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In type 2 diabetes, hyperuricemia is associated with cardiovascular disease (CVD) and the metabolic syndrome (MetS), but associations in type 1 diabetes (T1D) have not been well-defined. This study examined the relationships between serum urate (SU) concentrations, clinical and biochemical factors, and subsequent cardiovascular events in a well-characterized cohort of adults with T1D. In 973 participants with T1D in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study (DCCT/EDIC), associations were defined between SU, measured once in blood collected 1997–2000, and (a) concurrent MetS and (b) incident 'any CVD' and major adverse cardiovascular events (MACE) through 2013. SU was higher in men than women [mean (SD): 4.47 (0.99) vs. 3.39 (0.97) mg/dl, respectively, p < 0.0001], and was associated with MetS features in both (men: p = 0.0016; women: p < 0.0001). During follow-up, 110 participants (11%) experienced "any CVD", and 53 (5%) a MACE. Analyzed by quartiles, SU was not associated with subsequent CVD or MACE. In women, SU as a continuous variable was associated with MACE (unadjusted HR: 1.52; 95% CI 1.07–2.16; p = 0.0211) even after adjustment for age and HbA1c (HR: 1.47; 95% CI 1.01–2.14; p = 0.0467). Predominantly normal range serum urate concentrations in T1D were higher in men than women and were associated with features of the MetS. In some analyses of women only, SU was associated with subsequent MACE. Routine measurement of SU to assess cardiovascular risk in T1D is not merited. Trial registration clinicaltrials.gov NCT00360815 and NCT00360893. [ABSTRACT FROM AUTHOR]

Aims: Loop diuretics (LD) relieve symptoms and signs of congestion due to heart failure (HF), but many patients prescribed LD do not have such a diagnosis. We studied the relationship between HF diagnosis, use of LD, and outcomes in patients with type 2 diabetes mellitus (T2DM) enrolled in the EMPA-REG OUTCOME trial.Methods and Results: The relationship between HF diagnosis, use of LD, and outcomes was evaluated in four patient subgroups with T2DM: (i) investigator-reported HF on LD, (ii) investigator-reported HF not on LD, (iii) no HF on LD, and (iv) no HF and not on LD, and we assessed their risk of cardiovascular events. Of 7020 participants, 706 (10%) had a diagnosis of HF at baseline, of whom 334 were prescribed LD. However, 755 (11%) patients who did not have a diagnosis of HF were prescribed LD. Compared to those with neither HF nor prescribed LD (reference group; placebo), those with both HF and receiving LD had the highest rates for all-cause [hazard ratio (HR) (95% confidence interval) 3.19 (2.03-5.01)] and cardiovascular mortality [3.83 [(2.28-6.44)], and HF hospitalizations [9.51 (5.61-16.14)]. Patients without HF but prescribed LD had higher rates for all three outcomes [1.62 (1.10-2.39); 1.97 (1.26-3.08); 3.20 (1.90-5.39)], which were similar to patients with HF who were not receiving LD [1.42 (0.78-2.57); 1.56 (0.78-3.11); 3.00 (1.40-6.40)]. Empagliflozin had similar benefits regardless of subgroup (P for interaction >0.1 for all outcomes).Conclusion: Patients with T2DM prescribed LD are at greater risk of cardiovascular events even if they are not reported to have HF; this might reflect under-diagnosis. Empagliflozin was similarly effective in all subgroups investigated. [ABSTRACT FROM AUTHOR]

Background A preponderance of male fetuses in pregnancies complicated by pre-eclampsia was described over 40 years ago. Since then, however, there has been conflicting evidence in the literature, with some studies supporting a male preponderance, some demonstrating no relationship with fetal sex, and others reporting increased risk in pregnancies bearing females. Objectives In this context, we sought to conduct a systematic review and meta-analysis to objectively evaluate the relationship between fetal sex and maternal risk of pre-eclampsia/eclampsia. Search strategy Studies from January 1950 to April 2015 were identified from PUBMED and EMBASE. Selection criteria This systematic review and meta-analysis evaluated 22 articles reporting data on fetal sex and prevalence of pre-eclampsia/eclampsia. Data collection and analysis Data were extracted by two independent reviewers. Pooled estimates of the relative risk ( RR) were calculated by random-effects model. Main results Male fetus was considered the exposure and prevalence of maternal pre-eclampsia/eclampsia was the outcome of interest. We identified 534 studies through electronic searches and three studies through manual searches. Twenty-two studies fulfilled the inclusion criteria, yielding data on 3 163 735 women. Pooled analyses of these studies showed no association between male fetal sex and maternal risk of pre-eclampsia/eclampsia ( RR 1.01; 95% confidence interval, 95% CI 0.97-1.05); however, a subgroup analysis including only studies that evaluated the non-Asian population ( n = 2 931 771 women) demonstrated that male fetal sex was associated with increased maternal risk of pre-eclampsia/eclampsia ( RR 1.05; 95% CI 1.03-1.06; I2 = 10%; P = 0.33). Conclusion Male fetal sex is associated with maternal risk of pre-eclampsia/eclampsia in the non-Asian population. Tweetable abstract Fetal sex is associated with maternal risk of pre-eclampsia/eclampsia in the non-Asian population. [ABSTRACT FROM AUTHOR]

The article discusses canagliflozin as an effective treatment for Type 2 diabetes by reducing Hemoglobin A1c (HbA1c), blood pressure, and body weight. Particular focus is given to the evaluation of the relationship between canagliflozin effectiveness and the function of baseline ß-cell by analyzing placebo-controlled canagliflozin and sitagliptin. The result of the analysis by comparing canagliflozin and sitagliptin are also discussed.

Aims A prospective meta-analysis of phase 3 trials showed lower rates of nocturnal hypoglycaemia with insulin degludec vs. insulin glargine. We investigated the consistency of the results across different definitions of hypoglycaemia. Methods This post-hoc, patient-level meta-analysis included six randomized, controlled, 26- or 52-week phase 3a trials in insulin-naïve participants with Type 2 diabetes mellitus (Type 2 diabetesinsulin naïve), participants with Type 2 diabetes mellitus using basal−bolus therapy (Type 2 diabetes BB) and those with Type 1 diabetes mellitus. We used three definitions of hypoglycaemia and different timescales for the nocturnal period. Rates were analysed for the entire core trial period, the 'maintenance period' only, and the extension trial set population. Analyses utilized a negative binomial regression model. Results In Type 2 diabetesinsulin naïve participants, risk of nocturnal hypoglycaemia was significantly lower with insulin degludec vs. insulin glargine for all hypoglycaemia definitions and trial periods. Risk was also lower for the timescale 21.59-05.59, but not 00.01-07.59. For Type 2 diabetes BB, nocturnal hypoglycaemia rates were lower with insulin degludec vs. insulin glargine across all definitions, timescales and trial periods, with one exception. For individuals with Type 1 diabetes mellitus, nocturnal hypoglycaemia risk was significantly lower with insulin degludec during the maintenance period for the original definition (plasma glucose < 3.1 mmol/l, timescale 00.01-05.59) and in the extension trial set population for all hypoglycaemia definitions except for the nocturnal timescale 00.01-07.59. Conclusions Compared with insulin glargine, insulin degludec is associated with lower rates of nocturnal hypoglycaemia in people with Type 2 diabetes mellitus, and similar or lower rates in Type 1 diabetes mellitus, across different definitions. [ABSTRACT FROM AUTHOR]

Summary: Background: As ethnicity is typically recorded as a single demographic variable in clinical studies, little is known about the relative impact of maternal vs. paternal ethnicity on fat distribution. Objectives: The objective of this study was to determine whether there is a differential impact of maternal and paternal ethnicity on infant adiposity. Methods: Three hundred fifty‐five infants underwent anthropometric assessment at age 3 months, including skin‐fold thickness (SFT) measurement at subscapular, suprailiac and triceps. Maternal (M) and paternal (P) ethnicity were classified as white (M = 241, P = 252), Asian (M = 50, P = 42) or other (M = 64, P = 61). Results: Infants with either Asian mother (compared with white) or Asian father (compared with white) had increased subscapular, suprailiac and triceps SFT (all P < 0.05). On logistic regression analysis, however, only maternal Asian ethnicity (compared with white) independently predicted the likelihood of an infant being in the highest tertile for SFT at subscapular (odds ratio [OR] = 2.72, 95% confidence interval 1.17–6.34, P = 0.02), suprailiac (OR = 3.56, 1.51–8.42, P = 0.004) and triceps (OR = 3.26, 1.40–7.55, P = 0.005). In contrast, paternal Asian ethnicity was independently associated with sum of SFT only (OR = 2.46, 1.02–5.97, P = 0.04). Conclusion: Maternal and paternal Asian ethnicity have differential effects on infant fat distribution. Future clinical studies on obesity and fat composition should consider the distinct contributions of both parents to the ethnic classification of participants. [ABSTRACT FROM AUTHOR]

Objective: To evaluate glycemic control, hypoglycemic events, and quality of life in patients treated with continuous subcutaneous insulin infusion (CSII) and multiple daily insulin injection (MDI), with insulin lispro as the principal insulin.Research Design and Methods: This clinical trial enrolled 27 patients with type 1 diabetes. They were randomly assigned to CSII (n = 13) or MDI (n = 14) treatment regimens. Glycemic control (HbA(1c) level) was the primary outcome and was measured monthly for 9 months. Secondary outcomes were patient reports of hypoglycemic events (recorded monthly for 9 months) and quality of life assessed at 9 months using the Diabetes Quality of Life (DQOL) questionnaire.Results: A significant decrease in HbA(1c) from baseline was shown for both groups. However, the overall treatment effect (CSII - MDI) for HbA(1c) was +0.08% (95% CI -0.23 to +0.39, P > 0.10). This was significantly less than the a priori limit of +/-0.5% (P = 0.004). The relative treatment effect ([CSII - MDI]/MDI) for the overall number of hypoglycemic events was +9% (95% CI -37 to +87, P > 0.10). There were no statistically significant differences between treatment groups for any of the DQOL subscales.Conclusions: No statistically significant differences in glycemic control, reported hypoglycemic events, or quality of life were found in this study. Furthermore, a clinically significant difference of more than +/-0.5% HbA(1c) between the two regimens can be confidently ruled out. We conclude that the choice of intensive insulin therapy should be a matter of patient preference, consistent with lifestyle. [ABSTRACT FROM AUTHOR]

Objective: Women are at a much lower risk of coronary disease mortality than men are. It is widely believed that diabetes "erases" this female advantage, increasing the risk of heart disease much more in women than in men. In reality, the extent of this increased risk is controversial, with studies showing conflicting results and wide confidence intervals. Clarification of this issue has implications for the pathogenesis of coronary disease, and for public health efforts to reduce coronary disease in women.Research Design and Methods: We performed a meta-analysis to calculate a summary estimate of the relative risk of coronary death among women with diabetes as compared to those without. For comparison, we also calculated the analogous risk among men. All prospective cohort studies containing both men and women, and both patients with and without diabetes, were examined. Sixteen studies were identified; 10 had sufficient data for statistical analysis.Results: After combining studies that adjusted for other cardiac risk factors, the relative risk of coronary death from diabetes was 2.58 (95% CI 2.05-3.26) for women and 1.85 (1.47-2.33) for men. This difference is statistically significant (P = 0.045). Other sensitivity analyses did not change these estimates appreciably.Conclusions: The impact of diabetes on the risk of coronary death is significantly greater for women than men. Further research is required to explain this clinically meaningful difference between the sexes. [ABSTRACT FROM AUTHOR]

Aims To report preliminary data on baseline serum calcitonin concentrations and associated clinical characteristics in a global population with type 2 diabetes before liraglutide or placebo randomization. Methods The ongoing LEADER trial has enrolled 9340 people with type 2 diabetes and at high risk of cardiovascular disease at 410 centres worldwide. People with baseline serum calcitonin ≤50 ng/l were randomized to liraglutide once daily or placebo and will be followed for up to 5 years. Serum calcitonin was measured at baseline and will be measured annually thereafter. An independent committee of thyroid experts will oversee calcitonin monitoring throughout the trial and will review all calcitonin concentrations ≥20 ng/l. Results The mean age of participants was 64.3 ± 7.2 years, 64.3% were men, and mean the body mass index was 32.5 ± 6.3 kg/m2. The median (interquartile range) baseline serum calcitonin values were 3.9 (1.0 to >7.6) ng/l in men and 1.0 (1.0 to >1) ng/l in women. Serum calcitonin was >10 ng/l in 14.6% of men and in 0.96% of women. In sex-specific multivariable linear analysis of covariance models, a reduced glomerular filtration rate ( GFR) was associated with higher serum calcitonin concentrations that were statistically significant. A 20 ml/min/1.73 m2 decrease in estimated GFR ( eGFR) was associated with a 14% increase in serum calcitonin in women and an 11% increase in men. Conclusions In the LEADER population, the prevalence of elevated serum calcitonin concentrations at baseline was high, and there was an inverse association between eGFR and serum calcitonin concentrations. [ABSTRACT FROM AUTHOR]

Aims In patients with Type 2 diabetes, a short course of intensive insulin therapy can improve β-cell function and even induce transient remission of diabetes. However, not all patients respond to this therapy. Although the achievement of fasting glucose < 7.0 mmol/l one day after stopping intensive insulin therapy can identify patients in whom β-cell function has improved, we sought to determine clinical predictors for the early identification of such responders and the time course of response. Methods We pooled data from two studies in which 97 patients with Type 2 diabetes mellitus (median 3 years duration) and HbA1c 51 ± 8.7 mmol/mol (6.8 ± 0.8%) underwent 4-8 weeks of intensive insulin therapy, consisting of basal detemir and pre-meal insulin aspart. They were classified as responders ( n = 74) or non-responders ( n = 23), defined by the achievement of fasting glucose < 7.0 mmol/l after stopping intensive insulin therapy. Results On logistic regression analyses, duration of diabetes (odds ratio [ OR] = 0.72, 95% confidence interval [ CI] 0.56-0.92, P = 0.009) and baseline fasting glucose ( OR = 0.40, 95% CI 0.24-0.68, P = 0.001) emerged as predictors of the likelihood of responding. Ninety per cent of patients with duration ≤ 4 years and fasting glucose ≤ 8.0 mmol/l responded to intensive insulin therapy. Despite having lower glucose levels during intensive insulin therapy, responders had less hypoglycaemia than non-responders (median 0.3 vs. 1.6 episodes/week, P < 0.0001), with rates of hypoglycaemia diverging sharply from the third week onwards. Conclusion At baseline, shorter duration of diabetes and lower fasting glucose can identify patients most likely to benefit from short-term intensive insulin therapy. Most importantly, during therapy, responders had less hypoglycaemia from the third week onwards, despite lower glycaemia, suggesting that 2 weeks of intensive insulin therapy may be needed to improve endogenous islet function. [ABSTRACT FROM AUTHOR]

Insulin degludec ( IDeg) is a new basal insulin with an ultra-long and stable glucose-lowering effect. We compared once-daily IDeg and insulin glargine ( IGlar), both in combination with metformin ± dipeptidyl peptidase-4 inhibitors, in a 52-week, open-label, treat-to-target trial in patients with type 2 diabetes followed by a 52-week extension trial in which subjects [n = 725/1030 (70.4%)] maintained their initial randomised treatment. Health status was assessed at baseline and 105 weeks using the Short Form-36 ( SF-36 v2) questionnaire. SF-36 scores were analysed ( ITT population) using anova, with adjustments for covariates. At 105 weeks, the overall physical component score was significantly better with IDeg versus IGlar [treatment contrast ( TC): 1.1 (0.1; 2.1)95% CI, p < 0.05]. This was largely because of significantly better physical functioning [ TC: 1.1 (0.0; 2.3)95% CI, p < 0.05] and bodily pain sub-domain scores [ TC: 1.5 (0.2; 2.9)95% CI, p < 0.05]. Improvements in health status with IDeg compared to IGlar were maintained after 2 years. [ABSTRACT FROM AUTHOR]

Aim Two treatment strategies were compared in patients with type 2 diabetes ( T2DM) on basal insulin requiring intensification: addition of once-daily ( OD) liraglutide (Lira) or OD insulin aspart ( IAsp) with largest meal. Methods Subjects completing 104 weeks (52-week main trial BEGIN ONCE-LONG + 52-week extension) on insulin degludec ( IDeg) OD + metformin with HbA1c ≥ 7.0% (≥53 mmol/mol) were randomized to IDeg+Lira [n = 88, mean HbA1c: 7.7% (61 mmol/mol)] or IDeg+ IAsp (n = 89, mean HbA1c: 7.7%) for 26 weeks, continuing metformin. Subjects completing 104 weeks with HbA1c <7.0% continued IDeg + metformin in a third, non-randomized arm (n = 236). Results IDeg+Lira reduced HbA1c (−0.74%-points) significantly more than IDeg+ IAsp (−0.39%-points); estimated treatment difference (ETD) ( IDeg+Lira− IDeg+ IAsp) −0.32%-points (95% CI −0.53; −0.12); p = 0.0024. More IDeg+Lira (49.4%) than IDeg+ IAsp (7.2%) subjects achieved HbA1c <7.0% without confirmed hypoglycaemia [plasma glucose <3.1 mmol/l (<56 mg/dl) or severe hypoglycaemia) and without weight gain; estimated odds ratio ( IDeg+Lira/ IDeg+ IAsp) 13.79 (95% CI 5.24; 36.28); p < 0.0001. IDeg+Lira subjects had significantly less confirmed and nocturnal confirmed hypoglycaemia, and significantly greater weight loss (−2.8 kg) versus IDeg+ IAsp (+0.9 kg); ETD ( IDeg+Lira− IDeg+ IAsp) −3.75 kg (95% CI −4.70; −2.79); p < 0.0001. Other than more gastrointestinal side effects with IDeg+Lira, no safety differences occurred. Durability of IDeg was established in the non-randomized arm, as mean HbA1c remained <7.0% [mean 6.5% (48 mmol/mol) at end-of-trial]. Conclusions IDeg+Lira improved long-term glycaemic control, with weight loss and less hypoglycaemia versus adding a single daily dose of IAsp in patients with T2DM inadequately controlled with IDeg + metformin. [ABSTRACT FROM AUTHOR]

Aims The aim of this study was to compare long-term safety and efficacy of the basal insulin analogue degludec with glargine in insulin-naive subjects with Type 2 diabetes. Methods This open-label trial included a 52-week core period followed by a 52-week extension. Participants were randomized 3:1 to once-daily degludec or glargine, administered with metformin ± dipeptidyl peptidase-4 inhibitors. Basal insulin was titrated to target pre-breakfast plasma glucose 3.9-4.9 mmol/l. Results At end of treatment (104 weeks), mean HbA1c reductions were similar for degludec and glargine; estimated treatment difference between degludec and glargine was 1 mmol/mol (95% CI −1 to 3) [0.07% (95% CI −0.07 to 0.22)], P = 0.339 in the extension trial set (degludec 551, glargine 174), comprising subjects who completed core trial and continued into the extension trial. Overall confirmed hypoglycaemia rates (1.72 vs. 2.05 episodes/patient-year), rates of adverse events possibly or probably related to trial product (0.19 events/patient-year), weight gain (2.7 vs. 2.4 kg) and mean daily insulin doses (0.63 U/kg) were similar between treatments in the safety analysis set (degludec 766, glargine 257) comprising all treated subjects. Rates of nocturnal confirmed hypoglycaemia (0.27 vs. 0.46 episodes/patient-year; P = 0.002) and severe hypoglycaemia (0.006 vs. 0.021 episodes/patient-year, P = 0.023) were significantly lower with degludec for the safety analysis set (analysis based on intention-to-treat full analysis set comprising all randomized subjects). Conclusions In Type 2 diabetes, insulin degludec in combination with oral anti-diabetic drugs, safely and effectively improves long-term glycaemic control, with a significantly lower risk of nocturnal hypoglycaemia as compared with glargine. [ABSTRACT FROM AUTHOR]

Aim Hypoglycaemia and the fear of hypoglycaemia are barriers to achieving normoglycaemia with insulin. Insulin degludec ( IDeg) has an ultra-long and stable glucose-lowering effect, with low day-to-day variability. This pre-planned meta-analysis aimed to demonstrate the superiority of IDeg over insulin glargine ( IGlar) in terms of fewer hypoglycaemic episodes at equivalent HbA1c in type 2 and type 1 diabetes mellitus (T2DM/T1DM). Methods Pooled patient-level data for self-reported hypoglycaemia from all seven (five in T2DM and two in T1DM) randomized, controlled, phase 3a, treat-to-target trials in the IDeg clinical development programme comparing IDeg once-daily ( OD) vs. IGlar OD were analysed. Results Four thousand three hundred and thirty subjects (2899 IDeg OD vs. 1431 IGlar OD) were analysed. Among insulin-naïve T2DM subjects, significantly lower rates of overall confirmed, nocturnal confirmed and severe hypoglycaemic episodes were reported with IDeg vs. IGlar: estimated rate ratio ( RR):0.83[0.70;0.98]95% CI, RR:0.64[0.48;0.86]95% CI and RR:0.14[0.03;0.70]95% CI. In the overall T2DM population, significantly lower rates of overall confirmed and nocturnal confirmed episodes were reported with IDeg vs. IGlar [ RR:0.83[0.74;0.94]95% CI and RR:0.68[0.57;0.82]95% CI). In the T1DM population, the rate of nocturnal confirmed episodes was significantly lower with IDeg vs. IGlar during maintenance treatment ( RR:0.75[0.60;0.94]95% CI). Reduction in hypoglycaemia with IDeg vs. IGlar was more pronounced during maintenance treatment in all populations. Conclusions The limitations of this study include the open-label design and exclusion of subjects with recurrent severe hypoglycaemia. This meta-analysis confirms that similar improvements in HbA1c can be achieved with fewer hypoglycaemic episodes, particularly nocturnal episodes, with IDeg vs. IGlar across a broad spectrum of patients with diabetes. [ABSTRACT FROM AUTHOR]

Aim We investigated the relationship between weight change and related factors in subjects with type 2 diabetes mellitus ( T2DM) treated with liraglutide versus comparator diabetes therapies. Methods Twenty-six-week data from seven phase 3, randomized trials in the liraglutide T2DM development programme were analysed by trial and treatment group: liraglutide (1.2 and 1.8 mg), active comparator and placebo. Outcome measures included proportions of subjects in various weight change categories and their percentage weight change from baseline; impact of body mass index ( BMI) and gastrointestinal ( GI) adverse events ( AEs) on weight change and correlation of weight change with change in glycosylated haemoglobin ( HbA1c). Results A number of subjects experienced >5% weight loss during the trials (24.4% liraglutide 1.8 mg and 17.7% liraglutide 1.2 mg; 17.7% exenatide, 10.0% sitagliptin, 3.6−7.0% sulphonylurea, 2.6% thiazolidinedione and 2.6% glargine; 9.9% placebo). More weight loss was seen with liraglutide 1.2 and 1.8 mg than with active comparators except exenatide. Across trials, higher initial BMI was associated with slightly greater weight loss with liraglutide. Mean weight loss increased slightly the longer GI AEs persisted. Although HbA1c reduction was slightly larger in higher weight loss categories across treatments (including placebo), sample sizes were small and no clear correlation could be determined. Liraglutide-treated subjects experienced additional HbA1c reduction beyond that which appeared weight induced; thus, not all HbA1c-lowering effect appears weight mediated. Conclusions The majority of liraglutide-treated T2DM subjects experienced weight loss in this analysis. Weight loss was greater and occurred more in glucagon-like peptide-1 receptor agonist-treated subjects than in active comparator-treated subjects. [ABSTRACT FROM AUTHOR]

Objective: To compare ultra-long-acting insulin degludec with glargine for efficacy and safety in insulin-naive patients with type 2 diabetes inadequately controlled with oral antidiabetic drugs (OADs).Research Design and Methods: In this 1-year, parallel-group, randomized, open-label, treat-to-target trial, adults with type 2 diabetes with A1C of 7-10% taking OADs were randomized 3:1 to receive once daily degludec or glargine, both with metformin. Insulin was titrated to achieve prebreakfast plasma glucose (PG) of 3.9-4.9 mmol/L. The primary end point was confirmation of noninferiority of degludec to glargine in A1C reduction after 52 weeks in an intent-to-treat analysis.Results: In all, 1,030 participants (mean age 59 years; baseline A1C 8.2%) were randomized (degludec 773, glargine 257). Reduction in A1C with degludec was similar (noninferior) to that with glargine (1.06 vs. 1.19%), with an estimated treatment difference of degludec to glargine of 0.09% (95% CI -0.04 to 0.22). Overall rates of confirmed hypoglycemia (PG <3.1 mmol/L or severe episodes requiring assistance) were similar, with degludec and glargine at 1.52 versus 1.85 episodes/patient-year of exposure (PYE). There were few episodes of nocturnal confirmed hypoglycemia in the overall population, and these occurred at a lower rate with degludec versus glargine (0.25 vs. 0.39 episodes/PYE; P = 0.038). Similar percentages of patients in both groups achieved A1C levels <7% without hypoglycemia. End-of-trial mean daily insulin doses were 0.59 and 0.60 units/kg for degludec and glargine, respectively. Adverse event rates were similar.Conclusions: Insulins degludec and glargine administered once daily in combination with OADs provided similar long-term glycemic control in insulin-naive patients with type 2 diabetes, with lower rates of nocturnal hypoglycemia with degludec. [ABSTRACT FROM AUTHOR]

Wavelength-modulated differential laser photothermal radiometry (WM-DPTR) is introduced for potential development of clinically viable non-invasive glucose biosensors. WM-DPTR features unprecedented glucose-specificity and sensitivity by combining laser excitation by two out-of-phase modulated beams at wavelengths near the peak and the baseline of a prominent and isolated mid-IR glucose absorption band. Measurements on water-glucose phantoms (0 to 300 mg/dl glucose concentration) demonstrate high sensitivity to meet wide clinical detection requirements ranging from hypoglycemia to hyperglycemia. The measurement results have been validated by simulations based on fully developed WM-DPTR theory. For sensitive and accurate glucose measurements, the key is the selection and tight control of the intensity ratio and the phase shift of the two laser beams. [ABSTRACT FROM AUTHOR]

The natural history of type 2 diabetes ( T2DM) is characterized by progressive deterioration of pancreatic β-cell function, leading to worsening glycemia over time. As current antidiabetic therapies have not yet been shown to profoundly alter this natural history, many patients ultimately will require exogenous insulin therapy to obtain adequate glycemic control. Interestingly, the temporary use of short-term intensive insulin therapy early in the course of T2DM has recently emerged as a therapeutic option that may offer favourable long-term effects on β-cell function. Indeed, after receiving this treatment, many patients will experience sustained euglycemia without requiring any antidiabetic therapy. This apparent 'remission' of diabetes is likely secondary to improved β-cell function and can last for more than a year, although it is not sustained and hyperglycemia eventually will return. Nevertheless, owing to its effects on β-cell function, short-term intensive insulin therapy holds promise as a means for modifying the natural history of T2DM and warrants further study in this context. In this report, we will review the rationale and evidence underlying this interesting therapeutic option, and its implications for both clinical research and the management of patients with T2DM. [ABSTRACT FROM AUTHOR]

Aims: Traditional lipid indices have been associated with type 2 diabetes, but limited data are available regarding non-high-density lipoprotein (non-HDL) cholesterol. In view of recent guidelines for the clinical management of dyslipidemia recommending the monitoring of non-HDL cholesterol as a secondary target after achieving the low-density lipoprotein (LDL) cholesterol goal, we aimed to assess the association of non-HDL cholesterol with incident type 2 diabetes and compare its utility as a risk predictor with traditional lipid variables in Aboriginal Canadians. Methods: Of 606 diabetes-free participants at baseline, 540 (89.1%) returned for 10-year follow-up assessments. Baseline anthropometry, blood pressure, fasting insulin and serum lipids were measured. Fasting and 2-h postload glucose were obtained at baseline and follow-up to determine the incidence of type 2 diabetes. Results: The cumulative incidence of type 2 diabetes was 17.5%. Higher non-HDL cholesterol, total-to-HDL cholesterol ratio, apolipoprotein B, triglyceride and LDL cholesterol and lower HDL cholesterol concentrations were individually associated with incident type 2 diabetes in univariate analyses (all p < 0.05). Non-HDL cholesterol was a superior determinant of incident diabetes compared with LDL cholesterol (comparing C-statistics of univariate models p = 0.01) or HDL cholesterol (p = 0.004). With multivariate adjustment including waist circumference, non-HDL cholesterol remained associated with incident diabetes [odds ratio (OR) 1.42 (95% confidence interval, CI 1.07-1.88)], while LDL cholesterol and HDL cholesterol became non-significant. Conclusions: Non-HDL cholesterol was associated with incident type 2 diabetes and was superior to LDL cholesterol as a risk predictor in this population. Further studies are required to establish the utility of non-HDL cholesterol in non-Aboriginal populations. [ABSTRACT FROM AUTHOR]

Objective: A common approach to screening for gestational diabetes mellitus (GDM) is the universal testing of all pregnant women with a 1-h, 50-g glucose challenge test (GCT), followed by a diagnostic oral glucose tolerance test (OGTT) in those in whom the GCT is positive (≥7.8 mmol/L). More important, the GCT is performed at any time of day, but there has been limited study of the effect of time of day on test performance. Thus, using their subsequent OGTT (performed in the morning), we sought to characterize the metabolic function of women with positive GCTs in relation to the timing of their test.Research Design and Methods: A total of 927 women with positive GCTs underwent a 3-h 100-g OGTT. They were stratified into four groups by time of day (hours) of their GCT: <0900 (n = 171), 0900-1059 (n = 288), 1100-1259 (n = 189), and ≥1300 (n = 279).Results: On the OGTT, the prevalence of GDM progressively decreased across the GCT groups from <0900 h (26.9%) to 0900-1059 h (25.0%) to 1100-1259 h (21.7%) to ≥1300 h (21.5%; P = 0.0022). After adjustment for GDM risk factors, mean adjusted glucose area under the curve (AUC(gluc)) similarly decreased across the groups, while insulin sensitivity (Matsuda index) and β-cell function (Insulin Secretion-Sensitivity Index-2) progressively increased (all P < 0.0001). In particular, compared with the <0900- and 0900-1059-h groups, women whose positive GCT occurred after 1300 h had superior metabolic function, as evidenced by lower AUC(gluc), higher insulin sensitivity, and better β-cell function (all P ≤ 0.0097).Conclusions: Among women with a positive GCT, those tested in the afternoon have better metabolic function and a lower risk of GDM on subsequent OGTT. [ABSTRACT FROM AUTHOR]

Aim: Effective type 2 diabetes management requires a multifactorial approach extending beyond glycaemic control. Clinical practice guidelines suggest targets for HbA1c, blood pressure and lipids, and emphasize weight reduction and avoiding hypoglycaemia. The phase 3 clinical trial programme for liraglutide, a human glucagon-like peptide 1 analogue, showed significant improvements in HbA1c and weight with a low risk of hypoglycaemia compared to other diabetes therapies. In this context, we performed a meta-analysis of data from these trials evaluating the proportion of patients achieving a clinically relevant composite measure of diabetes control consisting of an HbA1c <7% without weight gain or hypoglycaemia. Methods: A prespecified meta-analysis was performed on 26-week patient-level data from seven trials ( N = 4625) evaluating liraglutide with commonly used therapies for type 2 diabetes: glimepiride, rosiglitazone, glargine, exenatide, sitagliptin or placebo, adjusting for baseline HbA1c and weight, for a composite outcome of HbA1c <7.0%, no weight gain and no hypoglycaemic events. Results: At 26 weeks, 40% of the liraglutide 1.8 mg group, 32% of the liraglutide 1.2 mg group and 6-25% of comparators (6% rosiglitazone, 8% glimepiride, 15% glargine, 25% exenatide, 11% sitagliptin, 8% placebo) achieved this composite outcome. Odds ratios favoured liraglutide 1.8 mg by 2.0- to 10.5-fold over comparators. Conclusions: As assessed by the composite outcome of HbA1c <7%, no hypoglycaemia and no weight gain, liraglutide was clearly superior to the other commonly used therapies. However, the long-term clinical impact of this observation remains to be shown. [ABSTRACT FROM AUTHOR]

OBJECTIVE The increased risk of type 2 diabetes in women with glucose intolerance in pregnancy is mediated by deterioration of their β-cell function, which occurs as early as the first year postpartum. We thus sought to identify early determinants of their declining β-cell function. RESEARCH DESIGN AND METHODS Women with recent gestational glucose intolerance (166) underwent oral glucose tolerance test at 3 and 12 months postpartum. They were stratified into those in whom β-cell function (Insulin Secretion-Sensitivity Index-2 [ISSI-2]) declined over this time (decliners; n = 92) and those in whom it did not (nondecliners; n = 74). RESULTS Between 3 and 12 months, hepatic insulin sensitivity (1/homeostasis model assessment of insulin resistance [HOMA-IR]) decreased in decliners but not in nondecliners. Over this time, the change in 1/HOMA-IR emerged as an independent predictor of the change in ISSI-2 (t = 5.5; P < 0.0001). Increased hepatic insulin sensitivity independently predicted a lower likelihood of declining β-cell function (odds ratio = 0.13 [95% CI 0.06-0.29]; P < 0.0001). CONCLUSIONS Hepatic insulin resistance is an early determinant of declining β-cell function after gestational dysglycemia. [ABSTRACT FROM AUTHOR]

Objective: To examine the prospective associations of baseline vitamin D [25-hydroxyvitamin D; 25(OH)D] with insulin resistance (IR), β-cell function, and glucose homeostasis in subjects at risk for type 2 diabetes.Research Design and Methods: We followed 489 subjects, aged 50 ± 10 years, for 3 years. At baseline and follow-up, 75-g oral glucose tolerance tests (OGTTs) were administered. IR was measured using the Matsuda index (IS(OGTT)) and the homeostasis model assessment of IR (HOMA-IR), β-cell function was determined using both the insulinogenic index divided by HOMA-IR (IGI/IR) and the insulin secretion sensitivity index-2 (ISSI-2), and glycemia was assessed using the area under the glucose curve (AUC(glucose)). Regression models were adjusted for age, sex, ethnicity, season, and baseline value of the outcome variable, as well as baseline and change in physical activity, vitamin D supplement use, and BMI.Results: Multivariate linear regression analyses indicated no significant association of baseline 25(OH)D with follow-up IS(OGTT) or HOMA-IR. There were, however, significant positive associations of baseline 25(OH)D with follow-up IGI/IR (β = 0.005, P = 0.015) and ISSI-2 (β = 0.002, P = 0.023) and a significant inverse association of baseline 25(OH)D with follow-up AUC(glucose) (β = -0.001, P = 0.007). Progression to dysglycemia (impaired fasting glucose, impaired glucose tolerance, or type 2 diabetes) occurred in 116 subjects. Logistic regression analyses indicated a significant reduced risk of progression with higher baseline 25(OH)D (adjusted odds ratio 0.69 [95% CI 0.53-0.89]), but this association was not significant after additional adjustment for baseline and change in BMI (0.78 [0.59-1.02]).Conclusions: Higher baseline 25(OH)D independently predicted better β-cell function and lower AUC(glucose) at follow-up, supporting a potential role for vitamin D in type 2 diabetes etiology. [ABSTRACT FROM AUTHOR]

Objective: In the Canadian Normoglycemia Outcome Evaluation (CANOE) trial, low-dose rosiglitazone/metformin reduced the risk of diabetes in subjects with impaired glucose tolerance by 66% over a median of 3.9 years. We evaluate the temporal changes in glycemic control, insulin sensitivity, and β-cell function during this trial.Research Design and Methods: CANOE participants (n=207) underwent annual oral glucose tolerance testing, enabling temporal comparison of glycemia, insulin sensitivity (Matsuda index), and β-cell function (insulin secretion-sensitivity index-2 [ISSI-2]) between the rosiglitazone/metformin and placebo arms.Results: Glycemic parameters and insulin sensitivity improved in the rosiglitazone/metformin arm in year 1, but deteriorated in the years thereafter as in the placebo arm. Generalized estimating equation analysis confirmed that both insulin sensitivity and β-cell function decreased over time (Matsuda: β=-0.0515, P<0.0001; ISSI-2: β=-6.6507, P<0.0001), with no significant time-by-treatment interaction (Matsuda: P=0.57; ISSI-2: P=0.22).Conclusions: Despite preventing incident diabetes, low-dose rosiglitazone/metformin did not modify the natural history of worsening insulin resistance and β-cell dysfunction. [ABSTRACT FROM AUTHOR]

Aim: Studies evaluating the effects of oral antidiabetic drugs (OADs) on beta-cell function in type 2 diabetes mellitus (T2DM) are confounded by an inability to establish the actual baseline degree of beta-cell dysfunction, independent of the deleterious effects of hyperglycaemia (glucotoxicity). Because intensive insulin therapy (IIT) can induce normoglycaemia, we reasoned that short-term IIT could enable evaluation of the beta-cell protective capacity of OADs, free from confounding hyperglycaemia. We applied this strategy to assess the effect of sitagliptin on beta-cell function. Methods: In this pilot study, 37 patients with T2DM of 6.0 + 6.4 years duration and A1c 7.0 + 0.8% on 0–2 OADs were switched to 4–8 weeks of IIT consisting of basal detemir and premeal insulin aspart. Subjects achieving fasting glucose <7.0 mmol/l 1 day after completing IIT ( n = 21) were then randomized to metformin with either sitagliptin ( n = 10) or placebo ( n = 11). Subjects were followed for 48 weeks, with serial assessment of beta-cell function [ratio of AUCCpep to AUCgluc over Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) (AUCCpep/gluc/HOMA-IR)] on 4-h meal tests. Results: During the study, fasting glucagon-like-peptide-1 was higher (p = 0.003) and A1c lower in the sitagliptin arm (p = 0.016). Nevertheless, although beta-cell function improved during the IIT phase, it declined similarly in both arms over time (p = 0.61). By study end, AUCCpep/gluc/HOMA-IR was not significantly different between the placebo and sitagliptin arms (median 71.2 vs 80.4; p = 0.36). Conclusions: Pretreatment IIT can provide a useful strategy for evaluating the beta-cell protective capacity of diabetes interventions. In this pilot study, improved A1c with sitagliptin could not be attributed to a significant effect on preservation of beta-cell function. [ABSTRACT FROM AUTHOR]

Aim: To show that vildagliptin added to metformin is non-inferior to glimepiride in reducing HbA1c levels from baseline over 2 years. Methods: A randomized, double-blind, active-comparator study of patients with type 2 diabetes mellitus inadequately controlled (HbA1c 6.5–8.5%) by metformin monotherapy. Patients received vildagliptin (50 mg twice daily) or glimepiride (up to 6 mg/day) added to metformin. Results: In all, 3118 patients were randomized (vildagliptin, n = 1562; glimepiride, n = 1556). From similar baseline values (7.3%), after 2 years adjusted mean (s.e.) change in HbA1c was comparable between vildagliptin and glimepiride treatment: −0.1% (0.0%) and −0.1% (0.0%), respectively. The primary objective of non-inferiority was met. A similar proportion of patients reached HbA1c <7% (36.9 and 38.3%, respectively), but with vildagliptin more patients reached this target without hypoglycaemia (36.0% vs. 28.8%; p = 0.004). The initial response (IR) was sustained for a mean (s.d.) of 309 (244) days with vildagliptin versus 270 (223) days for glimepiride (p < 0.001) (IR = nadir HbA1c where change from baseline ≥0.5% or HbA1c ≤6.5% within the first six months of treatment. After IR was detected, sustained response = time between nadir and an increase of >0.3% above IR). Independent of disease duration, age was a predictor of effect sustainability. Fewer patients experienced hypoglycaemia with vildagliptin (2.3% vs. 18.2% with glimepiride) with a 14-fold difference in the number of hypoglycaemic events (59 vs. 838). Vildagliptin had a beneficial effect on body weight [mean (s.e.) change from baseline −0.3 (0.1) kg; between-group difference −1.5 kg; p < 0.001]. Overall, both treatments were well tolerated and displayed similar safety profiles. Conclusions: Vildagliptin add-on has similar efficacy to glimepiride after 2 years' treatment, with markedly reduced hypoglycaemia risk and no weight gain. [ABSTRACT FROM AUTHOR]

Objective: Both gestational diabetes mellitus (GDM) and mild glucose intolerance in pregnancy identify women at increased risk of future type 2 diabetes. In this context, we queried whether metabolic changes that occur in the 1st year postpartum vary in relation to gestational glucose tolerance status.Research Design and Methods: Three-hundred-and-ninety-two women underwent glucose challenge test (GCT) and oral glucose tolerance test (OGTT) in pregnancy followed by repeat OGTT at both 3 months' postpartum and 12 months' postpartum. The antepartum testing defined four gestational glucose tolerance groups: GDM (n = 107); gestational impaired glucose tolerance (GIGT) (n = 75); abnormal GCT with normal glucose tolerance (NGT) on OGTT (abnormal GCT NGT) (n = 137); and normal GCT with NGT on OGTT (normal GCT NGT) (n = 73).Results: The prevalence of dysglycemia progressively increased across the groups from normal GCT NGT to abnormal GCT NGT to GIGT to GDM at both 3 months' postpartum (2.7% to 10.2% to 18.7% to 34.6%, P < 0.0001) and 12 months' postpartum (2.7% to 11.7% to 17.3% to 32.7%, P < 0.0001). Between 3 and 12 months' postpartum, the groups did not differ with respect to changes in waist circumference, weight, or insulin sensitivity. Importantly, however, they exhibited markedly different changes in beta-cell function (Insulin Secretion-Sensitivity Index-2 [ISSI-2]) (P = 0.0036), with ISSI-2 declining in both the GDM and GIGT groups. Furthermore, on multiple linear regression analysis, both GDM (t = -3.06, P = 0.0024) and GIGT (t = -2.18, P = 0.03) emerged as independent negative predictors of the change in ISSI-2 between 3 and 12 months' postpartum.Conclusions: Women with GDM and GIGT exhibit declining beta-cell function in the 1st year postpartum that likely contributes to their future diabetic risk. [ABSTRACT FROM AUTHOR]

We examined whether retinal vessel diameter in persons with type 1 diabetes mellitus is associated with changes in subclinical anatomical and functional indicators of diabetic nephropathy. Persons with type 1 diabetes mellitus had gradable fundus photographs and renal biopsy data at baseline and 5-year follow-up ( n = 234). Retinal arteriolar and venular diameters were measured at baseline and follow-up. Central retinal arteriole equivalent (CRAE) and central retinal venule equivalent (CRVE) were computed. Baseline and 5-year follow-up renal structural variables were assessed by masked electron microscopic morphometric analyses from percutaneous renal biopsy specimens. Variables assessed included: mesangial fractional volume, glomerular basement membrane width, mesangial matrix fractional volume and glomerular basement membrane width composite glomerulopathy index. While controlling for other covariates, baseline CRAE was positively associated with change in the glomerulopathy index over the 5-year period. Change in CRAE was inversely related to a change in mesangial matrix fractional volume and abnormal mesangial matrix fractional volume, while change in CRVE was directly related to change in the volume fraction of cortex that was interstitium [ Vv(Int/cortex)] over the 5-year period. Baseline CRAE or CRVE or changes in these diameters were not related to changes in other anatomical or functional renal endpoints. Independently of other factors, baseline CRAE correlated with changes in glomerulopathy index, a composite measure of extracellular matrix accumulation in the mesangium and glomerular basement membrane. A narrowing of the CRAE was related to mesangial matrix accumulation. Changes in CRVE were related to changes in Vv(Int/cortex), a measure of interstitial expansion in persons with type 1 diabetes mellitus. [ABSTRACT FROM AUTHOR]

OBJECTIVE The objective of this study was to determine the degree to which ramipril and/or rosiglitazone changed beta-cell function over time among individuals with impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) who participated in the Diabetes Reduction Assessment With Ramipril and Rosiglitazone Medication (DREAM) Trial, which evaluated whether ramipril and/or rosiglitazone could prevent or delay type 2 diabetes in high-risk individuals. RESEARCH DESIGN AND METHODS The present analysis included subjects (n = 982) from DREAM trial centers in Canada who had oral glucose tolerance tests at baseline, after 2 years, and at the end of the study. beta-Cell function was assessed using the fasting proinsulin-to-C-peptide ratio (PI/C) and the insulinogenic index (defined as 30-0 min insulin/30-0 min glucose) divided by homeostasis model assessment of insulin resistance (insulinogenic index [IGI]/insulin resistance [IR]). RESULTS Subjects receiving rosiglitazone had a significant increase in IGI/IR between baseline and end of study compared with the placebo group (25.59 vs. 1.94, P < 0.0001) and a significant decrease in PI/C (-0.010 vs. -0.006, P < 0.0001). In contrast, there were no significant changes in IGI/IR or PI/C in subjects receiving ramipril compared with placebo (11.71 vs. 18.15, P = 0.89, and -0.007 vs. -0.008, P = 0.64, respectively). The impact of rosiglitazone on IGI/IR and PI/C was similar within subgroups of isolated IGT and IFG + IGT (all P < 0.001). Effects were more modest in those with isolated IFG (IGI/IR: 8.95 vs. 2.13, P = 0.03; PI/C: -0.003 vs. -0.001, P = 0.07). CONCLUSIONS Treatment with rosiglitazone, but not ramipril, resulted in significant improvements in measures of beta-cell function over time in pre-diabetic subjects. Although the long-term sustainability of these improvements cannot be determined from the present study, these findings demonstrate that the diabetes preventive effect of rosiglitazone was in part a consequence of improved beta-cell function. [ABSTRACT FROM AUTHOR]

Objective: Blockade of the renin-angiotensin system (RAS) plays an important role in preventing end-organ injury associated with diabetes. The recent development of direct renin inhibitors (DRIs) provides a new approach to block the RAS, but the effects of DRIs on renal and systemic vascular function in uncomplicated type 1 diabetes have not been elucidated.Research Design and Methods: Renal hemodynamic function (inulin and paraaminohippurate clearance), augmentation index and pulse wave velocity, endothelial dependent vasodilatation (flow-mediated dilation [FMD]), and endothelial independent vasodilatation (response to sublingual nitroglycerin) were evaluated before and after administration of aliskiren (300 mg daily for 30 days) in 10 adult subjects with uncomplicated type 1 diabetes during clamped euglycemia (4-6 mmol/l) and hyperglycemia (9-11 mmol/l).Results: In response to the DRI, plasma renin activity decreased (from 0.40 to 0.13 ng . ml(-1) . h(-1), P < 0.05) and plasma renin increased (from 5.2 to 75.0 ng/l, P < 0.05). Peripheral and central blood pressures decreased, and effective renal plasma flow and glomerular filtration rate increased during clamped euglycemia and hyperglycemia (P < 0.05). The carotid augmentation index during clamped euglycemia decreased (from 26 +/- 6 to 20 +/- 5%, P < 0.05) as did pulse wave velocity during clamped hyperglycemia (from 7.8 +/- 0.6 to 6.8 +/- 0.5 m/s, P < 0.05). In response to the DRI, FMD increased during both clamped euglycemia (from 1.92 +/- 1.13 to 5.55 +/- 0.81%) and hyperglycemia (from 1.86 +/- 0.98 to 5.63 +/- 0.62) as did the vasodilatory response to sublingual nitroglycerin.Conclusions: DRIs exert a renal vasodilatory effect and improve parameters of systemic vascular function, suggesting that blockade of the RAS with this new class of agents has important functional effects in subjects with uncomplicated type 1 diabetes. [ABSTRACT FROM AUTHOR]

The postpartum phase following gestational diabetes (GDM) is characterised by subtle metabolic defects, including the beta cell dysfunction that is believed to mediate the increased future risk of type 2 diabetes in this patient population. Low circulating levels of adiponectin and increased leptin and C-reactive protein (CRP) have recently emerged as novel diabetic risk factors, although their relevance to GDM and subsequent diabetes has not been characterised. Thus, we sought to determine whether adiponectin, leptin and CRP levels during pregnancy relate to the postpartum metabolic defects linking GDM with type 2 diabetes. Metabolic characterisation, including oral glucose tolerance testing, was undertaken in 487 women during pregnancy and at 3 months postpartum. Based on the antepartum OGTT, there were 137 women with GDM, 91 with gestational impaired glucose tolerance and 259 with normal glucose tolerance. Adiponectin levels were lowest ( p < 0.0001) and CRP levels highest ( p = 0.0008) in women with GDM. Leptin did not differ between the glucose tolerance groups ( p = 0.4483). Adiponectin ( r = 0.41, p < 0.0001), leptin ( r = −0.36, p < 0.0001) and CRP ( r = −0.30, p < 0.0001) during pregnancy were all associated with postpartum insulin sensitivity (determined using the insulin sensitivity index of Matsuda and DeFronzo [ISOGTT]). Intriguingly, adiponectin levels were also related to postpartum beta cell function (insulinogenic index/HOMA of insulin resistance; r = 0.16, p = 0.0009). Indeed, on multiple linear regression analyses, adiponectin levels during pregnancy independently predicted both postpartum insulin sensitivity ( t = 3.97, p < 0.0001) and beta cell function ( t = 2.37, p = 0.0181), even after adjustment for GDM. Furthermore, adiponectin emerged as a significant negative independent determinant of postpartum fasting glucose ( t = −3.01, p = 0.0027). Hypoadiponectinaemia during pregnancy predicts postpartum insulin resistance, beta cell dysfunction and fasting glycaemia, and hence may be relevant to the pathophysiology relating GDM with type 2 diabetes. [ABSTRACT FROM AUTHOR]

Aim: Although a short course of intensive insulin therapy (IIT) can improve beta-cell function and glycaemic control in most patients with newly diagnosed type 2 diabetes (T2DM), the impact of this intervention in diabetes of longer duration has not been carefully studied. Thus, we sought to evaluate the effect of short-term IIT in patients with established T2DM. Methods: Thirty-four patients, with diabetes of mean 5.9 ± 6.6 years duration, underwent 4–8 weeks of IIT, with 4-h meal test administered at baseline and at 1 day post-IIT. A positive clinical response was defined as fasting glucose < 7.0 mmol/l off any antidiabetic therapy at the latter test. Results: A positive response was achieved in 68% (n = 23) of the subjects. At baseline meal test, the responders had lower glucose levels than the non-responders from 120 to 240 min (all timepoints p ≤ 0.0008) and higher late incremental area-under-the-C-peptide-curve (AUCCpep), particularly from 60 to 150 min (all p < 0.005). Beta-cell function (ratio of AUCCpep to AUCgluc divided by HOMA-IR) was similar between the groups at baseline (median 54.1 vs. 51.3, p = 0.62) but after IIT was significantly higher in the responders (109.3 vs. 57.4, p = 0.009). At baseline, the strongest predictors of the change in beta-cell function were glucose levels between 180 and 240 min (all r = −0.5, p = 0.005) and incremental AUCCpep from 120 to 180 min (all r ≥ 0.66, p ≤ 0.0001), both reflecting late-phase insulin secretion. Conclusions: The clinical response to short-term IIT is variable, consistent with the heterogeneity of T2DM. However, preserved late-phase insulin secretion may identify those patients who can benefit from this intervention with improved beta-cell function. [ABSTRACT FROM AUTHOR]

Objective: C-reactive protein (CRP) is closely associated with obesity and cardiovascular disease in both diabetic and nondiabetic populations. In the short term, commonly prescribed antidiabetic agents have different effects on CRP; however, the long-term effects of those agents are unknown.Research Design and Methods: In A Diabetes Outcome Progression Trial (ADOPT), we examined the long-term effects of rosiglitazone, glyburide, and metformin on CRP and the relationship among CRP, weight, and glycemic variables in 904 subjects over 4 years.Results: Baseline CRP was significantly correlated with homeostasis model assessment of insulin resistance (HOMA-IR), A1C, BMI, waist circumference, and waist-to-hip ratio. CRP reduction was greater in the rosiglitazone group by -47.6% relative to glyburide and by -30.5% relative to metformin at 48 months. Mean weight gain from baseline (at 48 months) was 5.6 kg with rosiglitazone, 1.8 kg with glyburide, and -2.8 kg with metformin. The change in CRP from baseline to 12 months was correlated positively with change in BMI in glyburide (r = 0.18) and metformin (r = 0.20) groups but not in the rosiglitazone (r = -0.05, NS) group. However, there was no longer a significant correlation between change in CRP and change in HOMA-IR, A1C, or waist-to-hip ratio in any of the three treatment groups.Conclusions: Rosiglitazone treatment was associated with durable reductions in CRP independent of changes in insulin sensitivity, A1C, and weight gain. CRP in the glyburide and metformin groups was positively associated with changes in weight, but this was not the case with rosiglitazone. [ABSTRACT FROM AUTHOR]

Aim: To examine the efficacy and safety of vildagliptin vs. glimepiride as add-on therapy to metformin in patients with type 2 diabetes mellitus in a 52-week interim analysis of a large, randomized, double-blind, multicentre study. The primary objective was to demonstrate non-inferiority of vildagliptin vs. glimepiride in glycosylated haemoglobin (HbA1c) reduction at week 52. Methods: Patients inadequately controlled on metformin monotherapy (HbA1c 6.5–8.5%) and receiving a stable dose of metformin (mean dose 1898 mg/day; mean duration of use 36 months) were randomized 1:1 to receive vildagliptin (50 mg twice daily, n = 1396) or glimepiride (titrated up to 6 mg/day; mean dose 4.5 mg/day, n = 1393). Results: Non-inferiority of vildagliptin was demonstrated (97.5% confidence interval 0.02%, 0.16%) with a mean (SE) change from baseline HbA1c (7.3% in both groups) to week 52 endpoint of −0.44% (0.02%) with vildagliptin and −0.53% (0.02%) with glimepiride. Although a similar proportion of patients reached a target HbA1c level of <7% with vildagliptin and glimepiride (54.1 and 55.5%, respectively), a greater proportion of patients reached this target without hypoglycaemia in the vildagliptin group (50.9 vs. 44.3%; p < 0.01). Fasting plasma glucose (FPG) reductions were comparable between groups (mean [SE] −1.01 [0.06] mmol/l and −1.14 [0.06] mmol/l respectively). Vildagliptin significantly reduced body weight relative to glimepiride (mean [SE] change from baseline −0.23 [0.11] kg; between-group difference −1.79 kg; p < 0.001) and resulted in a 10-fold lower incidence of hypoglycaemia than glimepiride (1.7 vs. 16.2% of patients presenting at least one hypoglycaemic event; 39 vs. 554 hypoglycaemic events, p < 0.01). No severe hypoglycaemia occurred with vildagliptin compared with 10 episodes with glimepiride (p < 0.01), and no patient in the vildagliptin group discontinued because of hypoglycaemia compared with 11 patients in the glimepiride group. The incidence of adverse events (AEs), serious AEs and adjudicated cardiovascular events was 74.5, 7.1 and 0.9%, respectively, in patients receiving vildagliptin, and 81.1, 9.5 and 1.6%, respectively, in patients receiving glimepiride. Conclusions: When metformin alone fails to maintain sufficient glycaemic control, the addition of vildagliptin provides comparable efficacy to that of glimepiride after 52 weeks and displays a favourable AE profile, with no weight gain and a significant reduction in hypoglycaemia compared with glimepiride. [ABSTRACT FROM AUTHOR]

The consensus algorithm for the medical management of type 2 diabetes was published in August 2006 with the expectation that it would be updated, based on the availability of new interventions and new evidence to establish their clinical role. The authors continue to endorse the principles used to develop the algorithm and its major features. We are sensitive to the risks of changing the algorithm cavalierly or too frequently, without compelling new information. An update to the consensus algorithm published in January 2008 specifically addressed safety issues surrounding the thiazolidinediones. In this revision, we focus on the new classes of medications that now have more clinical data and experience. [ABSTRACT FROM AUTHOR]

The consensus algorithm for the medical management of type 2 diabetes was published in August 2006 with the expectation that it would be updated, based on the availability of new interventions and new evidence to establish their clinical role. The authors continue to endorse the principles used to develop the algorithm and its major features. We are sensitive to the risks of changing the algorithm cavalierly or too frequently, without compelling new information. An update to the consensus algorithm published in January 2008 specifically addressed safety issues surrounding the thiazolidinediones. In this revision, we focus on the new classes of medications that now have more clinical data and experience. [ABSTRACT FROM AUTHOR]

Objectives: To characterise the diet of First Nations in north-western Ontario, highlight foods for a lifestyle intervention and develop a quantitative food-frequency questionnaire (QFFQ).Design: Cross-sectional survey using single 24 h dietary recalls.Setting: Eight remote and semi-remote First Nations reserves in north-western Ontario.Subjects: 129 First Nations (Oji-Cree and Ojibway) men and women aged between 18 and 80 years.Results: The greatest contributors to energy were breads, pasta dishes and chips (contributing over 20 % to total energy intake). 'Added fats' such as butter and margarine added to breads and vegetables made up the single largest source of total fat intake (8.4 %). The largest contributors to sugar were sugar itself, soda and other sweetened beverages (contributing over 45 % combined). The mean number of servings consumed of fruits, vegetables and dairy products were much lower than recommended. The mean daily meat intake was more than twice that recommended. A 119-item QFFQ was developed including seven bread items, five soups or stews, 24 meat- or fish-based dishes, eight rice or pasta dishes, nine fruits and 14 vegetables. Frequency of consumption was assessed by eight categories ranging from 'Never or less than one time in one month' to 'two or more times a day'.Conclusion: We were able to highlight foods for intervention to improve dietary intake based on the major sources of energy, fat and sugar and the low consumption of fruit and vegetable items. The QFFQ is being used to evaluate a diet and lifestyle intervention in First Nations in north-western Ontario. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to investigate associations of adiponectin, leptin, C-reactive protein (CRP), interleukin (IL)-6, and serum amyloid A (SAA), individually or in combinations, with risk of incident type 2 diabetes in a Aboriginal Canadian [corrected] population.Research Design and Methods: Of the 606 Sandy Lake Health and Diabetes Project cohort subjects who were free of diabetes at baseline, 540 (89.1%) participated in 10-year follow-up assessments. Concentrations of fasting adiponectin, leptin, CRP, IL-6, SAA, and covariates were measured at baseline. Fasting glucose and a 75-g oral glucose tolerance test were obtained at baseline and follow-up to determine incident type 2 diabetes, defined as clinically diagnosed type 2 diabetes or as fasting plasma glucose > or =7.0 mmol/l or 2-h postload plasma glucose > or =11.1 mmol/l at follow-up.Results: Low adiponectin, high leptin, and low adiponectin-to-leptin ratio at baseline were associated with increased risk of incident type 2 diabetes after adjustment for age, sex, triglycerides, HDL cholesterol, hypertension, and impaired glucose tolerance (odds ratio 0.63 [95% CI 0.48-0.83], 1.50 [1.02-2.21], and 0.54 [0.37-0.77], respectively). When the models were additionally adjusted for waist circumference or BMI, however, only low adiponectin remained significantly associated with increased incident diabetes (0.68 [0.51-0.90]). Combinations of leptin, CRP, IL-6, and/or SAA with adiponectin, assessed using either the ratio or joint effects, did not improve diabetes prediction.Conclusions: Low baseline adiponectin is associated with increased risk of incident type 2 diabetes independent of leptin, CRP, IL-6, SAA, and metabolic syndrome variables including obesity. [ABSTRACT FROM AUTHOR]

OBJECTIVE: The purpose of this study was to examine possible factors associated with the increased risk of fractures observed with rosiglitazone in A Diabetes Outcome Progression Trial (ADOPT). RESEARCH DESIGN AND METHODS: Data from the 1,840 women and 2,511 men randomly assigned in ADOPT to rosiglitazone, metformin, or glyburide for a median of 4.0 years were examined with respect to time to first fracture, rates of occurrence, and sites of fractures. RESULTS: In men, fracture rates did not differ between treatment groups. In women, at least one fracture was reported with rosiglitazone in 60 patients (9.3% of patients, 2.74 per 100 patient-years), metformin in 30 patients (5.1%, 1.54 per 100 patient-years), and glyburide in 21 patients (3.5%, 1.29 per 100 patient-years). The cumulative incidence (95% CI) of fractures in women at 5 years was 15.1% (11.2-19.1) with rosiglitazone, 7.3% (4.4-10.1) with metformin, and 7.7% (3.7-11.7) with glyburide, representing hazard ratios (95% CI) of 1.81 (1.17-2.80) and 2.13 (1.30-3.51) for rosiglitazone compared with metformin and glyburide, respectively. The increase in fractures with rosiglitazone occurred in pre- and postmenopausal women, and fractures were seen predominantly in the lower and upper limbs. No particular risk factor underlying the increased fractures in female patients who received rosiglitazone therapy was identified. CONCLUSIONS: Further investigation into the risk factors and underlying pathophysiology for the increased fracture rate in women taking rosiglitazone is required to relate them to preclinical data and better understand the clinical implications of and possible interventions for these findings. [ABSTRACT FROM AUTHOR]

Background: Exenatide therapy is effective in combination with metformin or sulfonylureas for treating type 2 diabetes. Thiazolidinediones (TZDs) also are commonly used, but the efficacy of exenatide with a TZD has not been reported.Objective: To compare the effects of exenatide versus placebo on glycemic control.Design: Placebo run-in, randomized, double-blind, placebo-controlled trial conducted from May 2004 to August 2005.Setting: 49 sites in Canada, Spain, and the United States.Patients: 233 (exenatide group, n = 121; placebo group, n = 112) patients with type 2 diabetes that was suboptimally controlled with TZD treatment (with or without metformin). Mean (+/-SE) baseline glycated hemoglobin A1c level was 7.9% +/- 0.1%.Interventions: Subcutaneous abdominal injections of 10 microg of exenatide or placebo twice daily, added to a TZD (with or without metformin) for 16 weeks.Measurements: The primary outcome was change from baseline in hemoglobin A1c level. Other outcomes were fasting serum glucose level, body weight, self-monitored blood glucose level, and any adverse events.Results: Exenatide treatment reduced hemoglobin A(1c) level (mean difference, -0.98% [95% CI, -1.21% to -0.74%]), serum fasting glucose level (mean difference, -1.69 mmol/L [-30.5 mg/dL] [CI, -2.22 to -1.17 mmol/L {-40.0 to -21.1 mg/dL}]), and body weight (mean difference, -1.51 kg [CI, -2.15 to -0.88 kg]). Sixteen percent of patients in the exenatide group and 2% of patients in the placebo group discontinued treatment because of adverse events. In the exenatide group, 40% (n = 48) of patients experienced nausea (mostly mild [n = 21] or moderate [n = 19]), 13% experienced vomiting, and 11% experienced hypoglycemia. In the placebo group, 15% of patients experienced nausea, 1% experienced vomiting, and 7% experienced hypoglycemia.Limitations: Combinations with TZDs and sulfonylureas were not tested. Trial duration was relatively short. Only 71% and 86% of patients in the exenatide and placebo groups, respectively, completed the study.Conclusions: Exenatide therapy improved glycemic control, reduced body weight, and caused gastrointestinal symptoms more than placebo in patients with type 2 diabetes that was suboptimally controlled with TZD therapy. ClinicalTrials.gov registration number: NCT00099320. For more information on exenatide click here. [ABSTRACT FROM AUTHOR]

Aims Low serum concentrations of the insulin-sensitizing protein adiponectin predict the development of incident Type 2 diabetes (T2DM). It has recently emerged that the anti-diabetic activity of adiponectin may be mediated by its high-molecular-weight (HMW) isoform, circulating levels of which are decreased in T2DM. The relevance of decreased HMW adiponectin to incident T2DM, however, has not been assessed. Since gestational diabetes (GDM) identifies a population of young women at high risk of future T2DM (i.e. representing an early stage in the natural history of the disease), we sought to determine if decreased HMW adiponectin is a feature of GDM. Methods HMW and total adiponectin were measured in 121 women at the time of oral glucose tolerance testing (OGTT) in late pregnancy, following an abnormal glucose challenge test. Based on the OGTT, there were 41 women with and 80 without GDM. Results Median HMW adiponectin concentration was lower in women with GDM (3.5 µg/ml) than in those without GDM (5.5 µg/ml) ( P < 0.0001). After full adjustment for covariates, mean HMW adiponectin remained significantly lower in women with GDM compared with their peers (3.6 vs. 5.3 µg/ml, P = 0.0035). HMW adiponectin was positively associated with insulin sensitivity (ISOGTT) ( r = 0.38, P < 0.0001) and pancreatic B-cell function [insulin secretion-sensitivity index (ISSI)] ( r = 0.33, P = 0.0002) and inversely related to blood glucose levels, including area-under-the-glucose-curve during the OGTT (AUCglucose) ( r = −0.31, P = 0.0007). On separate multiple linear regression analyses, HMW adiponectin emerged as an independent determinant of AUCglucose, ISOGTT and ISSI, respectively, mirroring the relationships of total adiponectin. Conclusions HMW adiponectin is significantly decreased in women with GDM. Deficiency of HMW adiponectin may be an early event in the natural history of T2DM. [ABSTRACT FROM AUTHOR]

Aims To examine baseline characteristics of patients recruited into ADOPT, a multinational trial comparing three oral glucose-lowering monotherapies. Methods Between April 2000 and June 2002, 4360 patients aged 30–75 years with Type 2 diabetes diagnosed for < 3 years and remaining on diet therapy alone with fasting plasma glucose levels (FPG) between 7.0 and 10.0 mmol/l were enrolled by 488 North American and European centres. Medical histories, anthropometric data and laboratory measurements were determined using common methodologies. Results The mean (sd) age of the patients was 57 (10) years, body mass index 32.2 (6.4) kg/m2, HbA1c 7.4 (0.9)%; 58% were male, 88% Caucasian and 15% smoked. North American Caucasians (NAC) were younger, more obese, and more insulin resistant than European Caucasians (EUC), but had better pancreatic B-cell function. NAC had lower total, low-density lipoprotein- and high-density liporpotein-cholesterol concentrations with higher triglyceride concentrations and were more often on lipid-lowering treatment. They had lower blood pressure levels but were equally likely to be on antihypertensive treatment. Metabolic syndrome was more frequent and microalbuminuria less frequent in NAC. Within North America, NAC had lower HbA1c concentrations than Blacks, Hispanics and Asians despite similar or higher FPG and 30-min postchallenge glucose concentrations. Conclusions Caucasian North American and European ADOPT patients differ with respect to adiposity, insulin resistance and metabolic syndrome prevalence. North American Blacks, Hispanics and Asians had lower HbA1c concentrations than NAC despite similar or higher glucose concentrations. These phenotypic differences may influence the progression of Type 2 diabetes and the response to initial oral glucose-lowering monotherapy. [ABSTRACT FROM AUTHOR]

Aims Although heart disease and stroke are the underlying causes of death in most people with diabetes, vascular risk modification targets are frequently not met. This study examined whether vascular risk-modifying medication utilization for diabetic patients differed among physician specialties. Methods A population-based study using administrative data from 105 715 people aged ≥ 65 years with newly diagnosed diabetes in Ontario between 1994 and 2001. The receipt of antihypertensive and lipid-lowering drugs was compared between patients who had regular care from endocrinologists, internists/geriatricians and family physicians. Hierarchical logistic regression adjusted for patient-level differences, physician-level differences and patient clustering within physicians. Results Only two-thirds of patients received antihypertensive drugs and about one-quarter received lipid-lowering drugs. Compared with patients of family physicians, the adjusted odds ratios for antihypertensive drug use were 1.27 [95% confidence interval (CI) 1.16, 1.38] for patients of internists/geriatricians and 1.03 (95% CI 0.94, 1.12) for patients of endocrinologists. For lipid-lowering drugs, the odds ratios were 1.20 (95% CI 1.11, 1.30) for patients of internists/geriatricians and 1.58 (95% CI 1.42, 1.76) for patients of endocrinologists. Conclusions Despite recommendations to use vascular risk-modifying medication for most older people with diabetes, many patients were not receiving these medications. Medication utilization differed between physician specialties, with family physicians having the lowest rates of use. Notably, although blood pressure control has the greatest evidence of benefit and is cost-saving, endocrinologists did not use antihypertensive drugs more often than family physicians after adjustment for other differences. [ABSTRACT FROM AUTHOR]