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Impaired beta-cell function is a recognized cornerstone of diabetes pathophysiology. Estimates of insulin secretory capacity are useful to inform clinical practice, helping to classify types of diabetes, complication risk stratification and to guide treatment decisions. Because C-peptide secretion mirrors beta-cell function, it has emerged as a valuable clinical biomarker, mainly in autoimmune diabetes and especially in adult-onset diabetes. Nonetheless, the lack of robust evidence about the clinical utility of C-peptide measurement in type 2 diabetes, where insulin resistance is a major confounder, limits its use in such cases. Furthermore, problems remain in the standardization of the assay for C-peptide, raising concerns about comparability of measurements between different laboratories. To approach the heterogeneity and complexity of diabetes, reliable, simple and inexpensive clinical markers are required that can inform clinicians about probable pathophysiology and disease progression, and so enable personalization of management and therapy. This review summarizes the current evidence base about the potential value of C-peptide in the management of the two most prevalent forms of diabetes (type 2 diabetes and autoimmune diabetes) to address how its measurement may assist daily clinical practice and to highlight current limitations and areas of uncertainties to be covered by future research.

Several risk factors for severe hypoglycaemia (SH) are associated with insulin-treated diabetes. This study explored potential risk factors in adults with insulin-treated type 2 diabetes mellitus (T2DM).In this case-control study, adults with T2DM initiating insulin were identified in the IQVIA PharMetrics® Plus database. The index date was the date of the first SH event (cases). Using incidence-density sampling, controls were selected from those who had been exposed 'at risk' of SH for the same amount of time as each case. After exact-matching on the well-established factors, previously unreported risk factors were evaluated through conditional logistic regression.In 3153 case-control pairs, pregnancy [odds ratios (OR) = 3.20, p = .0003], alcohol abuse (OR = 2.43, p .0001), short-/rapid-acting insulin (OR = 2.22/1.47, p .0001), cancer (OR = 1.87, p .0001), dementia/Alzheimer's disease (OR = 1.73, p = .0175), peripheral vascular disease (OR = 1.59, p .0001), antipsychotics (OR = 1.59; p = .0059), anxiolytics (OR = 1.51, p = .0012), paralysis/hemiplegia/paraplegia (OR = 1.51, p = .0416), hepatitis (OR = 1.50, p = .0303), congestive heart failure (OR = 1.47, p = .0002), adrenergic-corticosteroid combinations (OR = 1.45, p = .0165), β-adrenoceptor agonists (OR = 1.40, p = .0225), opioids (OR = 1.38, p .0001), corticosteroids (OR = 1.35, p = .0159), cardiac arrhythmia (OR = 1.29. p = .0065), smoking (OR = 1.28, p = .005), Charlson Comorbidity Index score 2 (OR = 1.28, p = .0026), 3 (OR = 1.41, p = .0016) or ≥4 (OR = 1.57, p = .0002), liver/gallbladder/pancreatic disease (OR = 1.26, p = .0182) and hypertension (OR = 1.19, p = .0164) were independently associated with SH.Although all people with insulin-treated diabetes are at risk of SH, these results have identified some previously unrecognized risk factors and sub-groups of insulin-treated adults with T2DM at greater risk. Scrutiny of current therapies and comorbidities are advised as well as additional glucose monitoring and education, when identifying and managing SH in vulnerable populations.

Aims To collect and analyse representative data of structural and process quality in the management of diabetic emergencies in Germany in 2020. Methods A standardised questionnaire comprising detailed items concerning clinically relevant parameters on the structural and process quality of out-of-hospital management of diabetic emergencies was sent nationwide to medical directors of emergency medical service districts (EMSDs). Results were compared with those from a similar study conducted in 2001. Results The return rate of the questionnaires represented 126 EMSDs, serving a total population of > 40.1 million. Only 4% of ambulances carried glucagon (6% in 2001). In 2020, blood glucose determination increased significantly to 71% of all emergency interventions and to 29% of suspected cardiac emergencies (24% and 15%, respectively, in 2001). In 100% of EMSDs severe hypoglycaemia (SH) was treated by paramedics by administering intravenous dextrose before the arrival of a doctor compared to 63% in 2001. The potential value of nasal glucagon was acknowledged by 43% of responders. In selected patients, treatment of SH was conducted without hospital admission in 78% of EMDs (60% in 2001). Fifty-three percent of medical directors acknowledged the need for further training in diabetic emergencies (47% in 2001). Cooperation for medical education between emergency teams and a diabetes centre was reported by 14% (41% in 2001). Conclusion Structural and process quality of the management of diabetic emergencies in Germany has improved considerably since 2001. Persisting deficiencies could be improved by providing better medical equipment in ambulances and ongoing education to the entire emergency teams.

OBJECTIVE The risk of hypoglycemia in people with insulin-treated diabetes has debarred them from certain “safety-critical” occupations, including flying commercial aircraft. This report evaluates the effectiveness of a protocol enabling a large cohort of insulin-treated pilots to fly commercially. RESEARCH DESIGN AND METHODS This was an observational study of pilots with insulin-treated diabetes who were granted medical certification to fly commercial and noncommercial aircraft. Clinical details, pre- and in-flight (hourly and 30 min before landing) blood glucose values were correlated against the protocol-specified ranges: green (5–15 mmol/L), amber (low, 4–4.9 mmol/L; high, 15.1–20 mmol/L), and red (low, 20 mmol/L). RESULTS A total of 49 pilots with type 1 (84%) or type 2 (16%) diabetes who had been issued class 1 or class 2 certificates were studied. Median diabetes duration was 10.9 years. Mean HbA1c was 7.2% (55.0 mmol/mol) before certification and 7.2% (55.1 mmol/mol) after certification (P = 0.97). Blood glucose values (n = 38,621) were recorded during 22,078 flying hours. Overall, 97.69% of measurements were within the green range, 1.42% within the low amber range, and 0.75% within the high amber range. Only 0.12% of readings were within the low red range and 0.02% within the high red range. Out-of-range readings declined from 5.7% in 2013 to 1.2% in 2019. No episodes of pilot incapacitation occurred, and glycemic control did not deteriorate. CONCLUSIONS The protocol is practical to implement, and no events compromising safety were reported. This study represents what is, to our knowledge, the most extensive data set from people with insulin-treated diabetes working in a “safety-critical” occupation, which may be relevant when estimating risk in other safety-critical occupations.

Introduction Many commercially available glucagon products for treatment of severe hypoglycaemia require cumbersome reconstitution and potentially intimidating injection during an emergency. Nasal glucagon (NG) is a novel drug-device combination product consisting of a single-use dosing device that delivers glucagon dry powder through nasal administration. The present study assessed whether 3 mg NG was non-inferior to 1 mg intramuscular glucagon (IMG) in adults with type 1 diabetes. Methods This randomised, open-label, two-period, crossover trial was conducted at two clinical sites. Hypoglycaemia (plasma glucose [PG] target of

Throughout history, up to the early part of the 20th century, diabetes has been a devastating disorder, particularly when diagnosed in childhood when it was usually fatal. Consequently, the successful pancreatic extraction of insulin in 1921 was a miraculous, life-changing advance. In this review, the truly transformative effect that insulin has had on the lives of people with type 1 diabetes and on those with type 2 diabetes who are also dependent on insulin is described, from the time of its first successful use to the present day. We have highlighted in turn how each of the many facets of improvements over the last century, from advancements in the properties of insulin and its formulations to the evolution of different methods of delivery, have led to continued improvement in clinical outcomes, through the use of illustrative stories from history and from our own clinical experiences. This review concludes with a brief look at the current challenges and where the next century of technological innovation in insulin therapy may take us.

Some therapies for diabetes increase the risk of hypoglycaemia, in particular all insulins and insulin secretagogues, including the glinides and sulfonylureas. Hypoglycaemia remains a major limiting factor to successful glycaemic management, despite the availability of prevention options such as insulin analogues, continuous glucose monitoring, insulin pumps, and dogs that have been trained to detect hypoglycaemia. Non‐severe (self‐treated) and severe (requiring assistance for recovery) hypoglycaemia rates are higher in people with type 1 diabetes, but those with insulin‐treated type 2 diabetes are also at risk. Education and regular review are essential between people with diabetes and their caregivers and healthcare professionals about symptoms, prevention and treatment. Awareness of the potential dangers of hypoglycaemia is fundamental to the optimal management of diabetes. When therapy is intensified to achieve glycaemic targets, it is important that people at risk of severe hypoglycaemia, and particularly their caregivers, have ready access to effective treatment for hypoglycaemia emergencies. The current and potential formulations of glucagon available for treatment of severe hypoglycaemia are reviewed.

Objective To evaluate the use of two questionnaires assessing awareness of hypoglycemia, in a pediatric type 1 diabetes (T1D) population. Methods Prospective observational study with children (aged 9‐18 years) and parents (for children aged 2‐11 years) answering the Gold and Clarke questionnaires assessing awareness of hypoglycemia. Psychometric properties of the questionnaires were evaluated, and the most appropriate cut‐off score to classify participants as having normal vs impaired awareness of hypoglycemia (IAH) was determined by ability to recognize subsequent hypoglycemia and hypoglycemia severity, documented in a 4‐week blood glucose diary. Questionnaires were readministered at follow‐up assessment approximately 1.5 years later. Results In total, 112 participants (51% male) with median (IQR) age 13.7 (11.1‐15.8) years, T1D duration 4.7 (2.2‐7.8) years, and HbA1c 62 (57‐73) mmol/mol (7.8%) were included. Both questionnaires demonstrated acceptable psychometric properties. Using score ≥3 to classify IAH gave a prevalence of IAH of 41% (Gold) and 22% (Clarke). When classified using the Gold questionnaire, IAH participants had higher incidences of mild asymptomatic hypoglycemia, whereas with the Clarke questionnaire, they had higher incidences of clinically significant and severe hypoglycemia. Subgroup analyses confirmed these associations only in participants aged ≥9 years. Follow‐up was completed in 90% of the participants, and a change of awareness status was observed in 22% to 36%. Conclusions The Gold and Clarke questionnaires may be used to assess awareness of hypoglycemia in pediatric T1D in those ≥9 years of age, but the more detailed Clarke questionnaire has higher specificity and is superior in predicting risk of clinically significant hypoglycemia. © 2019 The Authors. Pediatric Diabetes published by John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

Aim To examine the relationship between baseline fasting C-peptide (FCP) and outcomes in insulin-naive people with type 2 diabetes initiating basal insulin glargine 100 U/mL (Gla-100). Materials and methods Post hoc pooled analysis of nine randomized, treat-to-target trials in patients with type 2 diabetes inadequately controlled on oral antihyperglycaemic drugs initiating once-daily Gla-100. Participants (n = 2165) were stratified at baseline according to FCP (≤0.40, >0.40-1.20, >1.20-2.00, >2.00 nmol/L). Glycaemic control, body weight, insulin dose and hypoglycaemia were determined at 24 weeks. Results At baseline low FCP levels were associated with longer known diabetes duration, lower body mass index and higher fasting plasma glucose (FPG). Following Gla-100 introduction, the mean HbA1c reduction at week 24 was similar in all four FCP groups, albeit fewer people in the lowest FCP group achieved HbA1c 0.40 nmol/L. By contrast, FPG reduction and proportion reaching FPG ≤5.6 mmol/L were greatest in the lowest FCP group, diminishing at higher FCP levels. Gla-100 dose at week 24 was lowest in the ≤0.40 nmol/L FCP group and highest in the >1.20 nmol/L FCP group. Incidence and event rate of overall, nocturnal and severe hypoglycaemia were higher at week 24 in groups with lower FCP levels. In multivariable regression analysis baseline FCP, concomitant sulphonylurea use and endpoint HbA1c were strong predictors of hypoglycaemia. Conclusions FCP levels identified patients with type 2 diabetes experiencing different responses to basal insulin Gla-100. A low FCP identifies a markedly insulin-deficient, insulin-sensitive subgroup/phenotype with an enhanced risk of hypoglycaemia, which requires a low initial basal insulin dose, cautious titration and earlier addition of prandial glucose-lowering therapy.

Aim Hypoglycaemia affects many people with Type 2 diabetes using insulin and other glucose-lowering therapies. This systematic review examined the impact of severe hypoglycaemia (episodes requiring external assistance) on psychological outcomes (e.g. emotional well-being, health status and quality of life) in adults with Type 2 diabetes. Methods MEDLINE Complete, PsycINFO and CINAHL databases were searched for peer-reviewed empirical studies, published in English, reporting the occurrence and severity of hypoglycaemia and its relationship with patient-reported outcomes (PROs) in adults with Type 2 diabetes. Data were extracted from published reports and analysed. Results Of 3756 potentially relevant abstracts, 29 studies met the inclusion criteria. Most reported cross-sectional data and sample sizes varied widely (N = 71 to 17 563). Although definitions of mild and severe hypoglycaemia were largely consistent between studies, additional non-standard categorizations (e.g. moderate, very severe) were apparent and recall periods varied. Overall, severe hypoglycaemia was associated with increased fear of hypoglycaemia and decreased emotional well-being, health status and diabetes-specific quality of life. Effect sizes show that the association with fear of hypoglycaemia was stronger than with general health status. Conclusions Notwithstanding the limitations of the empirical studies, these findings indicate that severe hypoglycaemia in adults with Type 2 diabetes (insulin- and non-insulin-treated) is associated with impaired psychological outcomes. Healthcare professionals should address the psychological impact of severe hypoglycaemia during clinical consultations, to support individuals to minimize exposure to, and the psychological consequences of, severe hypoglycaemia.

Diabetic ketoacidosis (DKA) is a life-threatening metabolic derangement, defined by the presence of severe hyperglycaemia, ketosis and metabolic acidosis. Recently, DKA was redefined to be present when the latter two abnormalities occur without severe hyperglycaemia. Munro and colleagues in Edinburgh described ‘euglycaemic diabetic ketoacidosis’ in 1973 and suggested this new terminology. The same year the critical feature of this subclass of DKA – that is, an increased urinary loss of glucose – was identified by Ireland and Thomson in Glasgow. In the subsequent 40 years (from 1974 to 2014), clinical interest in this condition was limited to a few case reports. The emergence of a new class of antidiabetes medications, the sodium-glucose cotransporter (SGLT) inhibitors, which promote profuse glycosuria, has reawakened interest in euglycaemic DKA, as this is a side effect of these drugs. The earlier perceptive observations of these physicians in Scotland deserve to be recognised for their contribution in identifying and describing euglycaemic DKA and correctly identifying its underlying pathogenesis. Recent international consensus has provided guidance to physicians to aid timely recognition of the condition by testing for ketosis in the appropriate clinical context and to manage it effectively by discontinuing the SGLT inhibitor and provision of insulin, carbohydrate and hydration (the STICH protocol). This may be particularly relevant in view of the recent licensing developments for use of certain members of the SGLT inhibitors in type 1 diabetes.

Hypoglycaemia is a common side‐effect of diabetes therapies, particularly insulin, and imposes a substantial burden on individuals and healthcare systems. Consequently, regulatory approval of newer basal insulin (BI) therapies has relied on demonstration of a balance between achievement of good glycaemic control and less hypoglycaemia. Randomized controlled trials (RCTs) are the gold standard for assessing efficacy and safety, including hypoglycaemia risk, of BIs and are invaluable for obtaining regulatory approval. However, their highly selected patient populations and their conditions lead to results that may not be representative of real‐life situations. Real‐world evidence (RWE) studies are more representative of clinical practice, but they also have limitations. As such, data both from RCTs and RWE studies provide a fuller picture of the hypoglycaemia risk with BI therapies. However, substantial differences exist in the way hypoglycaemia is reported across these studies, which confounds comparisons of hypoglycaemia frequency among different BIs. This problem is ongoing and persists in recent trials of second‐generation BI analogues. Although they provide a lower risk of hypoglycaemia when compared with earlier BIs, they do not eliminate it. This review describes differences in the way hypoglycaemia is reported across RCTs and RWE studies of second‐generation BI analogues and examines potential reasons for these differences. For studies of BIs, there is a need to standardize aspects of design, analysis and methods of reporting to better enable interpretation of the efficacy and safety of such insulins among studies; such aspects include length of follow‐up, glycaemic targets, hypoglycaemia definitions and time intervals for determining nocturnal events.

Nonsevere hypoglycemia in people with diabetes is usually treated with rapid-acting carbohydrate, of which glucose is the most suitable form. A quantity of 15 g is recommended and repeated after 15 min if hypoglycemia persists. This recommendation has not changed for several years despite the introduction of continuous glucose monitoring, newer and more flexible insulin regimens and improved insulin delivery. The present review has examined published studies that have explored how effectively defined amounts of carbohydrate treat nonsevere hypoglycemia in adults with insulin-treated diabetes. For most nonsevere episodes of hypoglycemia, the optimal treatment is 15 to 20 g of oral glucose. However, this dose may not be appropriate with many current insulins and insulin pump therapy, where doses of glucose may have to be individualized, and based on body weight or the type of insulin delivery system. Current guidelines on hypoglycemia treatment for newer glucose-lowering therapies may require re-evaluation.

Publisher Copyright: © 2022 Aims: Newly-defined subgroups of type 2 diabetes mellitus (T2DM) have been reported from real-world cohorts but not in detail from randomised clinical trials (RCTs). Methods: T2DM participants, uncontrolled on different pre-study therapies (n = 12.738; 82 % Caucasian; 44 % with diabetes duration > 10 years) from 14 RCTs, were assigned to new subgroups according to age at onset of diabetes, HbA1c, BMI, and fasting C-peptide using the nearest centroid approach. Subgroup distribution, characteristics and influencing factors were analysed. Results: In both, pooled and single RCTs, “mild-obesity related diabetes” predominated (45 %) with mean BMI of 35 kg/m2. “Severe insulin-resistant diabetes” was found least often (4.6 %) and prevalence of “mild age-related diabetes” (23.9 %) was mainly influenced by age at onset of diabetes and age cut-offs. Subgroup characteristics were widely comparable to those from real-world cohorts, but all subgroups showed higher frequencies of diabetes-related complications which were associated with longer diabetes duration. A high proportion of “severe insulin-deficient diabetes” (25.4 %) was identified with poor pre-study glycaemic control. Conclusions: Classification of RCT participants into newly-defined diabetes subgroups revealed the existence of a heterogeneous population of T2DM. For future RCTs, subgroup-based randomisation of T2DM will better define the target population and relevance of the outcomes by avoiding clinical heterogeneity.

AIM To examine blood glucose measurements recorded as part of the diabetes protocol operated by the UK, Ireland and Austria, which allows commercial airline pilots with insulin-treated diabetes to fly. METHODS An observational study was conducted in pilots with insulin-treated diabetes, granted medical certification to fly commercial or noncommercial aircraft, who recorded pre-flight and hourly in-flight blood glucose measurements. These values were correlated to a traffic light system (green 5.0 to 15.0 mmol/L; amber 4.0 to 4.9 mmol/L and 15.1 to 20.0 mmol/L; and red 20.0 mmol/L) and studied for trends in glucose concentrations, time course within flight and any consequences. Pilot demographics were also analysed. RESULTS Forty-four pilots (90%) recorded one or more blood glucose value outside the green range during the 7 years of the study. Pilot age, diabetes type and duration, and follow-up period were comparable among subgroups, and mean glycated haemoglobin did not differ before and after certification in a way which would indicate poorer glycaemic control in any subgroup. A total of 892 blood glucose values (2.31%) were outside the green range, with half reported in-flight at various time intervals. There were 48 (0.12%) low red range values recorded, 14 (0.04%) of which occurred in-flight; all but four were restored to within the green range by the time of the next measurement. Appropriate corrective action was taken for all out-of-range values, with no reports of pilot incapacitation from any cause. CONCLUSIONS The traffic light system appears effective in identifying and reducing the frequency and severity of out-of-range values.

BACKGROUND The incidence of cirrhosis and hepatocellular carcinoma (HCC) is increased in Type 2 diabetes, primarily secondary to non-alcoholic fatty liver disease (NAFLD). European guidelines recommend screening for NAFLD in Type 2 diabetes. American guidelines, while not advocating a screening protocol, suggest using non-invasive markers of fibrosis for risk-stratification and guiding onward referral. AIMS To test the ability of individual fibrosis scores and the European screening algorithm to predict 11-year incident cirrhosis/HCC in an asymptomatic community cohort of older people with Type 2 diabetes. METHODS The Edinburgh Type 2 Diabetes Study investigated men and women with Type 2 diabetes (n = 1066, aged 60-75 at baseline). Liver markers were measured at baseline and year 1; steatosis and fibrosis markers were calculated according to independently published calculations. During 11 years of follow-up, cases of cirrhosis and HCC were identified. RESULTS Forty-three out of 1059 participants with no baseline cirrhosis/HCC developed incident disease. All scores were significantly associated with incident liver disease by odds ratio (P < .05). The ability of the risk-stratification tools to accurately identify those who developed incident cirrhosis/HCC was poor with low-positive predictive values (5-46%) and high false-negative and -positive rates (up to 60% and 77%) respectively. When fibrosis risk scores were used in conjunction with the European algorithm, they performed modestly better than when applied in isolation. CONCLUSIONS In a cohort with a moderately low incidence of cirrhosis/HCC, existing risk scores did not reliably identify participants at high risk. Better prediction models for cirrhosis/HCC in people with Type 2 diabetes are required.

Aims: Hypoglycemia provokes a profound autonomic response in humans including cardiovascular effects. This study examined the effect of experimentally-induced hypoglycemia on measures of myocardial blood flow and myocardial injury in adults with, and without, type 1 diabetes.Methods and Results: In a prospective, randomized, open-label, blinded, endpoint cross-over study, 17 young adults with type 1 diabetes with no cardiovascular risk factors, and 10 healthy non-diabetic volunteers, underwent hyperinsulinemic euglycemic (blood glucose 4.5-5.5 mmol/L) and hypoglycemic (2.2-2.5 mmol/L) clamps. Myocardial blood flow was assessed using transthoracic echocardiography Doppler coronary flow reserve (CFR) and myocardial injury using plasma high-sensitivity cardiac troponin I (hs-cTnI) concentration. During euglycemia, a non-significant trend for lower CFR was observed in participants with type 1 diabetes than in those without type 1 diabetes (3.66±0.47 versus 3.92±0.85), and a non-significant lower trend also occurred during hypoglycemia (type 1 diabetes: 3.54±0.58 versus non-diabetes: 3.80±0.84). A generalized linear mixed-model analysis was performed, with diabetes status and euglycemia or hypoglycemia as factors affecting CFR. No significant statistical difference in CFR was observed for diabetes status (p=0.23) or between euglycemia and hypoglycemia (p=0.31). No changes in hs-cTnI occurred during hypoglycemia or in the recovery period (p=0.86).Conclusions: While the observed reduction in coronary flow reserve did not achieve significance during exposure to insulin-induced hypoglycemia in healthy young men with type 1 diabetes, with no evidence of myocardial injury, adverse cardiovascular effects of hypoglycemia cannot be excluded in older people who have coronary disease. Further studies are required to investigate this putative problem.

AIMS To identify factors associated with achievement of glycated haemoglobin A1c (HbA1c) target at 24 weeks after commencing basal insulin therapy in individuals with type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS Post-hoc pooled analysis of 16 randomized, treat-to-target trials involving individuals with T2DM inadequately controlled with oral anti-hyperglycaemic drugs (n = 3415) initiated on once-daily insulin glargine 100 U/mL (Gla-100). Clinical outcomes were assessed by HbA1c response at 24 weeks and individuals were classified as "good responders" with HbA1c

Aims: The aims of the study were to assess the degree of knowledge and adherence to the recommended safe practice for driving and the risk of road traffic accidents among people with diabetes mellitus in Armenia. Methods: A total of 628 respondents, including 200 drivers, out of 641 consecutive attendees at six diabetes clinics, participated in the survey. A modified British questionnaire on driving and diabetes was used to obtain the relevant data. The information from all 103 drivers treated with insulin and 73 taking sulfonylureas was reviewed. Results: The study revealed that of 176 insulin and sulfonylurea-treated drivers, 161 (91.5%) had never received any advice about safe driving practices. Among the drivers, 156 (88.6%) never measured their blood glucose before, or during driving. The survey revealed that 86 (51.2%) of 168 patients had a history of at least one motor vehicle accident within the previous 5 years. The average road traffic accident rate per person/year was 0.21. Conclusions: The study revealed a lack of knowledge among drivers with diabetes treated with insulin or sulfonylureas concerning recommended safe practices for driving. This was associated with significant hypoglycemia while driving and an elevated rate of road traffic accidents.

Driving is an important everyday activity for many people with diabetes, which is designated a prospective disability as it may impair driving performance as it progresses in severity. In effect, the principal threat to driving performance is hypoglycaemia associated with insulin therapy. Regular assessment of medical fitness to drive is undertaken to identify drivers with diabetes who are at greatest risk of experiencing motor vehicle accidents. Many countries do not restrict the licensing of drivers with insulin-treated diabetes and fail to review and/or restrict the driving of large goods vehicles or those carrying passengers. The European Union has formulated regulations for driving licensing for diabetes through successive directives, which have been implemented by individual countries including the UK. In response to submissions to relax licensing restrictions, some of these have been amended recently and were implemented in the UK in January 2018. Their rationale and potential value are discussed.

BACKGROUND: With improved treatment, individuals with type 1 diabetes are living longer but there is minimal information on the effects of type 1 diabetes on cognitive ability as they become older adults. METHODS: 1,051 participants with type 1 diabetes enrolled in the Diabetes Control and Complications Trial (DCCT) and its follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) study completed cognitive assessments: baseline (median age 27 years) and 2, 5, 18, and 32 years later (median age 59). Glycated hemoglobin levels, frequency of severe hypoglycemia, non-glycemic risk factors such as elevated blood pressure, and micro- and macro-vascular complications were assessed repeatedly. We examined the effects of these on measures of memory and psychomotor and mental efficiency. FINDINGS: Over 32 years of follow-up, we found substantive declines in memory and psychomotor and mental efficiency. Between years 18 and 32, the decline in psychomotor and mental efficiency was five times larger than the change from baseline to year 18. Independent of the other risk factors and comorbidities, exposure to higher HbA1c levels, more episodes of severe hypoglycemia, and elevated systolic blood pressure were associated with greater decrements in psychomotor and mental efficiency that was most notable by year 32 (p

Basal p53 levels are tightly suppressed under normal conditions. Disrupting this regulation results in elevated p53 levels to induce cell cycle arrest, apoptosis, and tumor suppression. Here, we report the suppression of basal p53 levels by a nuclear, p53-regulated long noncoding RNA that we termed PURPL (p53 upregulated regulator of p53 levels). Targeted depletion of PURPL in colorectal cancer cells results in elevated basal p53 levels and induces growth defects in cell culture and in mouse xenografts. PURPL associates with MYBBP1A, a protein that binds to and stabilizes p53, and inhibits the formation of the p53-MYBBP1A complex. In the absence of PURPL, MYBBP1A interacts with and stabilizes p53. Silencing MYBBP1A significantly rescues basal p53 levels and proliferation in PURPL-deficient cells, suggesting that MYBBP1A mediates the effect of PURPL in regulating p53. These results reveal a p53-PURPL auto-regulatory feedback loop and demonstrate a role for PURPL in maintaining basal p53 levels.

Aims/hypothesis The aim of this study was to compare cognitive function in adults with type 1 diabetes who have impaired awareness of hypoglycaemia with those who have normal awareness of hypoglycaemia. A putative association was sought between cognitive test scores and a history of severe hypoglycaemia. Methods A total of 68 adults with type 1 diabetes were included: 33 had impaired and 35 had normal awareness of hypoglycaemia, as confirmed by formal testing. The groups were matched for age, sex and diabetes duration. Cognitive tests of verbal memory, object-location memory, pattern separation, executive function, working memory and processing speed were administered. Results Participants with impaired awareness of hypoglycaemia scored significantly lower on the verbal and object-location memory tests and on the pattern separation test (Cohen’s d −0.86 to −0.55 [95% CI −1.39, −0.05]). Participants with impaired awareness of hypoglycaemia had reduced planning ability task scores, although the difference was not statistically significant (Cohen’s d 0.57 [95% CI 0, 1.14]). Frequency of exposure to severe hypoglycaemia correlated with the number of cognitive tests that had not been performed according to instructions. Conclusions/interpretation Impaired awareness of hypoglycaemia was associated with diminished learning, memory and pattern separation. These cognitive tasks all depend on the hippocampus, which is vulnerable to neuroglycopenia. The findings suggest that hypoglycaemia contributes to the observed correlation between impaired awareness of hypoglycaemia and impaired cognition. © The Author(s) 2017. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

Aim: This study aimed to investigate the safety of insulin degludec (degludec) in relation to age and risk of hypoglycaemia post hoc in individuals with type 2 diabetes (T2D) (SWITCH 2 trial). Methods: In this crossover study, individuals with T2D who were at risk of hypoglycaemia were randomized to double-blind treatment with degludec or insulin glargine 100 units/mL (glargine U100) ± oral antidiabetic drugs. After 32 weeks, patients crossed over to the other treatment. Primary endpoint was number of overall severe (positively adjudicated) or glucose-confirmed (plasma glucose 65 (n = 270) years, baseline median (range) duration of diabetes was 12 (1–40) vs 15 (1–54) years, mean HbA1c was 7.7% vs 7.4% and mean estimated glomerular filtration rate was 87.0 vs 63.7 mL/min/1.73 m 2 , respectively. No significant differences in HbA1c reduction were seen in individuals ≤65 or >65 years. During both maintenance periods, treatment with degludec lowered rates of hypoglycaemia (overall/nocturnal symptomatic) vs those with glargine U100 in individuals ≤65 (31% vs 43%) and >65 (30% vs 41%) years. With degludec and glargine U100, respectively, six vs nine severe hypoglycaemic events occurred in individuals ≤65 years and four vs eight events occurred in those >65 years. Adverse event rates were 3.2 and 3.3 events/patient-year for individuals ≤65 years and were 3.5 and 4.1 events/patient-year for individuals >65 years with degludec and glargine U100, respectively. Conclusion: Treatment with degludec was safe and effective, with a frequency of hypoglycaemia lower than that with glargine U100 in both younger and older individuals (>65 years) with T2D.