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.

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.

Effect of structured self-monitoring of blood glucose, with and without additional TeleCare support, on overall glycaemic control in non-insulin treated Type 2 diabetes: the SMBG Study, a 12-month randomized controlled trial.

AIM: To examine the impact of structured self-monitoring of blood glucose, with or without TeleCare support, on glycaemic control in people with sub-optimally controlled Type 2 diabetes. METHODS: We conducted a 12-month, multicentre, randomized controlled trial in people with established (>1 year) Type 2 diabetes not on insulin therapy, with sub-optimal glycaemic control [HbA1c ≥58 to ≤119 mmol/mol (≥7.5% to ≤13%)]. A total of 446 participants were randomized to a control group (n =151) receiving usual diabetes care, a group using structured self-monitoring of blood glucose alone (n =147) or a group using structured self-monitoring of blood glucose with additional monthly 'TeleCare' support (n =148). The primary outcome was HbA1c at 12 months. RESULTS: A total of 323 participants (72%) completed the study; 116 (77%) in the control group, 99 (67%) in the self-monitoring of blood glucose alone group and 108 (73%) in the self-monitoring of blood glucose plus TeleCare group. Compared to baseline, the mean HbA1c was lower in all groups at 12 months, with reductions of 3.3 mmol/mol (95% CI -5.71 to -0.78) or 0.3% (95% CI -0.52 to -0.07; P=0.01) in the control group, 11.4 mmol/mol (95% CI -14.11 to -8.76) or 1.1% (-1.29 to -0.81; P<0.0001) in the group using self-monitoring of blood glucose alone and 12.8 mmol/mol (95% CI -15.34 to -10.31) or 1.2% (95% CI -1.40 to -0.94; P<0.0001) in the group using self-monitoring of blood glucose plus TeleCare. This represents a reduction in HbA1c of 8.9 mmol/mol (95% CI -11.97 to -5.84) or 0.8% (95% CI -1.10 to -0.54; P≤0.0001) with structured self-monitoring of blood glucose compared to the control group. Participants with lower baseline HbA1c , shorter duration of diabetes and higher educational achievement were more likely to achieve HbA1c ≤53 mmol/mol (7.0%). CONCLUSIONS: Structured self-monitoring of blood glucose provides clinical and statistical improvements in glycaemic control in Type 2 diabetes. No additional benefit, over and above the use of structured self-monitoring of blood glucose, was observed in glycaemic control with the addition of once-monthly TeleCare support. (Clinical trial registration no.: ISRCTN21390608).

Utility of HbA1c assessment in people with diabetes awaiting liver transplantation.

AIMS: To investigate the relationship between HbA1c and glucose in people with co-existing liver disease and diabetes awaiting transplant, and in those with diabetes but no liver disease. METHODS: HbA1c and random plasma glucose data were collected for 125 people with diabetes without liver disease and for 29 people awaiting liver transplant with diabetes and cirrhosis. Cirrhosis was caused by non-alcoholic fatty liver disease, hepatitis C, alcoholic liver disease, hereditary haemochromatosis, polycystic liver/kidneys, cryptogenic/non-cirrhotic portal hypertension and α-1-antitrypsin-related disease. RESULTS: The median (interquartile range) age of the diabetes with cirrhosis group was 55 (49-63) years compared to 60 (50-71) years (P=0.13) in the group without cirrhosis. In the diabetes with cirrhosis group there were 21 men (72%) compared with 86 men (69%) in the group with diabetes and no cirrhosis (P=0.82). Of the group with diabetes and cirrhosis, 27 people (93%) were of white European ethnicity, two (7%) were South Asian and none was of Afro-Caribbean/other ethnicity compared with 94 (75%), 16 (13%), 10 (8%)/5 (4%), respectively, in the group with diabetes and no cirrhosis (P=0.20). Median (interquartile range) HbA1c was 41 (32-56) mmol/mol [5.9 (5.1-7.3)%] vs 61 (52-70) mmol/mol [7.7 (6.9-8.6)%] (P<0.001), respectively, in the diabetes with cirrhosis group vs the diabetes without cirrhosis group. The glucose concentrations were 8.4 (7.0-11.2) mmol/l vs 7.3 (5.2-11.5) mmol/l (P=0.17). HbA1c was depressed by 20 mmol/mol (1.8%; P<0.001) in 28 participants with cirrhosis but elevated by 28 mmol/mol (2.6%) in the participant with α-1-antitrypsin disorder. Those with cirrhosis and depressed HbA1c had fewer larger erythrocytes, and higher red cell distribution width and reticulocyte count. This was reflected in the positive association of glucose with mean cell volume (r=0.39) and haemoglobin level (r=0.49) and the negative association for HbA1c (r=-0.28 and r=-0.26, respectively) in the diabetes group with cirrhosis. CONCLUSION: HbA1c is not an appropriate test for blood glucose in people with cirrhosis and diabetes awaiting transplant as it reflects altered erythrocyte presentation.

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.

HbA1c measurement and relationship to incident stroke.

AIMS: To determine the proportion of people with diabetes who have HbA1c measured, what proportion achieve an HbA1c level of < 58 mmol/mol (7.5%), the frequency of testing and if there was any change in HbA1c level in the year before and the year after an incident stroke. METHODS: This study used the Secure Anonymised Information Linkage (SAIL) databank, which stores hospital data for the whole of Wales and ~ 65% of Welsh general practice records, to identify cases of stroke in patients with diabetes between 2000 and 2010. These were matched against patients with diabetes but without stroke disease. We assessed the frequency of HbA1c testing and change in HbA1c in the first year after stroke. Estimation was made of the proportion of patients achieving an HbA1c measurement ≤ 58 mmol/mol (7.5%). RESULTS: There were 1741 patients with diabetes and stroke. Of these, 1173 (67.4%) had their HbA1c checked before their stroke and 1137 (65.3%) after their stroke. In the control group of 16 838 patients with diabetes but no stroke, 8413 (49.9%) and 9288 (55.1%) had their HbA1c checked before and after the case-matched stroke date, respectively. In patients with diabetes and stroke, HbA1c fell from 61-56 mmol/mol (7.7-7.3%) after their stroke (P < 0.001). Before the study, 55.0% of patients with stroke had an HbA1c ≥ 58 mmol/mol compared with 65.2% of control patients, these figures were 62.5% and 65.3% after the stroke. CONCLUSIONS: The frequency of diabetes testing was higher in patients who had experienced a stroke before and after their incident stroke compared with control patients but did not increase after their stroke. Glucose control improved significantly in the year after a stroke.

Algorithm that delivers an individualized rapid-acting insulin dose after morning resistance exercise counters post-exercise hyperglycaemia in people with Type 1 diabetes.

AIMS: To develop an algorithm that delivers an individualized dose of rapid-acting insulin after morning resistance exercise to counter post-exercise hyperglycaemia in individuals with Type 1 diabetes. METHODS: Eight people with Type 1 diabetes, aged 34 ± 7 years with HbA1c concentrations 72 ± 12 mmol/mol (8.7 ± 1.1%), attended our laboratory on two separate mornings after fasting, having taken their usual basal insulin the previous evening. These people performed a resistance exercise session comprising six exercises for two sets of 10 repetitions at 60% of the maximum amount of force that was generated in one maximal contraction (60% 1RM). In a randomized and counterbalanced order, the participants were administered an individualized dose of rapid-acting insulin (2 ± 1 units, range 0-4 units) immediately after resistance exercise (insulin session) by means of an algorithm or were not administered this (no-insulin session). Venous blood glucose concentrations were measured for 125 min after resistance exercise. Data (mean ± sem values) were analysed using anova (P ≤ 0.05). RESULTS: Participants had immediate post-resistance exercise hyperglycaemia (insulin session 13.0 ± 1.6 vs. no-insulin session 12.7 ± 1.5 mmol/l; P = 0.834). The decline in blood glucose concentration between peak and 125 min after exercise was greater in the insulin exercise session than in the no-insulin session (3.3 ± 1.0 vs. 1.3 ± 0.4 mmol/l: P = 0.015). There were no episodes of hypoglycaemia (blood glucose <3.9 mmol/l). CONCLUSIONS: Administration of rapid-acting insulin according to an individualized algorithm reduced the hyperglycaemia associated with morning resistance exercise without causing hypoglycaemia in the 2 h post-exercise period in people with Type 1 diabetes.

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.

Preferences of people with diabetes for diabetic retinopathy screening: a discrete choice experiment.

AIMS: The ever-increasing prevalence of diabetes places pressure on the provision of diabetic retinopathy screening services. As the first study of its kind, we aimed to determine preferences for diabetic retinopathy screening in people with diabetes and to examine the trade-offs between frequency of screening and other service attributes. METHODS: A questionnaire including a discrete choice experiment was administered to people (n = 198) attending diabetic retinopathy screening at eight clinics across Wales, United Kingdom. The discrete choice experiment contained eight pairwise choices in which screening provision was described by five attributes: frequency of screening; travel time; results time; ability of screening to detect other changes; and explanation of results. Data were analysed using logistic regression techniques. RESULTS: We gained a response rate of 86.4% from the 198 questionnaires administered at clinics; 160 complete responses were analysed. Respondents valued four out of the five attributes [ability of screening to detect other changes (P = 0.000), explanation of results (P = 0.024), frequency of screening (P = 0.000) and travel time (P = 0.007)]. Results time was insignificant (P = 0.122). Respondents were willing to wait an additional 12, 2 and 1 month between screening tests to have a test that was able to detect additional changes, to have their results explained in person rather than by letter and to have a 15-min reduction in travel time, respectively. CONCLUSIONS: Respondents were willing to accept a longer screening interval, as long as preferences for other attributes of service provision (ability of screening to detect other changes, explanation of results and travel time) were made available.

Diabetic retinopathy screening: perspectives of people with diabetes, screening intervals and costs of attending screening.

AIMS: To obtain the views of people with diabetes about the provision of diabetic retinopathy screening services; and the interval of screening. METHODS: Between October 2009 and January 2010, people with diabetes attending diabetic retinopathy screening clinics across Wales were asked to complete a questionnaire comprising of two parts: the first asking about their health, diabetes history, demographic characteristics and views about the diabetic retinopathy screening service, and the second asking about the costs of attending the screening. RESULTS: The response rate was 40% (n = 621) from 1550 questionnaires distributed at diabetic retinopathy clinics, with 600 complete responses analysed. Respondents had a mean known duration of diabetes of 8.5 years (sd 7.8) and had attended for screening on average 3.2 times (sd 1.6) in the last 5 years. Sixty-eight per cent (n = 408) of respondents reported having their eyes screened approximately once a year. Eighty-five per cent (n = 507) felt that they should have their eyes screened every year. However, 65% (n = 390) of respondents would accept screening at 2- or 3-year intervals if medical evidence showed that it was safe. The reported personal costs incurred by respondents attending diabetic retinopathy screening were low. CONCLUSION: Our study suggests that people with diabetes undergoing diabetic retinopathy screening would accept a greater screening interval, provided that adequate clinical evidence and medical reassurance were given.

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.

Impact of pre-exercise rapid-acting insulin reductions on ketogenesis following running in Type 1 diabetes.

AIM: This study examined the effects of reductions to pre-exercise rapid-acting insulin dose on changes in blood beta-hydroxybutyrate, glucose, acid-base balance and counter-regulatory hormone responses to prolonged running in individuals with Type 1 diabetes. METHODS: Following ethical approval, seven participants with Type 1 diabetes (34±2 years, BMI 27±1 kg/m(2) ) completed this study. After preliminary testing, participants attended the laboratory four times, each time consuming a 1.12 MJ meal (60 g carbohydrate, 2 g fat, 2 g protein), with randomized amounts of their rapid-acting insulin: Full dose (mean 7.3±0.2 units), 75% dose (mean 5.4±0.1 units), 50% dose (mean 3.7±0.1 units) or 25% dose (mean 1.8±0.1 units). After 2-h rest, participants completed 45 min running at 70±1% peak rate of oxygen consumption (VO(2peak) ). Blood metabolites and hormones were recorded over the 2-h rest and 3-h recovery. Data were analysed using repeated-measures ANOVA. RESULTS: Serum insulin peaked at 60 min in all conditions and was lowest after 25% insulin dose compared with full dose (P=0.03). After the 25% insulin dose immediately pre-exercise glucose concentration was higher than after the full or 50% dose (P<0.05). Resting beta-hydroxybutyrate gradually decreased during 2-h rest (P<0.05) with a similar post-exercise peak of beta-hydroxybutyrate at 3 h (P>0.05). Post-exercise blood pH increased for 5 min to a similar extent with all insulin doses , but the rise with the 25% dose was less compared with the full dose (P=0.01). Blood lactate and plasma catecholamines increased after running similarly with all insulin reduction conditions (P<0.05). Blood glucose area under the curve (BG(auc) ) after the 25% insulin dose was greater than after the 75% dose (P=0.02). CONCLUSION: Ketogenesis following running was not influenced by reductions in pre-exercise rapid-acting insulin dose. This important preparatory strategy aids preservation of blood glucose but poses no greater risk to exercise-induced ketone body formation.

Effects of initiation and titration of a single pre-prandial dose of insulin glulisine while continuing titrated insulin glargine in type 2 diabetes: a 6-month 'proof-of-concept' study.

AIM: Stepwise intensification of insulin treatment to match the progressive decline of endogenous insulin secretion has been shown to be an effective management strategy in type 2 diabetes mellitus (T2DM). The efficacy of initiating and titrating a single bolus dose of insulin glulisine to baseline insulin glargine plus oral hypoglycaemic agents (OHAs) was investigated. METHODS: This was a 6-month, parallel-group, randomized, open-label, Phase IV study conducted in the US, UK and Russia. People with T2DM (HbA(1c) 7.5-9.5%) using any basal insulin underwent a 3-month run-in period on insulin glargine titrated to optimize fasting blood glucose (BG) control. Those with HbA(1c) >7.0% were randomized to either continue prior therapy (n = 57) or to add a single dose of insulin glulisine (n = 49) immediately prior to the main meal for a further 3 months. Two different titration algorithms were employed for the bolus dose, targeting 2-h postprandial BG ≤135 mg/dL (≤7.5 mmol/l; Russia and UK) or pre-meal/bedtime BG 100-120 mg/dl (5.5-6.7 mmol/l; US). RESULTS: HbA(1c) and fasting plasma glucose levels decreased during the run-in period. In the 3 months after randomization, more participants in the basal-plus-bolus group reached HbA(1c) <7.0% than the basal-only control group (22.4 vs. 8.8%; p < 0.05), with significantly greater reduction of HbA(1c) (-0.37 vs. -0.11%; p = 0.0290). Rates of hypoglycaemia and mean weight change were comparable between the treatment groups. CONCLUSIONS: In people with T2DM inadequately controlled on basal insulin plus OHAs, adding a single injection of insulin glulisine prior to the main meal significantly improves glucose control without undesired side effects.

Comparative pharmacodynamic and pharmacokinetic characteristics of subcutaneous insulin glulisine and insulin aspart prior to a standard meal in obese subjects with type 2 diabetes.

AIMS: A multinational, randomized, double-blind, two-way crossover trial to compare the pharmacokinetic and pharmacodynamic properties of bolus, subcutaneously administered insulin glulisine (glulisine) and insulin aspart (aspart) in insulin-naÏve, obese subjects with type 2 diabetes. METHODS: Thirty subjects [9/21 females/males; mean ± SD age: 60.7 ± 7.7 years; body mass index (BMI): 33.5 ± 3.3 kg/m(2) ; duration of diabetes: 6.8 ± 4.6 years; HbA1c: 7.1 ± 0.8%] were included in the analysis. They fasted overnight and then received a 0.2 U/kg subcutaneous dose of glulisine or aspart 2 min before starting a standardized test meal, 7 days apart, according to a randomization schedule. Blood samples were taken every 15 min, starting 20 min before the meal and ending 6 h postprandially. RESULTS: The area under the absolute glucose concentration-time curve between 0 and 1 h after insulin injection and maximal glucose concentration was significantly lower with glulisine than with aspart (p = 0.0455 and 0.0337, respectively). However, for the total study period, plasma glucose concentration was similar for glulisine and aspart. Peak insulin concentration was significantly higher for glulisine than for insulin aspart (p < 0.0001). Hypoglycaemic events (≤ 70 mg/dl with or without symptoms) occurred in 13 and 16 subjects treated with glulisine and aspart, respectively, but there were no cases of severe hypoglycaemia requiring intervention. CONCLUSIONS: Glulisine was associated with lower glucose levels during the first hour after a standard meal; the remaining glucose profiles were otherwise equivalent, with higher insulin levels observed throughout the study period.

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.

Extremely low frequency electromagnetic fields modulate expression of inducible nitric oxide synthase, endothelial nitric oxide synthase and cyclooxygenase-2 in the human keratinocyte cell line HaCat: potential therapeutic effects in wound healing.

BACKGROUND: Extremely low frequency (ELF) electromagnetic fields (EMF) are known to produce a variety of biological effects. Clinical studies are ongoing using EMF in healing of bone fractures and skin wounds. However, little is known about the mechanisms of action of ELF-EMF. Several studies have demonstrated that expression and regulation of nitric oxide synthase (NOS) and cyclooxygenase-2 (COX-2) are vital for wound healing; however, no reports have demonstrated a direct action of ELF-EMF in the modulation of these inflammatory molecules in human keratinocytes. OBJECTIVES: The present study analysed the effect of ELF-EMF on the human keratinocyte cell line HaCaT in order to assess the mechanisms of action of ELF-EMF and to provide further support for their therapeutic use in wound healing. METHODS: Exposed HaCaT cells were compared with unexposed control cells. At different exposure times, expression of inducible NOS (iNOS), endothelial NOS (eNOS) and COX-2 was evaluated by Western blot analysis. Modulation of iNOS and eNOS was monitored by evaluation of NOS activities, production of nitric oxide (NO) and O(2)(-) and expression of activator protein 1 (AP-1). In addition, catalase activity and prostaglandin (PG) E(2) production were determined. Effects of ELF-EMF on cell growth and viability were monitored. RESULTS: The exposure of HaCaT cells to ELF-EMF increased iNOS and eNOS expression levels. These ELF-EMF-dependent increased expression levels were paralled by increased NOS activities, and increased NO production. In addition, higher levels of AP-1 expression as well as a higher cell proliferation rate were associated with ELF-EMF exposure. In contrast, ELF-EMF decreased COX-2 expression, PGE(2) production, catalase activity and O(2)(-) production. CONCLUSIONS: Mediators of inflammation, such as reactive nitrogen and PGE(2), and keratinocyte proliferation are critical for the tissue regenerative processes. The ability of ELF-EMF to upmodulate NOS activities, thus nitrogen intermediates, as well as cell proliferation, and to downregulate COX-2 expression and the downstream intermediate PGE(2), highlights the potential therapeutic role of ELF-EMF in wound healing processes.

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.