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Objective: To assess the effects of incremental doses of repaglinide on postprandial insulin and glucose profiles after a standard 500-kcal test meal.Research Design and Methods: Sixteen diet-treated Caucasians with type 2 diabetes (mean HbA(1c) 8.4%) were enrolled in this randomized, open-label, crossover trial. Subjects received 0.5, 1, 2, and 4 mg repaglinide or placebo in a random fashion, followed by a standard 500-kcal test meal on 5 separate study days, 1 week apart.Results: The insulinogenic index (DeltaI30/DeltaG30) and insulin area under the curve (AUC) from 0 to 30 min (AUC(0-30)) were higher with the 4-mg drug dose compared with the two lower doses and with 2 mg compared with 0.5 mg. On subgroup analysis, the incremental insulin responses were apparent only in the fasting plasma glucose (FPG) < 9-mmol/l subgroup of subjects and not in the FPG >9-mmol/l subgroup. There was a significant dose-related increase in the late postprandial insulin secretion (insulin AUC(120-240)), which resulted in hypoglycemia in four subjects. Proinsulin-to-insulin ratios at 30 and 60 min improved with increasing doses of repaglinide; higher drug doses (2 and 4 mg) were more effective than the 0.5- and 1-mg doses.Conclusions: Significant dose-related increases in early insulin secretion were found only in less advanced diabetic subjects. In advanced diabetic patients, only the maximum dose (4 mg) was significant compared with placebo. Better proinsulin-to-insulin processing was noted with increasing drug doses. [ABSTRACT FROM AUTHOR]

Background: Self-monitoring of glucose is important to the successful management of diabetes; however, existing monitoring methods require a degree of invasive measurement which can be unpleasant for users. This study investigates the accuracy of a noninvasive glucose monitoring system that analyses spectral variations in microwave signals., Methods: An open-label, pilot design study was conducted with four cohorts (N = 5/cohort). In each session, a dial-resonating sensor (DRS) attached to the wrist automatically collected data every 60 seconds, with a novel artificial intelligence (AI) model converting signal resonance output to a glucose prediction. Plasma glucose was measured in venous blood samples every 5 minutes for Cohorts 1 to 3 and every 10 minutes for Cohort 4. Accuracy was evaluated by calculating the mean absolute relative difference (MARD) between the DRS and plasma glucose values., Results: Accurate plasma glucose predictions were obtained across all four cohorts using a random sampling procedure applied to the full four-cohort data set, with an average MARD of 10.3%. A statistical analysis demonstrates the quality of these predictions, with a surveillance error grid (SEG) plot indicating no data pairs falling into the high-risk zones., Conclusions: These findings show that MARD values approaching accuracies comparable to current commercial alternatives can be obtained from a multiparticipant pilot study with the application of AI. Microwave biosensors and AI models show promise for improving the accuracy and convenience of glucose monitoring systems for people with diabetes., 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: MRAQ, CH, DJF, BL, ICM, and JAMR are employees of Afon Technology, and MSC is the chief executive officer of Afon Technology.

Background: We compared the performance of three currently available laboratory benchtop glucose analyzers with the outgoing YSI 2300 Stat Plus., Methods: Plasma samples (100), across a wide glucose concentration range were analysed on the YSI 2500, Randox daytona+ (glucose oxidase) and EKF Biosen in a single laboratory and compared to the YSI 2300 Stat Plus., Results: All three analyzers showed good agreement with the YSI 2300 Stat Plus, and only a small bias (≤1% YSI 2500 and Randox daytona+, 4.6% EKF Biosen) was observed for each analyzer. None of the three comparator analyzers were affected by either proportional or constant bias, thus no significant differences between the YSI 2300 Stat Plus and the comparator methods were identified., Conclusions: The results from this study suggest all could be considered as suitable reference laboratory glucose analyzers and replacements for the recently withdrawn YSI 2300 Stat Plus., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objectives: Cardiovascular disease (CVD) and associated risk factors within the prison population often present at a younger age in this cohort. Given CVD is largely preventable, it warrants investigation to fully quantify this risk. This study explored the relative predicted 10-year CVD risk and examined the calculated heart age in a representative sample of male individuals aged 25-84 years within the prison environment., Study Design: This was a cross-sectional study., Methods: Data were collected on 299 men who underwent a cardiometabolic risk assessment in HMP Parc, Bridgend. The QRISK2 algorithm was used to calculate 10-year CVD risk, relative risk (to general population) and the predicted heart age of an individual. Between-group differences (prison population vs general community) in cardiovascular risk predictions (10-year CVD risk and heart age) were assessed., Results: We observed that at all age groups, the relative risk of predicted 10-year CVD scores in the prison population was double that of the community risk (2.1 ± 0.6), and this was most apparent in the oldest age group (≥50 years: 17.0% compared to 8.8%; P < 0.001). Overall, the heart age of the sample was 7.5 (6.7-8.2) years higher than their own chronological age, and this difference increased to above 9 years in those aged ≥40 years., Conclusions: This study provides quantifiable evidence to the elevated CVD risk in prison. Heart age predictions were almost a decade higher in those aged ≥40 years. Lowering the screening age for CVD by around 5 years in the prison population should be considered., (Copyright © 2023 The Royal Society for Public Health. Published by Elsevier Ltd. All rights reserved.)

Background: The increasing number of cases of prediabetes in the UK is concerning, particularly in Wales where there is no standard programme of support. The aim of the current service evaluation was to examine the effectiveness of brief lifestyle interventions on glucose tolerance in people at risk of developing type 2 diabetes., Methods: In this pragmatic service evaluation clinical data on people deemed at risk of developing type 2 diabetes were evaluated from two GP clusters. Patients (n = 1207) received a single 15 to 30-min, face-to-face, consultation with a health care practitioner. Interventions were assessed by changes in HbA1c and distribution across the HbA1c ranges 12 months following intervention. Statistical significance of reversion to normoglycaemia and development of diabetes were assessed through comparison with expected rates without intervention., Results: Between baseline and 12-month follow-up HbA1c fell from 43.85 ± 1.57 mmol/mol (6.16 ± 0.14%) to 41.63 ± 3.84 mmol/mol (5.96 ± 0.35%), a decrease of 2.22 mmol/mol (0.20%) (95% CI 2.01 (0.18%), 2.42 (0.22%); p < 0.0001). The proportion of people with normal glucose tolerance at 12 months (0.50 95%CI 0.47, 0.52) was significantly larger than the lower (0.06 (p < 0.0001) and the upper (0.19 (p < 0.0001)) estimates based on no intervention., Conclusion: Results indicate significant improvement in glucose tolerance across GP clusters. The brief intervention has the potential to offer a robust and effective option to support people at risk of developing type 2 diabetes. Further research in the form of a randomised trial is needed to confirm this and identify those likely to benefit most from this intervention., (© 2022. The Author(s).)

Aims: The two predominant pathophysiological defects resulting in glucose intolerance are beta-cell dysfunction and insulin insensitivity. This study aimed to re-examine beta-cell function and insulin sensitivity across a continuum from normal glucose tolerance (NGT) to early type 2 diabetes (T2DM) employing highly specific insulin, C-peptide and intact proinsulin assays., Materials and Methods: A total of 104 persons with NGT, 85 with impaired glucose tolerance (IGT) and 554 with newly diagnosed T2DM were investigated. Following an overnight fast, all underwent a 4-h standardised mixed meal tolerance test (MTT), and on a second day, a sub-group underwent a frequently sampled insulin-modified intravenous glucose tolerance test (FSIVGTT) over a 3-h period. The participants were stratified according to fasting glucose and BMI for analysis., Results: The MTT revealed that increasing FPG was accompanied by progressively elevated and delayed postprandial glucose peaks. In parallel, following an initial compensatory increase in fasting and postprandial insulin responses there followed a progressive demise in overall beta-cell secretory capacity. FSIVGTT demonstrated a major reduction in the early insulin response to IV glucose in persons with IGT accompanied by a dramatic fall in insulin sensitivity. Beyond pre-diabetes, ever-increasing fasting and postprandial hyperglycaemia resulted predominantly from a progressively decreasing beta-cell secretory function., Conclusion: This study utilising improved assay technology re-affirms that beta-cell dysfunction is evident throughout the spectrum of glucose intolerance, whereas the predominant fall in insulin sensitivity occurs early in its evolution., (© 2021. The Author(s).)

Aims: Identifying and modulating risk factors is essential to prevent visual impairment due to diabetic retinopathy (DR). This study examines incident DR with metabolic and hormonal factors in newly-diagnosed, treatment naïve, individuals with Type2 Diabetes Mellitus (T2DM), over a 5 year period from diagnosis., Methods: 233 T2DM subjects underwent serial DR screening using digital photography and standardised Meal Tolerance Tests at diagnosis and after 1, 2 and 5 years. Subjects (179) with no DR throughout the 5-year study period were compared with those who developed DR (54)., Results: Of 233 subjects, 54(23.2%) developed DR by 5 years, background DR in 50(93%) and exudative maculopathy in 4(7%) individuals. Of these subjects, 12(22%) developed DR after 1 year, 15(28%) after 2 years and 27(50%) after 5 years. At baseline, those with DR at 5 years had higher HbA 1c (p = 0.017), higher fasting plasma glucose (PG) (p = 0.031) and postprandial PG (p = 0.009). They were associated with reduced basal β-cell secretory function (M 0 ) (p = 0.025), lower (p = 0.000) postprandial β-cell responsiveness (M 1 ) and β-cell function (HOMA-B) (p = 0.044)., Conclusions: There is an independent association between glycaemic control and β-cell dysfunction at the time of diagnosis of T2DM, with incident DR over a follow-up period of 5 years., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Although limited, global evidence suggests that the cardiometabolic health of those in prison is poorer than their community peers. Type 2 diabetes (T2DM) is a public health challenge and community rates are continuing to rise. Given that cardiometabolic risk factors are prevalent amongst younger individuals within the prison population, it is reasonable to assume that the prison environment will also experience an increase in new cases of T2DM. Therefore, the aim of this study was, to predict in a current prison population, how many potential new cases of T2DM could develop in the next 10 years. This study used health data collected from a prison sample (n = 299) aged 25-84 years in HMP Parc, UK, and the Diabetes UK Risk Score was used to predict T2DM risk. In terms of projecting new cases, it was estimated that in the next decade 6.4 individuals per 100 would develop T2DM, and this value increased to 16.4 individuals per 100 in those aged 50 years and older. The development of new cases across all age groups is a concern, and it appears that the prison community are a 'target population' for prevention opportunities., (Copyright © 2021 Primary Care Diabetes Europe. Published by Elsevier Ltd. All rights reserved.)

Background: The health of people in prisons is a public health issue. It is well known that those in prison experience poorer health outcomes than those in the general community. One such example is the burden of non-communicable diseases, more specifically cardiovascular disease (CVD), stroke and type 2 diabetes (T2DM). However, there is limited evidence research on the extent of cardiometabolic risk factors in the prison environment in Wales, the wider UK or globally., Methods: Risk assessments were performed on a representative sample of 299 men at HMP Parc, Bridgend. The risk assessments were 30 min in duration and men aged 25-84 years old and free from pre-existing CVD and T2DM were eligible. During the risk assessment, a number of demographic, anthropometric and clinical markers were obtained. The 10-year risk of CVD and T2DM was predicted using the QRISK2 algorithm and Diabetes UK Risk Score, respectively., Results: The majority of the men was found to be either overweight (43.5%) or obese (37.5%) and/or demonstrated evidence of central obesity (40.1%). Cardiometabolic risk factors including systolic hypertension (25.1%), high cholesterol (29.8%), low HDL cholesterol (56.2%) and elevated total cholesterol: HDL ratios (23.1%) were observed in a considerable number of men. Ultimately, 15.4% were calculated at increased risk of CVD, and 31.8% predicted at moderate or high risk of T2DM., Conclusions: Overall, a substantial prevalence of previously undiagnosed cardiometabolic risk factors was observed and men in prison are at elevated risk of cardiometabolic disease at a younger age than current screening guidelines., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Public Health Association. All rights reserved.)

Aim: To detail the extent and prevalence of post-exercise and nocturnal hypoglycemia following peri-exercise bolus insulin dose adjustments in individuals with type 1 diabetes (T1D) using multiple daily injections of insulins aspart (IAsp) and degludec (IDeg)., Methods and Results: Sixteen individuals with T1D, completed a single-centred, randomised, four-period crossover trial consisting of 23-h inpatient phases. Participants administered either a regular (100%) or reduced (50%) dose (100%; 5.1 ± 2.4, 50%; 2.6 ± 1.2 IU, p < 0.001) of individualised IAsp 1 h before and after 45-min of evening exercise at 60 ± 6% V̇O 2max . An unaltered dose of IDeg was administered in the morning. Metabolic, physiological and hormonal responses during exercise, recovery and nocturnal periods were characterised. The primary outcome was the number of trial day occurrences of hypoglycemia (venous blood glucose ≤ 3.9 mmol L - 1 ). Inclusion of a 50% IAsp dose reduction strategy prior to evening exercise reduced the occurrence of in-exercise hypoglycemia (p = 0.023). Mimicking this reductive strategy in the post-exercise period decreased risk of nocturnal hypoglycemia (p = 0.045). Combining this strategy to reflect reductions either side of exercise resulted in higher glucose concentrations in the acute post-exercise (p = 0.034), nocturnal (p = 0.001), and overall (p < 0.001) periods. Depth of hypoglycemia (p = 0.302), as well as ketonic and counter-regulatory hormonal profiles were similar., Conclusions: These findings demonstrate the glycemic safety of peri-exercise bolus dose reduction strategies in minimising the prevalence of acute and nocturnal hypoglycemia following evening exercise in people with T1D on MDI. Use of newer background insulins with current bolus insulins demonstrates efficacy and advances current recommendations for safe performance of exercise., Clinical Trials Register: DRKS00013509., (Copyright © 2020 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Introduction: This study sought to compare the metabolomic, hormonal and physiological responses to hypoglycemia versus euglycemia during exercise in adults with type 1 diabetes (T1D)., Research Design and Methods: Thirteen individuals with T1D (hemoglobin; 7.0%±1.3% (52.6±13.9 mmol/mol), age; 36±15 years, duration diabetes; 15±12 years) performed a maximum of 45 min submaximal exercise (60%±6% V̇O 2max ). Retrospectively identified exercise sessions that ended in hypoglycemia ((HypoEx) blood glucose (BG)≤3.9 mmol/L) were compared against a participant-matched euglycemic condition ((EuEx) BG≥4.0, BG≤10.0 mmol/L). Samples were compared for detailed physiological and hormonal parameters as well as metabolically profiled via large scale targeted ultra-high-performance liquid chromatography coupled to tandem mass spectrometry. Data were assessed using univariate and multivariate analysis techniques with false discovery rate adjustment. Significant results were considered at p≤0.05., Results: Cardiorespiratory and counterregulatory hormone responses, whole-body fuel use and perception of fatigue during exercise were similar under conditions of hypoglycemia and euglycemia (BG 3.5±0.3 vs 5.8±1.1 mmol/L, respectively p<0.001). HypoEx was associated with greater adenosine salvage pathway activity (5'-methylthioadenosine, p=0.023 and higher cysteine and methionine metabolism), increased utilization of glucogenic amino acids (glutamine, p=0.021, alanine, aspartate and glutamate metabolism and homoserine/threonine, p=0.045) and evidence of enhanced β-oxidation (lower carnitine p<0.001, higher long-chain acylcarnitines)., Conclusions: Exposure to acute hypoglycemia during exercise potentiates alterations in subclinical indices of metabolic stress at the level of the metabolome. However, the physiological responses induced by dynamic physical exercise may mask the symptomatic recognition of mild hypoglycemia during exercise in people with T1D, a potential clinical safety concern that reinforces the need for diligent glucose management., Trial Registration Number: DRKS00013509., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Bariatric surgery is an effective treatment for morbid obesity and glycaemic dysfunction., Objectives: The aim of the work was to examine both the static and dynamic changes of glucose-insulin homeostasis and incretin hormone response following sleeve gastrectomy (SG) in a sample of 55 participants preoperatively and 1 month and 6 months postoperatively. The focus was on a sample of patients with impaired glucose tolerance and type 2 diabetes (T2D)., Setting: Morriston Hospital, UK., Methods: Prospective study comprising of 55 participants with impaired glucose homeostasis and T2D undergoing SG (mean body mass index [BMI] 50.4 kg/m 2 , mean glycated haemoglobin [A1C] 7.4%). Serial measurements of glucose, insulin, C-peptide, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic hormone (GIP) were performed during oral glucose tolerance testing preoperatively and 1 and 6 months postoperatively. Areas under the curve (AUC) were examined at 30, 60, and 120 min., Results: We observed significant improvements in measures of obesity, as well as static and dynamic measures of glucose, insulin, C-peptide and HOMA. Furthermore, significant increases in GLP-1 response as early as 6 months postoperatively were also seen., Conclusions: To our knowledge, no study has examined the detailed dynamic changes in glucose and insulin homeostasis in this number of participants undergoing SG in relation to incretin hormones GIP and GLP-1. This current study supports the role of SG for the treatment of obesity-related glucose dysregulation.

Background and Aims: There is inconsistent evidence supporting the self-monitoring of blood glucose (SMBG) in people with non-insulin treated type 2 diabetes (T2D). Structured SMBG protocols have a greater impact on glycaemic control than unstructured SMBG and may improve measures of glycaemic variability (GV), though few previous studies have reported on specific GV outcomes. Our aim was to determine the impact of structured SMBG on simple measures of GV in people with T2D., Methods: Participants undertook structured SMBG over 12 months, with HbA 1c recorded at baseline and at 3-monthly follow-up. For each participant, the mean blood glucose (MBG), fasting blood glucose (FBG), standard deviation BG (SD-BG), coefficient of variation of BG (CV-BG), mean absolute glucose change (MAG) and HbA 1c were determined for each 3-month period. Responders were participants with an improvement in HbA 1c of ≥5 mmol/mol (0.5%) over 12 months., Results: Data from two hundred and thirty-one participants were included for analysis. Participants had a baseline median [interquartile range] HbA 1c 68.0 [61.5-75.5] mmol/mol (8.4%). Participants demonstrated significant improvements in the MBG (-1.25 mmol/L), FBG (-0.97 mmol/L), SD-BG (-0.44 mmol/L), CV-BG (-1.43%), MAG (-0.97 mmol/L), and HbA 1c (-7.0 mmol/mol) (all p < 0.001) at 12 months compared to these measures collected within the first 3 months of SMBG. Responders had a significantly higher baseline median [interquartile range] HbA 1c of 70.0 [63.0-78.0] mmol/mol compared to 61.0 [56.5-66.0] mmol/mol in non-responders (P < 0.001)., Conclusions: Structured SMBG improved all the observed measures of GV. These results support the use of structured SMBG in people with non-insulin treated T2D., Competing Interests: Declaration of competing interest The authors have no disclosures of interest to declare., (Copyright © 2020 Diabetes India. Published by Elsevier Ltd. All rights reserved.)

Background: Previously developed in vitro cultures of the human retina have been solo or dual cell cultures. We developed a triple-cell culture in vitro model utilizing a membrane system to produce a better representation of a functional and morphological human retina., Methods: Retinal microvascular endothelial cells (HRMVEC/ACBRI181, cell systems), retinal pigment epithelium cells (RPE/ARPE-19, ATCC) and Müller glial cells (Moorfield Institute of Ophthalmology-Müller 1, UCL) were grown in a triple culture. Our optimized triple-culture media contained a mix of specific endothelial medium and high glucose Dulbecco's Modified Eagle's medium, where all three layers were viable for up to 5 days. Co-culture effect on morphological changes (cell staining) and gene expression of functional genes (pigment epithelium derived factor [PEDF] and vascular endothelial growth factor [VEGF]) were measured from RNA via real-time polymerase chain reaction. Expression of tight junction protein 1 (TJP1) was measured in RNA isolated from ARPE-19s, to assess barrier stability., Results: The triple-culture promotes certain cell functionality through up-regulation of TJP1, increasing PEDF and decreasing VEGF expression highlighting its importance for the assessment of disease mechanisms distinct from a solo culture which would not allow the true effect of the native microenvironment to be elucidated., Conclusions: This model's novelty and reliability allows for the assessment of singular cellular function within the retinal microenvironment and overall assessment of retinal health, while eliminating the requirement of animal-based models., (© 2019 Royal Australian and New Zealand College of Ophthalmologists.)

Aim: To evaluate the performance of the current, pre-production version of a novel home oral glucose tolerance test (Home OGTT) device when administered by trained research nurses, compared with a reference laboratory glucose analyser and a second laboratory analyser, incorporating a sample processing delay to simulate normal practice., Methods: One hundred women (aged 19-48 years), with and without known glucose intolerance were recruited. Following an overnight fast, participants attended for a 75-g OGTT. A fasting capillary sample was applied to the Home OGTT device with a corresponding venous sample collected and measured immediately on the reference YSI 2300 stat plus analyser, and following a 1-h delay on the Randox Daytona Plus analyser. The sampling process was repeated 2 h after the oral glucose load., Results: Some 97% of tested devices gave complete data for analysis. Good agreement was observed between the reference glucose analyser and the Home OGTT device, with the Home OGTT device displaying a small negative bias (-0.18 mmol/l, -1.75 to 1.39 mmol/mol; -1.0%, -26.4% to 24.5%; absolute and relative mean, 95% limits of agreement). When classified as normal glucose tolerant or glucose intolerant, the Home OGTT device showed 100% and 90% sensitivity, and 99% and 99% specificity using fasting plasma glucose and 2-h glucose respectively. Similar sensitivity (100% and 100%) and specificity (96% and 99%) for fasting plasma glucose and 2-h glucose were observed using the secondary analyser., Conclusions: The novel Home OGTT device was reliable and easy to use and showed excellent agreement with two separate laboratory analysers. The Home OGTT offers potential as an effective alternative for clinic-based OGTT testing., (© 2019 Diabetes UK.)

Hematocrit is known to influence glucose values obtained on some blood glucose meters, with bias observed especially at low and high hematocrit levels. We evaluated the performance of a meter with hematocrit correction technology alongside 3 other commercially available meters. Capillary blood samples from 100 subjects were analyzed in duplicate and compared to the plasma values obtained by reference laboratory analyzer. Bias, error grid, and sensitivity to hematocrit analyses were performed for each meter. Average percentage bias was similar for all meters, however the evaluated meter performed best with respect to error grid analysis, with 100% of values falling within the "no effect on clinical action" and "no risk" categories and did not display any hematocrit associated bias.

Background: Microsampling techniques are alternative methods to venous sampling for obtaining blood for measurement of circulating biomarkers, offering the convenience of reduced sample volume and elimination of the need for phlebotomists. Dried blood spot (DBS) microsampling methods have been used for many years while more recently a volumetric absorptive microsampling device (VAMS™) has been introduced. In diabetes mellitus, circulating C-peptide is commonly used as an indicator of endogenous insulin secretion and clinical measurement can aid in diagnosis as well as informing on therapy. This pilot study investigated the effectiveness of microsampling collection of capillary blood for measurement of C-peptide., Methods: Capillary blood was collected into capillary tubes and centrifuged for plasma samples. Simultaneous samples were also collected using both microsampling methods (DBS and VAMS). Blood from both microsamplers was extracted prior to assaying for C-peptide alongside the corresponding plasma samples, using specific immunoassays and results obtained from microsampling compared to the reference plasma concentrations. Stability was determined by collecting duplicate DBS and VAMS and assaying both in a single assay after storing one at -20°C immediately and one at room temperature for 48 hours post-collection., Results: Good agreement was observed between C-peptide concentrations in plasma and equivalent DBS and VAMS samples ( R 2 = .929 and .9231, DBS and VAMS, respectively), with mean differences of 75.7 and 8.4 pmol/L observed for DBS and VAMS. Small decreases in C-peptide of 11.6% and 0.1% were observed after 48 hours storage for DBS and VAMS, respectively., Conclusions: C-peptide collected using DBS and VAMS showed good agreement with reference plasma concentrations, suggesting both would be an effective microsampling method for collection and measurement of C-peptide.

Introduction: Gestational diabetes mellitus (GDM) is a common metabolic disorder occurring in up to 10% of pregnancies in the western world. Most women with GDM are asymptomatic; therefore, it is important to screen, diagnose and manage the condition as it is associated with an increased risk of maternal and perinatal complications. Diagnosis of GDM is made in the late second trimester or early third trimester because accurate diagnosis or risk stratification in the first trimester is still lacking. An increase in serum proinsulin may be seen earlier in pregnancy and before a change in glycaemic control can be identified. This study will aim to establish if fasting proinsulin concentrations at 16-18 weeks gestation will help to identify or risk stratify high-risk pregnant women with GDM., Methods and Analysis: This is a prospective, longitudinal cohort study. Two oral glucose tolerance tests will be carried out at 16-18 and 24-28 weeks gestation in 200 pregnant women with at least one risk factor for GDM (body mass index>30 kg/m 2 , previous macrosomic baby (>4.5 kg), previous gestational diabetes, first degree relative with type 2 diabetes mellitus) recruited from antenatal clinics. Blood samples will be taken fasting and at 30 min, 1 and 2 hours following the 75 g glucose load. In addition, a fasting blood sample will be taken 6-weeks post delivery. All samples will be analysed for glucose, insulin, C peptide and proinsulin. Recruitment began in November 2017. Optimal cut-off points for proinsulin to diagnose gestational diabetes according to National Institute for Health and Care Excellence (2015) criteria will be established by the receiver operating characteristic plot and sensitivity and specificity will be calculated to assess the diagnostic accuracy of proinsulin at 16-18 weeks gestation., Ethics and Dissemination: This study received ethical approval from the Wales Research Ethics Committee (Panel 6) (Ref. 17/WA/0194). Data will be presented at international conferences and published in peer-reviewed journals., Trial Registration Number: ISRCTN16416602; Pre-results., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Aims/hypothesis: Islet-specific autoantibodies can predict the development of type 1 diabetes. However, it remains unclear if B cells, per se, contribute to the causal pancreatic immunopathology. We aimed to identify phenotypic signatures of disease progression among naive and memory B cell subsets in the peripheral blood of individuals with type 1 diabetes., Methods: A total of 69 participants were recruited across two separate cohorts, one for discovery purposes and the other for validation purposes. Each cohort comprised two groups of individuals with type 1 diabetes (one with newly diagnosed type 1 diabetes and the other with long-standing type 1 diabetes) and one group of age- and sex-matched healthy donors. The phenotypic characteristics of circulating naive and memory B cells were investigated using polychromatic flow cytometry, and serum concentrations of various chemokines and cytokines were measured using immunoassays., Results: A disease-linked phenotype was detected in individuals with long-standing type 1 diabetes, characterised by reduced C-X-C motif chemokine receptor 3 (CXCR3) expression on switched (CD27 + IgD - ) and unswitched (CD27 intermediate IgD + ) memory B cells. These changes were associated with raised serum concentrations of B cell activating factor and of the CXCR3 ligands, chemokine (C-X-C motif) ligand (CXCL)10 and CXCL11. A concomitant reduction in CXCR3 expression was also identified on T cells., Conclusions/interpretation: Our data reveal a statistically robust set of abnormalities that indicate an association between type 1 diabetes and long-term dysregulation of a chemokine ligand/receptor system that controls B cell migration.

Proinsulin, the precursor for insulin, is secreted in higher concentrations when β-cells are under stress and previous studies have shown that elevated proinsulin could be used as a marker for individuals in a pre-diabetic state. The aim of this study was to assess the stability of proinsulin across a wide concentration range (3-882 and 2-187pmol/L; total and intact proinsulin respectively) in whole blood to determine whether it could be used in routine clinical care. 51 subjects (26 normal glucose tolerance, 17 impaired glucose tolerance and 8 type 2 diabetes) had blood taken into EDTA tubes at 0, 60 & 120min following a glucose load. The samples were kept at room temperature (~20°C) with aliquots taken, centrifuged and frozen at 0, 24, 48 and 72h. Comparison of the combined data (pre and post-glucose load) of baseline with 72h as a percentage of baseline gave an average of 123% (95% CI: 119-127) and 107% (95% CI: 105-109) for total and intact proinsulin respectively. A small change in the stability of total proinsulin was observed whilst there was no clinical difference over the 72h period for intact proinsulin., (Copyright © 2017 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Aims: As the use of Point of Care Testing (POCT) devices for measurement of glycated haemoglobin (HbA1c) increases, it is imperative to determine how their performance compares to laboratory methods. This study compared the performance of the automated Quo-Test POCT device (EKF Diagnostics), which uses boronate fluorescence quenching technology, with a laboratory based High Performance Liquid Chromatography (HPLC) method (Biorad D10) for measurement of HbA1c., Methods: Whole blood EDTA samples from subjects (n=100) with and without diabetes were assayed using a BioRad D10 and a Quo-Test analyser. Intra-assay variation was determined by measuring six HbA1c samples in triplicate and inter-assay variation was determined by assaying four samples on 4 days. Stability was determined by assaying three samples stored at -20 °C for 14 and 28 days post collection., Results: Median (IQR) HbA1c was 60 (44.0-71.2) mmol/mol (7.6 (6.17-8.66) %) and 62 (45.0-69.0) mmol/mol (7.8 (6.27-8.46) %) for D10 and Quo-Test, respectively, with very good agreement (R 2 =0.969, P<0.0001). Mean (range) intra- and inter-assay variation was 1.2% (0.0-2.7%) and 1.6% (0.0-2.7%) for the D10 and 3.5% (0.0-6.7%) and 2.7% (0.7-5.1%) for the Quo-Test. Mean change in HbA1c after 28 days storage at -20 °C was -0.7% and +0.3% for D10 and Quo-Test respectively. Compared to the D10, Quo-Test showed 98% agreement for diagnosis of glucose intolerance (IGT and T2DM) and 100% for diagnosis of T2DM., Conclusion: Good agreement between the D10 and Quo-Test was seen across a wide HbA1c range. The Quo-Test POCT device provided similar performance to a laboratory based HPLC method.

Purpose: The association of hyperglycemia and diabetic retinopathy (DR) in established type 2 diabetes mellitus (T2DM) subjects is well accepted. However, the association between β-cell responsiveness and insulin sensitivity leading to fasting and postprandial hyperglycemia with DR in newly diagnosed treatment-naïve T2DM subjects remain unreported., Methods: A total of 544 newly diagnosed treatment-naïve T2DM subjects were screened for DR (digital photography) and underwent a standardized meal tolerance test. Serial plasma glucose and insulin levels were measured, and fasting (M0) and postprandial β-cell responsiveness calculated Calculating Pancreatic Response Program along with homeostasis model assessment-β cell function (HOMA-B) and HOMA-Insulin Sensitivity. A subgroup of 201 subjects also underwent a frequently sampled IV glucose tolerance test and the acute insulin response to glucose, insulin sensitivity, and glucose effectiveness (SG) estimated (MINMOD model)., Results: A total of 16.5% (90) subjects had DR at diagnosis. Subjects with DR had significantly reduced M0, HOMA-B and SG leading to higher fasting and postprandial (2 hour) glucose and significantly lower fasting and postprandial (2 hour) insulin. Factors independently associated with DR in multivariate logistic regression analysis were M0, HOMA-B, and SG with fasting and postprandial (2 hour) glucose and insulin. There was no statistical difference in glycated hemoglobin, systolic blood pressure, acute insulin response to glucose, and insulin sensitivity between those with or without DR., Principal Conclusions: In this cohort of newly diagnosed T2DM subjects, DR is associated with reduced β-cell responsiveness, resulting from β-cell failure rather than insulin resistance, leading to fasting and postprandial hyperglycemia and hypoinsulinemia.

Objective: WHO, IDF and ADA recommend HbA(1c) ≥6.5% (48 mmol/mol) for diagnosis of diabetes with pre-diabetes 6.0% (42 mmol/mol) [WHO] or 5.7% (39 mmol/mol) [ADA] to 6.4% (47 mmol/mol). We have compared HbA(1c) from several methods for research relating glycaemic markers., Research Design and Methods: HbA1c was measured in EDTA blood from 128 patients with diabetes on IE HPLC analysers (Bio-Rad Variant II NU, Menarini HA8160 and Tosoh G8), point of care systems, POCT, (A1cNow+ disposable cartridges and DCA 2000(®)+ analyser), affinity chromatography (Primus Ultra2) and the IFCC secondary reference method (Menarini HA8160 calibrated using IFCC SRM protocol)., Results: Median (IQ range) on IFCC SRM was 7.5% (6.8-8.4) (58(51-68) mmol/mol) HbA(1c) with minimum 5.3%(34 mmol/mol)/maximum 11.9%(107 mmol/mol). There were positive offsets between IFCC SRM and Bio-Rad Variant II NU, mean difference (1SD), +0.33%(0.17) (+3.6(1.9) mmol/mol), r(2)=0.984, p<0.001 and Tosoh G8, +0.22%(0.20) (2.4(2.2) mmol/mol), r(2)=0.976, p<0.001 with a very small negative difference -0.04%(0.11) (-0.4(1.2) mmol/mol), r(2)=0.992, p<0.001 for Menarini HA8160. POCT methods were less precise with negative offsets for DCA 2000(®)+ analyser -0.13%(0.28) (-1.4(3.1) mmol/mol), r(2)=0.955, p<0.001 and A1cNow+ cartridges -0.70%(0.67) (-7.7(7.3) mmol/mol), r(2)=0.699, p<0.001 (n=113). Positive biases for Tosoh and Bio-Rad (compared with IFCC SRM) have been eliminated by subsequent revision of calibration., Conclusions: Small differences observed between IFCC-calibrated and NGSP certified methods across a wide HbA(1c) range were confirmed by quality control and external quality assurance. As these offsets affect estimates of diabetes prevalence, the analyser (and calibrator) employed should be considered when evaluating diagnostic data., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Aim: The pharmacodynamic properties of a single dose of 0.5 U/kg insulin detemir and insulin glargine were compared during two 24-h isoglycaemic clamps, one week apart., Methods: The order of treatments was randomised. At approximately 0830 h, persons with T2DM received subcutaneous administration of a 0.5 U/kg dose of either insulin detemir or insulin glargine into the anterior abdominal wall. Plasma glucose was measured at 10-min intervals throughout the 24-h clamp period and isoglycaemia was maintained by variable infusion of 20% glucose. Glucose infusion rates (GIR) and plasma C-peptide were determined throughout each 24-h period., Results: Eleven persons with type 2 diabetes (8 male) with mean (SD) age 58.5 years (8.5), BMI 30.8 kg/m² (2.8) and HbA1c 7.5% (0.6) were studied. Plasma glucose remained constant during the clamp (CV: insulin detemir 3.7%; insulin glargine 3.8%). Following injection of insulin detemir, GIR increased, reaching a mean peak of 2.29 mg/kg/min (95% CI 1.64, 2.94) at 11.6h (range 8.9 to 14.3) compared to 1.71 mg/kg/min (95% CI 1.4, 2.0) at 10.2 h (8.1 to 12.3) for insulin glargine (P=0.025 for GIR(max)). Plasma C-peptide decreased during the study period, remaining significantly lower than the fasting level at the study end after both analogues, insulin detemir (P=0.01) and insulin glargine (P=0.02)., Conclusion: In persons with T2DM, no difference in duration of action following a single subcutaneous dose of insulin detemir and insulin glargine could be observed. Insulin detemir showed greater between subject variability and achieved a significantly higher maximum GIR than insulin glargine., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)

A comparison of the plasma glucose and insulin day profiles between two prandial rapid-acting insulin analogues, insulin glulisine (glulisine) and insulin lispro (lispro), in 18 obese subjects with Type 2 diabetes. Subjects (body mass index: males, 36.7 [33.2-43.8] kg/m(2); females, 40.0 [35.7-46.5] kg/m(2)) received subcutaneous glulisine or lispro (0.15 U/kg) at 4-h intervals immediately (within 2 min) before three standard test meals during each of two 12-h, randomised, open-label, crossover studies (7+/-2-day interval between each). Overall, preprandial-subtracted glucose concentrations (area under the curve) were similar on the glulisine and lispro study days. However, the mean of the three maximal preprandial subtracted plasma glucose concentrations (DeltaGLU(max)) were lower with glulisine versus lispro (12%; p<0.01). Mean concentrations of insulin analogue were significantly higher post-meal with glulisine (p<0.01 for all). Post hoc analysis showed a significantly faster absorption rate for glulisine versus lispro in the first 30 min post-meal (estimated difference 0.48 microU/min; p<0.0001). Only two cases of hypoglycaemia were reported; both from one subject during the lispro day. When glulisine is injected immediately before a meal in obese patients with Type 2 diabetes, glulisine achieves significantly lower glucose excursions over lispro. Significantly faster absorption with higher and sustained post-meal levels of insulin analogue was achieved at every meal with glulisine versus lispro.

Objective: The aim of the study was to determine whether the loss of fasting and postprandial glycemic control occurs in parallel or sequentially in the evolution of type 2 diabetes., Research Design and Methods: In 130 type 2 diabetic patients, 24-h glucose profiles were obtained using a continuous glucose monitoring system. The individuals with type 2 diabetes were divided into five groups according to A1C levels: 1 (<6.5%, n = 30), 2 (6.5-6.9%, n = 17), 3 (7-7.9%, n = 32), 4 (8-8.9%, n = 25), and 5 (> or =9%, n = 26). The glucose profiles between the groups were compared. The overall glucose concentrations for the diurnal, nocturnal, and morning periods, which represent the postprandial, fasting, and the dawn phenomenon states, respectively, were also compared., Results: Glucose concentrations increased steadily from group 1 to 5 in a stepwise manner. The initial differences in mean glucose concentrations reaching statistical significance occurred 1) between groups 1 and 2 (6.4 vs. 7.7 mmol/l, P = 0.0004) for daytime postprandial periods, followed by differences; 2) between groups 2 and 3 (7.5 vs. 9.3 mmol/l, P = 0.0003) for the morning periods (dawn phenomenon); and finally 3) between groups 3 and 4 (6.3 vs. 8.4 mmol/l, P < 0.0001) for nocturnal fasting periods., Conclusions: The deterioration of glucose homeostasis in individuals with type 2 diabetes progressed from postprandial to fasting hyperglycemia following a three-step process. The first step related to the three diurnal postmeal periods considered as a whole, the second step occurred during the morning period, and the third and final step corresponded to sustained hyperglycemia over the nocturnal fasting periods. Such a description of the key stages in the evolution of type 2 diabetes may be of interest for implementing antidiabetes treatment.

Objective: To compare the effects of repaglinide, glipizide, and glibenclamide on insulin secretion and postprandial glucose after a single standard 500-kcal test meal., Research Design and Methods: A total of 12 type 2 diabetic patients with early diabetes (mean HbA(1c) of 6.1%) and 12 matched control subjects were enrolled in this randomized, double-blind, crossover trial. Subjects received placebo, 2 mg repaglinide, 5 mg glipizide, and 5 mg glibenclamide in a random fashion during the trial. Administration of each drug was followed by a single standard 500-kcal test meal. A washout period of 7-12 days existed between the four study visits., Results: All three drugs were equally effective on the total prandial insulin secretion (area under the curve [AUC] -15 to 240 min). However, clear differences were noted in the early insulin secretion (AUC -15 to 30 min); both repaglinide and glipizide increased secretion in nondiabetic subjects by approximately 61 and 34%, respectively, compared with placebo. In the diabetic patients, the difference versus placebo was 37 and 47%, respectively. The difference between glipizide and glibenclamide reached significance in both groups of subjects, whereas repaglinide was more effective than glibenclamide only in the healthy nondiabetic subject group. All three drugs were effective in decreasing total glucose AUC in the nondiabetic and diabetic population. In the nondiabetic subjects, however, repaglinide was significantly more effective than glibenclamide. The differences disappeared in the diabetic subjects, probably as a result of increased prevalence of insulin resistance in this group., Conclusions: Repaglinide and glipizide but not glibenclamide significantly enhanced the early insulin secretion in both nondiabetic and diabetic subjects with preserved beta-cell function after a single standard meal.