recorded hypoglycemia. www.clinicaltrials.gov (#NCT02192450).

Introduction: Loss of awareness of hypoglycaemia is the major risk factor for severe hypoglycaemia in type 1 diabetes. Three methods for assessment of self-reported awareness have been validated and used more widely: the Gold, the Clarke and the Pedersen-Bjergaard classification. Comparisons between the methods are hampered by the latter operating with three classes, whereas the other methods are bimodal. We have therefore updated the Pedersen-Bjergaard classification and here present a comparison of the three methods., Methods: Adult people with type 1 diabetes (n = 325) completed a validated questionnaire. Hypoglycaemia awareness was self-reported by the three methods: Gold, Clarke and Pedersen-Bjergaard scores. The latter was updated by renaming the previous "impaired" class to "intermediate"., Results: A total of 24%, 17% and 14% of patients were classified as having loss of awareness by the Gold, Clarke and updated Pedersen-Bjergaard methods, respectively, with reasonably good agreement and all with increased rates of severe hypoglycaemia. The latter classified 43% with normal and 43% with intermediate awareness and low and average rate of severe hypoglycaemia, respectively., Conclusion: The three classifications identified people with loss of awareness with a reasonably high degree of concordance. In contrast to the others, the updated Pedersen-Bjergaard method identified groups with normal and intermediate awareness with clinically significant different risks of severe hypoglycaemia., Funding: The Research Foundation of Nordsjællands Hospital and the Beckett Foundation., Trial Registration: not relevant., (Articles published in the DMJ are “open access”. This means that the articles are distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits any non-commercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.)

Context: The Arg16 variant in the β2-receptor gene is associated with increased risk of severe hypoglycemia in subjects with type 1 diabetes mellitus., Objective: We hypothesized that the Arg16 variant is associated with decreased metabolic and symptomatic responses to recurrent hypoglycemia., Methods: Twenty-five healthy male subjects selected according to ADRB2 genotype and being homozygous for either Arg16 (AA; n = 13) or Gly16 (GG; n = 12) participated in 2 consecutive trial days with 3 periods of hypoglycemia (H1-H3) induced by a hyperinsulinemic hypoglycemic clamp. The main outcome measure was mean glucose infusion rate (GIR) during H1-H3., Results: During H1-H3, there was no difference between AA or GG subjects in GIR, counter-regulatory hormones (glucagon, epinephrine, cortisol, growth hormone), or substrate levels of lactate, glycerol, and free fatty acids (FFAs), and no differences in symptom response score or cognitive performance (trail making test, Stroop test). At H3, lactate response was reduced in both genotype groups, but AA subjects had decreased response (mean ± standard error of the mean of area under the curve) of glycerol (-13.1 ± 3.8 μmol L-1 hours; P = .0052), FFA (-30.2 ± 11.1 μmol L-1 hours; P = .021), and β-hydroxybutyrate (-0.008 ± 0.003 mmol L-1 hour; P = .027), while in GG subjects alanine response was increased (negative response values) (-53.9 ± 20.6 μmol L-1 hour; P = .024)., Conclusion: There was no difference in GIR between genotype groups, but secondary outcomes suggest a downregulation of the lipolytic and β-hydroxybutyrate responses to recurrent hypoglycemia in AA subjects, in contrast to the responses in GG subjects., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Aim: Continuous glucose monitoring (CGM) is widely used in clinical practice and research to detect hypoglycemia. A consensus definition of CGM-recorded hypoglycemia is made by a group of international experts under the auspice of the Advanced Technologies and Treatments for Diabetes (ATTD). The purpose of this study is to compare the definition with patient-reported hypoglycemia. Methods: In a prospective, observational study of 186 patients with type 1 diabetes using blinded Medtronic iPro 2 CGM for 6 days, every patient-reported symptomatic hypoglycemic event and interstitial glucose (IG) values at the registration time were classified according to the ATTD definition of CGM-recorded hypoglycemia. For comparison between CGM and self-monitored blood glucose (SMBG) values, the International Hypoglycemia Study Group (IHSG) classification of hypoglycemia and chi-square test were used. Results: A total of 321 events of symptomatic hypoglycemia were reported by 68% of the patients, corresponding to 2.0 ± 2.3 events (mean ± standard deviation) per patient-week. A total of 206 (64%) events met the CGM consensus definition. In the remaining 115 (36%) not-confirmed events, 5 events had an IG <3.9 mmol/L, which lasted <15 min. The overall mean IG value was 3.6 ± 1.1 mmol/L (median 3.1, range 2.2-10.4). In symptomatic hypoglycemic events with both CGM and SMBG data, SMBG confirmed significantly more symptomatic hypoglycemic events than CGM ( P  < 0.001). Conclusion: CGM-recorded hypoglycemia according to the consensus definition is present at two thirds of all patient-reported events when recorded by the Medtronic iPro 2 system. The recommended minimum duration of a hypoglycemic event of 15 min is supported by the study. SMBG measurements detect significantly more symptomatic hypoglycemic events than Medtronic iPro 2 CGM.

Aim: To investigate whether the long-acting insulin analogue insulin degludec compared with insulin glargine U100 reduces the risk of nocturnal symptomatic hypoglycaemia in patients with type 1 diabetes (T1D)., Methods: Adults with T1D and at least one episode of nocturnal severe hypoglycaemia during the last 2 years were included in a 2-year prospective, randomized, open, multicentre, crossover trial. A total of 149 patients were randomized 1:1 to basal-bolus therapy with insulin degludec and insulin aspart or insulin glargine U100 and insulin aspart. Each treatment period lasted 1 year and consisted of 3 months of run-in or crossover followed by 9 months of maintenance. The primary endpoint was the number of blindly adjudicated nocturnal symptomatic hypoglycaemic episodes. Secondary endpoints included the occurrence of severe hypoglycaemia. We analysed all endpoints by intention-to-treat., Results: Treatment with insulin degludec resulted in a 28% (95% CI: 9%-43%; P = .02) relative rate reduction (RRR) of nocturnal symptomatic hypoglycaemia at level 1 (≤3.9 mmol/L), a 37% (95% CI: 16%-53%; P = .002) RRR at level 2 (≤3.0 mmol/L), and a 35% (95% CI: 1%-58%; P = .04) RRR in all-day severe hypoglycaemia compared with insulin glargine U100., Conclusions: Patients with T1D prone to nocturnal severe hypoglycaemia have lower rates of nocturnal symptomatic hypoglycaemia and all-day severe hypoglycaemia with insulin degludec compared with insulin glargine U100., (© 2021 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Formation of reactive oxygen species has been linked to the development of diabetes complications. Treatment with metformin has been associated with a lower risk of developing diabetes complications, including when used in combination with insulin. Metformin inhibits Complex 1 in isolated mitochondria and thereby decreases the formation of reactive oxygen species. Thus, we post-hoc investigated the effect of metformin in combination with different insulin regimens on RNA and DNA oxidation in individuals with type 2 diabetes. Four hundred and fifteen individuals with type 2 diabetes were randomized (1:1) to blinded treatment with metformin (1,000 mg twice daily) versus placebo and to (1:1:1) open-label biphasic insulin, basal-bolus insulin, or basal insulin therapy in a 2 × 3 factorial design. RNA and DNA oxidation were determined at baseline and after 18 months measured as urinary excretions of 8-oxo-7,8-dihydroguanosine (8-oxoGuo) and 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), respectively. Urinary excretion of 8-oxoGuo changed by +7.1% (95% CI: 0.5% to 14.0%, P = 0.03) following metformin versus placebo, whereas changes in 8-oxodG were comparable between intervention groups. Biphasic insulin decreased urinary excretion of 8-oxoGuo (within-group: -9.6% (95% CI: -14.4% to -4.4%)) more than basal-bolus insulin (within-group: 5.2% (95% CI: -0.5% to 11.2%)), P = 0.0002 between groups, and basal insulin (within-group: 3.7% (95% CI: -2.0% to 9.7%)), P = 0.0007 between groups. Urinary excretion of 8-oxodG decreased more in the biphasic insulin group (within-group: -9.9% (95% CI: -14.4% to -5.2%)) than basal-bolus insulin (within group effect: -1.2% (95% CI: -6.1% to 3.9%)), P = 0.01 between groups, whereas no difference was observed compared with basal insulin. In conclusion, eighteen months of metformin treatment in addition to different insulin regimens increased RNA oxidation, but not DNA oxidation. Biphasic insulin decreased both RNA and DNA oxidation compared with other insulin regimens., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Introduction: Type 1 diabetes is characterized by insulin deficiency and requires near-physiological insulin replacement. In most patients, this is accomplished by basal bolus therapy consisting of a long-acting basal insulin administered once or twice daily and short-acting insulin with main meals. Several long-acting insulin analogs have been developed to optimize basal insulin therapy., Areas Covered: This paper reviews the design of - and data from - randomized controlled trials (RCTs) to assess glucose lowering efficacy and safety of long-acting insulin analogs for the treatment of type 1 diabetes., Expert Opinion: Due to the non-inferiority treat-to-target design of insulin, RCTs treatment differences primarily appear as differences in hypoglycemia risk. Data suggest that the first generation long-acting insulin analogs insulin glargine U100 and insulin detemir have a similar glucose lowering efficacy compared to NPH insulin but a lower risk of hypoglycemia, particularly during nighttime. The newer analogs insulin glargine U300 and insulin degludec provide non-inferior efficacy, although insulin glargine U300 is less potent unit-to-unit. Insulin degludec reduces hypoglycemia risk compared to insulin glargine U100. Future studies should explore the potential for further improvement of treatment results in type 1 diabetes by a structured approach to personalization of basal insulin therapy.

Objective: Gustatory sweating (GS) is characterized by profuse sweating during or immediately after ingestion of food and is known as a complication of diabetes mellitus (DM). This study aimed to determine the prevalence of GS and to characterize the sweating in a cohort of patients with type 1 and type 2 diabetes mellitus (T1DM and T2DM) as compared with a control group., Methods: In a cross-sectional study, 665 outpatients with T1DM and 505 outpatients with T2DM filled in an 8-point questionnaire about GS. Answers were paired with medical data from the electronic patient records to explore associations with DM complications. The control group consisted of 1158 persons without DM answering the same questionnaire in an online version., Results: In people with T1DM and T2DM, the prevalence of GS was 10% (95% CI 7%-12%) and 13% (95% CI 10%-16%), respectively. In the control group, the prevalence of GS was 5% (95% CI 3%-6%). Most commonly, people sweat on the face and/or head and upper body with a duration of 10-30 min albeit in the control group <10 min. In patients with T1DM, increased HbA1c was associated with GS (OR 1.3 [95% CI 1.05-1.6], p = .016), and in T2DM, younger age (OR 0.95 [95% CI 0.92-0.99), p = .006), presence of severe peripheral neuropathy (OR 2.33 [95% CI 1.04-5.2], p = .039) and absence of proliferative retinopathy were associated with GS (OR 0.22 [95% CI 0.07-0.71], p = .011)., Conclusion: We found the prevalence of gustatory sweating of 11% in a hospital-based cohort of patients with T1DM and T2DM. This was twice as high as in non-diabetic control persons. Associations between GS and known diabetes complications could only be demonstrated in T2DM. Compared with a control group without DM, odds for GS are higher in people with DM and age >45., (© 2021 The Authors. Endocrinology, Diabetes & Metabolism published by John Wiley & Sons Ltd.)