Concentrations of legacy and new contaminants are related to metabolite profiles in Hudson Bay polar bears.

There are very few metabolomics assessments based on field accumulated, uncontrolled contaminant exposures in wildlife, particularly in the Arctic. In the present study, targeted metabolomics and contaminant data were analyzed together to assess potential influences of contaminant exposure on the hepatic metabolome of male polar bears (n = 29) from the southern and western Hudson Bay (SHB and WHB respectively), Canada. The 29 metabolites identified as important in the differentiation of the two subpopulations after partial least squares discriminant analysis (PLS-DA) included phosphatidylcholines (PCs), acylcarnitines (ACs; involved in ß-oxidation of fatty acids), and the fatty acid (FA) arachidonic acid (ARA). Perfluorinated alkyl substances, polybrominated diphenyl ethers, dichlorodiphenyldichloroethylene (p,p'-DDE) and some highly chlorinated ortho-polychlorinated biphenyl congeners were greater in the SHB bears and were consistently inversely correlated with discriminating ACs and PCs between the subpopulations. The concentrations of discriminatory, legacy organochlorine pesticides along with one tetrachlorobiphenyl were greater in the WHB and were directly correlated with the VIP-identified ACs and PCs. ARA, glycerophospholipid and several amino acid metabolic pathways were identified as different between subpopulations and/or were impacted. ARA is an important, conditionally essential, dietary n-6 FA and is also part of the inflammation response, and elevated concentrations in the SHB could be related to differences in chronic contaminant exposure and/or differences in diet and/or season, among a number of possible explanations. Dietary tracers (stable isotopes of carbon and nitrogen) were correlated with some discriminatory metabolites, supporting the hypothesis that dietary variation was also an important factor in the differentiation of the subpopulations. The results suggest linkages between contaminant exposure in Hudson Bay polar bears and elements of the hepatic metabolome, particularly those related to lipid metabolism.

Effects of cocoa-enriched diet on orofacial pain in a murine model.

OBJECTIVES: To investigate and discuss the effects of cocoa on orofacial pain. SETTING AND SAMPLE POPULATION: The Department of Orthodontics at the University of Florida (UF). Male and female hairless rats (N=20/group) were tested. MATERIALS AND METHODS: Rats were tested using the Orofacial Pain Assessment Device (OPAD) before and after changing their food from the standard chow to a cocoa-enriched or control-equivalent diet. RESULTS: Male rats fed the cocoa diet had a significantly higher operant pain index when tested at 37°C as compared to control diet-fed animals. Female rats on the cocoa diet had a significantly higher pain index when tested at 18°C and 44°C, as compared to animals fed the control diet. Capsaicin-induced pain was inhibited, with cocoa-diet male rats having a significantly higher pain index than control-diet male rats and cocoa-diet female rats at both 37°C and 44°C. Cocoa-diet female rats had a significantly higher pain index at 44°C than control-diet females. Mechanical sensitivity was affected following capsaicin cream, with a significantly decreased tolerated bottle distance in both cocoa- and control-diet animals, but there was no difference between cocoa- and control-diet groups. CONCLUSION: Using the OPAD operant system, we demonstrated that a diet rich in cocoa was effective in inhibiting neurogenic inflammatory pain in rats. This has implications for the use of novel alternative therapies such as diet modification for pain control.

A genome-wide association study identifies variants in KCNIP4 associated with ACE inhibitor-induced cough.

The most common side effect of angiotensin-converting enzyme inhibitor (ACEi) drugs is cough. We conducted a genome-wide association study (GWAS) of ACEi-induced cough among 7080 subjects of diverse ancestries in the Electronic Medical Records and Genomics (eMERGE) network. Cases were subjects diagnosed with ACEi-induced cough. Controls were subjects with at least 6 months of ACEi use and no cough. A GWAS (1595 cases and 5485 controls) identified associations on chromosome 4 in an intron of KCNIP4. The strongest association was at rs145489027 (minor allele frequency=0.33, odds ratio (OR)=1.3 (95% confidence interval (CI): 1.2-1.4), P=1.0 × 10(-8)). Replication for six single-nucleotide polymorphisms (SNPs) in KCNIP4 was tested in a second eMERGE population (n=926) and in the Genetics of Diabetes Audit and Research in Tayside, Scotland (GoDARTS) cohort (n=4309). Replication was observed at rs7675300 (OR=1.32 (1.01-1.70), P=0.04) in eMERGE and at rs16870989 and rs1495509 (OR=1.15 (1.01-1.30), P=0.03 for both) in GoDARTS. The combined association at rs1495509 was significant (OR=1.23 (1.15-1.32), P=1.9 × 10(-9)). These results indicate that SNPs in KCNIP4 may modulate ACEi-induced cough risk.

Predicted impact of extending the screening interval for diabetic retinopathy: the Scottish Diabetic Retinopathy Screening programme.

AIMS/HYPOTHESIS: The aim of our study was to identify subgroups of patients attending the Scottish Diabetic Retinopathy Screening (DRS) programme who might safely move from annual to two yearly retinopathy screening. METHODS: This was a retrospective cohort study of screening data from the DRS programme collected between 2005 and 2011 for people aged ≥12 years with type 1 or type 2 diabetes in Scotland. We used hidden Markov models to calculate the probabilities of transitions to referable diabetic retinopathy (referable background or proliferative retinopathy) or referable maculopathy. RESULTS: The study included 155,114 individuals with no referable diabetic retinopathy or maculopathy at their first DRS examination and with one or more further DRS examinations. There were 11,275 incident cases of referable diabetic eye disease (9,204 referable maculopathy, 2,071 referable background or proliferative retinopathy). The observed transitions to referable background or proliferative retinopathy were lower for people with no visible retinopathy vs mild background retinopathy at their prior examination (respectively, 1.2% vs 8.1% for type 1 diabetes and 0.6% vs 5.1% for type 2 diabetes). The lowest probability for transitioning to referable background or proliferative retinopathy was among people with two consecutive screens showing no visible retinopathy, where the probability was <0.3% for type 1 and <0.2% for type 2 diabetes at 2 years. CONCLUSIONS/INTERPRETATION: Transition rates to referable diabetic eye disease were lowest among people with type 2 diabetes and two consecutive screens showing no visible retinopathy. If such people had been offered two yearly screening the DRS service would have needed to screen 40% fewer people in 2009.

Investigation of known estimated glomerular filtration rate loci in patients with type 2 diabetes.

AIMS: To replicate the association of genetic variants with estimated glomerular filtration rate (GFR) and albuminuria, which has been found in recent genome-wide studies in patients with Type 2 diabetes. METHODS: We evaluated 16 candidate single nucleotide polymorphisms for estimated GFR in 3028 patients with Type 2 diabetes sampled from clinics across Tayside, Scotland, UK, who were included in the Genetics of Diabetes Audit and Research Tayside (GoDARTs) study. These single nucleotide polymorphisms were tested for their association with estimated GFR at entry to the study, with albuminuria, and with time to stage 3B chronic kidney disease (estimated GFR<45 ml/min/1.73 m(2)). We also stratified the effects on estimated GFR in patients with (n = 2096) and without albuminuria (n = 613). RESULTS: rs1260326 in GCKR (ß=1.30, P = 3.23E-03), rs17319721 in SHROOM3 (ß = -1.28, P-value = 3.18E-03) and rs12917707 in UMOD (ß = 2.0, P-value = 8.84E-04) were significantly associated with baseline estimated GFR. Analysis of effects on estimated GFR, stratified by albuminuria status, showed that in those without albuminuria (normoalbuminura; n = 613), UMOD had a significantly stronger effect on estimated GFR (ß(normo) = 4.03 ± 1.23 vs ß(albuminuria) = 1.72 ± 0.76, P = 0.002) compared with those with albuminuria, while GCKR (ß(normo) = 0.45 ± 0.89 vs ß(albuminuria) = 1.12 ± 0.55, P = 0.08) and SHROOM3 (ß(normo) = -0.07 ± 0.89 vs ß(albuminuria) = -1.43 ± 0.53, P = 0.003) had a stronger effect on estimated GFR in those with albuminuria. UMOD was also associated with a lower rate of transition to stage 3B chronic kidney disease (hazard ratio = 0.83[0.70, 0.99], P = 0.03). CONCLUSION: The genetic variants that regulate estimated GFR in the general population tend to have similar effects in patients with Type 2 diabetes and in this latter population, it is important to adjust for albuminuria status while investigating the genetic determinants of renal function.

The Limitations of Frailty Assessment Tools in ANCA-Associated Vasculitis.

Anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV) can be associated with a high burden of morbidity and mortality in an ageing population. It is increasingly recognised that individualised management is needed. Few studies have looked specifically at frailty related outcomes in AAV and a gap remains in understanding the application of frailty assessment tools in these patients. We carried out a single centre, cohort study between 2017 to 2022. Forty-one patients who had newly diagnosed or relapsing AAV and aged ≥65 years were included. The Clinical Frailty Scale (CFS) score at presentation was assessed by health care practitioners and interval CFS scores were carried out a minimum of 6 weeks from diagnosis. The aim was to determine if patients living with frailty had worse outcomes or if their perceived frailty improved with immunosuppressive treatment. The median CFS at diagnosis was 4 (vulnerable) and this remained at follow up. There was no significant interval change in CFS (P=0.16) suggesting that the patients did not become frailer and instead there was a tendency towards improved frailty scores at re-assessment. There was no significant difference in end stage kidney disease between those with higher (>5) or lower (≤5) CFS (P=1.0), although crude mortality was higher among those with an initial CFS >5 (P=0.03). Overall, we demonstrated that CFS has limitations in determining patients that may be frail as a result of disease burden with the potential to improve with treatment and clinicians should be mindful of this when making decisions relating to management.

Area-based socioeconomic status, type 2 diabetes and cardiovascular mortality in Scotland.

AIMS/HYPOTHESIS: The aim of this study was to explore the relationships between type 2 diabetes mellitus, area-based socioeconomic status (SES) and cardiovascular disease mortality in Scotland. METHODS: We used an area-based measure of SES, Scottish national diabetes register data linked to mortality records, and general population cause-specific mortality data to investigate the relationships between SES, type 2 diabetes and mortality from ischaemic heart disease (IHD) and cerebrovascular disease (CbVD), for 2001-2007. We used negative binomial regression to obtain age-adjusted RRs of mortality (by sex), comparing people with type 2 diabetes with the non-diabetic population. RESULTS: Among 216,652 people aged 40 years or older with type 2 diabetes (980,687 person-years), there were 10,554 IHD deaths and 4,378 CbVD deaths. Age-standardised mortality increased with increasing deprivation, and was higher among men. IHD mortality RRs were highest among the least deprived quintile and lowest in the most deprived quintile (men: least deprived, RR 1.94 [95% CI 1.61, 2.33]; most deprived, RR 1.46 [95% CI 1.23, 1.74]) and were higher in women than men (women: least deprived, RR 2.84 [95% CI 2.12, 3.80]; most deprived, RR 2.04 [95% CI 1.55, 2.69]). A similar, weaker, pattern was observed for cerebrovascular mortality. CONCLUSIONS/INTERPRETATION: Absolute risk of cardiovascular mortality is higher in people with diabetes than in the non-diabetic population and increases with increasing deprivation. The relative impact of diabetes on cardiovascular mortality differs by SES, and further efforts to reduce cardiovascular risk both in deprived groups and people with diabetes are required. Prevention of diabetes may reduce socioeconomic health inequalities.

The effect of deprivation and HbA1c on admission to hospital for diabetic ketoacidosis in type 1 diabetes.

AIMS/HYPOTHESIS: Diabetic ketoacidosis is a potentially life-threatening complication of diabetes and has a strong relationship with HbA(1c). We examined how socioeconomic group affects the likelihood of admission to hospital for diabetic ketoacidosis. METHODS: The Scottish Care Information - Diabetes Collaboration (SCI-DC), a dynamic national register of all cases of diagnosed diabetes in Scotland, was linked to national data on hospital admissions. We identified 24,750 people with type 1 diabetes between January 2005 and December 2007. We assessed the relationship between HbA(1c) and quintiles of deprivation with hospital admissions for diabetic ketoacidosis in people with type 1 diabetes adjusting for patient characteristics. RESULTS: We identified 23,479 people with type 1 diabetes who had complete recording of covariates. Deprivation had a substantial effect on odds of admission to hospital for diabetic ketoacidosis (OR 4.51, 95% CI 3.73, 5.46 in the most deprived quintile compared with the least deprived). This effect persisted after the inclusion of HbA(1c) and other risk factors (OR 2.81, 95% CI 2.32, 3.39). Men had a reduced risk of admission to hospital for diabetic ketoacidosis (OR 0.71, 95% CI 0.63, 0.79) and those with a history of smoking had increased odds of admission to hospital for diabetic ketoacidosis by a factor of 1.55 (95% CI 1.36, 1.78). CONCLUSIONS/INTERPRETATION: Women, smokers, those with high HbA(1c) and those living in more deprived areas have an increased risk of admission to hospital for diabetic ketoacidosis. The effect of deprivation was present even after inclusion of other risk factors. This work highlights that those in poorer areas of the community with high HbA(1c) represent a group who might be usefully supported to try to reduce hospital admissions.

Hospitalised hip fracture risk with rosiglitazone and pioglitazone use compared with other glucose-lowering drugs.

AIMS/HYPOTHESIS: Current drug labels for thiazolidinediones (TZDs) warn of increased fractures, predominantly for distal fractures in women. We examined whether exposure to TZDs affects hip fracture in women and men and compared the risk to that found with other drugs used in diabetes. METHODS: Using a nationwide database of prescriptions, hospital admissions and deaths in those with type 2 diabetes in Scotland we calculated TZD exposure among 206,672 individuals. Discrete-time failure analysis was used to model the effect of cumulative drug exposure on hip fracture during 1999-2008. RESULTS: There were 176 hip fractures among 37,479 exposed individuals. Hip fracture risk increased with cumulative exposure to TZD: OR per year of exposure 1.18 (95% CI 1.09, 1.28; p = 3 × 10(-5)), adjusted for age, sex and calendar month. Hip fracture increased with cumulative exposure in both men (OR 1.20; 95% CI 1.03, 1.41) and women (OR 1.18; 95% CI 1.07, 1.29) and risks were similar for pioglitazone (OR 1.18) and rosiglitazone (OR 1.16). The association was similar when adjusted for exposure to other drugs for diabetes and for other potential confounders. There was no association of hip fracture with cumulative exposure to sulfonylureas, metformin or insulin in this analysis. The 90-day mortality associated with hip fractures was similar in ever-users of TZD (15%) and in never-users (13%). CONCLUSIONS/INTERPRETATION: Hip fracture is a severe adverse effect with TZDs, affecting both sexes; labels should be changed to warn of this. The excess mortality is at least as much as expected from the reported association of pioglitazone with bladder cancer.

Diabetic retinopathy at diagnosis of type 2 diabetes in Scotland.

AIMS/HYPOTHESIS: The aim of this study was to examine the prevalence of and risk factors for diabetic retinopathy in people with newly diagnosed type 2 diabetes mellitus, using Scottish national data. METHODS: We identified individuals diagnosed with type 2 diabetes mellitus in Scotland between January 2005 and May 2008 using data from the national diabetes database. We calculated the prevalence of retinopathy and ORs for risk factors associated with retinopathy at first screening. RESULTS: Of the 51,526 people with newly diagnosed type 2 diabetes mellitus identified, 91.4% had been screened by 31 December 2010. The median time to first screening was 315 days (interquartile range [IQR] 111-607 days), but by 2008 the median was 83 days (IQR 51-135 days). The prevalence at first screening of any retinopathy was 19.3%, and for referable retinopathy it was 1.9%. For individuals screened after a year the prevalence of any retinopathy was 20.5% and referable retinopathy was 2.3%. Any retinopathy at screening was associated with male sex (OR 1.19, 95% CI 1.14, 1.25), HbA(1c) (OR 1.07, 95% CI 1.06, 1.08 per 1% [11 mmol/mol] increase), systolic BP (OR 1.06, 95% CI 1.05, 1.08 per 10 mmHg increase), time to screening (OR for screening >1 year post diagnosis = 1.12, 95% CI 1.07, 1.17) and obesity (OR 0.87, 95% CI 0.82, 0.93) in multivariate analysis. CONCLUSIONS/INTERPRETATION: The prevalence of retinopathy at first screening is lower than in previous UK studies, consistent with earlier diagnosis of diabetes. Most newly diagnosed type 2 diabetic patients in Scotland are screened within an acceptable interval and the prevalence of referable disease is low, even in those with delayed screening.

Inpatient costs for people with type 1 and type 2 diabetes in Scotland: a study from the Scottish Diabetes Research Network Epidemiology Group.

AIMS/HYPOTHESIS: The rising prevalence of diabetes worldwide has increased interest in the cost of diabetes. Inpatient costs for all people with diabetes in Scotland were investigated. METHODS: The Scottish Care Information-Diabetes Collaboration (SCI-DC), a real-time clinical information system of almost all diagnosed cases of diabetes in Scotland, UK, was linked to data on all hospital admissions for people with diabetes. Inpatient stay costs were estimated using the 2007-2008 Scottish National Tariff. The probability of hospital admission and total annual cost of admissions were estimated in relation to age, sex, type of diabetes, history of vascular admission, HbA(1c), creatinine, body mass index and diabetes duration. RESULTS: In Scotland during 2005-2007, 24,750 people with type 1 and 195,433 people with type 2 diabetes were identified, accounting for approximately 4.3% of the total Scottish population (5.1 million). The estimated total annual cost of admissions for all people diagnosed with type 1 and type 2 diabetes was £26 million and £275 million, respectively, approximately 12% of the total Scottish inpatient expenditure (£2.4 billion). Sex, increasing age, serum creatinine, previous vascular history and HbA(1c) (the latter differentially in type 1 and type 2) were all associated with likelihood and total annual cost of admission. CONCLUSIONS/INTERPRETATION: Diabetes inpatient expenditure accounted for 12% of the total Scottish inpatient expenditure, whilst people with diabetes account for 4.3% of the population. Of the modifiable risk factors, HbA(1c) was the most important driver of cost in type 1 diabetes.

Do men develop type 2 diabetes at lower body mass indices than women?

AIMS/HYPOTHESIS: To describe the associations between age, sex and BMI at diagnosis of type 2 diabetes, and test the hypothesis that men are diagnosed with diabetes at lower average BMI than women of similar age. METHODS: Linear regression was used to estimate and compare the relationship between age and BMI at diagnosis among 51,920 men and 43,137 women included in a population-based diabetes register in Scotland for whom an index BMI measurement was taken within 1 year of diabetes diagnosis. We also examined HbA(1c) values by sex within the same timescale. RESULTS: Mean BMI closest to date of diagnosis of type 2 diabetes mellitus was 31.83 kg/m(2) (SD 5.13) in men and 33.69 kg/m(2) (SD 6.43) in women. The inverse relationship between age and BMI at diagnosis of type 2 diabetes mellitus was significantly steeper in women than in men (slope estimate in men -0.12 kg/m(2) per year [95% CI -0.13, -0.12] women -0.18 kg/m(2) per year [95% CI -0.18, -0.17], p < 0.0001 for formal test of interaction). Mean BMI difference was most marked at younger ages and narrowed with advancing age. However, HbA(1c) levels within 1 year of diagnoses were broadly similar in men and women. CONCLUSIONS/INTERPRETATION: Men are diagnosed with type 2 diabetes at lower BMI than women across the age range. This observation may help explain why type 2 diabetes is more common among middle-aged men in populations of European extraction. Whether the same pattern is also observed in other ethnic groups requires confirmation.

A role for coding functional variants in HNF4A in type 2 diabetes susceptibility.

AIMS/HYPOTHESIS: Rare mutations in the gene HNF4A, encoding the transcription factor hepatocyte nuclear factor 4α (HNF-4A), account for ~5% of cases of MODY and more frequent variants in this gene may be involved in multifactorial forms of diabetes. Two low-frequency, non-synonymous variants in HNF4A (V255M, minor allele frequency [MAF] ~0.1%; T130I, MAF ~3.0%)-known to influence downstream HNF-4A target gene expression-are of interest, but previous type 2 diabetes association reports were inconclusive. We aimed to evaluate the contribution of these variants to type 2 diabetes susceptibility through large-scale association analysis. METHODS: We genotyped both variants in at least 5,745 cases and 14,756 population controls from the UK and Denmark. We also undertook an expanded association analysis that included previously reported and novel genotype data obtained in Danish, Finnish, Canadian and Swedish samples. A meta-analysis incorporating all published association studies of the T130I variant was subsequently carried out in a maximum sample size of 14,279 cases and 26,835 controls. RESULTS: We found no association between V255M and type 2 diabetes in either the initial (p = 0.28) or the expanded analysis (p = 0.44). However, T130I demonstrated a modest association with type 2 diabetes in the UK and Danish samples (additive per allele OR 1.17 [95% CI 1.08-1.28]; p = 1.5 × 10⁻4), which was strengthened in the meta-analysis (OR 1.20 [95% CI 1.10-1.30]; p = 2.1 × 10⁻5). CONCLUSIONS/INTERPRETATION: Our data are consistent with T130I as a low-frequency variant influencing type 2 diabetes risk, but are not conclusive when judged against stringent standards for genome-wide significance. This study exemplifies the difficulties encountered in association testing of low-frequency variants.

The effect of different doses of vitamin D(3) on markers of vascular health in patients with type 2 diabetes: a randomised controlled trial.

AIMS/HYPOTHESIS: Low 25-hydroxyvitamin D levels predict future cardiovascular events and are common in patients with type 2 diabetes. We compared the effect of 100,000 and 200,000 IU doses of vitamin D(3) on endothelial function, blood pressure and markers of glycaemic control in patients with type 2 diabetes. METHODS: This was a randomised, parallel group, placebo-controlled trial. Patients with type 2 diabetes and baseline 25-hydroxyvitamin D levels <100 nmol/l were enrolled from community and hospital-based diabetes clinics. Participants were assessed in a university department of clinical pharmacology and received a single oral dose of placebo or vitamin D(3) (100,000 IU or 200,000 IU) at baseline, randomly allocated via numbered bottles prepared offsite; participants and investigators were both blinded to treatment allocation. Endothelial function, office blood pressure, B-type natriuretic peptide, insulin resistance and glycosylated haemoglobin were measured at baseline, and at 8 and 16 weeks. RESULTS: We randomised 61 participants to the three groups (placebo 22, 100,000 IU vitamin D(3) 19, 200,000 IU vitamin D(3) 20). There was no significant difference in the primary outcome of endothelial function at 8 weeks (placebo 5.2%, n = 22; 100,000 IU 4.3%, n = 19; 200,000 IU 4.9%, n = 17) or at 16 weeks. Insulin resistance and glycosylated haemoglobin did not improve with either dose of vitamin D(3). On covariate analysis, systolic blood pressure was significantly lower in both treatment arms than in the placebo group at 8 weeks (placebo 146.4 mmHg, 100,000 IU 141.4 mmHg [p = 0.04 vs placebo], 200,000 IU 136.8 mmHg [p = 0.03 vs placebo]). B-type natriuretic peptide levels were significantly lower in the 200,000 IU group by 16 weeks (placebo 34 pg/ml, 200,000 IU 21 pg/ml, p = 0.02). No significant excess of adverse effects was noted in the treatment arms. CONCLUSIONS/INTERPRETATION: High-dose vitamin D(3) improved systolic blood pressure and B-type natriuretic peptide levels, but not endothelial function, insulin resistance or glycosylated haemoglobin in patients with type 2 diabetes.

Genetic association analysis of LARS2 with type 2 diabetes.

AIMS/HYPOTHESIS: LARS2 has been previously identified as a potential type 2 diabetes susceptibility gene through the low-frequency H324Q (rs71645922) variant (minor allele frequency [MAF] 3.0%). However, this association did not achieve genome-wide levels of significance. The aim of this study was to establish the true contribution of this variant and common variants in LARS2 (MAF > 5%) to type 2 diabetes risk. METHODS: We combined genome-wide association data (n = 10,128) from the DIAGRAM consortium with independent data derived from a tagging single nucleotide polymorphism (SNP) approach in Dutch individuals (n = 999) and took forward two SNPs of interest to replication in up to 11,163 Dutch participants (rs17637703 and rs952621). In addition, because inspection of genome-wide association study data identified a cluster of low-frequency variants with evidence of type 2 diabetes association, we attempted replication of rs9825041 (a proxy for this group) and the previously identified H324Q variant in up to 35,715 participants of European descent. RESULTS: No association between the common SNPs in LARS2 and type 2 diabetes was found. Our replication studies for the two low-frequency variants, rs9825041 and H324Q, failed to confirm an association with type 2 diabetes in Dutch, Scandinavian and UK samples (OR 1.03 [95% CI 0.95-1.12], p = 0.45, n = 31,962 and OR 0.99 [0.90-1.08], p = 0.78, n = 35,715 respectively). CONCLUSIONS/INTERPRETATION: In this study, the largest study examining the role of sequence variants in LARS2 in type 2 diabetes susceptibility, we found no evidence to support previous data indicating a role in type 2 diabetes susceptibility.

A 12-year follow-up study of all-cause and cardiovascular mortality among 10,532 people newly diagnosed with Type 2 diabetes in Tayside, Scotland.

AIMS: To determine absolute and relative risks of all-cause and cardiovascular mortality among patients newly diagnosed with Type 2 diabetes. METHODS: In an observational cohort study using record-linkage databases, based in Tayside, Scotland, UK, we identified newly diagnosed patients with Type 2 diabetes in 1993-2004. We also identified a set of non-diabetic comparators from lists of patients registered with a general practice, individually matched to the diabetic patients by sex, age and deprivation. We followed up patients for mortality and cardiovascular mortality over a 12-year period and calculated hazard ratios using Cox regression. RESULTS: There were 10,532 patients with Type 2 diabetes and 21,056 non-diabetic comparators. Diabetic patients in every age/sex group had higher absolute mortality rates. Even taking deprivation into account, the hazard ratio for mortality was 1.32 (95% CI 1.25-1.40), decreasing to 1.15 (1.09-1.22) after adjusting for pre-existing cardiovascular disease. The hazard ratios for cardiovascular mortality were higher, decreasing from 1.51 (1.37-1.67) to 1.23 (1.11-1.36) after adjusting for pre-existing cardiovascular disease. The hazard ratios decreased with increasing age at diagnosis, although the difference in absolute rate of mortality increased slightly with age. Increased mortality risks were only evident 2 years after diagnosis and increased thereafter. CONCLUSIONS: Patients with Type 2 diabetes have an increased risk of all-cause and cardiovascular mortality compared with non-diabetic comparators, although this is not observable immediately after diagnosis. Age at diagnosis and duration of the disease independently affect absolute and relative mortality risk.

A cohort study of the risk of cancer associated with type 2 diabetes.

BACKGROUND: There is evidence to suggest that diabetes may increase the risk of incidence and mortality from cancer. METHODS: In a cohort study using record-linkage health-care datasets for Tayside, Scotland in 1993-2004, we followed up 9577 newly diagnosed patients with type 2 diabetes, and two matched non-diabetic comparators, in the national cancer register. RESULTS AND CONCLUSIONS: The risk ratio for any cancer, adjusted for deprivation, was 0.99 (95%CI 0.90-1.09). Significantly increased risks were observed for pancreatic, liver and colon cancer.

Some principles and practices of genetic biobanking studies.

Genetic biobanking studies are becoming increasingly common as researchers recognise the need for large samples to identify the genetic basis of susceptibility to complex disease. In the present review, the authors give a brief overview of some of the issues that should be considered when implementing such a large-scale project, from study design to sample management, data coding and storage to the statistical analysis and engagement with the public. Specific solutions to these issues are presented, as implemented in the Generation Scotland projects, but the general principles outlined are relevant to any biobanking study.

Which people with Type 2 diabetes achieve good control of intermediate outcomes? Population database study in a UK region.

AIMS: To measure quality of vascular risk factor measurement and control in people with Type 2 diabetes after comprehensive pay-for-performance implementation and to examine variation by patient and practice characteristics. METHODS: Multi-level regression analysis of 10 191 patients with Type 2 diabetes registered with 59 practices in the Tayside region. Quality measures examined were recording of glycated haemoglobin (HbA(1c)), blood pressure (BP), cholesterol and smoking status in the last 12 months; achievement of recommended intermediate outcome targets (HbA(1c)< or = 7.4%, BP < 140/80 mmHg, cholesterol < or = 5.0 mmol/l, not smoking); and simple and all-or-none composite measures. RESULTS: Ninety-five per cent of all recommended processes were received by patients, with 88% of patients receiving all four. Half of all intermediate outcomes targets were achieved, but only 16% of patients achieved all four targets. Process and outcome of care were consistently worse for 1523 (15.0%) patients aged < 55 years. HbA(1c) and BP targets were progressively less likely to be achieved as body mass index increased. Women were less likely to achieve cholesterol targets, but apart from smoking status, there were no associations with socio-economic status. CONCLUSION: Under comprehensive pay-for-performance, process of care is remarkably reliable, but intermediate outcome control less so. Previously identified socio-economic variations in diabetes care have been largely eliminated, but gender inequality is persistent. Younger people were considerably less likely to achieve intermediate outcome targets. Mitigating increased vascular risk in younger patients with Type 2 diabetes presents major challenges for health services in the face of the evolving epidemics of obesity and diabetes.