Quantifying cardiovascular disease risk and heart age predictions for men in the prison environment.

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.

Safety of the use of gold nanoparticles conjugated with proinsulin peptide and administered by hollow microneedles as an immunotherapy in type 1 diabetes.

Antigen-specific immunotherapy is an immunomodulatory strategy for autoimmune diseases, such as type 1 diabetes, in which patients are treated with autoantigens to promote immune tolerance, stop autoimmune ß-cell destruction and prevent permanent dependence on exogenous insulin. In this study, human proinsulin peptide C19-A3 (known for its positive safety profile) was conjugated to ultrasmall gold nanoparticles (GNPs), an attractive drug delivery platform due to the potential anti-inflammatory properties of gold. We hypothesised that microneedle intradermal delivery of C19-A3 GNP may improve peptide pharmacokinetics and induce tolerogenic immunomodulation and proceeded to evaluate its safety and feasibility in a first-in-human trial. Allowing for the limitation of the small number of participants, intradermal administration of C19-A3 GNP appears safe and well tolerated in participants with type 1 diabetes. The associated prolonged skin retention of C19-A3 GNP after intradermal administration offers a number of possibilities to enhance its tolerogenic potential, which should be explored in future studies.

Temporal Effects of Sleeve Gastrectomy on Glucose-Insulin Homeostasis and Incretin Hormone Response at 1 and 6 Months.

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/m2, 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.

Detecting autoreactive B cells in the peripheral blood of people with type 1 diabetes using ELISpot.

Type 1 diabetes mellitus (T1D) is an autoimmune disorder where T lymphocytes damage the islet beta cells but B lymphocytes also play an important role. Although changes in peripheral B cell phenotype have been observed, little is known about the B cells that secrete the autoantibodies. We developed a sensitive B cell enzyme-linked immunospot assay (ELISpot assay) to detect individual B cell antibody responses to glutamic acid decarboxylase (GAD) and islet antigen-2 (IA-2). We found that even healthy donors have B cells that secrete antibodies in response to GAD and IA-2 in the ELISpot. There was increased B cell reactivity to autoantigens in the peripheral blood of individuals with newly-diagnosed, but not long-standing, type 1 diabetes. However, no correlation with serum autoantibody levels was found, indicating that additional factors such as antigen affinity or exposure to antigens in vivo are required for antibody secretion, and that even healthy donors have potentially autoreactive B cells.

Performance evaluation of a self-administered home oral glucose tolerance test kit in a controlled clinical research setting.

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.

Comparison of a point-of-care analyser for the determination of HbA1c with HPLC method.

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 (R2=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.

Stimulated urine C-peptide creatinine ratio vs serum C-peptide level for monitoring of ß-cell function in the first year after diagnosis of Type 1 diabetes.

AIMS: To determine if urine C-peptide/creatinine ratio is a useful tool for monitoring ß-cell function in new-onset Type 1 diabetes. METHODS: Data were obtained from a prospective immunomodulation study in people with Type 1 diabetes ≤ 3 months from diagnosis, with a standard mixed-meal tolerance test and measurement of urine C-peptide/creatinine ratio carried out at 0, 3, 6, 9 and 12 months. The change in the insulin-dose-adjusted HbA1c level was also correlated with the change in serum/urine C-peptide level during the 12-month follow-up period. RESULTS: A significant reduction in urine C-peptide/creatinine ratio, measured after a mixed-meal, was reached at 9 months (-45.4%), whilst the reduction in stimulated serum C-peptide level reached significance after 3 months (-54.7%) in placebo-treated participants. Neither change in stimulated serum C-peptide nor change in urine C-peptide level correlated with each other, and nor did change in insulin-dose-adjusted HbA1c level in the first 6 months, but all measures correlated significantly in the second half of the 12-month follow-up period. CONCLUSION: Mixed-meal-stimulated urine C-peptide/creatinine ratio was similar to, although less sensitive than, stimulated serum C-peptide level in monitoring ß-cell function during the first year after diagnosis. Because the former is significantly less invasive, it warrants inclusion in further studies in Type 1 diabetes and may represent an attractive alternative outcome measure in cohort studies and in children.

Similar magnitude of post-exercise hyperglycemia despite manipulating resistance exercise intensity in type 1 diabetes individuals.

The aim of this study was to compare the glycemic and glucoregulatory hormone responses to low- and moderate-intensity morning resistance exercise (RE) sessions in type 1 diabetes (T1DM). Following maximal strength assessments (1RM), eight T1DM (HbA1C :72 ± 12 mmol/mol, age:34 ± 7 years, body mass index:25.7 ± 1.6 kg/m(2) ) participants attended the research facility on two separate occasions, having fasted and taken their usual basal insulin but omitting rapid-acting insulin. Participants performed six exercises for two sets of 20 repetitions at 30%1RM during one session [low-intensity RE session (LOW)] and two sets of 10 repetitions at 60%1RM during another session [moderate-intensity RE session (MOD)], followed by 65-min recovery. Sessions were matched for total mass lifted (kg). Venous blood samples were taken before and after exercise. Data (mean ± SEM) were analyzed using analysis of variance (P ≤ 0.05). There were no hypoglycemic occurrences throughout the study. Blood glucose rose similarly between sessions during exercise (P = 0.382), remaining comparable between sessions throughout recovery (P > 0.05). There was no effect of RE intensity on metabolic acidosis (P > 0.05) or peak growth hormone responses (P = 0.644), but a tendency for greater catecholamine responses under LOW (individualized peak concentrations: adrenaline MOD 0.55 ± 0.13 vs LOW 1.04 ± 0.37 nmol/L, P = 0.155; noradrenaline MOD 4.59 ± 0.86 vs LOW 7.11 ± 1.82 nmol/L, P = 0.082). The magnitude of post-exercise hyperglycemia does not differ between equal volume low and moderate intensity RE sessions performed in the morning.

Impact of single and multiple sets of resistance exercise in type 1 diabetes.

To examine glycemic and glucoregulatory responses to resistance exercise (RE) sessions of different volume in type 1 diabetes (T1DM). Eight T1DM (seven males: one female; age: 38 ± 6 years, HbA1C : 8.7 ± 1.0%/71 ± 11 mmol/mol) attended the research facility fasted and on four separate occasions, having taken their usual basal insulin, but omitted morning rapid-acting insulin. Participants completed a 1SET (14 min), 2SET (28 min), 3SET (42 min) RE session (eight exercises × 10 repetitions) at 67 ± 3% one-repetition-maximum followed by 60-min recovery, or a resting trial (CON). Venous blood samples were taken before and after exercise. Data (mean ± SEM) were analyzed using repeated-measures analysis of variance (P ≤ 0.05). RE did not induce hypoglycemia (BG < 4 mmol/L). During recovery, blood glucose (BG) concentrations remained above pre-exercise after 1SET (15-60 min, P < 0.05) and 2SET (0-60 min, P < 0.05) but comparable (P > 0.05) with pre-exercise after 3SET. BGIAUC(area-under-curve) (mmol/L/60 min) was greater after 1SET and 2SET vs CON (1SET 103.6 ± 36.9 and 2SET 128.7 ± 26.1 vs CON -24.3 ± 15.2, P < 0.05), but similar between 3SET and CON (3SET 40.7 ± 59.3, P > 0.05). Under all trials, plasma creatine kinase levels at 24 h post-exercise were similar (P > 0.05) to pre-exercise. RE does not induce acute hypoglycemia or damage muscle. BG progressively rose after one and two sets of RE. However, inclusion of a third set attenuated exercise-induced hyperglycemia and returned BG to that of a non-exercise trial.

Central arterial stiffness and diastolic dysfunction are associated with insulin resistance and abdominal obesity in young women but polycystic ovary syndrome does not confer additional risk.

STUDY QUESTION: Are arterial stiffness, carotid intima-media thickness and diastolic dysfunction increased in young women with polycystic ovary syndrome (PCOS) independently of the effects of obesity? SUMMARY ANSWER: Insulin resistance and central obesity are associated with subclinical cardiovascular dysfunction in young women, but a diagnosis of PCOS does not appear to confer additional risk at this age. WHAT IS KNOWN ALREADY: Some studies have shown that young women with PCOS may have increased measures of cardiovascular risk, including arterial stiffness, carotid intima-media thickness and myocardial dysfunction. However, it is difficult to establish how much of this risk is due to PCOS per se and how much is due to obesity and insulin resistance, which are common in PCOS and themselves associated with greater vascular risk. STUDY DESIGN, SIZE, DURATION: This cross-sectional study comprised 84 women with PCOS and 95 healthy volunteers, aged 16-45 years. PARTICIPANTS/MATERIALS, SETTING, METHODS: The study was conducted in a university hospital. Subjects underwent a comprehensive assessment of body composition (including computed tomography (CT) assessment of visceral fat; VF), measurements of arterial stiffness (aortic pulse wave velocity; aPWV), common carotid intima-media thickness (ccIMT), diastolic function (longitudinal tissue velocity; e':a') and endocrinological measures. A sample size of 80 in each group gave 80% power for detecting a difference of 0.45 m/s in aPWV or a difference of 0.25 in e':a'. MAIN RESULTS AND THE ROLE OF CHANCE: After adjustment for age and body mass index (BMI), PCOS subjects had a greater insulin response (insulin area under the curve-IAUC) following glucose challenge (adjusted difference [AD] 35 900 pmol min/l, P < 0.001) and higher testosterone (AD 0.57 nmol/l, P < 0.001) and high molecular weight adiponectin than controls (AD 3.01 µg/ml, P = 0.02), but no significant differences in aPWV (AD -0.13 m/s, P = 0.33), ccIMT (AD -0.01 mm, P = 0.13), or e':a' (AD -0.01, P = 0.86) were observed. After adjustment for age, height and central pulse pressure, e':a' and aPWV were associated with logVF and IAUC. ccIMT was not related to logVF. The relationships between e':a' or aPWV and insulin resistance were only partly attenuated by adjusting for logVF. There was no significant relationship between aPWV or e':a' and either testosterone or adiponectin. LIMITATIONS, REASONS FOR CAUTION: The study recruited young women meeting the Rotterdam criteria for PCOS diagnosis; hence our findings may not be generalizable to older patients or those meeting other definitions of the syndrome. Biochemical hyperandrogenism was based solely on measurement of total testosterone. Cases and controls were not matched in advance for age and BMI, although the influence of these variables on the cardiovascular outcome measures was adjusted for. WIDER IMPLICATIONS OF THE FINDINGS: This study shows that central arterial stiffness and diastolic dysfunction are not increased in young women with PCOS, whereas they are associated with both insulin resistance and central obesity. Obesity thus represents the greatest modifiable risk factor for cardiovascular disease in young women with PCOS and lifestyle measures which target weight reduction are critical. STUDY FUNDING/COMPETING INTERESTS: This study received no specific grant support from any funding body. The authors have no conflicts of interest to declare.

Reductions in resistance exercise-induced hyperglycaemic episodes are associated with circulating interleukin-6 in type 1 diabetes.

AIMS: To determine the influence of different volumes of resistance exercise on circulating interleukin-6 (IL-6) and to explore the relationships between IL-6 and glycaemia. METHODS: Eight participants with complication-free type 1 diabetes, whose mean ± SEM age was 38 (6) years, mean ± SEM HbA(1c) concentration was 71 ±11 mmol/mol (8.7 ±1.0%) and mean ± SEM type 1 diabetes duration was 15 ±13 years, attended the research facility after an overnight fast on four separate occasions, having administered their basal insulin the night before (glargine 27.5±3.1U, n=8), but omitted morning rapid-acting insulin. Participants completed either a one-set (14-min), two-set (28-min), or three-set (42-min) resistance exercise trial (eight exercises × 10 repetitions) at 67±3% one-repetition maximum followed by a 60-min recovery, or a resting control trial. Venous blood samples were taken before and after exercise. Data were analysed using repeated-measures ANOVA (P≤0.05). RESULTS: Whereas IL-6 levels remained similar to baseline levels after one set of resistance exercises (30 min, P=0.287; 60 min, P=0.318), IL-6 levels were > baseline levels at 60 min post-exercise after a two-set exercise trial (2.94 ± 0.94 pg/ml, P=0.002) and doubled at both 30 min (4.01 ± 1.00 pg/ml, P=0.048) and 60 min (4.28 ± 1.25 pg/ml, P=0.084) post-exercise after the three-set resistance exercise trial. Post-exercise blood glucose area under the curve (mmol/l/60 min) was greater after both the one-set (P=0.025) and two-set trials (P=0.008), than after the control trial, but similar between the three-set trial and the control trial (P=0.240). The rise in IL-6 from baseline to peak concentration significantly correlated inversely with blood glucose area under the curve (r=-0.65, P=0.041). CONCLUSIONS: Circulating IL-6 is increased by resistance exercise in a volume-dependent manner, and resistance exercise-induced increases in IL-6 correlated with reductions in post-exercise hyperglycaemia in type 1 diabetes, suggesting a role for IL-6 in improving post-resistance exercise glycaemic disturbances in type 1 diabetes.

A comparison of the pharmacodynamic profiles of insulin detemir and insulin glargine: a single dose clamp study in people with type 2 diabetes.

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.

Estimates of the relative and absolute diurnal contributions of fasting and post-prandial plasma glucose over a range of hyperglycaemia in type 2 diabetes.

AIMS: To re-examine the relative and absolute contributions of fasting/pre-prandial glucose (FPG) and post-prandial glucose (PPG) to 24-h hyperglycaemia and HbA1c respectively in non-insulin treated subjects with type 2 diabetes (T2DM). MATERIALS AND METHODS: A total of 52 T2DM subjects (37 men) had daytime 12h plasma glucose (PG) profiles determined in response to three serial identical test meals commencing at 08 00h with pre-prandial and frequent post-prandial blood samples collected. The overnight PG profile was derived by projecting the 20 00h glucose concentration to the pre-breakfast value at 08 00h. PPG exposure was calculated above fasting/pre-prandial value for each meal. Excess hyperglycaemia was calculated based on a PG>5.5mmol/L with fasting hyperglycaemia being the difference between the two measurements. The subjects were divided into five groups according to the HbA1c (Group 1<7.0%; Group 2: 7.0-<7.5; Group 3: 7.5-<8.0%; Group 4: 8.0-<9.0%; Group 5:≥9.0%). The 24h relative contribution of PPG exposure and fasting hyperglycaemia to excess hyperglycaemia and the absolute contribution of PPG and fasting hyperglycaemia to excess HbA1c (HbA1c - 5.1%) was calculated. RESULTS: With deteriorating glycaemia, the relative contribution of PPG exposure decreased across the groups from 43.5% (HbA1c<7.0%) to 17.8% (HbA1c≥9.0%), whilst the contributions of fasting hyperglycaemia increased from 56.5% to 82.2% (P=0.004), respectively. The absolute contributions of PPG to excess HbA1c was 0.7%, which remained relatively stable across the spectrum of HbA1c, whilst fasting hyperglycaemia increased significantly from groups 1 to 5 (P<0.001). CONCLUSIONS: Fasting hyperglycaemia contributes substantially in all groups, increasing as HbA1c deteriorates. The absolute contribution of PPG to excess HbA1c did not vary across the range of HbA1c, representing a significant relative contribution even in well-controlled subjects with a HbA1c<7.0%.

Effects of short-term therapy with glibenclamide and repaglinide on incretin hormones and oxidative damage associated with postprandial hyperglycaemia in people with type 2 diabetes mellitus.

AIM: To examine the effects of glibenclamide and repaglinide on glucose stimulated insulin release, incretins, oxidative stress and cell adhesion molecules in patients with type 2 diabetes suboptimally treated with metformin. METHODS: A randomized clinical trial was performed recruiting 27 subjects (HbA(1c) between 7.5 and 10.5%) free from cardiovascular and renal disease. Glucose, insulin, C-peptide, glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), total antioxidant status, F(2)-isoprostane, interleukin-6 and cell adhesion molecules were measured during an oral glucose load at baseline and after eight weeks of treatment. The areas under the curve were analysed at 45, 60 and 120 min (AUC(45), AUC(60), AUC(120)). RESULTS: Significant improvements in glucose were observed with repaglinide (HBA(1c): -1.5%, fasting glucose: -2.8 mmol/L, 2-h glucose: -3.7 mmol/L, AUC(120): -18.9%) and glibenclamide (-1.0%, -2.2 mmol/L, -2.5 mmol/L, -17.5%). Repaglinide was also associated with an increase in the AUC(60) and AUC(120) for insulin (+56%, +61%) and C-peptide (+41%, +36%). GLP-1, GIP, IL-6, ICAM-1 and E-selectin levels did not change in either group. No association was observed between GLP-1, GIP-1 and plasma markers of oxidative stress. CONCLUSION: Repaglinide is associated with improved postprandial glycaemic control via insulin and C-peptide release. We observed no direct effects of glibenclamide or repaglinide on plasma levels of GLP-1 or GIP. We observed no associations of GLP-1 and GIP with plasma markers of oxidative stress.

Experience of the introduction of routine antibody testing in primary care and of running a trial for latent autoimmune diabetes in adults (LADA).

This brief report discusses the introduction of routine Glutamic Acid Decarboxylase Antibody (GADA) testing in primary care for newly diagnosed diabetes. GADA testing is well used and the majority of people found to be positive are initiated on insulin rapidly and progress to require a basal bolus regime.

Daytime variability of postprandial glucose tolerance and pancreatic B-cell function using 12-h profiles in persons with Type 2 diabetes.

AIMS: To study the variation in daytime glucose tolerance and pancreatic B-cell function at different levels of glycated haemoglobin (HbA(1c)) in subjects with Type 2 diabetes (T2DM). METHODS: T2DM subjects (n = 49; 34 men) had 12-h daytime plasma glucose (PG), insulin (PI), total (PTp) and intact proinsulin (PIp) profiles determined in response to three identical test meals at 4-h intervals. Subjects were divided into three groups according to HbA(1c)--group 1: < 7.3% (n = 18); group 2: 7.3-8.0% (n = 17); group 3: > 8.0% (n = 14). Fasting and preprandial (prior to meals 2 and 3) concentrations, total area under the curve (AUC), AUC above fasting (dAUC) and maximum postprandial metabolic concentrations (C(max)) were compared between the three meals and across the groups. RESULTS: Subjects in group 1 had significantly higher fasting plasma glucose (FPG) compared with preprandial PG concentrations (7.1 +/- 0.2 vs. 5.9 +/- 0.3 vs. 5.4 +/- 0.2; P < 0.01). Subjects in groups 2 and 3 had significantly higher FPG compared with preprandial PG levels prior to meal 3. PG.dAUC was highest in response to meal 1 and lowest following meal 2 (P < 0.05). FPI concentrations were significantly lower compared with preprandial PI concentrations. Subjects in group 1 had significantly higher PI prior to meal 2 compared with meal 3. PI.dAUC was highest in response to meal 1. Subjects in group 1 had lowest PI.dAUC following meal 2. FTp and FIp concentrations were also significantly lower compared with preprandial concentrations. PTp.dAUC and PIp.dAUC was highest in response to meal 1. CONCLUSIONS: There appears to be a shift in diurnal variation in glucose homeostasis and pancreatic B-cell function. Subjects had decreased glucose tolerance in response to the first and third meal of the day irrespective of glycaemic control. The variability in glucose tolerance was reflected by both quantitative and qualitative dysfunction of the pancreatic B-cell.

The glucose lowering effect of an oral insulin (Capsulin) during an isoglycaemic clamp study in persons with type 2 diabetes.

AIM: Randomized, open, single-centre, two-way crossover study comparing the pharmacokinetic (PK) and pharmacodynamic (PD) properties of subcutaneous (sc) regular human insulin (Actrapid) and oral insulin in a capsule form (Capsulin). METHODS: Sixteen persons (12 males) with type 2 diabetes on oral hypoglycaemic agents (OHAs) participated. Mean (s.d.) age 60.2 (5.5) years, BMI 28.3 (3.4) kg/m(2), haemoglobin A(1c) (HbA(1c)) 7.4% (1.1). Two 6-h isoglycaemic glucose clamp studies were conducted 11 days apart. All subjects received in random order 12U sc Actrapid on one clamp study day and either 150U or 300U Capsulin (Cap) on the other day. Glucose infusion rates (GIRs), plasma insulin and C-peptide concentrations were determined throughout each 6-h isoglycaemic clamp. Between the clamp study days, all patients received 150U Capsulin twice daily, dropping all their standard OHAs apart from metformin. Self-monitored blood glucose (SMBG) levels were taken four times a day between the clamp study days. RESULTS: Administration of either Actrapid or Capsulin (150 and 300U) increased GIRs reaching a maximum values at approximately 280-330 min. Overall values for maximum GIR values were higher for Actrapid than either dose of Capsulin (p < 0.05). The significantly greater systemic insulin concentrations following Actrapid were reflected in the AUC(0-6 h) (910 +/- 270 vs. 472 +/- 245 pmol h/L; 950 +/- 446 vs. 433 +/- 218 pmol h/L; both p < 0.05 for Actrapid vs. 150U Capsulin and 300U Capsulin respectively). No difference was observed between 150U and 300U Capsulin. During the repeat-dosing period, good safety and tolerability were observed with Capsulin, and SMBG levels remained stable. At the poststudy visit, significant falls in HbA(1c), weight and triglycerides were observed. CONCLUSIONS: Administration of the oral insulin Capsulin preparation demonstrated a significant hypoglycaemic action over a period of 6 h associated with only a small increase in circulating plasma insulin concentrations.

Relative and absolute contributions of postprandial and fasting plasma glucose to daytime hyperglycaemia and HbA(1c) in subjects with Type 2 diabetes.

AIMS: To determine the relative and absolute contributions of postprandial glucose (PPG) and fasting or preprandial plasma glucose (FPG) to daytime hyperglycaemia and HbA(1c) respectively, in persons with type 2 diabetes (T2DM). METHODS: Subjects (n = 52; 37 men) had 12hr plasma glucose (PG) profiles determined in response to three serial identical test meals. PPG exposure was calculated for each meal. Excess hyperglycaemia was calculated above a PG concentration of 5.5 mmol/l. Fasting hyperglycaemia was the difference between excess hyperglycaemia and PPG exposure. Subjects were divided into three groups according to HbA(1c)-(Gp1:<7.3%;Gp2:7.3%-8.0%;Gp3:>8.0%) and the relative contribution of PPG exposure and fasting hyperglycaemia to excess hyperglycaemia calculated for each meal. The absolute contribution of PPG and fasting hyperglycaemia to excess HbA(1c) (mean HbA(1c)-5.1%) was also calculated. RESULTS: The relative contributions of PPG exposure to excess hyperglycaemia for the three groups were: 58.3%, 54.3% and 35.4% (P = 0.483-Group 1 vs. Group 2; P = 0.002-Group 2 vs. Group 3) for meal 1; 69.8%, 54.7% and 23.7% (P = 0.163-Group 1 vs. Group 2; P = 0.005-Group 2 vs. Group 3) for meal 2; 85.8%, 70.2% and 48.6% (P = 0.153-Group 1 vs. Group 2; P = 0.046-Group 2 vs. Group 3) for meal 3. Absolute contributions of PPG to excess HbA(1c) in the three groups were 1.4%, 1.6% and 1.3% (P = NS). CONCLUSION: The relative contribution of postprandial glucose to excess hyperglycaemia decreases as glycaemic control deteriorates, being dominant with HbA(1c)

GADA testing: the current state of knowledge.

This review considers the current knowledge and practice of GADA testing people with diabetes in Europe and the UK. Important issues are raised, including interpretation of the results and the clinical relevance of the GADA titre. Recommendations are made towards standardising GADA testing, using World Health Organization units.

Use of cystatin C-based estimations of glomerular filtration rate in patients with type 2 diabetes.

AIMS/HYPOTHESIS: The Modification of Diet in Renal Disease (MDRD) equation has recognised limitations when using estimated GFR in persons at risk of chronic kidney disease. Equations based on cystatin C provide an alternative method. We compared performance of the MDRD equation with a selection of cystatin C-based formulae for estimation of GFR in normoalbuminuric patients with type 2 diabetes. METHODS: Estimated GFR was calculated using the MDRD equation and the cystatin C formulae proposed by several investigator teams. Isotopic GFR was measured using plasma clearance of (51)Cr-EDTA. RESULTS: We studied 106 participants, of whom 83 (78%) were men with the following characteristics, mean (SD): age 61 (9) years, HbA(1c) 7.10 (1.27)%, creatinine 89.0 (12.7) micromol/l, cystatin C 0.859 (0.234) mg/l and isotopic GFR 104.5 (20.1) ml min(-1) 1.73 m(-2). MDRD estimated GFR was 77.4 (13.6) ml min(-1) 1.73 m(-2) (p < 0.05 for difference from isotopic GFR). Cystatin C-based calculations of estimated GFR were: Perkins 124.5 (31.8), Rule 90.0 (30.0), Stevens (age) 96.0 (30.4) and Stevens (creatinine) 85.6 (19.0) ml min(-1) 1.73 m(-2) (p < 0.05 for difference with isotopic GFR). For Arnal's, MacIsaac's and Tan's formulae cystatin-C estimated GFR were 101.7 (34.8), 102.1 (27.0) and 101.6 (27.8) ml min(-1) 1.73 m(-2), respectively (p = NS for difference with isotopic GFR). Cystatin C-based formulae were less biased and, with the exception of Perkins' formula, more accurate to within 10% of isotopic GFR than MDRD. CONCLUSIONS/INTERPRETATION: Performance of cystatin C equations was superior to MDRD in normoalbuminuric patients with type 2 diabetes. These results support further evaluation of cystatin C for estimation of GFR in persons at risk of chronic kidney disease.