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).

Near normal HbA1c with stable glucose homeostasis: the ultimate target/aim of diabetes therapy.

Achieving near normal glucose homeostasis implies that all components of dysglycemia that are present in diabetes states be eliminated. Reducing ambient/overall hyperglycemia is a pre-requisite to eliminate the risk of development and progression of diabetes complications. More controversially however, are the relative and related contributions of postprandial glucose excursions, glucose variability, hypoglycemia and the dawn phenomenon across the spectrum of dysglycemia. For instance, it is likely that the dawn phenomenon contributes to ambient hyperglycemia and that postprandial glucose excursions are at the cross road of ambient hyperglycemia and glucose variability with glucose fluctuations as causative risk factors for hypoglycemia. Proof-of-concept trials such as the ongoing FLAT-SUGAR study are necessary for gaining further insight into the possible harmful effects of some of these features such as excessive glycemic variability and glucose excursions, still considered to be of minor relevance by several diabetologists. Whether their role will be more thoroughly proven through further intervention trials with "hard" endpoints, remains to be seen. In the meantime more consideration should be given to medications aimed at concomitantly reducing ambient/overall hyperglycemia and those additional abnormal glycemic features of dysglycemia.

Lixisenatide, a novel GLP-1 receptor agonist: efficacy, safety and clinical implications for type 2 diabetes mellitus.

Recent advances in therapies for the treatment of type 2 diabetes mellitus (T2DM) have led to the development of glucagon-like peptide-1 receptor agonists (GLP-1 RAs), which, unlike insulin and sulphonylurea, are effective, with a low risk of hypoglycaemia. Lixisenatide is recommended as a once-daily GLP-1 RA for the treatment of T2DM. In persons with T2DM, lixisenatide 20 µg once-daily given by bolus subcutaneous injection improves insulin secretion and suppresses glucagon secretion in a glucose-dependent manner. Compared with the longer-acting GLP-1 RA liraglutide, lixisenatide achieved a significantly greater reduction in postprandial plasma glucose (PPG) during a standardized test breakfast in persons with T2DM otherwise insufficiently controlled on metformin alone. This is primarily due to the greater inhibition of gastric motility by lixisenatide compared with liraglutide. The efficacy and safety of lixisenatide was evaluated across a spectrum of T2DM in a series of phase III, randomized, placebo-controlled trials known as the GetGoal programme. Lixisenatide monotherapy or as add-on to oral antidiabetic agents or basal insulin achieved significant reductions in glycated haemoglobin, PPG and fasting plasma glucose, with either weight loss or no weight gain. The most frequent adverse events were gastrointestinal and transient in nature. Lixisenatide provides an easy, once-daily, single-dose, add-on treatment to oral antidiabetic agents or basal insulin for the management of T2DM, with little or no increased risk of hypoglycaemia and a potential beneficial effect on body weight.

Linagliptin treatment in subjects with type 2 diabetes with and without mild-to-moderate renal impairment.

AIMS: Renal disease is a frequent comorbidity of type 2 diabetes mellitus (T2DM) and an important factor complicating the choice of glucose-lowering drugs. The aim of this analysis was to evaluate the efficacy and safety of the dipeptidyl peptidase (DPP)-4 inhibitor linagliptin (5 mg/day) in mono, dual or triple oral glucose-lowering regimens in subjects with T2DM and mild or moderate renal impairment (RI). METHODS: In this pooled analysis of three 24-week, placebo-controlled, phase 3 trials, subjects with mild (estimated glomerular filtration rate (eGFR) 60-<90 ml/min/1.73 m(2) , n = 838) or moderate RI (30-<60 ml/min/1.73 m(2), n = 93) were compared with subjects with normal renal function (≥90 ml/min/1.73 m(2), n = 1212). RESULTS: Subjects with RI were older, had longer duration of diabetes, and increased prevalence of diabetes-related comorbidities. After 24 weeks, linagliptin achieved consistent placebo-corrected mean glycated haemoglobin (HbA1c) changes across the three renal function categories: normal (-0.63%; p < 0.0001), mild RI (-0.67%; p < 0.0001) and moderate RI (-0.53%; p < 0.01), with no inter-group difference (p = 0.74). Renal function with linagliptin remained stable across all categories. In linagliptin-treated subjects, overall adverse event (AE) rates and serious AE rates were similar to placebo. The incidence of hypoglycaemia with linagliptin and placebo was 11.1 versus 6.9%, 11.9 versus 9.0% and 15.9 versus 12.0% in the normal, mild RI and moderate RI categories, respectively. CONCLUSIONS: This pooled analysis provides evidence that linagliptin is an effective, well-tolerated and convenient treatment in subjects with T2DM and mild or moderate RI.

Stepwise intensification of insulin therapy in type 2 diabetes management--exploring the concept of the basal-plus approach in clinical practice.

Basal insulin provides an effective method for initiating insulin therapy in people with Type 2 diabetes, resulting in significant improvements in glycaemic control, lower rates of hypoglycaemia and less weight gain than either prandial or premixed insulin regimens. However, the progressive nature of Type 2 diabetes and the inability of basal insulin to correct excessive postprandial glucose excursions mean that insulin therapy will eventually need to be intensified, typically by adding prandial insulin as part of a basal-bolus or premixed insulin regimen. The aim of this review is to summarize recent clinical evidence for a staged 'basal-plus' strategy for insulin intensification where one, two or three prandial insulin injections are added to basal insulin according to individual need. In the early stages of insulin therapy, most individuals seem to achieve favourable glycaemic control with basal insulin alone, or in combination with a single prandial insulin injection. The addition of a single prandial insulin injection at the largest meal is well tolerated and associated with significant improvements in glycated haemoglobin (HbA(1c)), low rates of hypoglycaemia and limited weight gain. More people achieve recommended HbA(1c) targets with a basal-plus strategy, compared with twice-daily premixed insulin therapy, with lower rates of hypoglycaemia. The data indicate that a step-by-step approach with the basal-plus strategy is a promising alternative method of insulin intensification that allows for individualization of treatment and may delay progression to a full basal-bolus insulin replacement therapy for many individuals.

Does feeding by Halyomorpha halys (Hemiptera: Pentatomidae) reduce soybean seed quality and yield?

The nonnative brown marmorated stink bug, Halyomorpha halys Stål (Hemiptera: Pentatomidae), has become an abundant pest of mid-Atlantic soybean since its introduction in the mid-1990s. Currently, there is little information indicating how this new pest should be managed in soybean or if economic thresholds developed for native stink bugs should be adjusted. In 2010 and 2011, field cage studies were conducted in Beltsville, MD, and Suffolk, VA, to evaluate H. halys injury to three different soybean reproductive development stages. Cages were infested for 2 wk using densities of zero, one, two, four, or eight stink bugs (fifth instars and adults) per 0.3 row-m. Cage plots were harvested, and subsamples were taken to determine pod losses and seed quality. Feeding injury to soybean caused by H. halys was similar to that of native stink bugs, as evidenced by seed destruction, punctures, and destroyed pods. Densities of four stink bugs per 0.3 row-m resulted in significant seed damage in three of four experiments. The full flowering (R2) soybean development stage was least affected by H. halys feeding. The full pod (R4) and the full seed (R6) stage were similarly sensitive to injury. There was no significant yield loss was associated with stink bug densities at either location, although there were significant differences among stages in two of four experiments. The data do not indicate that threshold densities for H. halys should be different than for the native stink bugs.

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.

Modified release terbutaline (SKP1052) for hypoglycaemia prevention: a proof-of-concept study in people with type 1 diabetes mellitus.

AIMS: In this randomized, single blind, cross-over study 2.5 mg and 5 mg of the modified-release terbutaline formulation (SKP-1052) were compared with conventional immediate-release terbutaline (IRT, 5 mg) and placebo on overnight blood glucose (BG) and hypoglycaemia in 30 subjects with type 1 diabetes mellitus. METHODS: Subjects received subcutaneous injections of insulin glargine (individualized doses) before dinner. SKP-1052, IRT or placebo was administered around 21:00 hours. BG and terbutaline concentrations were monitored overnight for 10 h post-dosing. Endpoints comprised of the nadir BG (BGn 0-10 h, primary endpoint), mean overnight BG (BGmean), morning BG (BGmorning) and hypoglycaemia rates as well as pharmacokinetic (PK) endpoints. RESULTS: SKP-1052 delayed release of terbutaline by 2 h [PK-tmax (mean ± SD) 5.0 ± 2.1 h (2.5 mg) and 4.7 ± 1.7 h (5 mg) vs. 2.6 ± 1.3 h with IRT, p < 0.01, respectively]. Compared with placebo, no significant differences were observed for BGn 0-10 h across treatments, but both 5 mg formulations showed less hypoglycaemic events [10 (IRT), 16 (SKP-1052) vs. 33], higher BGmean (120, 114 and 95 mg/dl) and BGmorning (126, 126 and 101 mg/dl, all comparisons p < 0.05 vs. placebo). Numerically higher BG-levels between 3 and 8 h post-dosing were observed with 2.5 mg SKP-1052 vs. placebo. CONCLUSIONS: Compared with IRT SKP-1052 delays release of terbutaline. 2.5 mg SKP-1052 led to numerically higher BG 3 to 8 h post-dose without fasting hyperglycaemia while 5 mg SKP-1052 resulted in fasting hyperglycaemia vs. placebo. Future studies will investigate optimized doses of SKP-1052 for nocturnal hypoglycaemia prevention.

Long-term safety and efficacy of linagliptin as monotherapy or in combination with other oral glucose-lowering agents in 2121 subjects with type 2 diabetes: up to 2 years exposure in 24-week phase III trials followed by a 78-week open-label extension.

Aim: The aim of this study was to evaluate the long-term safety, tolerability and efficacy of the dipeptidyl peptidase-4 inhibitor linagliptin given either alone or in combination with other oral glucose-lowering agents in persons with type 2 diabetes. Methods: A 78-week open-label extension study evaluated subjects who participated in one of four preceding 24-week, randomised, double-blind, placebo-controlled parent trials and who received linagliptin, linagliptin + metformin, linagliptin + metformin + a sulphonylurea or linagliptin + pioglitazone (all with linagliptin administered orally once daily). Individuals receiving one of these treatments during a previous trial continued the same treatment (n = 1532) for up to a total of 102 weeks, whereas those previously receiving placebo were switched to linagliptin (n = 589). All 2121 participants received at least one dose of the trial medication and were included in the primary safety analysis. Results: In subjects previously receiving active treatment, the glycosylated haemoglobin A(1c) reduction achieved during the 24-week parent trials was sustained through the 78-week extension period (change from baseline to week 102: -0.8%). Drug-related adverse events were experienced by 14.3% of participants. Hypoglycaemia occurred in 13.9% of participants and was similar between those previously receiving treatment (13.6%) and those switching from placebo to linagliptin (14.6%). Hypoglycaemia occurred most frequently with the use of metformin + a sulphonylurea background therapy (11%). Overall, no clinically relevant changes in body weight were observed. Conclusion: Long-term treatment with linagliptin was well tolerated with no change in the safety profile observed during the extension study. Sustained long-term glycaemic control was maintained for up to 102 weeks with either linagliptin monotherapy or linagliptin in combination with other oral glucose-lowering agents.

Paediatric nutrition risk scores in clinical practice: children with inflammatory bowel disease.

BACKGROUND: There has been increasing interest in the use of nutrition risk assessment tools in paediatrics to identify those who need nutrition support. Four non-disease specific screening tools have been developed, although there is a paucity of data on their application in clinical practice and the degree of inter-tool agreement. METHODS: The concurrent validity of four nutrition screening tools [Screening Tool for the Assessment of Malnutrition in Paediatrics (STAMP), Screening Tool for Risk On Nutritional status and Growth (STRONGkids), Paediatric Yorkhill Malnutrition Score (PYMS) and Simple Paediatric Nutrition Risk Score (PNRS)] was examined in 46 children with inflammatory bowel disease. Degree of malnutrition was determined by anthropometry alone using World Health Organization International Classification of Diseases (ICD-10) criteria. RESULTS: There was good agreement between STAMP, STRONGkids and PNRS (kappa > 0.6) but there was only modest agreement between PYMS and the other scores (kappa = 0.3). No children scored low risk with STAMP, STRONGkids or PNRS; however, 23 children scored low risk with PYMS. There was no agreement between the risk tools and the degree of malnutrition based on anthropometric data (kappa < 0.1). Three children had anthropometry consistent with malnutrition and these were all scored high risk. Four children had body mass index SD scores < -2, one of which was scored at low nutrition risk. CONCLUSIONS: The relevance of nutrition screening tools for children with chronic disease is unclear. In addition, there is the potential to under recognise nutritional impairment (and therefore nutritional risk) in children with inflammatory bowel disease.

Efficacy and safety of linagliptin in persons with type 2 diabetes inadequately controlled by a combination of metformin and sulphonylurea: a 24-week randomized study.

AIMS: To examine the efficacy and safety of the dipeptidyl peptidase-4 inhibitor linagliptin in persons with Type 2 diabetes mellitus inadequately controlled [HbA(1c) 53-86 mmol/mol (7.0-10.0%)] by metformin and sulphonylurea combination treatment. METHODS: A multi-centre, 24-week, randomized, double-blind, parallel-group study in 1058 patients comparing linagliptin (5 mg once daily) and placebo when added to metformin plus sulphonylurea. The primary endpoint was the change in HbA(1c) after 24 weeks. RESULTS: At week 24, the linagliptin placebo-corrected HbA(1c) adjusted mean change from baseline was -7 mmol/mol (-0.62%) [95% CI -8 to -6 mmol/mol (-0.73 to -0.50%); P < 0.0001]. More participants with baseline HbA(1c) ≥ 53 mmol/mol (≥ 7.0%) achieved an HbA(1c) < 53 mmol/mol (<7.0%) with linagliptin compared with placebo (29.2% vs. 8.1%, P< 0.0001). Fasting plasma glucose was reduced with linagliptin relative to placebo (-0.7 mmol/l, 95% CI -1.0 to -0.4; P<0.0001). Improvements in homeostasis model assessment of ß-cell function were seen with linagliptin (P<0.001). The proportion of patients who reported a severe adverse event was low in both groups (linagliptin 2.4%; placebo 1.5%). Symptomatic hypoglycaemia occurred in 16.7 and 10.3% of the linagliptin and placebo groups, respectively. Hypoglycaemia was generally mild or moderate; severe hypoglycaemia was reported in 2.7 and 4.8% of the participants experiencing hypoglycaemic episodes in the linagliptin and placebo groups, respectively. No significant weight changes were noted. CONCLUSIONS: In patients with Type 2 diabetes, adding linagliptin to metformin given in combination with a sulphonylurea significantly improved glycaemic control and this was well tolerated. Linagliptin could provide a valuable treatment option for individuals with inadequate glycaemic control despite ongoing combination therapy with metformin and a sulphonylurea.

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.

Regulation of oxidative stress by glycaemic control: evidence for an independent inhibitory effect of insulin therapy.

AIMS/HYPOTHESIS: We examined whether type of diabetes and/or insulin treatment can modulate the impact of sustained hyperglycaemia and glycaemic variability as activators of oxidative stress. METHODS: This was an observational study in 139 patients with diabetes, 48 with type 1, 60 with type 2 treated by oral hypoglycaemic agents (OHAs) alone and 31 with type 2 treated with insulin plus OHAs. In addition, two groups of ten patients with type 2 diabetes were investigated either before and after introducing insulin treatment (add-on insulin group) or before and after add-on OHA therapy to metformin (add-on OHA group). Oxidative stress was estimated from 24 h urinary excretion rates of 8-isoprostaglandin F2alpha (8-iso-PGF2alpha). HbA(1c) was assessed and mean amplitude of glycaemic excursions (MAGE) was estimated by continuous monitoring. RESULTS: The 24 h excretion rate of 8-iso-PGF2alpha (median [range] picomoles per millimole of creatinine) was much higher (p < 0.0001) in type 2 diabetes patients treated with OHAs alone (112 [26-329]) than in the type 1 diabetes group (65 [29-193]) and the type 2 diabetes group treated with insulin (69 [30-198]). It was associated with HbA(1c) (F = 12.9, p = 0.0008) and MAGE (F = 7.7, p = 0.008) in non-insulin-treated, but not in insulin-treated patients. A significant reduction in 24 h excretion rate of 8-iso-PGF2alpha from 126 (47-248) to 62 (35-111] pmol/mmol of creatinine was observed in the add-on insulin group (p = 0.005) but not in the add-on OHA group. CONCLUSIONS/INTERPRETATION: In type 1 and type 2 diabetes, insulin exerts an inhibitory effect on oxidative stress, a metabolic disorder that is significantly activated by sustained hyperglycaemia and glucose variability in non-insulin-treated type 2 diabetes.

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.

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.

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)