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Introduction: To compare responses to basal insulin glargine 300 U/ml (IGlar‐300) and 100 U/ml (IGlar‐100) in newly defined subphenotypes of type 2 diabetes. Methods: Insulin‐naive participants (n = 858) from the EDITION 3 trial were assigned to subphenotypes 'Mild Age‐Related Diabetes (MARD)', 'Mild Obesity Diabetes (MOD)', 'Severe Insulin Resistant Diabetes (SIRD)' and 'Severe Insulin Deficient Diabetes (SIDD)'. Key variables were analysed at baseline and 26 weeks. Results: Participants were comprised of MOD 56.1% (n = 481), SIDD 22.1% (n = 190), MARD 18.2% (n = 156) and SIRD 3.0% (n = 26). After 26 weeks a similar decrease in glycated haemoglobin (HbA1c) and fasting plasma glucose (FPG) of 16‐19 mmol/mol and 1.4‐1.7 mmol/L, respectively, occurred in MARD and MOD with both insulins. SIDD had the most elevated HbA1c and FPG (80‐83 mmol/mol/11.1‐11.4 mmol/L) and reduction in both HbA1c and FPG was greater with IGlar‐100 than with IGlar‐300 (−18 vs. −15 mmol/mol and −1.6 vs. −1.3 mmol/L, respectively; each p =.03). In SIDD, despite receiving the highest basal insulin doses, HbA1c decline (57‐60 mmol/mol/7.3‐7.6%) was suboptimal at week 26. In MOD and SIDD lower incidences with IGlar‐300 were found for level 1 nocturnal hypoglycaemia [odds ratio (OR) 0.59, 95% confidence intervals (CI) 0.36‐0.97; OR 0.49, 95% CI 0.24‐0.99]. In addition, fewer level 2 hypoglycaemia episodes occurred at any time with IGlar‐300 in SIDD (OR 0.31, 95% CI 0.13‐0.77). Conclusion: Both insulins produce comparable outcomes in type 2 diabetes subphenotypes, but in SIDD, add‐on treatment to basal insulin is required to achieve glycaemic targets. [ABSTRACT FROM AUTHOR]

To assess insulin glargine 100 U/mL (IGlar-100) treatment outcomes according to newly-defined subgroups of type 2 diabetes mellitus (T2DM). Insulin-naïve T2DM participants (n = 2684) from nine randomised clinical trials initiating IGlar-100 were pooled and assigned to subgroups "Mild Age-Related Diabetes (MARD)" , "Mild Obesity Diabetes (MOD)" , " Severe Insulin Resistant Diabetes (SIRD)" , and " Severe Insulin Deficient Diabetes (SIDD)" , according to age at onset of diabetes, baseline HbA1c, BMI, and fasting C-peptide using sex-specific nearest centroid approach. HbA1c, FPG, hypoglycemia, insulin dose, and body weight were analysed at baseline and 24 weeks. Subgroup distribution was MARD 15.3 % (n = 411), MOD 39.8 % (n = 1067), SIRD 10.5 % (n = 283), SIDD 34.4 % (n = 923). From baseline HbA1c 8.0–9.6% adjusted least square mean reductions after 24 weeks were similar between subgroups (1.4–1.5 %). SIDD was less likely to achieve HbA1c < 7.0 % (OR: 0.40 [0.29, 0.55]) than MARD. While the final IGlar-100 dose (0.36 U/kg) in MARD was lower than in other subgroups (0.46–0.50 U/kg), it had the highest hypoglycemia risk. SIRD had lowest hypoglycemia risk and SIDD exhibited greatest body weight gain. IGlar-100 lowered hyperglycemia similarly in all T2DM subgroups, but level of glycemic control, insulin dose, and hypoglycemia risk differed between subgroups. • Response to basal insulin treatment in newly-defined diabetes subgroups is unknown. • Adjusted HbA1c and FPG reductions with IGlar-100 were similar in T2DM subgroups. • MARD achieved best and SIDD least glycaemic control with IGlar-100 at 24 weeks. • IGlar-100 dose at 24 weeks differed considerably between MARD and other subgroups. • SIRD experienced the lowest hypoglycaemia risk compared to other T2DM subgroups. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Aims: To understand factors associated with repeat non‐attendance at screening for diabetes‐related retinopathy. Methods: Retrospective observational study using anonymised data from Diabetic Eye Screening Wales for people with a full history of screening invitations and attendances was linked with primary and secondary care records held in the Secure Anonymised Information Linkage Databank. Repeat non‐attendance was defined as no record of attendance during any 36‐month period despite three cycles of annual screening invitations. The associations between repeat non‐attendance and potential risk factors were examined using multivariable logistic regression analysis, stratified according to type 1 and type 2 diabetes. Results: A total of 18% with type 1 diabetes (1146/6513) and 8% with type 2 diabetes (12,475/156,525) were repeat non‐attenders. Participants attending their very first appointment were least likely to become repeat non‐attenders [odds ratio (95% confidence interval)]: type 1 diabetes: 0.12 (0.09, 0.17) and type 2 diabetes: 0.08 (0.07, 0.09). For both types of diabetes, those of a younger age, living in areas of higher deprivation and subject to multiple house moves were at greater risk of becoming repeat non‐attenders. Conclusion/interpretation: A more tailored approach is needed for the younger population, those living in areas of higher deprivation and/or undergoing multiple residential relocation and to ensure attendance at their initial appointment to minimise future repeat non‐attendance. [ABSTRACT FROM AUTHOR]

Prediction models for population-based screening need, for global usage, to be resource-driven, involving predictors that are affordably resourced. Here, we report the development and validation of three resource-driven risk models to identify people with type 2 diabetes (T2DM) at risk of stage 3 CKD defined by a decline in estimated glomerular filtration rate (eGFR) to below 60 mL/min/1.73m2. The observational study cohort used for model development consisted of data from a primary care dataset of 20,510 multi-ethnic individuals with T2DM from London, UK (2007–2018). Discrimination and calibration of the resulting prediction models developed using cox regression were assessed using the c-statistic and calibration slope, respectively. Models were internally validated using tenfold cross-validation and externally validated on 13,346 primary care individuals from Wales, UK. The simplest model was simplified into a risk score to enable implementation in community-based medicine. The derived full model included demographic, laboratory parameters, medication-use, cardiovascular disease history (CVD) and sight threatening retinopathy status (STDR). Two less resource-intense models were developed by excluding CVD and STDR in the second model and HbA1c and HDL in the third model. All three 5-year risk models had good internal discrimination and calibration (optimism adjusted C-statistics were each 0.85 and calibration slopes 0.999–1.002). In Wales, models achieved excellent discrimination(c-statistics ranged 0.82–0.83). Calibration slopes at 5-years suggested models over-predicted risks, however were successfully updated to accommodate reduced incidence of stage 3 CKD in Wales, which improved their alignment with the observed rates in Wales (E/O ratios near to 1). The risk score demonstrated similar model performance compared to direct evaluation of the cox model. These resource-driven risk prediction models may enable universal screening for Stage 3 CKD to enable targeted early optimisation of risk factors for CKD. [ABSTRACT FROM AUTHOR]

The class of rapid‐acting insulin analogues were introduced more than 20 years ago to control postprandial plasma glucose (PPG) excursions better than unmodified regular human insulin. Insulins, lispro, aspart and glulisine all achieved an earlier onset of action, greater peak effect and shorter duration of action resulting in lower PPG levels and a reduced risk of late postprandial hypoglycaemia. However, the subcutaneous absorption rate of these analogues still fails to match the physiological profile of insulin in the systemic circulation following a meal. Recent reformulations of aspart and lispro have generated a second generation of more rapid‐acting insulin analogue candidates, including fast‐acting aspart (faster aspart), ultra‐rapid lispro and BioChaperone Lispro. These modifications have the potential to mimic physiological prandial insulin secretion better with an even earlier onset of action with improved PPG control, shorter duration of effect and reduced risk of hypoglycaemia. Recent phase 3 trials in type 1 and type 2 diabetes show that faster aspart and ultra‐rapid lispro compared with conventional aspart and lispro, achieved fewer PPG excursions with a small increase in post‐meal hypoglycaemia but similar or marginally superior glycated haemoglobin levels, and suggest the need for parallel optimization of basal insulin replacement. Phase 1 trials for BioChaperone Lispro are equally encouraging with phase 3 trials yet to be initiated. Comparative analysis of the clinical and pharmacological evidence for these new prandial insulin candidates in the treatment of type 1 and type 2 diabetes is the main focus of this review. [ABSTRACT FROM AUTHOR]

Aim: To examine the relationship between baseline fasting C‐peptide (FCP) and outcomes in insulin‐naïve 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 <7.0% versus FCP groups >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. [ABSTRACT FROM AUTHOR]

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. 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. 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). Structured SMBG improved all the observed measures of GV. These results support the use of structured SMBG in people with non-insulin treated T2D. • This secondary analysis of the SMBG study explores the impact of structured SMBG on glycaemic variability (GV) in people with T2D. • There were significant improvements observed in several measures of GV over the 12-month study period. • Participants with poorer baseline glycaemic control were more likely to achieve a significant response to SMBG. • These data add significantly to the existing literature about the impact of structured SMBG on GV in people with T2D. [ABSTRACT FROM AUTHOR]

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 <7.0% (<53 mmol/mol) or as "poor responders" with HbA1c ≥7.0% (≥53 mmol/mol). Univariable and multivariable stepwise logistic regression analyses were performed to identify predictive factors for attaining HbA1c <7.0%. Results: Lower levels of baseline HbA1c, fasting plasma glucose (FPG) and post‐prandial plasma glucose (PPG), higher body mass index (BMI), shorter diabetes duration and male sex were associated with a good glycaemic response, but not age or baseline C‐peptide levels. Gla‐100 dose (U/kg) was highest in the poor‐responder group, which had the fewest hypoglycaemia episodes. Univariable analysis for achievement of HbA1c <7.0% confirmed these observations. Multivariable analysis retained baseline HbA1c, body weight, BMI, sex, 2‐hours PPG and diabetes duration as predictors of a good response. Continued use of sulfonylureas, hypoglycaemia and change in body weight were indicative of poor response. Conclusions: Baseline HbA1c was the strongest determinant for achieving target HbA1c <7.0% by supplementary Gla‐100 therapy, while sex and BMI were also useful indicators. However, age and C‐peptide levels at baseline did not predict glycaemic response to the introduction of basal insulin. [ABSTRACT FROM AUTHOR]

Patient characteristics associated with hypoglycaemia frequency during insulin glargine 100 U/mL (Gla‐100) titration and clinical outcomes at Week 24 were examined using participant‐level data from 16 treat‐to‐target trials involving individuals with type 2 diabetes mellitus who were inadequately controlled with oral antidiabetes drugs and were initiating Gla‐100 (n = 3549). Hypoglycaemia (plasma glucose <3.9 mmol/L or severe) during the first 8 weeks of titration was stratified by number of events (0, 1‐3 and ≥4), resulting in 72.5%, 20.6% and 6.9% of participants in each group, respectively. Changes in glycaemia, body weight and insulin dose from baseline to Weeks 12 and 24 were analysed. Hypoglycaemia was more common in participants with lower BMI and fasting C‐peptide, and in those undergoing sulfonylurea treatment. Glycaemic outcomes at Week 24 were similar in each hypoglycaemia group, despite the fact that the Week 24 mean daily dose and dose increase for Gla‐100 were highest in participants without hypoglycaemia and were lowest in those experiencing ≥4 events. The risk of hypoglycaemia during Gla‐100 titration depends mainly on patient characteristics and on sulfonylurea use and may delay dose titration, which apparently has little effect on short‐term glycaemic control in a clinical trial setting. [ABSTRACT FROM AUTHOR]

Type 2 diabetes mellitus ( T2DM) is an independent risk factor for cardiovascular ( CV) comorbidities, with CV disease being the most common cause of death in adults with T2DM. Although glucocentric therapies may improve glycaemic control (as determined by glycated haemoglobin levels), evidence suggests that this approach alone has limited beneficial effects on CV outcomes relative to improvements in lipid and blood pressure control. This may be explained in part by the fact that current antidiabetic treatment regimens primarily address overall glycaemia and/or fasting plasma glucose, but not the postprandial plasma glucose ( PPG) excursions that have a fundamental causative role in increasing CV risk. This literature review evaluates the relationship between PPG and the risk of CV disease, discusses the treatment of T2DM with glucagon-like peptide-1 receptor agonists ( GLP-1 RAs) and examines the associated CV outcomes. The literature analysis suggests that exaggerated PPG excursions are a risk factor for CV disease because of their adverse pathophysiologic effects on the vasculature, resulting in increased all-cause and CV-related mortality. Although GLP-1 RAs are well established in the current T2DM treatment paradigm, a subgroup of these compounds has a particularly pronounced, persistent and short-lived effect on gastric emptying and, hence, lower PPG substantially. However, current long-term data on CV outcomes with GLP-1 RAs are contradictory, with both beneficial and adverse effects having been reported. This review explores the opportunity to direct treatment towards controlling PPG excursions, thereby improving not only overall glycaemic control but also CV outcomes. [ABSTRACT FROM AUTHOR]

Aims To analyse the effects of patient characteristics and different oral antidiabetes drug (OAD) use on standardised clinical outcomes in type 2 diabetes patients initiating insulin glargine 100 U/mL ( Gla-100). Materials and methods Patient-level data from 16 randomized, treat-to-target clinical trials that added Gla-100 to existing metformin ( MET), sulfonylurea ( SU) or metformin plus sulfonylurea ( MET+ SU) treatment in insulin-naïve patients inadequately controlled by oral therapy were analysed and patients were followed for ≥24 weeks. Change in glycated haemoglobin A1c ( HbA1c) from baseline to week 24, other glycaemic endpoints and incidence of hypoglycaemia (overall, nocturnal, and severe) were analysed by age (<65 vs ≥65 years), gender (male vs female), body mass index ( BMI; <25 vs ≥25 to <30 vs >30 kg/m2) and concomitant OAD ( MET vs SU vs MET+ SU). Results At baseline, the overall population ( N = 3188) had a mean age of 57.7 years, BMI of 30.5 kg/m2, HbA1c of 8.7%, fasting plasma glucose of 192 mg/dL, and 52.7% were male. Younger and older patients had similar HbA1c reductions with Gla-100 and a similar risk of hypoglycaemia. Females and patients with BMI <25 kg/m2 were less likely to achieve HbA1c targets and more likely to experience hypoglycaemia, regardless of concomitant OAD. Adding Gla-100 to SU therapy (alone or in combination with MET) increased hypoglycaemia risk across all analyses. Conclusions Our data suggest that female patients with type 2 diabetes and normal-weight patients treated with Gla-100 and MET ± SU are less likely to achieve glycaemic targets and, therefore, may require more clinical attention. Addition of Gla-100 to SU regimens may increase hypoglycaemia risk irrespective of age, gender, or BMI. [ABSTRACT FROM AUTHOR]

Objective: To define the threshold for excess glucose variability (GV), one of the main features of dysglycemia in diabetes.Research Design and Methods: A total of 376 persons with diabetes investigated at the University Hospital of Montpellier (Montpellier, France) underwent continuous glucose monitoring. Participants with type 2 diabetes were divided into several groups-groups 1, 2a, 2b, and 3 (n = 82, 28, 65, and 79, respectively)-according to treatment: 1) diet and/or insulin sensitizers alone; 2) oral therapy including an insulinotropic agent, dipeptidyl peptidase 4 inhibitors (group 2a) or sulfonylureas (group 2b); or 3) insulin. Group 4 included 122 persons with type 1 diabetes. Percentage coefficient of variation for glucose (%CV = [(SD of glucose)/(mean glucose)] × 100) and frequencies of hypoglycemia (interstitial glucose <56 mg/dL [3.1 mmol/L]) were computed.Results: Percentages of CV (median [interquartile range]; %) increased significantly (P < 0.0001) from group 1 (18.1 [15.2-23.9]) to group 4 (37.2 [31.0-42.3]). In group 1, the upper limit of %CV, which served as reference for defining excess GV, was 36%. Percentages of patients with %CVs above this threshold in groups 2a, 2b, 3, and 4 were 0, 12.3, 19.0, and 55.7%, respectively. Hypoglycemia was more frequent in group 2b (P < 0.01) and groups 3 and 4 (P < 0.0001) when subjects with a %CV >36% were compared with those with %CV ≤36%.Conclusions: A %CV of 36% appears to be a suitable threshold to distinguish between stable and unstable glycemia in diabetes because beyond this limit, the frequency of hypoglycemia is significantly increased, especially in insulin-treated subjects. [ABSTRACT FROM AUTHOR]

Aims: Evaluate efficacy and hypoglycaemia according to concomitant oral antidiabetes drug (OAD) in people with type 2 diabetes initiating insulin glargine 100U/mL (Gla-100) or neutral protamine Hagedorn (NPH) insulin once daily.Methods: Four studies (target fasting plasma glucose [FPG] ⩽100mg/dL [⩽5.6mmol/L]; duration ⩾24weeks) were included. Standardised data from 2091 subjects (Gla-100, n=1024; NPH insulin, n=1067) were analysed. Endpoints included glycated haemoglobin (HbA1c) and FPG change, glycaemic target achievement, hypoglycaemia, weight change, and insulin dose.Results: Mean HbA1c and FPG reductions were similar with Gla-100 and NPH insulin regardless of concomitant OAD (P=0.184 and P=0.553, respectively) and similar proportions of subjects achieved HbA1c <7.0% (P=0.603). There was a trend for more subjects treated with Gla-100 achieving FPG ⩽100mg/dL versus NPH insulin (relative risk [RR] 1.09 [95% confidence interval (CI) 0.97-1.23]; P=0.135). Plasma glucose confirmed (<70mg/dL) overall and nocturnal hypoglycaemia incidences and rates were lower with Gla-100 versus NPH insulin (overall RR 0.93 [95% CI 0.87-1.00]; P=0.041; nocturnal RR 0.73 [95% CI 0.65-0.83]; P<0.001). After 24weeks, weight gain and insulin doses were higher with Gla-100 versus NPH insulin (2.7kg vs 2.3kg, P=0.009 and 0.42U/kg vs 0.39U/kg; P=0.003, respectively). Insulin doses were higher when either insulin was added to sulfonylurea alone.Conclusions: Pooled results from treat-to-target trials in insulin-naïve people with type 2 diabetes demonstrate a significantly lower overall and nocturnal hypoglycaemia risk across different plasma glucose definitions with Gla-100 versus NPH insulin at similar glycaemic control. OAD therapy co-administered with Gla-100 or NPH insulin impacts glycaemic control and overall nocturnal hypoglycaemia risk. [ABSTRACT FROM AUTHOR]

Background: The benefit of Self-monitoring of Blood Glucose (SMBG) in people with non-insulin treated type 2 diabetes remains unclear with inconsistent evidence from randomised controlled trials fuelling the continued debate. Lack of a consistent finding has been attributed to variations in study population and design, including the SMBG intervention. There is a growing consensus that structured SMBG, whereby the person with diabetes and health care provider are educated to detect patterns of glycaemic abnormality and take appropriate action according to the blood glucose profiles, can prove beneficial in terms of lowering HbA1c and improving overall well-being. Despite this, many national health agencies continue to issue guidelines restricting the use of SMBG in non-insulin treated type 2 diabetes. Methods: The SMBG Study is a 12 month, multi-centre, randomised controlled trial in people with type 2 diabetes not on insulin therapy who have poor glycaemic control (HbA1c ≥58 mmol/mol / 7.5%). The participants will be randomised into three comparative groups: Group 1 will act as a control group and receive their usual diabetes care; Group 2 will undertake structured SMBG with clinical review every 3 months; Group 3 will undertake structured SMBG with additional monthly telecare support from a trained study nurse. A total of 450 participants will be recruited from 16 primary and secondary care sites across Wales and England. The primary outcome measure will be HbA1c at 12 months with secondary measures to include weight, BMI, total cholesterol and HbA1c levels at 3, 6, 9 and 12 months. Participant well-being and attitude towards SMBG will be monitored throughout the course of the study. Recruitment began in December 2012 with the last participant visit due in September 2016. Discussion: This study will attempt to answer the question of whether structured SMBG provides any benefits to people with poorly controlled type 2 diabetes who are not being treated with insulin. The data will also clarify whether the telecare support provides additional value. The overall acceptability of SMBG as a tool for self-management will be assessed. Trial registration: UKCRN 12038 (Registered March 2012). ISRCTN21390608 (Retrospectively registered 15th May 2014). [ABSTRACT FROM AUTHOR]

While glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are known to increase heart rate (HR), it is insufficiently recognized that the extent varies greatly between the various agonists and is affected by the assessment methods employed. Here we review published data from 24-h time-averaged HR monitoring in healthy individuals and subjects with type 2 diabetes mellitus (T2DM) treated with either short-acting GLP-1 RAs, lixisenatide or exenatide, or long-acting GLP-1 RAs, exenatide LAR, liraglutide, albiglutide, or dulaglutide (N = 1112; active-treatment arms). HR effects observed in two independent head-to-head trials of lixisenatide and liraglutide (N = 202; active-treatment arms) are also reviewed. Short-acting GLP-1 RAs, exenatide and lixisenatide, are associated with a transient (1-12 h) mean placebo- and baseline-adjusted 24-h HR increase of 1-3 beats per minute (bpm). Conversely, long-acting GLP-1 RAs are associated with more pronounced increases in mean 24-h HR; the highest seen with liraglutide and albiglutide at 6-10 bpm compared with dulaglutide and exenatide LAR at 3-4 bpm. For both liraglutide and dulaglutide, HR increases were recorded during both the day and at night. In two head-to-head comparisons, a small, transient mean increase in HR from baseline was observed with lixisenatide; liraglutide induced a substantially greater increase that remained significantly elevated over 24 h. The underlying mechanism for increased HR remains to be elucidated; however, it could be related to a direct effect at the sinus node and/or stimulation of the sympathetic nervous system, with this effect related to the duration of action of the respective GLP-1 RAs. In conclusion, this review indicates that the effects on HR differ within the class of GLP-1 RAs: short-acting GLP-1 RAs are associated with a modest and transient HR increase before returning to baseline levels, while some long-acting GLP-1 RAs are associated with a more pronounced and sustained increase during the day and night. Findings from recently completed trials indicate that a GLP-1 RA-induced increase in HR, regardless of magnitude, does not present an increased cardiovascular risk for subjects with T2DM, although a pronounced increase in HR may be associated with adverse clinical outcomes in those with advanced heart failure. [ABSTRACT FROM AUTHOR]

Even though the long-term variability of glucose homeostasis has emerged as a risk factor for adverse outcomes in diabetes, there exists no universal consensus on its definition and assessment, but the determination of quarterly HbA1c fluctuations would be an appropriate metric. From the analysis of retrospective studies conducted in persons with type 2 diabetes, the risk for adverse outcomes appears to become significantly increased when the coefficient of variation for HbA1c (%CV for HbA1c) is above 5.0%. However, should the number of HbA1c readings be greater than four for completing a clinically relevant assessment, the follow-up period would be longer than one year. Such a delay is not clinically acceptable for rapid clinical decisions. To conciliate the scientific relevance and practical approaches with minimal number of HbA1c measurements, we assessed the HbA1c variability from two successive HbA1c readings. For perspective in care the 5.0% threshold of the %CV for HbA1c was converted into lower and upper limits of visit-to-visit differences in absolute HbA1c levels. These HbA1c dependent limits (± 0.X% i.e., [X/10]% for an HbA1c level of X%) easily permit to decipher HbA1c stability and lability in diabetes across the spectrum of HbA1c levels and further to adjust the treatment. [ABSTRACT FROM AUTHOR]

Aims: To evaluate the efficacy and safety of adding a single bolus dose of insulin glulisine to basal insulin ('basal-plus') in persons with type 2 diabetes.Methods: Data from patients with poor glycemic control on oral antihyperglycemic drugs who were initiated on a 'basal-plus' regimen for up to 6 months were pooled from four randomized, multicenter studies. Glycated hemoglobin (HbA1c), fasting blood glucose, postprandial glucose (PPG), insulin dose and demographics were measured at baseline and end of study.Results: 711 patients with a mean age of 59.9 years and a mean duration of diabetes of 11.0 years were included in the analysis population. A 'basal-plus' regimen was associated with significant decreases in HbA1c and PPG at 6 months, an increase in glargine and glulisine doses and small, but statistically significant, changes in body weight and BMI in all patient subsets. The proportion of patients with HbA1c<7% also increased in all populations studied, while the prevalence of severe hypoglycemia was low and did not significantly differ across patient groups.Conclusions: These results suggest that the use of 'basal-plus' can achieve a good therapeutic response with a low risk of hypoglycemia and weight gain, regardless of a patient's age or BMI. [ABSTRACT FROM AUTHOR]

Aim Evaluate early (0–12 weeks) and later (12–24 weeks) treatment outcomes in subjects with type 2 diabetes not achieving glycaemic control with oral antidiabetes drugs (OADs). Methods Selected data were pooled from 15 randomised, controlled treat-to-target (fasting plasma glucose < 100 mg/dL [<5.6 mmol/L]) trials adding insulin glargine to metformin, a sulphonylurea, or both. Glycaemic and hypoglycaemia parameters, insulin dose, and body weight at weeks 12 and 24 were assessed using individualised subject-level data. Results Data from 2837 subjects were analysed. HbA1c decreased from 8.8% (73 mmol/mol) at baseline by 1.4% (15 mmol/mol) at Week 12, and a further 0.2% (2 mmol/mol) at Week 24 in the pooled population. Similar reductions were observed across the different treatment groups. HbA1c < 7.0% (<53 mmol/mol) was reached by 34.8% of participants at Week 12 and an additional 24.3% by Week 24. Hypoglycaemia incidence and rates were similar during the early and continued treatment periods across all treatment combinations, but were markedly lower for insulin glargine plus metformin versus the other 2 regimens. Conclusions Early and sustained glycaemic benefits with a low-risk of hypoglycaemia are observed after initiation of insulin glargine in a pooled type 2 diabetes cohort previously uncontrolled on OADs. [ABSTRACT FROM AUTHOR]

Insulin remains the most effective and consistent means of controlling blood glucose levels in diabetes. Since 1946, neutral protamine Hagedorn (NPH) has been the predominant basal insulin in clinical use. However, absorption is variable due to the need for resuspension and the time-action profile (peak activity 4-6 h after subcutaneous administration) confers an increased propensity for between-meal and nocturnal hypoglycaemia. In the 1980s, recombinant DNA technology enabled modifications to the insulin molecule resulting in the soluble long-acting insulin analogues, glargine and detemir. Both exhibit a lower risk of hypoglycaemia compared with neutral protamine Hagedorn due to improved time-action profiles and reduced day-to-day glucose variability. Glargine is indicated for administration once daily and detemir once or twice daily. Degludec is the latest prolonged-acting insulin which forms long subcutaneous multi-hexamers that delay absorption. Recent phase III trials in type 1 and type 2 diabetes show that degludec was non-inferior to comparators (predominantly glargine) with a minimal although inconsistent reduction in overall hypoglycaemia and a small absolute difference in nocturnal hypoglycaemia. Newer developmental agents include LY2605541 and glargine U300. LY2605541 comprises insulin lispro combined with polyethylene glycol, thereby increasing its hydrodynamic size and retarding absorption from the subcutaneous tissue. Glargine U300 is a new formulation of glargine resulting in a flatter and more prolonged time-action profile than its predecessor. This article reviews recent advances in basal insulin analogues, including a critical appraisal of the degludec trials. Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

OBJECTIVE--To assess the magnitude of the dawn phenomenon and its impact on the total glucose exposure in type 2 diabetes. RESEARCH DESIGN AND METHODS--A total of 248 noninsulin-treated persons with type 2 diabetes who underwent continuous glucose monitoring were divided into three groups selected by treatments: diet alone (n = 53); insulin sensitizers alone (n = 82); and insulin secreta-gogues alone or in combination with insulin sensitizers (n = 113). The dawn phenomenon (d glucose, mg/dL) was quantified by its absolute increment from nocturnal nadir to prebreakfast value. The participants were secondarily divided into two paired subsets after they had been separated by the presence/absence of a dawn phenomenon based on a threshold of 20 mg/dL and matched for glucose nadir. The impact of the dawn phenomenon was assessed on HbA1c and 24-h mean glucose. RESULTS--The median of d glucose (interquartile range) was 16.0 (0--31.5 mg/dL) in the 248 subjects, and no differences were observed across groups selected by HbA1c or treatments. In the overall population, the mean impacts on HbA1c and 24-h mean glucose were 4.3 ± 1.3 mmol/mol (0.39 6 0.12%) and 12.4 ± 2.4 mg/dL, respectively. The mean impact on 24-h mean glucose was not statistically different between those on diet alone (16.7 ± 5.9 mg/dL) compared with the two subsets treated with oral hypoglycemic agents (11.2 ± 5.3 and 8.5 ± 7.5 mg/dL). CONCLUSIONS--The impact of the dawn phenomenon on overall glycemic control in type 2 diabetes, as depicted by the HbA1c level, was ~0.4% and not eliminated by any of the currently available armamentarium of oral antidiabetes agents. [ABSTRACT FROM AUTHOR]

The first insulin preparation injected in humans in 1922 was short-acting, extracted from animal pancreas, contaminated by impurities. Ever since the insulin extracted from animal pancreas has been continuously purified, until an unlimited synthesis of regular human insulin (RHI) became possible in the '80s using the recombinant-DNA (rDNA) technique. The rDNA technique then led to the designer insulins (analogs) in the early '90s. Rapid-acting insulin analogs were developed to accelerate the slow subcutaneous (sc) absorption of RHI, thus lowering the 2-h post-prandial plasma glucose (PP-PG) and risk for late hypoglycemia as comparing with RHI. The first rapid-acting analog was lispro (in 1996), soon followed by aspart and glulisine. Rapid-acting analogs are more convenient than RHI: they improve early PP-PG, and 24-h PG and A1C as long as basal insulin is also optimized; they lower the risk of late PP hypoglycemia and they allow a shorter time-interval between injection and meal. Today rapid-acting analogs are the gold standard prandial insulins. Recently, even faster analogs have become available (faster aspart, ultra-rapid lispro) or are being studied (Biochaperone lispro), making additional gains in lowering PP-PG. Rapid-acting analogs are recommended in all those with type 1 and type 2 diabetes who need prandial insulin replacement. • The first insulin preparation injected in humans in 1922 was short-acting extracted from animal pancreas. • Rapid-acting insulin analogs accelerate the sc absorption of regular insulin improving prandial control. • Rapid-acting insulin analogs reduce interprandial hypoglycemia and improve the 24-h PG if basal insulin is optimized. • Faster analogs (faster aspart, ultra-rapid lispro, Biochaperone lispro) allow even shorter time injection-meal. [ABSTRACT FROM AUTHOR]

After years of intensive investigation, the definition of glycaemic variability remains unclear and the term variability in glucose homoeostasis might be more appropriate covering both short and long-term glycaemic variability. For the latter, we remain in the search of an accurate definition and related targets. Recent work leads us to consider that the within-subject variability of HbA1c calculated from consecutive determinations of HbA1c at regular time-intervals could be the most relevant index for assessing the long-term variability with a threshold value of 5% (%CV = SD of HbA1c/mean HbA1c) to separate stability from lability of HbA1c. Presently, no one can deny that short- and long-term glucose variability should be maintained within their lower ranges to limit the incidence of hypoglycaemia. Usually, therapeutic strategies aimed at reducing post-meal glucose excursions, i.e. the major contributor to daily glucose fluctuations, exert a beneficial effect on the short-term glucose variability. This explains the effectiveness of adjunct therapies with either GLP- receptor agonists or SGLT inhibitors in type 2 diabetes. In type 1 diabetes, the application of a CGM device alone reduces the short-term glycaemic variability. In contrast, sophisticated insulin delivery does not necessarily lead to such reductions despite marked downward shifts of 24-hour glycaemic profiles. Such contrasting observations raise the question as to whether the prolonged wear of CGM devices is or not the major causative factor for improvement in glucose variability among intensively insulin-treated persons with type 1 diabetes. [ABSTRACT FROM AUTHOR]

OBJECTIVES--To describe the prevalence and associated risk factors for diabetic retinopathy (DR) within a multiethnic population at presentation to a diabetes clinic in South Africa. RESEARCH DESIGN AND METHODS--Retinal photography was conducted using a nonmydriatic digital camera without mydriasis and graded by one of three senior graders. Logistic regression analyses were used to assess the association between any DR, referable DR, and clinical risk factors. RESULTS--A total of 1,537 persons with type 1 and 3,978 with type 2 diabetes were included. Prevalence of any DR in type 1 diabetes was 35.2%(background DR 26%and referable DR 9.2%) and in type 2 diabetes was 20.5% (14.1 and 6.4%, respectively). In type 1 diabetes, there was an increased risk of any DR in Asian Indians, whereas the risk of referable DR was increased for indigenous Africans compared with Caucasians. In type 2 diabetes, the risk was increased for all non-Caucasians compared with Caucasians. Longer duration of diabetes and elevated HbA1c were independently associated with any and referable DR in both type 1 and type 2 diabetes, with the addition of hypertension and smoking in type 1 diabetes when adjusted for age at diagnosis of diabetes, sex, and ethnicity. CONCLUSIONS--The prevalence of DR in this population from South Africa was similar to that reported globally; however, ethnic differences were observed. Increasing duration of diabetes and poor glycemic control were the strongest risk factors associated with any and referable DR in both type 1 and type 2 diabetes. [ABSTRACT FROM AUTHOR]

Advances in insulin therapy have made a positive contribution to improving disease management in both Type 1 and Type 2 diabetes. The development of insulin analogs with time-action characteristics has made it easier to mimic physiological insulin secretion. The parallel improvement in delivery devices has also made insulin therapy more convenient, flexible and acceptable. The inevitable progression of Type 2 diabetes means that the majority of those people will also require insulin therapy at some point in their disease course. Current treatment options are many; when to initiate insulin and which regimen to choose are among the major questions confronting physicians in today's rapidly evolving environment. This article summarizes the current strategies for initiating and optimizing the use of the basal insulin analog, insulin glargine, in Type 2 diabetes, leading to the intermediate stage of insulin therapy with the introduction of meal-related, rapid-acting insulin analogs in a stepwise manner prior to a full replacement basal-bolus regimen. [ABSTRACT FROM AUTHOR]

Lifestyle advice is routinely given to people with diabetes in primary care; however, the extent to which this advice improves body composition and glycaemic control is difficult to measure. The authors of this study investigated the impact of routine lifestyle advice on body composition and HbA1c level in newly diagnosed treatment-naïve people with type 2 diabetes. Participants underwent a thorough assessment including anthropometric measurements, metabolic parameters and dual energy X-ray absorptiometry (DXA) scan, and given lifestyle advice at baseline and 8 weeks. Assessment took place again at 24 weeks. The authors of this article report their primary care research. [ABSTRACT FROM AUTHOR]

LAPTOP (Lantus + Amaryl + metformin vs. premixed* insulin in Patients with Type-2 diabetes mellitus after failing Oral treatment Pathways) was a multinational study which compared the addition of once daily insulin glargine (IG, Lantus) with the oral antidiabetic drugs (OADs) glimepiride and metformin with twice daily 30% regular/70% human neutral protamine hagedorn (NPH) insulin (Actraphane 30) and no OADs in 371 type 2 diabetes patients over a 24-week period. IG plus OADs was seen to be significantly more effective in lowering glycated haemoglobin A1C (HbA1C) (-1.64% vs. - 1.31%). We undertook a cost minimisation analysis using data from the LAPTOP study to determine the relative costs of the two treatment regimens. Overall, the cost per patient for 24 weeks for the IG plus OADs group was £207.61 compared with £313.49 for biphasic insulin aspart (BIA), a difference of 34%. During the 24-week period of the study the cost of a 1% reduction in HbA1C was £126.59 for IG plus OADs and £239.31 for BIA only. A 1 mmol/L reduction in fasting blood glucose cost £97 with IG plus OADs and £142.50 with BIA. The cost of achieving an equivalent reduction in HbA1C was 34% less with IG plus OADs than twice daily BIA with no OADs. [ABSTRACT FROM PUBLISHER]

The aim of this study was to examine the effectiveness of either a standard care programme (n = 9) or a 12-week supported exercise programme (n = 10) on glycaemic control, β-cell responsiveness, insulin resistance, and lipid profiles in newly diagnosed Type 2 diabetes patients. The standard care programme consisted of advice to exercise at moderate to high intensity for 30 min five times a week; the supported exercise programme consisted of three 60-min supported plus two unsupported exercise sessions per week. Between-group analyses demonstrated a difference for changes in low-density lipoprotein cholesterol only (standard care programme 0.01 mmol · L-1, supported exercise programme -0.6 mmol · L-1; P = 0.04). Following the standard care programme, within-group analyses demonstrated a significant reduction in waist circumference, whereas following the supported exercise programme there were reductions in glycosylated haemoglobin (6.4 vs. 6.0%; P = 0.007), waist circumference (101.4 vs. 97.2 cm; P = 0.021), body mass (91.7 vs. 87.9 kg; P = 0.007), body mass index (30.0 vs. 28.7 kg · m-2; P = 0.006), total cholesterol (5.3 vs. 4.6 mmol · L-1; P = 0.046), low-density lipoprotein cholesterol (3.2 vs. 2.6 mmol · L-1; P = 0.028), fasting β-cell responsiveness (11.5 × 10-9 vs. 7.0 × 10-9 pmol · kg-1 · min-1; P = 0.009), and insulin resistance (3.0 vs. 2.1; P = 0.049). The supported exercise programme improved glycaemic control through enhanced β-cell function associated with decreased insulin resistance and improved lipid profile. This research highlights the need for research into unsupported and supported exercise programmes to establish more comprehensive lifestyle advice for Type 2 diabetes patients. [ABSTRACT FROM AUTHOR]

Tight glycaemic control is essential to reduce the risk of developing the micro- and macrovascular complications of diabetes. Plasma levels of glycosylated haemoglobin (HbA 1C) are a marker for long-term glycaemia; controlling these levels within tight limits forms the cornerstone of long-term diabetes management. As a result of evidence from key clinical trials in type 1 and type 2 diabetes, HbA1C targets ranging from < 6.5 to < 7.5% have been set by various authorities. To achieve these targets, insulin regimens need to reflect normal physiological insulin release. Several rapid- and long-acting insulin analogues have been developed to mimic aspects of insulin secretion. Insulin glulisine is a genetically engineered insulin which has a rapid onset and short lived action, allowing it to closely mimic prandial release of insulin. In addition to the structural change in the insulin molecule, the absence of excess zinc and the addition of polysorbate 20 as a surfactant facilitates its disassociation in the subcutaneous tissue and inhibits its aggregation when used in subcutaneous insulin delivery systems due to improved physical stability. [ABSTRACT FROM PUBLISHER]

OBJECTIVE -- The Cockcroft-Gault (CG) and Modification of Diet in Renal Disease (MDRD) equations previously have been recommended to estimate glomerular filtration rate (GFR). We compared both estimates with true GFR, measured by the isotopic 51Cr-EDTA method, in newly diagnosed, treatment-naïve subjects with type 2 diabetes. RESEARCH DESIGN AND METHODS -- A total of 292 mainly normoalbuminuric (241 of 292) subjects were recruited. Subjects were classified as having mild renal impairment (group 1, GFR <90 ml/min per 1.73 m²) or normal renal function (group 2, GFR ≥90 ml/min per 1.73 m²). Estimated GFR (eGFR) was calculated by the CG and MDRD equations. Blood samples drawn at 44, 120, 180, and 240 min after administration of 1 MBq of 51Cr-EDTA were used to measure isotopic GFR (iGFR). RESULTS -- For subjects in group 1, mean (±SD) iGFR was 83.8 ± 4.3 ml/min per 1.73 m². eGFR was 78.0 ± 16.5 or 73.7 ± 12.0 ml/min per 1.73 m² using CG and MDRD equations, respectively. Ninety-five percent CIs for method bias were -11.1 to -0.6 using CG and -14.4 to -7.0 using MDRD. Ninety-five percent limits of agreement (mean bias ± 2 SD) were -37.2 to 25.6 and -33.1 to 11.7, respectively. In group 2, iGFR was 119.4 ± 20.3 ml/min per 1.73 m². eGFR was 104.4 ± 26.3 or 92.3 ± 18.7 ml/min per 1.73 m² using CG and MDRD equations, respectively. Ninety-five percent CIs for method bias were -17.4 to -12.5 using CG and -29.1 to -25.1 using MDRD. Ninety-five percent limits of agreement were -54.4 to 24.4 and -59.5 to 5.3, respectively. CONCLUSIONS -- In newly diagnosed type 2 diabetic patients, particularly those with a GFR ≥90 ml/min per 1.73 m², both CG and MDRD equations significantly underestimate iGFR. This highlights a limitation in the use of eGFR in the majority of diabetic subjects outside the setting of chronic kidney disease. [ABSTRACT FROM AUTHOR]

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 (≥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. [ABSTRACT FROM AUTHOR]

Abstract: Type 2 diabetes is characterised by a gradual decline in insulin secretion in response to nutrient loads; hence, it is primarily a disorder of postprandial glucose (PPG) regulation. However, physicians continue to rely on fasting plasma glucose (FPG) and glycosylated haemoglobin (HbA1c) levels as indicators for disease management. There is a linear relationship between the risk of cardiovascular disease (CVD) and the two-hour oral glucose tolerance test (OGTT), while a recent study confirms postprandial hyperglycaemia as an independent risk factor for CVD in type 2 diabetes. At the same time, several intervention studies have shown that treating postprandial hyperglycaemia may reduce the incidence of new cardiovascular events. Evidence supports the hypothesis that postprandial hyperglycaemia may be linked to CVD through the generation of oxidative stress. Furthermore, clinical data suggest that postprandial hyperglycaemia is a common phenomenon, even in patients who may be considered in ‘good metabolic control’. Therefore, in addition to HbA1c and FPG, physicians should consider monitoring and targeting PPG in patients with type 2 diabetes. [Copyright &y& Elsevier]

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 HbA1c] 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 (ΔI30/ΔG30) and insulin area under the curve (AUC) from 0 to 30 min (AUC0-30) 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 t he 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]

OBJECTIVE-To know whether age has an independent effect on the dawn phenomenon in noninsulin-using type 2 diabetes. RESEARCH DESIGN AND METHOD-Eighty-one individuals with type 2 diabetes were matched for HbA1c and divided by age into three subgroups of 27 individuals (1: ⩾70 years; 2: 60-69 years; and 3: ⩽59 years). All underwent ambulatory continuous glucose monitoring for quantifying the dawn phenomenon (i.e., the absolute [∂G, mg/dL] or relative [∂G%] increments from nocturnal nadirs to prebreakfast time points). RESULT-HbA1c levels and 24-h glycemic profiles were similar across the three groups. Glucose increments (mean ± SEM) were identical in the three groups: ∂G (mg/dL), 22.0 ± 4.7 (1), 21.3±3.6 (2), and 18.0±3.6 (3) and δG(%), 19.9±4.9 (1), 21.6±4.4 (2), and 17.6± 4.2 (3). Using the most common definition (∂G >10 mg/dL), the prevalence of the dawn phenomenon was 52, 70, and 59% in groups 1, 2, and 3, respectively. CONCLUSION-The dawn phenomenon is present in the elderly. [ABSTRACT FROM AUTHOR]

The article discusses a study which is aimed at identifying whether body weight may explain variability in performance between the Cockcroft-Gault and Modification of Diet in Renal Disease (MDRD) equations in patients newly diagnosed with type 2 diabetes. Accordingly, the study consisted of 293 subjects newly diagnosed with type 2 diabetes; 96% were Caucasian and the remainder of South Asian origin. It has been found that both formulae presented introduced significant biases and, in average terms, underestimated glomerular filtration rate (GFR).

A letter to the editor is presented in response to the article "Glucose variability in a 26-week randomized comparison of mealtime treatment with rapid-acting insulin versus GLP-1 agonist in participants with type 2 diabetes at high cardiovascular risk" in the previous issue.

It has been shown that in response to a standard meal, the contribution of postprandial glucose (PPG) to excess hyperglycaemia is predominant in the well controlled; while the contribution of fasting glucose (FPG) increases with worsening glycaemia in persons with type 2 diabetes (T2DM). The aim of this study was to investigate the contributions of PPG and FPG to excess hyperglycaemia in response to each of 3 identical meals over a 12 hour period. Non-insulin treated persons with T2DM (n=52; 37 men) were stratified into tertiles according to HbA1c [(Gp1: <7.3% (n= 18); Gp2:7.3 - 8.0% (n=l 7); Gp3: >8.0% (n= 17)]. All were on a stable dose of gliclazide for at least 3 months, with or without metformin. All subjects undertook 3 consecutive standard meal tolerance tests (MTT) at 08.00, 12.00 and 16.00hrs following an overnight fast with samples taken for plasma glucose at regular intervals for the 12 hour duration of the test. Relative contributions were calculated using areas under the glucose curve (AUC). PPG exposure was the AUC above actual FPG and excess hyperglycaemia was the AUC above 5.5mmol/L (ADA upper limit of normal FPG). Fasting related hyperglycaemia was the difference between the above two AUC values. Absolute contributions of PPG and FPG to excess HbA1c (HbA1c -5.1%) were also calculated. In all groups, the relative contribution of PPG exposure to excess hyperglycaemia was highest following the third meal of the day (Gp1: 58.3, 69.8, 85.8%; Gp2: 54.3, 54.7. 70.2%; Gp3: 33.4, 23.7, 48.6% for meals1, 2 and 3 respectively). Absolute contributions of PPG and FPG to excess HbA1c (>5.1%) were: Gp1: 1.4 vs. 0.3%; Gp2: 1.6 vs. 0.9%, and Gp3: 1.3 vs. 2.5%; PPG vs. FPG contribution respectively. These results confirm that the relative contribution of postprandial glucose to excess hyperglycaemia increases as glycaemic control improves. The absolute contribution of postprandial glucose to HbA[sub 1c] remains stable across the HbA[sub 1c] range, with the contribution from fasting glucose increasing as glycaemia deteriorates. [ABSTRACT FROM AUTHOR]

Non-esterified fatty acids (NEFA) and glucose metabolism are highly linked, but NEFA metabolism in type 2 diabetes mellitus remains controversial. It is generally believed that NEFA levels are augmented in persons with type 2 diabetes mellitus in the face of hyperinsulinemia, and that this augmentation contributes to insulin resistance. Our aim was to investigate NEFA levels following a standard meal tolerance test (MTT) in a population of persons with newly diagnosed type 2 diabetes mellitus (T2DM) across a spectrum of glycemic control. 368 newly diagnosed subjects with T2DM and 70 non-diabetic subjects were fasted overnight and studied for 4 hours aider ingesting a standardised mixed meal (500 kcal: 58% carbohydrate, 22% fat and 19% protein; 75g glucose). Fasting plasma glucose (FPG), fasting plasma insulin (FPI) and fasting plasma NEFA (FPN) were higher in T2DM than in the control group. FPN correlated weakly, but statistically significantly, to FPG (R²=0.150, p<0.0001). Although there was a general trend in the patients with T2DM to have higher FPN levels than healthy subjects (mean FPN: 0.47 mM vs 0.66 mM), but with huge variations as some patients had normal or below normal FPN levels. The variations were not associated with BMI, fasting triglycerides, or FPI. At 60 min after the start of the MTT, NEFA levels were suppressed equally (by 0.3 mM) in both controls and persons with T2DM (mean NEFA: 0.14 mM vs 0.37 mM). Postprandial NEFA suppression was related to the postprandial insulin level and the severity of the disease. Patients with FPG above 13 mM had almost no postprandial suppression of NEFA. In newly diagnosed persons with T2DM NEFA levels are augmented despite fasting hyperinsulinemia, indicating that NEFA metabolism is insulin resistant. Following a mixed meal these subjects were still able to respond to insulin in respect to their NEFA metabolism, but postprandial NEFA levels are highly related to postprandial insulin secretion. [ABSTRACT FROM AUTHOR]

Background Insulin resistance and hypertension are common co-existing conditions. Antihypertensive agents have differing effects on insulin sensitivity (SI). We studied 11 mildly hypertensive insulin-resistant type 2 diabetic patients to observe any changes in SI, glucose effectiveness (SG), serum total cholesterol, serum triglycerides and blood pressure (BP) with the introduction of the angiotensin II inhibitor, losartan.Methods To assess SI and SG, we used the frequently sampled, intravenous glucose tolerance test with minimal model analysis prior to and after three months treatment with losartan potassium 50—100 mg daily. BP was assessed using a Space Labs 24-hour BP recording device before, during and after treatment with losartan.Results There were no significant differences in SI and SG pre-and post-treatment, however, there was a non-significant reduction in mean BP, total cholesterol and triglyceride concentrations.Conclusion There were no adverse effects of losartan on SI or SG. The lower but non-significant serum total cholesterol and triglyceride concentrations warrant further study. [ABSTRACT FROM PUBLISHER]

A response by the authors to a review of their article "Magnitude of the Dawn Phenomenon and Its Impact on the Overall Glucose Exposure in Type 2 Diabetes: Is This of Concern?" which appeared in a 2013 issue of the periodical "Diabetes Care" is presented.

Aims Liver disease is highly prevalent among people with type 2 diabetes mellitus (T2DM). We evaluated the dipeptidyl peptidase-4 inhibitor linagliptin in subjects with T2DM and hepatic disorders. Methods Data were pooled from 17 randomized, double-blind, placebo-controlled clinical trials of linagliptin in T2DM subjects that included individuals with self-reported history of hepatic disorders at baseline. The primary endpoint was change in HbA1c from baseline to week 24. Results Of the 7009 participants (56% white, 39% Asian), 574 had hepatic disorders, most commonly hepatic steatosis (60%). At week 24, adjusted mean ± standard error (SE) change in HbA1c from baseline in those with hepatic disorders was − 0.75% ± 0.05 with linagliptin and − 0.20% ± 0.08 with placebo [treatment difference: − 0.54% (95% confidence interval −0.72 to − 0.36); P < .0001]. There was no significant difference in HbA1c reduction between subjects with or without baseline hepatic disorders ( P = .4042). Among subjects with hepatic disorders, 13.5% and 14.8% of the linagliptin and placebo groups, respectively, reported drug-related adverse events while 10.4% and 15.9%, respectively, reported hypoglycemia. Overall, adverse event rates were similar in individuals with or without hepatic disorders. Conclusions This large pooled analysis suggests that linagliptin is effective and well tolerated in people with T2DM and liver disease. [ABSTRACT FROM AUTHOR]

It has been previously suggested that glycaemic excursions in subjects with type 2 diabetes vary during the day, following identical meals. The aim of this study was to investigate, in subjects with different levels of HbA[sub 1c] differences in B-cell secretory patterns during the day in response to 3 identical meals. Non- insulin treated persons with type 2 diabetes (n=49) were recruited into this study. All were on a stable dose of gliclazide for at least 3 months, with or without metformin. All subjects had 3 consecutive standard 500kcal meal tolerance tests (MTT) at 08.00, 12.00 and 16.00hrs following an overnight fast. Plasma glucose, insulin, C-peptide, total and intact proinsulin were measured over the 12 hour study period. Subjects were divided into groups according to their HbA[sub 1c] (Gp1 <7.3% [n=l 8]; Gp2 7.3-8.0% [n=17]; Gp3 >8.0% [n=14]). Excursions were determined by area under the curve above baseline level (δAUC), calculated by the trapezoidal rule. In all groups, the largest glucose excursion of the day was following the morning meal, with the middle meal having the smallest excursion (Gp1: 11.26±1.23, 4.70±0.97, 7.86±-0.91; Gp2: 14.24±1.02, 3.12±1.09, 7.05±0.85; Gp3:13.48±1.90, 2.93±0.76, 6.72±0.85mmol.h/L; meals 1, 2 and 3, respectively). In all three groups, plasma insulin, C-peptide, total and intact proinsulin were significantly different between meals 1 and 2 (p<0.05) and meals 1 and 3 (p<0.05), with the greatest excursion observed during meal 1. Plasma insulin excursions were significantly different between meals 2 and 3 in Gp1 (p<0.05), however no significant differences were observed in Gp2 and Gp3. There were no significant differences in C-peptide, total or intact proinsulin responses between meals 2 and 3. In these non-insulin treated persons with type 2 diabetes, the greatest glucose excursion was following the morning meal, irrespective of glycaemic control. In the better controlled subjects (HbA[sub 1e] <7.3%), the glucose stimulated insulin response was relatively maintained throughout the day, however, as glycaemic control deteriorated beta-cell secretion became insensitive to glucose stimulation particularly following the evening meal. [ABSTRACT FROM AUTHOR]

Introduction: Estimation of glomerular filtration rate (eGFR) based on creatinine underestimates isotopically measured glomerular filtration rate (iGFR), especially in patients with preserved kidney function (GFR >90 ml/min/1.73m²). Cystatin C a cysteine protease has been proposed as an alternative marker of kidney function. We compared the performance of Cystatin C, the creatinine based Modification of Diet in Renal Disease study (MDRD) and Cockcroft-Gault (CG) equations with iGPR in a small number of newly diagnosed type 2 diabetic subjects. Methods: 37 newly diagnosed treatment naive subjects with type 2 diabetes were studied. Subjects had a mean (+/-SD) age of 57.9 (8.18) years, weight of 91.64 (13.15) kg and BMI of 30.60 (4.38) kg/m². Subjects mean (+/-SD) fasting plasma glucose was 7.97 (1.54) mmol/l and HbA1c was 6.84 (1.41) %. eGFR was derived using 100/Cystatin C the MDRD and CG equations, iGFR was obtained by the simplified, 4-sample [sup 51]CrEDTA clearance method. Results: Mean (+/-SD) serum creatinine concentration was 86.54 (13.22) µmo1/1 and Cystatin C concentration was 0.697 (0.118) mg/l. Correlation between 1/creadnine and iGFR was r=0.443 compared to l/Cystatin C and iGFR of r=0.604. Mean iGFR was 107.4 (17.2) ml/min/1.73m² compared with mean eGFR of 82.8 (15.0), 90.6 (21.5) and 147.4 (22.9) ml/min/l.73m² for MDRD, CG and 100/Cystatin C respectively. Correlation between MDRD, CG and 100/Cystatin C with iGFR was r=0.514, r=0.577 mad r=0.601 respectively. Conclusion: In type 2 diabetic subjects with preserved kidney function correlation between 1/Cystatin C and iGFR was superior that of 1/creatinine and iGFR. Correlation between 100/Cystatin C and iGFR was comparable to that between MDRD and CG With iGFR. 100/Cystatin C derived eGFR significantly overestimated iGFR unlike the MDRD and CG equations which significantly underestimated iGFR. Cystatin C may in the future prove to be a useful marker of kidney function in this group of diabetic patients. [ABSTRACT FROM AUTHOR]

The routine use of the 75g oral glucose tolerance test (OGTT) in the diagnosis of diabetes is debatable, however it remains the reference method to categorise glucose tolerance. The aim of this study was to evaluate the reproducibility of the OGTT across a spectrum of glucose tolerance. A standard 75g OGTT was performed in 129 subjects (66 males) at approx 8.00 am following a 10 hour overnight fast. Based on the results, subjects were classified into four groups of glucose tolerance based on the WHO criteria; normal glucose tolerance (NGT, n=42), impaired fasting glucose (IFG, n=10), impaired glucose tolerance (IGT, n=37) and type 2 diabetes mellitus (T2DM, n=50). Subjects returned within one week for a repeat OGTT under identical conditions. Due to the relatively small numbers, subjects with IFG were excluded from further analysis. The mean (±SEM) time interval between the two OGTTs was 3.6 ± 0.2 days. The mean FPG for the whole group, was 6.3±0.1 mmol/L on both days with the mean 2-hour post prandial glucose (PPG) 9.1±0.3 and 9.3±0.3 mmol/L on study days 1 and 2 respectively. The diagnostic reproducibility and coefficient of variation (CV) for the FPG was 72% and 5.4% respectively and for PPG, 71% and 13.0% respectively. The mean (days 1 and 2) FPG values were 5.2±0.1 and 5.2±0.1 mmol/L in NGT, 6.0±0.1 and 5.9±0.1 mmol/L in IGT and 7.4±0.2 and 7.4±0.2 mmol/L in T2DM. The mean (days 1 and 2) PPG values were 5.8±0.2 and 6.4±0.3 mmol/L in NGT, 9.0±0..2 and 8.8±0.3 mmol/L in IGT and 12.5±0.5 and 12.4±0.6 mmol/L in T2DM. For the whole group, 67% of cases were similarly classified in OGTT1 and 2. In subjects with NGT at OGTT1, 71% remained NGT, while 5% progressed to IFG and 24% to IGT. In those with IGT, 59% remained IGT, while 19% reverted to NGT, 11% to IFG and 11% progressed to T2DM. Finally, of those classified as T2DM based on OGTT 1, 74% remained as T2DM, while 8% reverted to IFG and 18% to IGT. It is essential to be aware of the variability in the response to an oral-ghicose challenge in defining the level of glucose tolerance. [ABSTRACT FROM AUTHOR]

Aim: We examined the effects of adding glargine to metformin-sitagliptin (MS + G) or sitagliptin to metforminglargine (MG + S) therapy in type 2 diabetic persons uncontrolled after 24-week MS or MG dual therapy. Methods: Subjects with A1c ≥ 7% on MS or MG treatment were respectively given glargine (0.2 U/kg starting dose) or sitagliptin (100 mg daily) for 12 weeks. The primary endpoint was number of subjects attaining A1c goal defined as < 7%. Results: After receiving 24-week MS or MG dual therapy in the original EASIE Study, 42% (104/248) on MS and 68% (152/224) on MG attained A1c < 7% (p < 0.0001). The reduction in A1c was negatively associated with baseline fasting blood glucose (FBG) only in the MG group. Reduction in A1c was not related to baseline postprandial blood glucose (PPBG) in either the MG or MS group. Amongst 194 eligible patients, 57.7% (n = 111) entered the 12-week extension trial [MS + G:74/131, 57.3%; MG + S:37/63, 58.7%) with 55 (51.9%) subjects attaining goal [MS + G:59.2%; MG + S:37.1%] at week 12. The final insulin dosage was similar in both groups [MS + G: 0.46 U/kg; MG + S: 0.45 U/kg] with a higher rate of hypoglycemia in the MG + S (6.5 events/patient-year) than the MS + G group (3.2 events/patient-year), although neither group had severe hypoglycemia. Conclusion: In metformin-treated type 2 diabetes patients, high fasting BG predicted greater A1c reductions with the addition of glargine, but not with sitagliptin. In subjects uncontrolled with 6-month dual therapy of MS or MG, 50% attained A1c < 7% with triple therapy of MS + GorMG + S in 12 weeks. The increased rate of hypoglycemia with MG + S (but not with MS + G) underlines the need to take measures to avoid the hypoglycemia. [ABSTRACT FROM AUTHOR]

The prevention of type 2 diabetes mellitus (T2DM) is a target priority for the WHO and the United Nations and is a key priority in the 2018 Berlin Declaration, which is a global call for early actions related to T2DM. Health-care policies advocate that individuals at high risk of developing T2DM undertake lifestyle modification, irrespective of whether the prediabetes phenotype is defined by hyperglycaemia in the postprandial state (impaired glucose tolerance) and/or fasting state (impaired fasting glucose) or by intermediate HbA1c levels. However, current evidence indicates that diabetes prevention programmes based on lifestyle change have not been successful in preventing T2DM in individuals with isolated impaired fasting glucose. We propose that further research is needed to identify effective lifestyle interventions for individuals with isolated impaired fasting glucose. Furthermore, we call for the identification of innovative approaches that better identify people with impaired glucose tolerance, who benefit from the currently available lifestyle-based diabetes prevention programmes. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

"Mild dysglycemia" in type 2 diabetes can be defined by the range of HbA1c levels ≥ 6.5% (48 mmol/mol) and b 7% (53 mmol/mol), which corresponds to when the risk for vascular complications begins to increase. This "mild dysglycemia" is characterized by both a dawn phenomenon (a spontaneous blood glucose rise in the early morning) and an excess of post-prandial glucose excursions in the absence of abnormal elevation in basal glucose, especially during nocturnal periods. This represents an intermediary stage between pre-diabetes (HbA1c ≥ 5.7%, 39 mmol/mol, and b 6.5%, 48 mmol/mol) and those who begin to show a steadily progressive worsening in basal glucose (HbA1c ≥ 7%, 53 mmol/mol). Should this relatively minor intermediate dysglycemic phase deserve more attention, that is the question. The now available incretin-based therapies, and more specifically the DPP-4 inhibitors provide the clinician with the possibility to reduce or eradicate both the dawn phenomenon and post-meal glucose excursions with minimal side effects. The availability of 24-h glycemic profiles in those with "mild dysglycemia" will help to describe their individual glycemic phenotype, based on which the early and appropriate life style changes and/or pharmacological interventions can be introduced. [ABSTRACT FROM AUTHOR]

Aims: To assess the incidence and progression of diabetic retinopathy (DR) 12 months post bariatric surgery in persons with morbid obesity and type 2 diabetes. Methods: A retrospective pilot analysis of electronic hospital records between 1998 and 2012. Results: 40 of 148 subjects had pre- and post-surgery DR screening. Of those without DR pre-surgery 1.5% (n = 26) progressed to minimum background DR (BDR) post surgery. Those with minimum BDR (n = 9) pre-surgery revealed no progression, with 55.6% (n = 5) showing evidence of regression. One person with moderately severe BDR and two with pre-proliferative DR (PPDR) prior to surgery experienced progression. Two persons with PPDR prior to surgery remained under the hospital eye services and were therefore not eligible to be re-assessed by the screening service. Conclusions: There was a low incidence of new DR and progression of DR in those either without evidence of retinopathy or with minimal BDR prior to surgery with some subjects showing evidence of regression. There was however a risk of progression of DR in those with moderate BDR or worse, and should therefore be monitored closely post-surgery. [ABSTRACT FROM AUTHOR]