Benefits of combination of insulin degludec and liraglutide are independent of baseline glycated haemoglobin level and duration of type 2 diabetes.

AIM: To evaluate, using post hoc analyses, whether the novel combination of a basal insulin, insulin degludec, and a glucagon-like peptide-1 receptor agonist, liraglutide (IDegLira), was consistently effective in patients with type 2 diabetes (T2D), regardless of the stage of T2D progression. METHODS: Using data from the DUAL I extension [insulin-naïve patients uncontrolled on oral antidiabetic drugs (OADs), n = 1660, 52 weeks] and DUAL II (patients uncontrolled on basal insulin plus OADs, n = 398, 26 weeks) randomized trials, the efficacy of IDegLira was investigated with regard to measures of disease progression stage including baseline glycated haemoglobin (HbA1c), disease duration and previous insulin dose. RESULTS: Across four categories of baseline HbA1c (≤7.5-9.0%), HbA1c reductions were significantly greater with IDegLira (1.1-2.5%) compared with IDeg or liraglutide alone in DUAL I. In DUAL II, HbA1c reductions were significantly greater with IDegLira (0.9-2.5%) than with IDeg in all but the lowest HbA1c category. In DUAL I, insulin dose and hypoglycaemia rate were lower across all baseline HbA1c categories for IDegLira versus IDeg, while hypoglycaemia was higher with IDegLira than liraglutide, irrespective of baseline HbA1c. In DUAL II, insulin dose and hypoglycaemia rate were similar with IDegLira and IDeg (maximum dose limited to 50 U) independent of baseline HbA1c. The reduction in HbA1c with IDegLira was independent of disease duration and previous insulin dose but varied depending on pre-trial OAD treatment. CONCLUSIONS: IDegLira effectively lowered HbA1c across a range of measures, implying suitability for patients with either early or advanced T2D.

Severe hypoglycaemia in adults with insulin-treated diabetes: impact on healthcare resources.

AIMS: To assess resource utilization associated with severe hypoglycaemia across three insulin regimens in a large phase 3a clinical programme involving people with Type 1 diabetes treated with basal-bolus insulin, people with Type 2 diabetes treated with multiple daily injections and people with Type 2 diabetes treated with basal-oral therapy. METHODS: Data relating to severe hypoglycaemia events (defined as episodes requiring external assistance) from the insulin degludec and insulin degludec/insulin aspart programme (15 trials) were analysed using descriptive statistics. Comparators included insulin glargine, biphasic insulin aspart, insulin detemir and sitagliptin. Mealtime insulin aspart was used in some regimens. This analysis used the serious adverse events records, which documented the use of ambulance/emergency teams, a hospital/emergency room visit ≤ 24 h, or a hospital visit > 24 h. RESULTS: In total, 536 severe hypoglycaemia events were analysed, of which 157 (29.3%) involved an ambulance/emergency team, 64 (11.9%) led to hospital/emergency room attendance of ≤ 24 h and 36 (6.7%) required hospital admission (> 24 h). Although there were fewer events in people with Type 2 diabetes compared with Type 1 diabetes, once a severe episode occurred, the tendency to utilize healthcare resources was higher in Type 2 diabetes vs. Type 1 diabetes. A higher proportion (47.6%) in the basal-oral therapy group required hospital treatment for > 24 h versus the Type 1 diabetes (5.0%) and Type 2 diabetes multiple daily injections (5.3%) groups. CONCLUSION: This analysis suggests that severe hypoglycaemia events often result in emergency/ambulance calls and hospital treatment, incurring a substantial health economic burden, and were associated with all insulin regimens.

One-year efficacy and safety of a fixed combination of insulin degludec and liraglutide in patients with type 2 diabetes: results of a 26-week extension to a 26-week main trial.

AIMS: To confirm, in a 26-week extension study, the sustained efficacy and safety of a fixed combination of insulin degludec and liraglutide (IDegLira) compared with either insulin degludec or liraglutide alone, in patients with type 2 diabetes. METHODS: Insulin-naïve adults with type 2 diabetes randomized to once-daily IDegLira, insulin degludec or liraglutide, in addition to metformin ± pioglitazone, continued their allocated treatment in this preplanned 26-week extension of the DUAL I trial. RESULTS: A total of 78.8% of patients (1311/1663) continued into the extension phase. The mean glycated haemoglobin (HbA1c) concentration at 52 weeks was reduced from baseline by 1.84% (20.2 mmol/mol) for the IDegLira group, 1.40% (15.3 mmol/mol) for the insulin degludec group and 1.21% (13.2 mmol/mol) for the liraglutide group. Of the patients on IDegLira, 78% achieved an HbA1c of <7% (53 mmol/mol) versus 63% of the patients on insulin degludec and 57% of those on liraglutide. The mean fasting plasma glucose concentration at the end of the trial was similar for IDegLira (5.7 mmol/l) and insulin degludec (6.0 mmol/l), but higher for liraglutide (7.3 mmol/l). At 52 weeks, the daily insulin dose was 37% lower with IDegLira (39 units) than with insulin degludec (62 units). IDegLira was associated with a significantly greater decrease in body weight (estimated treatment difference, -2.80 kg, p < 0.0001) and a 37% lower rate of hypoglycaemia compared with insulin degludec. Overall, all treatments were well tolerated and no new adverse events or tolerability issues were observed for IDegLira. CONCLUSIONS: These 12-month data, derived from a 26-week extension of the DUAL I trial, confirm the initial 26-week main phase results and the sustainability of the benefits of IDegLira compared with its components in glycaemic efficacy, safety and tolerability.

Genetic variation in caveolin-1 correlates with long-term pancreas transplant function.

Pancreas transplantation is a successful treatment for a selected group of people with type 1 diabetes. Continued insulin production can decrease over time and identifying predictors of long-term graft function is key to improving survival. The aim of this study was to screen subjects for variation in the Caveolin-1 gene (Cav1), previously shown to correlate with long-term kidney transplant function. We genotyped 435 pancreas transplant donors and 431 recipients who had undergone pancreas transplantation at the Oxford Transplant Centre, UK, for all known common variation in Cav1. Death-censored cumulative events were analyzed using Kaplan-Meier and Cox regression. Unlike kidney transplantation, the rs4730751 variant in our pancreas donors or transplant recipients did not correlate with long-term graft function (p = 0.331-0.905). Presence of rs3801995 TT genotype (p = 0.009) and rs9920 CC/CT genotype (p = 0.010) in our donors did however correlate with reduced long-term graft survival. Multivariate Cox regression (adjusted for donor and recipient transplant factors) confirmed the association of rs3801995 (p = 0.009, HR = 1.83;[95% CI = 1.16-2.89]) and rs9920 (p = 0.037, HR = 1.63; [95% CI = 1.03-2.73]) with long-term graft function. This is the first study to provide evidence that donor Cav1 genotype correlates with long-term pancreas graft function. Screening Cav1 in other datasets is required to confirm these pilot results.

Biosimilar insulins: a European perspective.

Biosimilar insulins are likely to enter clinical practice in Europe in the near future. It is important that clinicians are familiar with and understand the concept of biosimilarity and how a biosimilar drug may differ from its reference product. The present article provides an overview of biosimilars, the European regulatory requirements for biosimilars and safety issues. It also summarizes the current biosimilars approved in Europe and the key clinical issues associated with the use of biosimilar insulins.

Abdominal subcutaneous adipose tissue insulin resistance and lipolysis in patients with non-alcoholic steatohepatitis.

BACKGROUND: Systemic insulin resistance (IR) is a primary feature in non-alcoholic steatohepatitis (NASH), however, there remain limited data on tissue-specific insulin sensitivity in vivo. METHODS: We examined tissue-specific (adipose, muscle and liver) insulin sensitivity and inflammation in 16 European Caucasian patients with biopsy-confirmed NASH and in 15 healthy controls. All underwent a two-step hyperinsulinaemic euglycaemic clamp incorporating stable isotope measurements of carbohydrate and lipid metabolism with concomitant subcutaneous adipose tissue (SAT) microdialysis. RESULTS: Hepatic and muscle insulin sensitivity were decreased in patients with NASH compared with controls, as demonstrated by reduced suppression of hepatic glucose production and glucose disposal (Gd) rates following insulin infusion. In addition, rates of lipolysis were higher in NASH patients with impaired insulin-mediated suppression of free fatty acid levels. At a tissue specific level, abdominal SAT in patients with NASH was severely insulin resistant, requiring >sixfold more insulin to cause ½-maximal suppression of glycerol release when compared with healthy controls. Furthermore, patients with NASH had significantly higher circulating levels of pro-inflammatory adipocytokines than controls. CONCLUSION: NASH patients have profound IR in the liver, muscle and in particular adipose tissues. This study represents the first in vivo description of dysfunctional SAT in patients with NASH.

Pancreas transplantation: a treatment option for people with diabetes.

Since the first pancreas transplants in the early 1960s, whole-organ pancreas transplantation, either alone or combined with kidney transplantation, has become commonplace in many countries around the world. Whole-organ pancreas transplantation is available in the UK, with ~200 transplants currently carried out per year. Patient survival and pancreas graft outcome rates are now similar to other solid organ transplant programmes, with high rates of long-term insulin independence. In the present review, we will discuss whole-pancreas transplantation as a treatment for diabetes, focusing on indications for transplantation, the nature of the procedure performed, graft survival rates and the consequences of pancreas transplantation on metabolic variables and the progression of diabetes-related complications.

Safety and efficacy of liraglutide in patients with type 2 diabetes and elevated liver enzymes: individual patient data meta-analysis of the LEAD program.

BACKGROUND: Non-alcoholic fatty liver disease has reached epidemic proportions in type 2 diabetes (T2D). Glucagon-like peptide-1 analogues are licensed in T2D, yet little data exist on efficacy and safety in liver injury. AIM: To assess the safety and efficacy of 26-week liraglutide on liver parameters in comparison with active-placebo. METHODS: Individual patient data meta-analysis was performed using patient-level data combined from six 26-week, phase-III, randomised controlled T2D trials, which comprise the 'Liraglutide Effect and Action in Diabetes' (LEAD) program. The LEAD-2 sub-study was analysed to assess the effect on CT-measured hepatic steatosis. RESULTS: Of 4442 patients analysed, 2241 (50.8%) patients had an abnormal ALT at baseline [mean ALT 33.8(14.9) IU/L in females; 47.3(18.3) IU/L in males]. Liraglutide 1.8 mg reduced ALT in these patients vs. placebo (-8.20 vs. -5.01 IU/L; P = 0.003), and was dose-dependent (no significant differences vs. placebo with liraglutide 0.6 or 1.2 mg). This effect was lost after adjusting for liraglutide's reduction in weight (mean ALT difference vs. placebo -1.41 IU/L, P = 0.21) and HbA1c (+0.57 IU/L, P = 0.63). Adverse effects with 1.8 mg liraglutide were similar between patients with and without baseline abnormal ALT. In LEAD-2 sub-study, liraglutide 1.8 mg showed a trend towards improving hepatic steatosis vs. placebo (liver-to-spleen attenuation ratio +0.10 vs. 0.00; P = 0.07). This difference was reduced when correcting for changes in weight (+0.06, P = 0.25) and HbA(1c) (0.00, P = 0.93). CONCLUSIONS: Twenty-six weeks' liraglutide 1.8 mg is safe, well tolerated and improves liver enzymes in patients with type 2 diabetes. This effect appears to be mediated by its action on weight loss and glycaemic control.

Insulin degludec: overview of a novel ultra long-acting basal insulin.

All the basal insulin products currently available have suboptimal pharmacokinetic (PK) properties, with none reliably providing a reproducible and peakless pharmacodynamic (PD) effect that endures over 24 h from once-daily dosing. Insulin degludec is a novel acylated basal insulin with a unique mechanism of protracted absorption involving the formation of a depot of soluble multihexamer chains after subcutaneous injection. PK/PD studies show that insulin degludec has a very long duration of action, with a half-life exceeding 25 h. Once-daily dosing produces a steady-state profile characterized by a near-constant effect, which varies little from injection to injection in a given patient. Clinically, insulin degludec has been shown consistently to carry a lower risk of nocturnal hypoglycaemia than once-daily insulin glargine, in both basal+bolus and basal-only insulin regimens. The constancy of the steady-state profile of insulin degludec also means that day-to-day irregularities at the time of injection have relatively little PD influence, thereby offering the possibility of greater treatment flexibility for patients.

Hypoglycaemia risk with insulin degludec compared with insulin glargine in type 2 and type 1 diabetes: a pre-planned meta-analysis of phase 3 trials.

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.

Liraglutide: from clinical trials to clinical practice.

Liraglutide, a once-daily glucagon-like peptide-1 receptor agonist, is approved for use as monotherapy in the USA and Japan (but not in Europe or Canada) and in combination with selected oral agents (all regions) for the treatment of patients with type 2 diabetes. Guidance from local advisory bodies is emerging on the most appropriate place for liraglutide in the treatment pathway. It is apparent from its phase 3 clinical trial programme that liraglutide provides superior glycaemic control compared with that achieved with other antidiabetic agents used early in the treatment pathway (e.g. glimepiride and sitagliptin). Key additional benefits include a low incidence of hypoglycaemia and clinically relevant weight loss, although these benefits may be ameliorated by concomitant sulphonylurea (SU) treatment and, in the case of hypoglycaemia, reduction of the SU dose may be necessary. Overall, the profile of liraglutide is similar and, in some aspects, superior to twice-daily exenatide. The implementation of liraglutide therapy is straightforward, with simple dose titration from the starting dose of 0.6 to 1.2 mg/day after 1 week; some patients may benefit from additional titration to 1.8 mg/day. Treatment is self-administered by subcutaneous injection. This contrasts with other agents used early in the treatment pathway, but clinical data suggest patients' overall treatment satisfaction with liraglutide is similar (1.2 mg) or better (1.8 mg) than that with sitagliptin despite differing administration methods. Some patients may experience nausea when initiating liraglutide treatment, but the titration regimen is designed to improve tolerability and clinical data indicate nausea is transient.

Genetics of thyroid autoimmunity and the role of the TSHR.

Graves' disease (GD) and Hashimoto's thyroiditis (HT) make up the autoimmune thyroid diseases (AITD), with classical clinical characteristics arising as a result of environmental factors in people who are genetically predisposed. Three gene regions consistently associated with AITD include the Human Leucocyte Antigen (HLA) region, CTLA4 and PTPN22, which represent general autoimmune risk loci and encode molecules vital for correct immune system function. AITD patients in addition are likely to carry at least one thyroid specific susceptibility locus. Recent genetic studies have refined association of the TSHR with GD to within a 40kb region including intron 1, of the TSHR itself, with preliminary evidence to suggest altered mRNA isoform expression. These findings, combined with previous functional data demonstrating that the TSHR A-subunit is the primary autoantigenic region, suggests novel mechanisms for the onset of GD and a potential therapeutic target.

Validation of an algorithm combining haemoglobin A(1c) and fasting plasma glucose for diagnosis of diabetes mellitus in UK and Australian populations.

AIM: To determine whether glycated haemoglobin (HbA(1c)) can be used in combination with fasting plasma glucose (FPG) for the diagnosis of diabetes in patients with impaired fasting glucose (IFG) and in a broader spectrum of patients. METHODS: An algorithm was derived from oral glucose tolerance test (OGTT) capillary samples in 500 consecutive UK patients with IFG by World Health Organization criteria. It was validated in a further 500 UK patients and, with venous specimens, in 1175 unselected Australian patients. RESULTS: The derivation cohort was aged 61 years (50-69 years) (median IQ range) with 52% male and 12% South Asian. Diabetes Control and Complications Trial-aligned HbA(1c) was 6.2% (5.8-6.6%) (reference interval < 6.0%) and FPG 6.7 mmol/l (6.3-7.2 mmol/l). FPG was in the diabetes range in 36% of patients, with an OGTT identifying a further 12% with diabetes. The derived algorithm, (HbA(1c) >or= 6.0% with FPG < 7.0 mmol/l) identified those patients requiring an OGTT to diagnose diabetes. When applied to the UK validation cohort, sensitivity was 97% and specificity 100%. The algorithm was equally effective in the unselected group, aged 59 years (49-68 years) and 54% male, with sensitivity 93% and specificity 100%. HbA(1c) was 6.0% (5.6-6.6%) and FPG 6.0 mmol/l (5.3-6.8 mmol/l), with 26% having IFG. Use of the algorithm would reduce the number of OGTTs performed in the UK validation cohort by 33% and by 66% in the Australian patients studied. CONCLUSIONS: Use of this algorithm would simplify procedures for diagnosis of diabetes and could also be used for monitoring pre-diabetes. Validation is now required in other populations and patient groups.

Prediction of cure and risk of hypothyroidism in patients receiving 131I for hyperthyroidism.

CONTEXT: There is little consensus regarding the most appropriate dose of radioiodine ((131)I) to be administered to patients with hyperthyroidism. OBJECTIVE: To compare the efficacy of fixed dose regimens of (131)I in curing hyperthyroidism and to define simple clinical and biochemical factors that predict outcome in individual patients. DESIGN: Consecutive series of hyperthyroid subjects treated with (131)I. SETTING: Single Secondary/Tertiary Care Hospital Clinic. PARTICIPANTS: A total of 1278 patients (1013 females and 262 males, mean age 49.7 years) presenting with hyperthyroidism between 1984 and 2006. INTERVENTION: Treatment with (131)I using a fixed dose regimen. MAIN OUTCOME MEASURES: Probability of cure and risk of development of hypothyroidism following a single dose of (131)I. RESULTS: Patients given a single dose of (131)I of 600 MBq (n = 485) had a higher cure rate (84.1%) compared with those receiving either 370 MBq (74.9%, P < 0.001) or those given 185 Bq (63%, P < 0.001). An increased incidence of hypothyroidism by 1 year was evident with higher doses (600 MBq: 60.4%; 370 MBq: 49.2%, P = 0.001; 185 Bq: 38.1%, P < 0.001). Binary logistic regression analysis identified a 600 Bq dose of (131)I [adjusted odds ratio, AOR 3.33 (2.28-4.85), P < 0.001], female gender [AOR 1.75 (1.23-2.47), P = 0.002], lower presenting serum free T4 concentration [AOR 1.01 (1.01-1.02), P < 0.001] and absence of a palpable goitre [AOR 3.33 (2.00-5.56), P < 0.001] to be independent predictors of cure. Similarly, a 600 MBq dose [AOR 3.79 (2.66-5.38), P < 0.001], female gender [AOR 1.46 (1.05-2.02), P = 0.02], younger age [AOR 1.03 (1.02-1.04), P < 0.001], absence of a palpable goitre [AOR 3.85 (2.38-5.88), P < 0.001] and presence of ophthalmopathy [AOR 1.57 (1.06-2.31), P = 0.02] were identified as independent factors predicting the probability of development of hypothyroidism at one year. Based on these findings, formulae to indicate probability of cure and risk of hypothyroidism for application to individual patients were derived. CONCLUSIONS: Simple clinical/biochemical criteria can be used to predict outcome after (131)I treatment. These factors determine that males, those with severe biochemical hyperthyroidism, and those with a palpable goitre require larger doses (600 MBq) in order to achieve cure.

CD226 Gly307Ser association with multiple autoimmune diseases.

Genome-wide association studies provide insight into multigenic diseases through the identification of susceptibility genes and etiological pathways. In addition, the identification of shared variants among autoimmune disorders provides insight into common disease pathways. We previously reported an association of a nonsynonymous single nucleotide polymorphism (SNP) rs763361/Gly307Ser in the immune response gene CD226 on chromosome 18q22 with type 1 diabetes (T1D) susceptibility. Here, we report efforts toward identifying the causal variant by exonic resequencing and tag SNP mapping of the 18q22 region in both T1D and multiple sclerosis (MS). In addition to the analysis of newly available samples in T1D (2088 cases and 3289 controls) and autoimmune thyroid disease (AITD) (821 cases and 1920 controls), resulting in strong support for the Ser(307) association with T1D (P=3.46 x 10(-9)) and continued potential evidence for AITD (P=0.0345), we provide evidence for association of Gly307Ser with MS (P=4.20 x 10(-4)) and rheumatoid arthritis (RA) (P=0.017). The Ser(307) allele of rs763361 in exon 7 of CD226 predisposes to T1D, MS, and possibly AITD and RA, and based on the tag SNP analysis, could be the causal variant.

Analysis of HLA class II genes in Hashimoto's thyroiditis reveals differences compared to Graves' disease.

Graves' disease (GD) and Hashimoto's thyroiditis (HT) represent the commonest forms of autoimmune thyroid disease (AITD) each presenting with distinct clinical features. Progress has been made in determining association of HLA class II DRB1, DQB1 and DQA1 loci with GD demonstrating a predisposing effect for DR3 (DRB1(*)03-DQB1(*)02-DQA1(*)05) and a protective effect for DR7 (DRB1(*)07-DQB1(*)02-DQA1(*)02). Small data sets have hindered progress in determining HLA class II associations with HT. The aim of this study was to investigate DRB1-DQB1-DQA1 in the largest UK Caucasian HT case control cohort to date comprising 640 HT patients and 621 controls. A strong association between HT and DR4 (DRB1(*)04-DQB1(*)03-DQA1(*)03) was detected (P=6.79 x 10(-7), OR=1.98 (95% CI=1.51-2.59)); however, only borderline association of DR3 was found (P=0.050). Protective effects were also detected for DR13 (DRB1(*)13-DQB1(*)06-DQA1(*)01) (P=0.001, OR=0.61 (95% CI=0.45-0.83)) and DR7 (P=0.013, OR=0.70 (95% CI=0.53-0.93)). Analysis of our unique cohort of subjects with well characterized AITD has demonstrated clear differences in association within the HLA class II region between HT and GD. Although HT and GD share a number of common genetic markers this study supports the suggestion that differences in HLA class II genotype may, in part, contribute to the different immunopathological processes and clinical presentation of these related diseases.

Delayed initiation of subcutaneous insulin therapy after failure of oral glucose-lowering agents in patients with Type 2 diabetes: a population-based analysis in the UK.

AIMS: The aim of this retrospective cohort study was to estimate the time to insulin initiation in patients with Type 2 diabetes inadequately controlled on oral glucose-lowering agents (OGLAs). METHODS: Insulin-naïve patients failing on OGLAs were identified from The Health Improvement Network database, which collects records from general practices throughout the UK. Patients were included if they were aged > or = 40 years, had concomitant prescriptions for > or = 2 OGLAs, and > or = 1 year of available records prior to the first occurrence of HbA(1c) > or = 8.0% after > or = 90 days of OGLA polytherapy at > or = 50% of maximum recommended dosages. RESULTS: A total of 2501 eligible patients with Type 2 diabetes who had an HbA(1c) above the OGLA failure threshold of > or = 8.0% were identified (54.0% male; 30.9% aged 60-69 years). It was estimated that if all the eligible patients were followed for 5 years, 25% would initiate insulin within 1.8 years of OGLA failure (95% CI 1.6-2.0), and 50% within 4.9 years (95% CI 4.6-5.8). The presence of diabetes-related complications had no substantial impact on the time to insulin initiation. CONCLUSIONS: This study found that 25% of patients with Type 2 diabetes had insulin initiation delayed for at least 1.8 years, and 50% of patients delayed starting insulin for almost 5 years after failure of glycaemic control with OGLA polytherapy, even in the presence of diabetes-related complications. Interventions that reduce this delay to insulin initiation are required to help achieve and maintain recommended glycaemic targets in patients with Type 2 diabetes.

Preliminary evidence for interaction of PTPN12 polymorphism with TSHR genotype and association with Graves' ophthalmopathy.

OBJECTIVE: Protein tyrosine phosphatases (PTPs), such as PTPN22, are important regulators of signal transduction from the T cell receptor and have been associated with autoimmunity. PTPN12 interacts with the same T cell activation accessory molecules, Grb2 and Csk kinase, as the Graves' disease (GD) associated PTPN22 encoded lymphoid tyrosine phosphatase (LYP) molecule and also plays a key role in T cell receptor signalling, leading to the hypothesis that it too may be involved in GD susceptibility. DESIGN: PTPN12 was tested for association in a large well-characterized UK Caucasian case control cohort using seven tagging single nucleotide polymorphisms (SNPs). Patients A total of 1058 GD patients and 864 controls. Measurements Tests for association with the disease. RESULTS: Despite adequate statistical power to detect an effect if present, none of the seven tag SNPs were associated with GD (P = 0.925-0.089). Three SNPs (rs1468682, rs4729535 and rs17467232), however, demonstrated association with the presence of ophthalmopathy NOSPECS classes 2-4 (P = 0.039-0.004). Four SNPs (rs1468682, rs4729535, rs17155601 and rs17467232) revealed evidence of interaction with the previously associated thyrotropin hormone receptor (TSHR) rs2268458 SNP (P = 0.035-0.002). CONCLUSIONS: No association was detected between individual PTPN12 tag SNPs and GD but preliminary evidence suggests PTPN12 confers an increased risk of mild/moderate ophthalmopathy (NOSPECS classes 2-4) and that PTPN12 interacts with the TSHR. Replication of these preliminary results is now required in larger independent datasets to validate these findings.

Tag SNP screening of the PDCD1 gene for association with Graves' disease.

OBJECTIVE: The Programmed Cell Death 1 gene (PDCD1) on chromosome 2q37.3 encodes PD-1 which is involved in providing a negative signal to activated T cells. Large case-control studies have shown association of PDCD1 with several autoimmune diseases although, to date, no such studies have been performed for Graves' disease (GD). The objective of our study was to investigate eight tag SNPs representing the majority of common variation in PDCD1 within a well-characterized large UK Caucasian GD dataset. DESIGN: A case control association study of eight polymorphisms. PATIENTS: 2671 Graves' disease patients and 864 controls. MEASUREMENTS: Tests for association with disease. RESULTS: No association with disease was seen for any of the +4163, +5049, +5318, +5640, +5678 and +7078 SNPs genotyped in this study. Association was detected between the +2375 SNP (P = 0.021, OR = 1.14 [95% CI = 1.01-1.29]) and GD and a small protective effect was seen with the +6799 SNP genotypes (P = 0.028, OR = 0.77 [95% CI = 0.58-1.03]). CONCLUSIONS: This study has, for the first time, shown that small effects within PDCD1 may contribute towards the development of GD, supporting the hypothesis that much of the currently unknown genetic contribution to GD could be due to several small genetic effects with ORs 1.2. Replication of this result is now needed to confirm our findings and justify more detailed fine mapping of a primary aetiological variant in this gene region.