The rationale, design and baseline data of FLOW, a kidney outcomes trial with once-weekly semaglutide in people with type 2 diabetes and chronic kidney disease.

BACKGROUND: Chronic kidney disease (CKD) is a common complication of type 2 diabetes (T2D). Glucagon-like peptide-1 receptor agonists (GLP-1RAs) improve glycaemic control and lower body weight in people with T2D, and some reduce the risk of cardiovascular (CV) events in those with high CV risk. GLP-1RAs might also have kidney-protective effects. We report the design and baseline data for FLOW (NCT03819153), a trial investigating the effects of semaglutide, a once-weekly (OW) GLP-1RA, on kidney outcomes in participants with CKD and T2D. METHODS: FLOW is a randomised, double-blind, parallel-group, multinational, phase 3b trial. Participants with T2D, estimated glomerular filtration rate (eGFR) ≥50‒≤75 ml/min/1.73 m2 and urine albumin:creatinine ratio (UACR) >300‒<5000 mg/g or eGFR ≥25‒<50 ml/min/1.73 m2 and UACR >100‒<5000 mg/g were randomised 1:1 to OW semaglutide 1.0 mg or matched placebo, with renin-angiotensin-aldosterone system blockade (unless not tolerated/contraindicated). The composite primary endpoint is time to first kidney failure (persistent eGFR <15 ml/min/1.73 m2 or initiation of chronic kidney replacement therapy), persistent ≥50% reduction in eGFR or death from kidney or CV causes. RESULTS: Enrolled participants (N = 3534) had a baseline mean age of 66.6 years [standard deviation (SD) 9.0], haemoglobin A1c of 7.8% (SD 1.3), diabetes duration of 17.4 years (SD 9.3), eGFR of 47.0 ml/min/1.73 m2 (SD 15.2) and median UACR of 568 mg/g (range 2‒11 852). According to Kidney Disease: Improving Global Outcomes guidelines categorisation, 68.2% were at very high risk for CKD progression. CONCLUSION: FLOW will evaluate the effect of semaglutide on kidney outcomes in participants with CKD and T2D, and is expected to be completed in late 2024.

Current and future therapies for type 1 diabetes.

In type 1 diabetes, insulin remains the mature therapeutic cornerstone; yet, the increasing number of individuals developing type 1 diabetes (predominantly children and adolescents) still face severe complications. Fortunately, our understanding of type 1 diabetes is continuously being refined, allowing for refocused development of novel prevention and management strategies. Hitherto, attempts based on immune suppression and modulation have been only partly successful in preventing the key pathophysiological feature in type 1 diabetes: the immune-mediated derangement or destruction of beta cells in the pancreatic islets of Langerhans, leading to low or absent insulin secretion and chronic hyperglycaemia. Evidence now warrants a focus on the beta cell itself and how to avoid its dysfunction, which is putatively caused by cytokine-driven inflammation and other stress factors, leading to low insulin-secretory capacity, autoantigen presentation and immune-mediated destruction. Correspondingly, beta cell rescue strategies are being pursued, which include antigen vaccination using, for example, oral insulin or peptides, as well as agents with suggested benefits on beta cell stress, such as verapamil and glucagon-like peptide-1 receptor agonists. Whilst autoimmune-focused prevention approaches are central in type 1 diabetes and will be a requirement in the advent of stem cell-based replacement therapies, managing the primarily cardiometabolic complications of established type 1 diabetes is equally essential. In this review, we outline selected recent and suggested future attempts to address the evolving profile of the person with type 1 diabetes.

Early postoperative continuous glucose monitoring in pancreas transplant recipients.

Continuous glucose monitoring (CGM) is used in people with type 1 diabetes to help with insulin treatment regimens. Its value in whole-organ pancreas transplantation (PT) is largely unknown. This study aimed to use CGM to assess the metabolic profile of pancreas transplant recipients in the early post-transplant period. We studied CGM data in 30 PT recipients and related findings to an early oral glucose tolerance test (OGTT). Complete data were available for 26 recipients. Seven days after a PT, normoglycaemia was present 77.9% of the time. Hypoglycaemic events (glucose <3.9 mmol/l) occurred in 10 of 26 (38.5%) of the cohort, but were infrequent (present 1.4% of the time). Hyperglycaemia (glucose >7.8 mmol/l) was present for 20.7% of the study period and correlated with a diagnosis of abnormal glucose tolerance. Whilst normoglycaemia is successfully achieved for the majority of the time after PT, hypoglycaemia can occur. Hyperglycaemia is more common and correlates well with the early postoperative OGTT, which is associated with graft failure. CGM is easier to perform and provides 24-h data that could inform clinical decision-making in patients in the postoperative period.

Endothelial nitric oxide synthase single nucleotide polymorphism and left ventricular function in early chronic kidney disease.

BACKGROUND: Chronic kidney disease (CKD) is associated with accelerated cardiovascular disease and heart failure. Endothelial nitric oxide synthase (eNOS) Glu298Asp single nucleotide polymorphism (SNP) genotype has been associated with a worse phenotype amongst patients with established heart failure and in patients with progression of their renal disease. The association of a cardiac functional difference in non-dialysis CKD patients with no known previous heart failure, and eNOS gene variant is investigated. METHODS: 140 non-dialysis CKD patients, who had cardiac magnetic resonance (CMR) imaging and tissue doppler echocardiography as part of two clinical trials, were genotyped for eNOS Glu298Asp SNP retrospectively. RESULTS: The median estimated glomerular filtration rate (eGFR) was 50 mls/min and left ventricular ejection fraction (LVEF) was 74% with no overt diastolic dysfunction in this cohort. There were significant differences in LVEF across eNOS genotypes with GG genotype being associated with a worse LVEF compared to other genotypes (LVEF: GG 71%, TG 76%, TT 73%, p = 0.006). After multivariate analysis, (adjusting for age, eGFR, baseline mean arterial pressure, contemporary CMR heart rate, total cholesterol, high sensitive C-reactive protein, body mass index and gender) GG genotype was associated with a worse LVEF, and increased LV end-diastolic and systolic index (p = 0.004, 0.049 and 0.009 respectively). CONCLUSIONS: eNOS Glu298Asp rs1799983 polymorphism in CKD patients is associated with relevant sub-clinical cardiac remodelling as detected by CMR. This gene variant may therefore represent an important genetic biomarker, and possibly highlight pathways for intervention, in these patients who are at particular risk of worsening cardiac disease as their renal dysfunction progresses.

Efficacy and safety of a fixed-ratio combination of insulin degludec and liraglutide (IDegLira) compared with its components given alone: results of a phase 3, open-label, randomised, 26-week, treat-to-target trial in insulin-naive patients with type 2 diabetes.

BACKGROUND: A fixed-ratio combination of the basal insulin analogue insulin degludec and the glucagon-like peptide-1 (GLP-1) analogue liraglutide has been developed as a once-daily injection for the treatment of type 2 diabetes. We aimed to compare combined insulin degludec-liraglutide (IDegLira) with its components given alone in insulin-naive patients. METHODS: In this phase 3, 26-week, open-label, randomised trial, adults with type 2 diabetes, HbA1c of 7-10% (inclusive), a BMI of 40 kg/m(2) or less, and treated with metformin with or without pioglitazone were randomly assigned (2:1:1) to daily injections of IDegLira, insulin degludec, or liraglutide (1·8 mg per day). IDegLira and insulin degludec were titrated to achieve a self-measured prebreakfast plasma glucose concentration of 4-5 mmol/L. The primary endpoint was change in HbA1c after 26 weeks of treatment, and the main objective was to assess the non-inferiority of IDegLira to insulin degludec (with an upper 95% CI margin of 0·3%), and the superiority of IDegLira to liraglutide (with a lower 95% CI margin of 0%). This study is registered with ClinicalTrials.gov, number NCT01336023. FINDINGS: 1663 adults (mean age 55 years [SD 10], HbA1c 8·3% [0·9], and BMI 31·2 kg/m(2) [4·8]) were randomly assigned, 834 to IDegLira, 414 to insulin degludec, and 415 to liraglutide. After 26 weeks, mean HbA1c had decreased by 1·9% (SD 1·1) to 6·4% (1·0) with IDegLira, by 1·4% (1·0) to 6·9% (1·1) with insulin degludec, and by 1·3% (1·1) to 7·0% (1·2) with liraglutide. IDegLira was non-inferior to insulin degludec (estimated treatment difference -0·47%, 95% CI -0·58 to -0·36, p<0·0001) and superior to liraglutide (-0·64%, -0·75 to -0·53, p<0·0001). IDegLira was generally well tolerated; fewer participants in the IDegLira group than in the liraglutide group reported gastrointestinal adverse events (nausea 8·8 vs 19·7%), although the insulin degludec group had the fewest participants with gastrointestinal adverse events (nausea 3·6%). We noted no clinically relevant differences between treatments with respect to standard safety assessments, and the safety profile of IDegLira reflected those of its component parts. The number of confirmed hypoglycaemic events per patient year was 1·8 for IDegLira, 0·2 for liraglutide, and 2·6 for insulin degludec. Serious adverse events occurred in 19 (2%) of 825 patients in the IDegLira group, eight (2%) of 412 in the insulin degludec group, and 14 (3%) of 412 in the liraglutide group. INTERPRETATION: IDegLira combines the clinical advantages of basal insulin and GLP-1 receptor agonist treatment, resulting in improved glycaemic control compared with its components given alone. FUNDING: Novo Nordisk.

Postoperative impaired glucose tolerance is an early predictor of pancreas graft failure.

AIMS/HYPOTHESIS: The management of pancreatic transplantation is limited by a lack of clinically relevant early markers of graft dysfunction to enable intervention prior to irreversible damage. The aim of this study was to assess the OGTT as an early predictor of pancreatic graft failure. METHODS: Patients with graft failure (return to insulin dependence) were identified from a prospectively maintained clinical database. Data from OGTTs performed within 2 weeks of the transplant were retrospectively collected for 210 subjects, 42 with graft failure (21 after simultaneous pancreas-kidney transplant and 21 after isolated pancreas transplant) matched to 168 with functioning grafts. The groups were compared to assess the relationship between early OGTT result and pancreas graft failure. RESULTS: Mean 2 h glucose from the OGTT was significantly higher in the overall graft failure group compared with the control group (8.36 vs 6.81 mmol/l, p = 0.014). When interpreted in combination with fasting glucose, abnormal glucose tolerance was more common in the failed graft group (50% vs 22%, p = 0.001). In an adjusted model, abnormal glucose tolerance emerged as the most predictive independent factor for graft failure, HR 1.66 (95% CI 1.22, 2.24), p = 0.001. These findings were consistent between the different transplant procedures performed. CONCLUSIONS/INTERPRETATION: We conclude that early post-transplant abnormal glucose tolerance is associated with later whole organ pancreas graft failure. An OGTT performed within the first month postoperatively provides an easily measurable assessment of an independent early risk factor of pancreatic graft dysfunction.

Comparison of IFCC-calibrated HbA(1c) from laboratory and point of care testing systems.

OBJECTIVE: WHO, IDF and ADA recommend HbA(1c) ≥6.5% (48 mmol/mol) for diagnosis of diabetes with pre-diabetes 6.0% (42 mmol/mol) [WHO] or 5.7% (39 mmol/mol) [ADA] to 6.4% (47 mmol/mol). We have compared HbA(1c) from several methods for research relating glycaemic markers. RESEARCH DESIGN AND METHODS: HbA1c was measured in EDTA blood from 128 patients with diabetes on IE HPLC analysers (Bio-Rad Variant II NU, Menarini HA8160 and Tosoh G8), point of care systems, POCT, (A1cNow+ disposable cartridges and DCA 2000(®)+ analyser), affinity chromatography (Primus Ultra2) and the IFCC secondary reference method (Menarini HA8160 calibrated using IFCC SRM protocol). RESULTS: Median (IQ range) on IFCC SRM was 7.5% (6.8-8.4) (58(51-68) mmol/mol) HbA(1c) with minimum 5.3%(34 mmol/mol)/maximum 11.9%(107 mmol/mol). There were positive offsets between IFCC SRM and Bio-Rad Variant II NU, mean difference (1SD), +0.33%(0.17) (+3.6(1.9) mmol/mol), r(2)=0.984, p<0.001 and Tosoh G8, +0.22%(0.20) (2.4(2.2) mmol/mol), r(2)=0.976, p<0.001 with a very small negative difference -0.04%(0.11) (-0.4(1.2) mmol/mol), r(2)=0.992, p<0.001 for Menarini HA8160. POCT methods were less precise with negative offsets for DCA 2000(®)+ analyser -0.13%(0.28) (-1.4(3.1) mmol/mol), r(2)=0.955, p<0.001 and A1cNow+ cartridges -0.70%(0.67) (-7.7(7.3) mmol/mol), r(2)=0.699, p<0.001 (n=113). Positive biases for Tosoh and Bio-Rad (compared with IFCC SRM) have been eliminated by subsequent revision of calibration. CONCLUSIONS: Small differences observed between IFCC-calibrated and NGSP certified methods across a wide HbA(1c) range were confirmed by quality control and external quality assurance. As these offsets affect estimates of diabetes prevalence, the analyser (and calibrator) employed should be considered when evaluating diagnostic data.

Impact of month of birth on the development of autoimmune thyroid disease in the United Kingdom and Europe.

CONTEXT: Viral/bacterial infection is proposed as a trigger for the autoimmune thyroid diseases (AITD): Graves' disease (GD) and Hashimoto's thyroiditis (HT). Previous studies in European Caucasian AITD subjects found higher birth rates in the autumn/winter, suggesting those born in the autumn/winter experience increased viral/bacterial exposure after birth, impacting upon immune system development and predisposing to AITD later in life. OBJECTIVE: Month of birth effects were investigated in three independent European Caucasian AITD datasets. DESIGN: Variation in GD and HT onset was compared across months and seasons, with fluctuations across all 12 months analyzed using a Walter-Elwood test. SETTING: The study was conducted at a research laboratory. PATIENTS: National UK Caucasian AITD Case Control Collection (2746 GD and 502 HT compared with 1 423 716 UK births), National UK Caucasian GD Family Collection (239 GD and 227 unaffected siblings), and OXAGEN AITD Caucasian Family Collection (885 GD, 717 HT, and 794 unaffected siblings of European Caucasian decent). MAIN OUTCOME MEASURES: Case-control and family-based association studies were measured. RESULTS: No consistent month of birth effects were detected in GD females or males across all three collections. In HT females from the OXAGEN AITD Caucasian Family Collection, slightly higher birth rates were detected in autumn (Walter's test statistic = 7.47, P = .024) however, this was not seen in the HT females from the case-control cohort. CONCLUSION: Our results suggest in UK/Northern European Caucasian GD subjects, month of birth does not impact on AITD development. Although some month of birth effects for HT females in one collection cannot be excluded, only further work in larger European Caucasian AITD collections can confirm these effects.

Skewed X chromosome inactivation and female preponderance in autoimmune thyroid disease: an association study and meta-analysis.

CONTEXT: A number of small data sets have suggested a potential role for skewed X chromosome activation (XCI), away from the expected 50:50 parent of origin ratio, as an explanation for the strong female preponderance seen in the common autoimmune thyroid diseases (AITD), Graves' disease (GD), and Hashimoto's thyroiditis (HT). OBJECTIVE: The objective of the study was to confirm a role for XCI skewing as a potential explanation for the strong female preponderance seen in AITD. DESIGN: The design of the study was to screen XCI in the largest GD, HT, and control case-control cohort and family cohort to date and undertake a meta-analysis of previous AITD XCI reports. SETTING: The study was conducted at a research laboratory. PATIENTS: Three hundred and nine GD, 490 HT, and 325 female UK Caucasians controls, 273 UK Caucasian GD families, and a meta-analysis of 454 GD, 673 HT, and 643 female Caucasian controls were included in the study. MAIN OUTCOME MEASURES: Case-control and family-based association studies and meta-analysis were measured. RESULTS: Skewed XCI was observed with GD [odds ratio (OR) 2.17 [95% confidence interval (CI) 1.43-3.30], P=2.1×10(-4)] and a trend toward skewing with HT (P=.08) compared with the control cohort. A meta-analysis of our UK data and that of four previous non-UK Caucasian studies confirmed significant skewing of XCI with GD [OR 2.54 (95% CI 1.58-4.10), P=1.0×10(-4), I2=30.2%] and HT [OR 2.40 (95% CI 1.10-5.26), P=.03, I2=74.3%]. CONCLUSIONS: Convincing evidence exists to support a role for skewed XCI in female subjects with AITD, which may, in part, explain the strong female preponderance observed in this disease.

Liraglutide efficacy and action in non-alcoholic steatohepatitis (LEAN): study protocol for a phase II multicentre, double-blinded, randomised, controlled trial.

INTRODUCTION: Non-alcoholic steatohepatitis (NASH) is now the commonest cause of chronic liver disease. Despite this, there are no universally accepted pharmacological therapies for NASH. Liraglutide (Victoza), a human glucagon-like peptide-1 (GLP-1) analogue, has been shown to improve weight loss, glycaemic control and liver enzymes in type 2 diabetes. There is currently a lack of prospective-controlled studies investigating the efficacy of GLP-1 analogues in patients with NASH. METHODS AND ANALYSIS: Liraglutide efficacy and action in NASH (LEAN) is a phase II, multicentre, double-blinded, placebo-controlled, randomised clinical trial designed to investigate whether a 48-week treatment with 1.8 mg liraglutide will result in improvements in liver histology in patients with NASH. Adult, overweight (body mass index ≥25 kg/m(2)) patients with biopsy-confirmed NASH were assessed for eligibility at five recruitment centres in the UK. Patients who satisfied the eligibility criteria were randomly assigned (1:1) to receive once-daily subcutaneous injections of either 1.8 mg liraglutide or liraglutide-placebo (control). Using A'Hern's single stage phase II methodology (significance level 0.05; power 0.90) and accounting for an estimated 20% withdrawal rate, a minimum of 25 patients were randomised to each treatment group. The primary outcome measure will be centrally assessed using an intention-to-treat analysis of the proportion of evaluable patients achieving an improvement in liver histology between liver biopsies at baseline and after 48 weeks of treatment. Histological improvement will be defined as a combination of the disappearance of active NASH and no worsening in fibrosis. ETHICS AND DISSEMINATION: The protocol was approved by the National Research Ethics Service (East Midlands-Northampton committee; 10/H0402/32) and the Medicines and Healthcare products Regulatory Agency. Recruitment into the LEAN started in August 2010 and ended in May 2013, with 52 patients randomised. The treatment follow-up of LEAN participants is currently ongoing and is due to finish in July 2014. The findings of this trial will be disseminated through peer-reviewed publications and international presentations. TRIAL REGISTRATION: clinicaltrials.gov NCT01237119.

Elderly patients with diabetes experience a lower rate of nocturnal hypoglycaemia with insulin degludec than with insulin glargine: a meta-analysis of phase IIIa trials.

BACKGROUND AND OBJECTIVE: Elderly patients with diabetes are more vulnerable to the occurrence and effects of hypoglycaemia; therefore, treatments with low risk of hypoglycaemia are preferred in this population. This study aimed to compare hypoglycaemia rates between insulin degludec (IDeg) and insulin glargine (IGlar) in elderly patients. METHODS: Hypoglycaemia data from patients ≥65 years of age with type 1 (T1DM) or type 2 (T2DM) diabetes from seven randomised, treat-to-target phase IIIa trials were used to compare IDeg and IGlar in a pre-planned meta-analysis. Overall, 917/4345 (21 %) randomised patients in the seven trials were elderly (634 IDeg, 283 IGlar). Overall confirmed hypoglycaemia was defined as <3.1 mmol/L or severe hypoglycaemia (symptoms requiring external assistance). Nocturnal hypoglycaemia included confirmed episodes from 0001 to 0559 hours (inclusive). Treatment comparisons of hypoglycaemia in T1DM patients were not performed due to low numbers of elderly patients with T1DM randomised (43 IDeg, 18 IGlar); statistical comparisons were also not made for severe hypoglycaemia due to the low number of events. RESULTS: In elderly patients with T2DM, the rate of overall confirmed hypoglycaemia was significantly lower with IDeg than IGlar [estimated rate ratio (ERR) 0.76 (0.61; 0.95)95 % CI]; nocturnal confirmed hypoglycaemia was also significantly lower with IDeg [ERR 0.64 (0.43; 0.95)95 % CI]. Confirmed hypoglycaemia occurred in the majority of T1DM patients, whereas severe episodes occurred infrequently and at similar rates in both treatment groups in T1DM and T2DM. CONCLUSION: Results of this pre-planned meta-analysis in elderly patients with diabetes demonstrate a significant reduction in hypoglycaemic events with IDeg relative to IGlar.

Safety and efficacy of sitagliptin-metformin in fixed combination for the treatment of type 2 diabetes mellitus.

The biguanide, metformin, is considered first-line treatment for type 2 diabetes. Sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor acts through the incretin pathway and has a glucose dependent mode of action. The complementary hypoglycemic properties of these drugs make fixed dose combination treatment an attractive prospect. Evidence from recent clinical trials suggests a beneficial effect of the combination on efficacy, demonstrated by significant improvement of hemoglobin A1c (HbA1c), fasting and postprandial glucose levels. The fixed dose combination is likely to have greater patient tolerability compared with monotherapy with either agent because of low rates of hypoglycemia, weight neutrality, and lower rates of side effects. High acquisition cost and paucity of long-term safety data are, however, potential barriers to their wider use. An overview of the pharmacology and clinical outcomes from recent trials of the metformin-sitagliptin combination and how the combination could fit into the type 2 diabetes treatment algorithm is presented in this review.

Negligible impact of rare autoimmune-locus coding-region variants on missing heritability.

Genome-wide association studies (GWAS) have identified common variants of modest-effect size at hundreds of loci for common autoimmune diseases; however, a substantial fraction of heritability remains unexplained, to which rare variants may contribute. To discover rare variants and test them for association with a phenotype, most studies re-sequence a small initial sample size and then genotype the discovered variants in a larger sample set. This approach fails to analyse a large fraction of the rare variants present in the entire sample set. Here we perform simultaneous amplicon-sequencing-based variant discovery and genotyping for coding exons of 25 GWAS risk genes in 41,911 UK residents of white European origin, comprising 24,892 subjects with six autoimmune disease phenotypes and 17,019 controls, and show that rare coding-region variants at known loci have a negligible role in common autoimmune disease susceptibility. These results do not support the rare-variant synthetic genome-wide-association hypothesis (in which unobserved rare causal variants lead to association detected at common tag variants). Many known autoimmune disease risk loci contain multiple, independently associated, common and low-frequency variants, and so genes at these loci are a priori stronger candidates for harbouring rare coding-region variants than other genes. Our data indicate that the missing heritability for common autoimmune diseases may not be attributable to the rare coding-region variant portion of the allelic spectrum, but perhaps, as others have proposed, may be a result of many common-variant loci of weak effect.

Low-volume insulin degludec 200 units/ml once daily improves glycemic control similarly to insulin glargine with a low risk of hypoglycemia in insulin-naive patients with type 2 diabetes: a 26-week, randomized, controlled, multinational, treat-to-target trial: the BEGIN LOW VOLUME trial.

OBJECTIVE: The 200 units/mL formulation of insulin degludec (IDeg 200 units/mL) contains equal units of insulin in half the volume compared with the 100 units/mL formulation. We compared the efficacy and safety of IDeg 200 units/mL once daily with 100 units/mL insulin glargine (IGlar) in insulin-naïve subjects with type 2 diabetes (T2DM) inadequately controlled with oral antidiabetic drugs. RESEARCH DESIGN AND METHODS: In this 26-week, open-label, treat-to-target trial, subjects (n = 457; mean HbA1c 8.3% [67 mmol/mol], BMI 32.4 kg/m(2), and fasting plasma glucose [FPG] 9.6 mmol/L [173.2 mg/dL]) were randomized to IDeg 200 units/mL or IGlar, both given once daily in combination with metformin with or without a dipeptidyl peptidase-4 inhibitor. Basal insulin was initiated at 10 units/day and titrated weekly to an FPG target of <5 mmol/L (<90 mg/dL) according to mean prebreakfast self-measured blood glucose values from the preceding 3 days. RESULTS: By 26 weeks, IDeg reduced HbA1c by 1.30% and was not inferior to IGlar. Mean observed FPG reductions were significantly greater with IDeg than IGlar (-3.7 vs. -3.4 mmol/L [-67 vs. -61 mg/dL]; estimated treatment difference: -0.42 [95% CI -0.78 to -0.06], P = 0.02). Despite this difference, rates of overall confirmed hypoglycemia were not higher with IDeg than with IGlar (1.22 and 1.42 episodes/patient-year, respectively), as were rates of nocturnal confirmed hypoglycemia (0.18 and 0.28 episodes/patient-year, respectively). Mean daily basal insulin dose was significantly lower by 11% with IDeg 200 units/mL compared with IGlar. IDeg was well-tolerated, and the rate of treatment-emergent adverse events was similar across groups. CONCLUSIONS: In this treat-to-target trial in insulin-naïve patients with T2DM, IDeg 200 units/mL improved glycemic control similarly to IGlar with a low risk of hypoglycemia.

Inhibition of islet immunoreactivity by adiponectin is attenuated in human type 1 diabetes.

CONTEXT: Adiponectin is an adipocyte-derived cytokine with insulin-sensitizing and antiinflammatory properties. These dual actions have not previously been examined in the context of human disease. OBJECTIVES: Our objective was to examine the adiponectin axis in type 1 diabetes (T1D). T1D is an autoimmune inflammatory disease resulting from pancreatic ß-cell destruction, in which insulin resistance associates with progression to disease. DESIGN, PATIENTS, AND INTERVENTIONS: We measured circulating adiponectin and adiponectin receptor expression on blood-immune cells from 108 matched healthy, T1D, and type 2 diabetic subjects. We tested adiponectin effect on T cell proliferation to islet antigens and antigen-presenting function of monocyte-derived dendritic cells (mDCs). Lastly, we assessed the effect of a 3-week lifestyle intervention program on immune cell adiponectin receptor expression in 18 healthy subjects. RESULTS: Circulating concentrations of adiponectin were not affected by T1D. However, expression of adiponectin receptors on blood monocytes was markedly reduced and inversely associated with insulin resistance. Reduced adiponectin receptor expression resulted in increased T cell proliferation to islet-antigen presented by autologous mDCs. We demonstrated a critical role for adiponectin in down-regulating the costimulatory molecule CD86 on mDCs, and this function was impaired in T1D. We proceeded to show that lifestyle intervention increased adiponectin receptor but reduced CD86 expression on monocytes. CONCLUSIONS: These data indicate that T cells are released from the antiinflammatory effects of adiponectin in T1D and suggest a mechanism linking insulin resistance and islet immunity. Furthermore, we suggest that interventions that reduce insulin resistance could modulate the inflammatory process in T1D.

The efficacy and safety of insulin degludec given in variable once-daily dosing intervals compared with insulin glargine and insulin degludec dosed at the same time daily: a 26-week, randomized, open-label, parallel-group, treat-to-target trial in individuals with type 2 diabetes.

OBJECTIVE: The requirement to inject current basal insulin analogs at a fixed time each day may complicate adherence and compromise glycemic control. This trial evaluated the efficacy and safety of varying the daily injection time of insulin degludec (IDeg), an ultra-long-acting basal insulin. RESEARCH DESIGN AND METHODS: This 26-week, open-label, treat-to-target trial enrolled adults (≥18 years) with type 2 diabetes who were either insulin naïve and receiving oral antidiabetic drugs (OADs) (HbA(1c) = 7-11%) or previously on basal insulin ± OAD(s) (HbA(1c) = 7-10%). Participants were randomized to 1) once-daily (OD) IDeg in a prespecified dosing schedule, creating 8-40-h intervals between injections (IDeg OD Flex; n = 229); 2) once-daily IDeg at the main evening meal (IDeg OD; n = 228); or 3) once-daily insulin glargine at the same time each day (IGlar OD; n = 230). The primary outcome was noninferiority of IDeg OD Flex to IGlar OD in HbA(1c) reduction after 26 weeks. RESULTS: After 26 weeks, IDeg OD Flex, IDeg OD, and IGlar OD improved HbA(1c) by 1.28, 1.07, and 1.26% points, respectively (estimated treatment difference [IDeg OD Flex - IGlar OD]: 0.04% points [-0.12 to 0.20], confirming noninferiority). No statistically significant differences in overall or nocturnal hypoglycemia were found between IDeg OD Flex and IGlar OD. Comparable glycemic control and rates of hypoglycemia were seen with IDeg OD Flex and IDeg OD. Adverse event profiles were similar across groups. CONCLUSIONS: The use of extreme dosing intervals of 8-40 h demonstrates that the daily injection time of IDeg can be varied without compromising glycemic control or safety.

Early change in blood glucose concentration is an indicator of mortality in critically ill children.

OBJECTIVE: Hyperglycaemia is associated with increased mortality in critically ill patients. A number of studies have highlighted an association between increased variability of blood glucose (BG) concentration and mortality, supporting a survival disadvantage if BG homeostasis is lost. By exploring the longitudinal BG profile of individual children over time, this study investigates the importance of intact homeostasis early after admission to the paediatric intensive care unit (PICU). DESIGN, SETTING, AND PATIENTS: Retrospective single-centre observational study in a large multi-specialty PICU in the UK. Children admitted between August 2003 and February 2006 were included unless they met exclusion criteria. Data were merged from the PICU clinical database and blood gas analyser database by means of a unique PICU identifier. BG was measured frequently on a blood gas analyser (Bayer Rapidlink). Primary outcome was 100-day mortality. BG parameters were investigated for possible associations with mortality. MEASUREMENTS AND MAIN RESULTS: A total of 1,763 patients were included (median age 1.1 years; IQR 0.1-5.8). Although admission BG was not associated with mortality, a survival advantage was found in children who showed a reduction in BG on day 1 relative to the admission BG value (p < 0.001). This remained statistically significant (p = 0.007) after adjusting for severity of illness. CONCLUSIONS: This study supports an association between early BG profile and mortality in children admitted to PICU, with increased survival in those who demonstrate a fall in BG on day 1 relative to PICU admission. These findings are consistent with a survival advantage of intact BG homeostasis.

Bayesian refinement of association signals for 14 loci in 3 common diseases.

To further investigate susceptibility loci identified by genome-wide association studies, we genotyped 5,500 SNPs across 14 associated regions in 8,000 samples from a control group and 3 diseases: type 2 diabetes (T2D), coronary artery disease (CAD) and Graves' disease. We defined, using Bayes theorem, credible sets of SNPs that were 95% likely, based on posterior probability, to contain the causal disease-associated SNPs. In 3 of the 14 regions, TCF7L2 (T2D), CTLA4 (Graves' disease) and CDKN2A-CDKN2B (T2D), much of the posterior probability rested on a single SNP, and, in 4 other regions (CDKN2A-CDKN2B (CAD) and CDKAL1, FTO and HHEX (T2D)), the 95% sets were small, thereby excluding most SNPs as potentially causal. Very few SNPs in our credible sets had annotated functions, illustrating the limitations in understanding the mechanisms underlying susceptibility to common diseases. Our results also show the value of more detailed mapping to target sequences for functional studies.