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Vitamin D deficiency and primary hyperparathyroidism (PHPT) are relatively common disorders. The coexistence of these conditions should be considered, as depletion of vitamin D may alter the clinical expression of autonomous parathyroid disease. We report details of a vitamin D deficient patient in whom replacement therapy led to the unmasking of occult PHPT. [ABSTRACT FROM AUTHOR]

Motivation: Metabolic phenotyping, using high-resolution spectroscopic molecular fingerprints of biological samples, has demonstrated diagnostic, prognostic, and mechanistic value in clinical studies. However, clinical translation is hindered by the lack of viable workflows and challenges in converting spectral data into usable information., Results: MetaboScope is an analytical and statistical workflow for learning, designing and analyzing clinically relevant 1 H nuclear magnetic resonance data. It features modular preprocessing pipelines, multivariate modeling tools including Principal Components Analysis (PCA), Orthogonal-Projection to Latent Structure Discriminant Analysis (OPLS-DA), and biomarker discovery tools (multiblock PCA and statistical spectroscopy). A simulation tool is also provided, allowing users to create synthetic spectra for hypothesis testing and power calculations., Availability and Implementation: MetaboScope is built as a pipeline where each module accepts the output generated by the previous one. This provides flexibility and simplicity of use, while being straightforward to maintain. The system and its libraries were developed in JavaScript and run as a web app; therefore, all the operations are performed on the local computer, circumventing the need to upload data. The MetaboScope tool is available at https://www.cheminfo.org/flavor/metabolomics/index.html. The code is open-source and can be deployed locally if necessary. Module notes, video tutorials, and clinical spectral datasets are provided for modeling., Competing Interests: None declared., (© The Author(s) 2024. Published by Oxford University Press.)

Diabetes mellitus is a central driver of multiple long-term conditions (MLTCs), but population-based studies have not clearly characterized the burden across the life course. We estimated the age of onset, years of life spent and loss associated with diabetes-related MLTCs among 46 million English adults. We found that morbidity patterns extend beyond classic diabetes complications and accelerate the onset of severe MLTCs by 20 years earlier in life in women and 15 years earlier in men. By the age of 50 years, one-third of those with diabetes have at least three conditions, spend >20 years with them and die 11 years earlier than the general population. Each additional condition at the age of 50 years is associated with four fewer years of life. Hypertension, depression, cancer and coronary heart disease contribute heavily to MLTCs in older age and create the greatest community-level burden on years spent (813 to 3,908 years per 1,000 individuals) and lost (900 to 1,417 years per 1,000 individuals). However, in younger adulthood, depression, severe mental illness, learning disabilities, alcohol dependence and asthma have larger roles, and when they occur, all except alcohol dependence were associated with long periods of life spent (11-14 years) and all except asthma associated with many years of life lost (11-15 years). These findings provide a baseline for population monitoring and underscore the need to prioritize effective prevention and management approaches., (© 2024. The Author(s).)

For 100 years, the Intravenous glucose tolerance test (IVGTT) has been used extensively in researching the pathophysiology of diabetes mellitus and AIRg-the IVGTT-induced acute insulin response to the rapid rise in circulating glucose-is a key measure of insulin secretory capacity. For an effective evaluation of AIRg, IVGTT glucose loading should be adjusted for glucose distribution volume (gVOL) to provide an invariant, trend-free immediate rise in circulating glucose (ΔG0). Body weight-based glucose loads have been widely used but whether these achieve a trend-free ΔG0 does not appear to have been investigated. By analysing variation in AIRg, ΔG0 and gVOL with a range of IVGTT loads, both observed and simulated, we explored the hypothesis that there would be an optimum anthropometry-based IVGTT load calculation that, by achieving a trend-free ΔG0, would not compromise evaluation of AIRg as an index of beta cell function. Data derived from patient and research volunteer records for 3806 IVGTT glucose and insulin profiles. Among the non-obese, as gVOL rose, weight increased disproportionately rapidly. Consequently, the IVGTT glucose load needed for an invariant ΔG0 was progressively overestimated, accounting for 47% of variation in AIRg. Among the obese, ΔG0 was trend-free yet AIRg increased by 11.6% per unit body mass index, consistent with a more proportionate increase in weight with gVOL and a hyperinsulinaemic adaptation to adiposity-associated insulin resistance. Simulations further confirmed our hypothesis by demonstrating that a body surface area-based IVGTT load calculation could provide for a more generally invariant IVGTT ΔG0., (© 2024. The Author(s).)

Objectives: To determine the prevalence of multiple long-term conditions (MLTC) at whole English population level, stratifying by age, sex, socioeconomic status and ethnicity., Design: A whole population study., Setting: Individuals registered with a general practice in England and alive on 31 March 2020., Participants: 60,004,883 individuals., Main Outcome Measures: MLTC prevalence, defined as two or more of 35 conditions derived from a number of national patient-level datasets. Multivariable logistic regression was used to assess the independent associations of age, sex, ethnicity and deprivation decile with odds of MLTC., Results: The overall prevalence of MLTC was 14.8% (8,878,231), varying from 0.9% (125,159) in those aged 0-19 years to 68.2% (1,905,979) in those aged 80 years and over. In multivariable regression analyses, compared with the 50-59 reference group, the odds ratio was 0.04 (95% confidence interval (CI): 0.04-0.04; p  < 0.001) for those aged 0-19 years and 10.21 (10.18-10.24; p  < 0.001) for those aged 80 years and over. Odds were higher for men compared with women, 1.02 (1.02-1.02; p  < 0.001), for the most deprived decile compared with the least deprived, 2.26 (2.25-2.27; p  < 0.001), and for Asian ethnicity compared with those of white ethnicity, 1.05 (1.04-1.05; p  < 0.001). Odds were lower for black, mixed and other ethnicities (0.94 (0.94-0.95) p  < 0.001, 0.87 (0.87-0.88) p  < 0.001 and 0.57 (0.56-0.57) p  < 0.001, respectively). MLTC for persons aged 0-19 years were dominated by asthma, autism and epilepsy, for persons aged 20-49 years by depression and asthma, for persons aged 50-59 years by hypertension and depression and for those aged 60 years and older, by cardiometabolic factors and osteoarthritis. There were large numbers of combinations of conditions in each age group ranging from 5936 in those aged 0-19 years to 205,534 in those aged 80 years and over., Conclusions: While this study provides useful insight into the burden across the English population to assist health service delivery planning, the heterogeneity of MLTC presents challenges for delivery optimisation.

Aims: The aim of this study is to evaluate the change in incidence rate of shoulder arthroplasty, indications, and surgeon volume trends associated with these procedures between January 2003 and April 2021 in the province of Nova Scotia, Canada., Methods: A total of 1,545 patients between 2005 and 2021 were analyzed. Patients operated on between 2003 and 2004 were excluded due to a lack of electronic records. Overall, 84.1% of the surgeries (n = 1,299) were performed by two fellowship-trained upper limb surgeons, with the remainder performed by one of the 14 orthopaedic surgeons working in the province., Results: Total shoulder arthroplasty (TSA) was the most frequent procedure (32.17%; n = 497), followed by stemmed hemiarthroplasty (SHA) (27.7%; n = 428). The most frequent indication for primary shoulder arthroplasty was degenerative osteoarthritis (58.1%; n = 882), followed by acute proximal humerus fracture in 15.11% (n = 245), and rotator cuff arthropathy in 14.18% (n = 220). The overall rate of revision was 7.7% (2.8% to 11.2%). The number of TSAs and reverse shoulder arthroplasties (RSAs) has been increasing since 2016. The amount of revision cases is proportional to the number of operations performed in the same year throughout the study period., Conclusion: The incidence of shoulder arthroplasty in the Maritime Provinces has increased over the last 16 years. Revision rates are similar the those found in other large database registries. Reverse shoulder arthroplasty prevalence has increased since 2016., Competing Interests: None declared., (© 2023 Author(s) et al.)

Aims/hypothesis: The reason for the observed lower rate of islet autoantibody positivity in clinician-diagnosed adult-onset vs childhood-onset type 1 diabetes is not known. We aimed to explore this by assessing the genetic risk of type 1 diabetes in autoantibody-negative and -positive children and adults., Methods: We analysed GAD autoantibodies, insulinoma-2 antigen autoantibodies and zinc transporter-8 autoantibodies (ZnT8A) and measured type 1 diabetes genetic risk by genotyping 30 type 1 diabetes-associated variants at diagnosis in 1814 individuals with clinician-diagnosed type 1 diabetes (1112 adult-onset, 702 childhood-onset). We compared the overall type 1 diabetes genetic risk score (T1DGRS) and non-HLA and HLA (DR3-DQ2, DR4-DQ8 and DR15-DQ6) components with autoantibody status in those with adult-onset and childhood-onset diabetes. We also measured the T1DGRS in 1924 individuals with type 2 diabetes from the Wellcome Trust Case Control Consortium to represent non-autoimmune diabetes control participants., Results: The T1DGRS was similar in autoantibody-negative and autoantibody-positive clinician-diagnosed childhood-onset type 1 diabetes (mean [SD] 0.274 [0.034] vs 0.277 [0.026], p=0.4). In contrast, the T1DGRS in autoantibody-negative adult-onset type 1 diabetes was lower than that in autoantibody-positive adult-onset type 1 diabetes (mean [SD] 0.243 [0.036] vs 0.271 [0.026], p<0.0001) but higher than that in type 2 diabetes (mean [SD] 0.229 [0.034], p<0.0001). Autoantibody-negative adults were more likely to have the more protective HLA DR15-DQ6 genotype (15% vs 3%, p<0.0001), were less likely to have the high-risk HLA DR3-DQ2/DR4-DQ8 genotype (6% vs 19%, p<0.0001) and had a lower non-HLA T1DGRS (p<0.0001) than autoantibody-positive adults. In contrast to children, autoantibody-negative adults were more likely to be male (75% vs 59%), had a higher BMI (27 vs 24 kg/m 2 ) and were less likely to have other autoimmune conditions (2% vs 10%) than autoantibody-positive adults (all p<0.0001). In both adults and children, type 1 diabetes genetic risk was unaffected by the number of autoantibodies (p>0.3). These findings, along with the identification of seven misclassified adults with monogenic diabetes among autoantibody-negative adults and the results of a sensitivity analysis with and without measurement of ZnT8A, suggest that the intermediate type 1 diabetes genetic risk in autoantibody-negative adults is more likely to be explained by the inclusion of misclassified non-autoimmune diabetes (estimated to represent 67% of all antibody-negative adults, 95% CI 61%, 73%) than by the presence of unmeasured autoantibodies or by a discrete form of diabetes. When these estimated individuals with non-autoimmune diabetes were adjusted for, the prevalence of autoantibody positivity in adult-onset type 1 diabetes was similar to that in children (93% vs 91%, p=0.4)., Conclusions/interpretation: The inclusion of non-autoimmune diabetes is the most likely explanation for the observed lower rate of autoantibody positivity in clinician-diagnosed adult-onset type 1 diabetes. Our data support the utility of islet autoantibody measurement in clinician-suspected adult-onset type 1 diabetes in routine clinical practice., (© 2022. The Author(s).)

Context: The importance of the autoantibody level at diagnosis of type 1 diabetes (T1D) is not clear., Objective: We aimed to assess the association of glutamate decarboxylase (GADA), islet antigen-2 (IA-2A), and zinc transporter 8 (ZnT8A) autoantibody levels with clinical and genetic characteristics at diagnosis of T1D., Methods: We conducted a prospective, cross-sectional study. GADA, IA-2A, and ZnT8A were measured in 1644 individuals with T1D at diagnosis using radiobinding assays. Associations between autoantibody levels and the clinical and genetic characteristics for individuals were assessed in those positive for these autoantibodies. We performed replication in an independent cohort of 449 people with T1D., Results: GADA and IA-2A levels exhibited a bimodal distribution at diagnosis. High GADA level was associated with older age at diagnosis (median 27 years vs 19 years, P = 9 × 10-17), female sex (52% vs 37%, P = 1 × 10-8), other autoimmune diseases (13% vs 6%, P = 3 × 10-6), and HLA-DR3-DQ2 (58% vs 51%, P = .006). High IA-2A level was associated with younger age of diagnosis (median 17 years vs 23 years, P = 3 × 10-7), HLA-DR4-DQ8 (66% vs 50%, P = 1 × 10-6), and ZnT8A positivity (77% vs 52%, P = 1 × 10-15). We replicated our findings in an independent cohort of 449 people with T1D where autoantibodies were measured using enzyme-linked immunosorbent assays., Conclusion: Islet autoantibody levels provide additional information over positivity in T1D at diagnosis. Bimodality of GADA and IA-2A autoantibody levels highlights the novel aspect of heterogeneity of T1D. This may have implications for T1D prediction, treatment, and pathogenesis., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.)

Aims/hypothesis: Among white European children developing type 1 diabetes, the otherwise common HLA haplotype DR15-DQ6 is rare, and highly protective. Adult-onset type 1 diabetes is now known to represent more overall cases than childhood onset, but it is not known whether DR15-DQ6 is protective in older-adult-onset type 1 diabetes. We sought to quantify DR15-DQ6 protection against type 1 diabetes as age of onset increased., Methods: In two independent cohorts we assessed the proportion of type 1 diabetes cases presenting through the first 50 years of life with DR15-DQ6, compared with population controls. In the After Diabetes Diagnosis Research Support System-2 (ADDRESS-2) cohort (n = 1458) clinician-diagnosed type 1 diabetes was confirmed by positivity for one or more islet-specific autoantibodies. In UK Biobank (n = 2502), we estimated type 1 diabetes incidence rates relative to baseline HLA risk for each HLA group using Poisson regression. Analyses were restricted to white Europeans and were performed in three groups according to age at type 1 diabetes onset: 0-18 years, 19-30 years and 31-50 years., Results: DR15-DQ6 was protective against type 1 diabetes through to age 50 years (OR < 1 for each age group, all p < 0.001). The following ORs for type 1 diabetes, relative to a neutral HLA genotype, were observed in ADDRESS-2: age 5-18 years OR 0.16 (95% CI 0.08, 0.31); age 19-30 years OR 0.10 (0.04, 0.23); and age 31-50 years OR 0.37 (0.21, 0.68). DR15-DQ6 also remained highly protective at all ages in UK Biobank. Without DR15-DQ6, the presence of major type 1 diabetes high-risk haplotype (either DR3-DQ2 or DR4-DQ8) was associated with increased risk of type 1 diabetes., Conclusions/interpretation: HLA DR15-DQ6 confers dominant protection from type 1 diabetes across the first five decades of life., (© 2021. The Author(s).)

Context: Prednisolone has been recommended rather than hydrocortisone for glucocorticoid replacement in adrenal insufficiency due its longer duration of action and lower cost., Objective: To determine mortality rates with prednisolone versus hydrocortisone., Methods: In this observational study, we used data extracted from a UK primary care database (Clinical Practice Research Datalink) to measure the relative mortality of patients with primary and secondary adrenal insufficiency, who were treated with either prednisolone or hydrocortisone, and control individuals who were individually matched for age, sex, period, and place of follow-up., Results: As expected, mortality in adrenal insufficiency irrespective of cause was increased, based on 5478 patients (4228 on hydrocortisone; 1250 on prednisolone) and 54 314 controls (41 934 and 12 380, respectively). Overall, the adjusted hazard ratio (HR) was similar with the 2 treatments (prednisolone, 1.76 [95% CI, 1.54-2.01] vs hydrocortisone 1.69 [1.57-1.82]; P = 0.65). This was also the case for secondary adrenal insufficiency. In primary disease (1405 on hydrocortisone vs 137 on prednisolone; 13 965 and 1347 controls, respectively), prednisolone users were older, more likely to have another autoimmune disease and malignancy, and less likely to have mineralocorticoid replacement. Nevertheless, after adjustment, the HR for prednisolone-treated patients remained higher than for those taking hydrocortisone (2.92 [2.19-3.91] vs 1.90 [1.66-2.16]; P = 0.0020)., Conclusion: In primary but not in secondary adrenal insufficiency, mortality was higher with prednisolone. The study was large, but the number of prednisolone-treated patients was small, and they had greater risk factors. Nonetheless, the increased mortality associated with prednisolone persisted despite statistical adjustment. Further evidence is needed regarding the long-term safety of prednisolone as routine replacement., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Context: Mortality data in patients with adrenal insufficiency are inconsistent, possibly due to temporal and geographical differences between patients and their reference populations., Objective: To compare mortality risk and causes of death in adrenal insufficiency with an individually matched reference population., Methods: A retrospective cohort study was done using a UK general practitioner database (CPRD). A total of 6821 patients with adrenal insufficiency (primary, 2052; secondary, 3948) were compared with 67564 individually-matched controls (primary, 20366; secondary, 39134). Main outcomes were all-cause and cause-specific mortality, and hospital admission from adrenal crisis., Results: With follow-up of 40 799 and 406 899 person-years for patients and controls respectively, the hazard ratio (HR [95% CI]) for all-cause mortality was 1.68 [1.58-1.77]. HRs were greater in primary (1.83 [1.66-2.02]) than in secondary (1.52 [1.40-1.64]) disease; primary versus secondary disease (1.16 [1.03-1.30]). The leading cause of death was cardiovascular disease (HR 1.54 [1.32-1.80]), along with malignant neoplasms and respiratory disease. Deaths from infection were also relatively high (HR 4.00 [2.15-7.46]). Adrenal crisis contributed to 10% of all deaths. In the first 2 years following diagnosis, the patients' mortality rate and hospitalization from adrenal crisis were higher than in later years., Conclusion: Mortality was increased in adrenal insufficiency, especially primary, even with individual matching and was observed early in the disease course. Cardiovascular disease was the major cause but mortality from infection was also high. Adrenal crisis was a common contributor. Early education for prompt treatment of infections and avoidance of adrenal crisis hold potential to reduce mortality., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Internationally, studies have shown associations between lipids and glycemia; however, whether the link varies by gender and population has been rarely examined. We investigated relationships between glycemia and HDL- and Non-HDL-cholesterol and their modification by gender. We undertook a cross-sectional analysis from the National Health Examination Survey for Thailand (NHES-Thailand) and the Health Survey for England (HS-England) in adults aged 18-75 year. Glycaemia was assessed by FPG in Thailand and by HbA1c in the UK. In population- and gender-stratified analyses, the relationships between glycemia and lipids were explored. A total of 15,145 Thai and 3484 UK adults with blood measurement were included. The prevalences of prediabetes were: in NHES-Thailand, 16% (SE = 0.004), based on FPG (5.6 to < 7.0 mmol/L) and in HS-England, 19% (0.007) based on HbA1c (39 to < 48 mmol/mol). Increasingly abnormal glucose homeostasis was associated with increasing age, adiposity, SBP, proportion of antihypertensive and lipid-lowering agent use and with decreasing HDL-cholesterol. Independent of age, adiposity, smoking, alcohol, physical activity, and lipid and BP lowering drug use, increasing glycemia was associated with decreasing HDL-cholesterol specifically in women with prediabetes (NHES-Thailand, beta-coefficient - 0.07 (95% CI - 0.15, - 0.001) p = 0.04 and HS-England, - 0.03 (- 0.04, - 0.006) p = 0.01). In both populations, among those with prediabetes, increasing glycaemia is associated with an adverse, significant decline in HDL cholesterol, specifically in women. These adverse effects are apparent in widely-differing international populations.

Context: Mortality studies have established that cardiovascular disease is the leading cause of death in patients with adrenal insufficiency and the risk is greater than that observed in individually matched controls., Objective: Here we have performed a detailed analysis of cardiovascular morbidity and mortality, taking account of the role of comorbidities., Methods: We performed a retrospective cohort study using the Clinical Practice Research Datalink (CPRD), a UK general practitioner database. The participant population comprised 6821 patients with adrenal insufficiency (primary, 2052; secondary, 3948) compared with 67 564 individually matched controls, with and without adjustment for comorbidities (diabetes, hypertension, dyslipidemia, previous cardiovascular disease, and smoking). The main outcome measures were composite cardiovascular events recorded in the CPRD and cardiovascular mortality in participants with linked national mortality data., Results: Hazard ratios (95% CI) for composite cardiovascular events in patients with adrenal insufficiency of any cause were 1.28 (1.20-1.36, unadjusted) and 1.07 (1.01-1.14, adjusted). Increased cerebrovascular events in patients with secondary adrenal insufficiency accounted for most of the increased hazard (1.53 [1.34-1.74, adjusted]) and were associated with cranial irradiation therapy. Cardiovascular mortality data were available for 3547 patients and 34 944 controls. The adjusted hazard ratio for ischemic heart disease mortality was 1.86 (1.25-2.78) for primary adrenal insufficiency and 1.39 (1.02-1.89) for secondary., Conclusion: Comorbidities largely accounted for the increased cardiovascular events but in secondary adrenal insufficiency, cerebrovascular events were independently increased and associated with irradiation treatment. However, the risk of cardiovascular mortality remained increased even following adjustment for comorbidities in both primary and secondary adrenal insufficiency., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Aims/hypothesis: This randomised controlled trial was performed in India and the UK in people with prediabetes to study whether mobile phone short message service (SMS) text messages can be used to motivate and educate people to follow lifestyle modifications, to prevent type 2 diabetes., Methods: The study was performed in people with prediabetes (n = 2062; control: n = 1031; intervention: n = 1031) defined by HbA 1c ≥42 and ≤47 mmol/mol (≥6.0% and ≤6.4%). Participants were recruited from public and private sector organisations in India (men and women aged 35-55 years) and by the National Health Service (NHS) Health Checks programme in the UK (aged 40-74 years without pre-existing diabetes, cardiovascular disease or kidney disease). Allocation to the study groups was performed using a computer-generated sequence (1:1) in India and by stratified randomisation in permuted blocks in the UK. Investigators in both countries remained blinded throughout the study period. All participants received advice on a healthy lifestyle at baseline. The intervention group in addition received supportive text messages using mobile phone SMS messages 2-3 times per week. Participants were assessed at baseline and at 6, 12 and 24 months. The primary outcome was conversion to type 2 diabetes and secondary outcomes included anthropometry, biochemistry, dietary and physical activity changes, blood pressure and quality of life., Results: At the 2 year follow-up (n = 2062; control: n = 1031; intervention: n = 1031), in the intention-to-treat population the HR for development of type 2 diabetes calculated using a discrete-time proportional hazards model was 0.89 (95% CI 0.74, 1.07; p = 0.22). There were no significant differences in the secondary outcomes., Conclusions/interpretation: This trial in two countries with varied ethnic and cultural backgrounds showed no significant reduction in the progression to diabetes in 2 years by lifestyle modification using SMS messaging., Trial Registration: The primary study was registered on www.ClinicalTrials.gov (India, NCT01570946; UK, NCT01795833)., Funding: The study was funded jointly by the Indian Council for Medical Research and the UK Medical Research Council.

Gestational diabetes mellitus is a common metabolic complication of pregnancy. Universal guidelines on gestational diabetes have been impeded by the long-term controversies on its definition and screening strategies. The prevalence of gestational diabetes is rising all over the world, is significantly influenced by ethnicity and its rise is mainly attributed to increasing maternal obesity and age. Gestational diabetes mellitus has important long-term implications, including gestational diabetes recurrence, increased risk for developing type 2 diabetes, metabolic syndrome and cardiovascular disease for the mother. Gestational diabetes mellitus may be viewed as a chronic metabolic disorder that is identified in women during gestation and may provide a unique opportunity for the early identification and primary prevention of type 2 diabetes mellitus and cardiovascular disease in these women. In this mini-review, the evolution of screening tests for gestational diabetes and guidelines are briefly described and metabolic and cardiovascular long-term consequences of women with a history of gestational diabetes are summarized. A summary of our own St. Mary's Hospital-UK Research series on long-term metabolic consequences of 368 women with a history of gestational diabetes of 3 different ethnic groups and 482 control women is also included. We found that approximately 2 years following delivery, 37% of women with a history of gestational diabetes had abnormal glucose concentrations, but, most importantly, even those who were normoglycaemic, postpartum displayed metabolic abnormalities on detailed testing. Future research needs to focus on the prevention of gestational diabetes long-term complications, but also in identification of pre-pregnancy predictors and risk reduction before conception., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Aims: Optimal glycaemic control benefits risk of microvascular and macrovascular complications in type 1 diabetes (T1DM) but the importance of other components of metabolic health is less certain, particularly in the context of routine clinical practice., Methods: Data for this cross-sectional analysis derived from a database covering inner North West London adult diabetes clinics. People with T1DM and with complete information for height, weight, blood pressure and serum high and low-density lipoprotein cholesterol (HDL-c and LDL-c) and triglyceride concentration measurements were included., Results: Among the 920 participants, those with complications were older and had longer duration of diabetes but had similar HbA1c to people without complications. Systolic hypertension and low HDL-c were independently associated with complications. From having 0 risk factors, the prevalence of micro and macrovascular disease increased with increasing number of risk factors. Relative to those with ≥1 risk factor, those with 0 risk factors (n = 179) were at lower risk of retinopathy (OR 0.6 (0.4-0.9), p = 0.01) and nephropathy [OR 0.1 (0.04-0.3), p = 0.002], independent of individual characteristics., Conclusions: In routine clinical management of T1DM, associations between lipid and blood pressure risk factors and prevalent micro and macrovascular disease remain, implying that more intensive risk factor management may be beneficial., (Crown Copyright © 2019. Published by Elsevier Inc. All rights reserved.)

Aims: People with recently-diagnosed type 1 diabetes mellitus (T1D) may undergo a transient period of glycaemic control with less exogenous insulin. Identification of predictors of this 'remission' could inform a better understanding of glycaemic control., Methods: Participants in the ADDRESS-2 study were included who had 1 or 2 assessments of remission status (coincident insulin dose and HbA1c measurement, with remission defined by ≤0.4 units insulin/kg-body-weight/day with HbA1c < 53 mmol/mol). Demographic and clinical presentation characteristics were compared according to remission status and predictors of remission were explored by logistic regression analysis., Results: 1470 first and 469 second assessments of remission status were recorded within 12 months of diagnosis of T1D. Step increases in the probability of remission were identified at age-at-diagnosis 20 years and 3 months after diagnosis (both p < 0.001). Among those aged < 20 years, remission was associated with male gender (p = 0.02), no ketoacidosis (p = 0.02) and fewer than 2 symptoms at presentation (p = 0.004). None of these characteristics predicted remission in those aged ≥ 20 years. In the subgroup with two assessments, transition to remission was independently associated with first remission assessment in months 1-2 post-diagnosis (p = 0.01), with age-at-diagnosis ≥ 20 years (p = 0.01) and, in those aged < 20 years, with an early HbA1c of <57 mmol/mol. Adiposity, ethnicity, autoantibody status and other autoimmune disease were unrelated to remission., Conclusions: For those diagnosed before 20 years of age, males, ketoacidosis-free, with fewer symptoms and low early HbA1c were more likely to experience remission, but remission was most likely in anyone aged ≥ 20 at diagnosis., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Aims/introduction: Relationships between cardiometabolic risk and glycemia have rarely been studied in people under clinical evaluation and treatment for cardiometabolic risk and with prediabetes. We investigated relationships between glycemia and cardiometabolic risk factors in clinic participants with prediabetes., Materials and Methods: This was a cross-sectional analysis of data collected at a center in Thailand. Clinic attendees were at high risk of diabetes or cardiovascular disease, with hemoglobin A1c (HbA1c) 39-<48 mmol/mol or fasting plasma glucose (FPG) 5.6-<7.0 mmol/L. The relationships between glycemia and cardiometabolic risk factors were explored., Results: Of 357 participants, two or more insulin resistance-related metabolic disturbances were present in 84%; 61% took a statin and 75% an antihypertensive agent. Independently of age, sex, adiposity, medication use, possible non-alcoholic fatty liver disease and sex-glycemia interaction, neither FPG nor HbA1c were associated with variation in any other cardiometabolic risk factors. High-density lipoprotein cholesterol decreased with HbA1c in women (female-HbA1c interaction, P = 0.03) but, unexpectedly, increased with FPG in men (male-FPG interaction, P = 0.02)., Conclusions: Overall, in Thai people treated for high cardiometabolic risk and with prediabetes defined by FPG and/or HbA1c, neither FPG nor HbA1c were associated with other cardiometabolic risk factors. However, according to sex, high-density lipoprotein cholesterol showed the expected relationship with glycemia in women, but the reverse in men., (© 2018 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Aim: The increased morbidity and mortality due to type 2 diabetes can be partly due to its delayed diagnosis. In developing countries, the cost and unavailability of conventional screening methods can be a setback. Use of random blood glucose (RBG) may be beneficial in testing large numbers at a low cost and in a short time in identifying persons at risk of developing diabetes. In this analysis, we aim to derive the values of RBG corresponding to the cut-off values of glycosylated hemoglobin (HbA1c) used to define prediabetes and diabetes., Methods: Based on their risk profile of developing diabetes, a total of 2835 individuals were screened for a large diabetes prevention study. They were subjected to HbA1c testing to diagnose prediabetes and diabetes. Random capillary blood glucose was also performed. Correlation of RBG with HbA1c was computed using multiple linear regression equation. The optimal cut-off value for RBG corresponding to HbA1c value of 5.7% (39 mmol/mol), and ≥ 6.5% (48 mmol/mol) were computed using the receiver operating curve (ROC). Diagnostic accuracy was assessed from the area under the curve (AUC) and by using the Youden's index., Results: RBG showed significant correlation with HbA1c (r=0.40, p<0.0001). Using the ROC analysis, a RBG cut-off value of 140.5 mg/dl (7.8 mmol/L) corresponding to an HbA1c value of 6.5% (48mmol/mol) was derived. A cut-off value could not be derived for HbA1c of 5.7% (39 mmol/mol) since the specificity and sensitivity for identifying prediabetes were low., Conclusion: Use of a capillary RBG value was found to be a simple procedure. The derived RBG cut-off value will aid in identifying people with undiagnosed diabetes. This preliminary screening will reduce the number to undergo more cumbersome and invasive diagnostic testing., Competing Interests: Conflicts of Interest All authors have no conflict of interest to declare.

Introduction: Obesity is a major risk factor for mortality from a range of causes. We investigated whether skinfold measurements were associated with mortality independently of variation in body mass index (BMI)., Methods: A prospective analysis of mortality in 870 apparently healthy adult Caucasian men participating in an occupational health cohort was undertaken. At baseline, skinfold measurements were taken at biceps, triceps, iliac and subscapular sites. Derived measurements included the sum of all four skinfolds and subscapular to triceps, subscapular to iliac and BMI to iliac ratios. All-cause mortality was analysed by Cox proportional hazards modelling and death in specific mortality subcategories by competing risks analysis., Results: During a mean of 27.7 years follow up, there were 303 deaths (119 cancer, 101 arteriovascular, 40 infection, 43 other). In univariable analysis, BMI was associated with all-cause, cancer, arteriovascular and other mortality and subscapular skinfold with all-cause and arteriovascular mortality. On bivariable analysis, with inclusion of BMI, subscapular skinfold ceased to be a associated with mortality but iliac skinfold emerged as strongly, negatively associated with all-cause and arteriovascular mortality. In multivariable analysis, with inclusion of age, BMI, smoking, alcohol and exercise, iliac skinfold was negatively associated with all-cause (Hazard ratio HR 0.77, 95% confidence interval CI 0.66-0.90, p = 0.002), arteriovascular (HR 0.75, 95%CI 0.58,0.97, p = 0.02) and infection (HR 0.63, 95%CI 0.42,0.94, p = 0.02) death. Among obese participants (BMI ≥ 30 kg/m 2 ), iliac skinfold of ≤9.7 mm was associated with a six-fold increase in all-cause mortality risk., Conclusion: Low iliac skinfold thickness is an independent risk factor for all-cause mortality in adult white males with risk apparently concentrated among people who are obese.

Objective: This was a 5 year comparative analysis of the incidence of type 2 diabetes in men who had persistent impaired glucose tolerance (P-IGT) versus transient impaired glucose tolerance (T-IGT). P-IGT (positive IGT on two oral glucose tolerance tests (OGTT), T-IGT (IGT in first OGTT and normal glucose tolerance (NGT) in the 2nd OGTT)., Methods: The samples were collected from a randomized controlled diabetes prevention study. The prevention study was done using lifestyle modification (LSM) promoted by use of mobile short message services (SMS) for 2 years. The control group of the randomized study who received advice on LSM at only the baseline formed the P-IGT group for the 3 years follow up study (n=236). T-IGT (n=569) were available from those who had NGT on the 2nd OGTT while screening for the prevention study. The total diabetes incidence at 5 years in the study groups were compared using standard OGTT (WHO criteria)., Results: The conversion rate to diabetes in 5 years was significantly lower among T-IGT than among P-IGT, OR=0.202 (95% CI, 0.145-0.296,p< 0.0001). P-IGT had higher rate of risk factors for diabetes than T-IGT., Conclusion: The risk of conversion to diabetes was 80 percent lower in T-IGT than in P-IGT. Identification of P-IGT will help in selecting persons who require early intervention for diabetes., (© Journal of the Association of Physicians of India 2011.)

Background: Type 2 diabetes is a serious clinical problem in both India and the UK. Adoption of a healthy lifestyle through dietary and physical activity modification can help prevent type 2 diabetes. However, implementing lifestyle modification programmes to high risk groups is expensive and alternative cheaper methods are needed. We are using a short messaging service (SMS) programme in our study as a tool to provide healthy lifestyle advice and an aid to motivation. The aim of the study is to assess the efficacy and user acceptability of text messaging employed in this way for people with pre-diabetes (HbA1c 6.0% to ≤6.4%; 42-47 mmol/mol) in the UK and India., Methods/design: This is a randomised, controlled trial with participants followed up for 2 years. After being screened and receiving a structured education programme for prediabetes, participants are randomised to a control or intervention group. In the intervention group, text messages are delivered 2-3 times weekly and contain educational, motivational and supportive content on diet, physical activity, lifestyle and smoking. The control group undergoes monitoring only. In India, the trial involves 5 visits after screening (0, 6, 12, 18 and 24 months). In the UK there are 4 visits after screening (0, 6, 12 and 24 months). Questionnaires (EQ-5D, RPAQ, Transtheoretical Model of Behavioural Change, and food frequency (UK)/24 h dietary recall (India)) and physical activity monitors (Actigraph GT3X+ accelerometers) are assessed at baseline and all follow-up visits. The SMS acceptability questionnaires are evaluated in all follow-up visits. The primary outcome is progression to type 2 diabetes as defined by an HbA1c of 6.5% or over(India) and by any WHO criterion(UK). Secondary outcomes are the changes in body weight, body mass index, waist circumference, blood pressure, fasting plasma glucose; lipids; proportion of participants achieving HbA1c ≤6.0%; HOMA-IR; HOMA-β; acceptability of SMS; dietary parameters; physical activity and quality of life., Discussion: The study is designed to assess the efficacy of tailored text messaging in addition to standard lifestyle advice to reduce the progression from prediabetes to type 2 diabetes in the two different countries., Trial Registration: ClinicalTrials.gov ; NCT01570946 , 4 th April 2012 (India); NCT01795833 , 21 st February 2013 (UK).

Aims: We had shown that mobile phone based text messaging was an effective tool to deliver lifestyle changes among Asian Indian men with a 36% relative risk reduction in incident diabetes over two years. The present analysis investigated whether beneficial effects of intervention on diabetes prevention persisted for an additional three years after withdrawal of active intervention., Methods: The primary two year randomized controlled trial (2010-2012) compared lifestyle changes with use of automated text messaging reminders in the intervention (n = 271) versus standard care advice (n = 266) at baseline. At the end of the study, both groups received additional advice on lifestyle changes by a trained dietician. Participants free of diabetes (n = 394) were invited three years later to ascertain the sustained effect of intervention. The primary outcome was incidence of type 2 diabetes. This trial is registered with ClinicalTrials.gov,number NCT02848547., Results: During the mean follow-up of 5 years, 346 out of 394 (87.8%) men were reviewed. Incidence of diabetes was reduced by 30% in the intervention group, with declining gap between-group differences over time (Kaplan-Meier analysis). Significant improvement in dietary adherence occurred in the intervention group at 2nd and 5th year follow up (trend χ 2  = 21.35, p < 0.0001). Cox regression analysis showed that the 5th year incidence of diabetes was significantly reduced in the intervention group. Higher body mass index and 2 h plasma glucose at 24 months increased the incidence of diabetes., Conclusions: Sustained reduction in incident diabetes was apparent after cessation of active lifestyle intervention. This was possibly associated with continuing practice of improved lifestyle., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objectives: To describe the characteristics of children and adults with incident type 1 diabetes in contemporary, multiethnic UK, focusing on differences between the islet autoantibody negative and positive., Design: Observational cohort study., Setting: 146 mainly secondary care centres across England and Wales., Participants: 3312 people aged ≥5 years were recruited within 6 months of a clinical diagnosis of type 1 diabetes via the National Institute for Health Research Clinical Research Network. 3021 were of white European ethnicity and 291 (9%) were non-white. There was a small male predominance (57%). Young people <17 years comprised 59%., Main Outcome Measures: Autoantibody status and characteristics at presentation., Results: The majority presented with classical osmotic symptoms, weight loss and fatigue. Ketoacidosis was common (42%), especially in adults, and irrespective of ethnicity. 35% were overweight or obese. Of the 1778 participants who donated a blood sample, 85% were positive for one or more autoantibodies against glutamate decarboxylase, islet antigen-2 and zinc transporter 8. Presenting symptoms were similar in the autoantibody-positive and autoantibody-negative participants, as was the frequency of ketoacidosis (43%vs40%, P=0.3). Autoantibody positivity was less common with increasing age (P=0.0001), in males compared with females (82%vs90%, P<0.0001) and in people of non-white compared with white ethnicity (73%vs86%, P<0.0001). Body mass index was higher in autoantibody-negative adults than autoantibody-positive adults (median, IQR 25.5, 23.1-29.2vs23.9, 21.4-26.7 kg/m 2 ; P=0.0001). Autoantibody-negative participants were more likely to have a parent with diabetes (28%vs16%, P<0.0001) and less likely to have another autoimmune disease (4%vs8%, P=0.01)., Conclusions: Most people assigned a diagnosis of type 1 diabetes presented with classical clinical features and islet autoantibodies. Although indistinguishable at an individual level, autoantibody-negative participants as a group demonstrated features more typically associated with other diabetes subtypes., Trial Registration Number: ISRCTN66496918; Pre-results., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Aims: Variation in cardiometabolic risk in prediabetes and any impacts of ethnicity on such variation have been little studied. In an ethnically diverse dataset, selected according to a high-risk HbA1c-based definition of prediabetes, we have investigated relationships between glycaemia and cardiometabolic risk factors and the influence of ethnicity on these relationships., Methods: We undertook a cross-sectional analysis of baseline data from a diabetes prevention study in the UK and a chronic care clinic in Thailand, selected for people without diabetes (fasting plasma glucose <7.0 mmol/l) with HbA1c 6.0-6.4% (42-47 mmol/mol). Thai (n=158) and UK White (n=600), South Asian (n=112), Black (n=70) and other/mixed (n=103) groups were distinguished and measurements included fasting plasma glucose (FPG), blood pressure (BP), lipids and insulin resistance-related risk factors (IRFs)., Results: Independently of individual characteristics including ethnicity, only systolic BP was weakly associated with FPG (beta coefficient 1.76 (95%CI 0.10-3.42), p 0.03) and only LDL-c with IFG (FPG 5.6 to <7) (adjusted -0.14 (-0.27, -0.003) p 0.04). There were no significant independent associations with cardiometabolic risk factors when categories of impaired fasting glucose (FPG ≥ 6.1 to <7.0 mmol/L) were considered. Relative to White, South Asian ethnicity was independently associated with lower systolic and diastolic BP, Black with lower triglycerides, cholesterol/HDL-c ratio and having 2 or more IRFs, and Thai with lower cholesterol/HDL-c ratio and all three non-white ethnicities with lower total and LDL cholesterol., Conclusion: In high-risk HbA1c-defined prediabetes additional measurement of FPG will add little to evaluation of cardiometabolic risk. Additionally, UK Whites tend to have the most adverse cardiometabolic profile of any ethnic group., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Introduction: Type 1 diabetes is heterogeneous in its presentation and progression. Variations in clinical presentation between children and adults, and with ethnic group warrant further study in the UK to improve understanding of this heterogeneity. Early interventions to limit beta cell damage in type 1 diabetes are undergoing evaluation, but recruitment is challenging. The protocol presented describes recruitment of people with clinician-assigned, new-onset type 1 diabetes to understand the variation in their manner of clinical presentation, to facilitate recruitment into intervention studies and to create an open-access resource of data and biological samples for future type 1 diabetes research., Methods and Analysis: Using the National Institute for Health Research Clinical Research Network, patients >5 years of age diagnosed clinically with type 1 diabetes (and their siblings) are recruited within 6 months of diagnosis. Participants agree to have their clinical, laboratory and demographic data stored on a secure database, for their clinical progress to be monitored using information held by NHS Digital, and to be contacted about additional research, in particular immunotherapy and other interventions. An optional blood sample is taken for islet autoantibody measurement and storage of blood and DNA for future analyses. Data will be analysed statistically to describe the presentation of incident type 1 diabetes in a contemporary UK population., Ethics and Dissemination: Ethical approval was obtained from the independent NHS Research Ethics Service. Results will be presented at national and international meetings and submitted for publication to peer-reviewed journals., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: Insulin bolus calculators assist people with Type 1 diabetes (T1D) to calculate the amount of insulin required for meals to achieve optimal glucose levels but lack adaptability and personalization. We have proposed enhancing bolus calculators by the means of case-based reasoning (CBR), an established problem-solving methodology, by individualizing and optimizing insulin therapy for various meal situations. CBR learns from experiences of past similar meals, which are described in cases through a set of parameters (eg, time of meal, alcohol, exercise). This work discusses the selection, representation and effect of case parameters used for a CBR-based Advanced Bolus Calculator for Diabetes (ABC4D)., Methods: We analyzed the usage and effect of selected parameters during a pilot study (n = 10), where participants used ABC4D for 6 weeks. Retrospectively, we evaluated the effect of glucose rate of change before the meal on the glycemic excursion. Feedback from study participants about the choice of parameters was obtained through a nonvalidated questionnaire., Results: Exercise and alcohol were the most frequently used parameters, which was congruent with the feedback from study participants, who found these parameters most useful. Furthermore, cases including either exercise or alcohol as parameter showed a trend in reduction of insulin at the end of the study. A significant difference ( P < .01) was found in glycemic outcomes for meals where glucose rate of change was rising compared to stable rate of change., Conclusions: Results from the 6-week study indicate the potential benefit of including parameters exercise, alcohol and glucose-rate of change for insulin dosing decision support.

Objective: To report the impact of continuous glucose monitoring (CGM) on glycemic variability (GV) indices, factors predictive of change, and to correlate variability with conventional markers of glycemia., Methods: Data from the JDRF study of CGM in participants with type 1 diabetes were used. Participants were randomized to CGM or self-monitored blood glucose (SMBG). GV indices at baseline, at 26 weeks in both groups, and at 52 weeks in the control group were analyzed. The associations of demographic and clinical factors with change in GV indices from baseline to 26 weeks were evaluated., Results: Baseline data were available for 448 subjects. GV indices were all outside normative ranges (P < 0.001). Intercorrelation between GV indices was common and, apart from coefficient of variation (CV), low blood glucose index (LBGI), and percentage of glycemic risk assessment diabetes equation score attributable to hypoglycemia (%GRADE hypoglycemia ), all indices correlate positively with HbA1c. There was strong correlation between time spent in hypoglycemia, and CV, LBGI, and %GRADE hypoglycemia , but not with HbA1c. A significant reduction in all GV indices, except lability index and mean absolute glucose change per unit time (MAG), was demonstrated in the intervention group at 26 weeks compared with the control group. Baseline factors predicting a change in GV with CGM include baseline HbA1c, baseline GV, frequency of daily SMBG, and insulin pump use., Conclusions: CGM reduces most GV indices compared with SMBG in people with type 1 diabetes. The strong correlation between time spent in hypoglycemia and CV, LBGI, and %GRADE hypoglycemia highlights the value of these metrics in assessing hypoglycemia as an adjunct to HbA1c in the overall assessment of glycemia.

Objective: To undertake a comprehensive evaluation of apolipoprotein risk markers for cardiovascular disease (CVD) according to gender, age and menopausal status., Design: Cross-sectional analysis of independent associations of gender, age and menopause with serum apolipoproteins., Participants: Apparently healthy Caucasian premenopausal (n = 109) and postmenopausal (n = 252) women not taking oral contraceptives or hormone replacement, and Caucasian men (n = 307)., Measurements: Serum apolipoprotein (apo) B, A-I and A-II concentrations were measured, plus serum total cholesterol, low-density and high-density lipoprotein cholesterol (LDL-C and HDL-C, respectively), triglycerides, cholesterol in HDL subfractions and the apoB/apoA-I, LDL-C/apoB, HDL-C/apoA-I and HDL-C/apoA-II ratios. Analyses were undertaken with and without standardization for confounding characteristics and in 5-year age ranges., Results: Overall, apoB concentrations were highest in men but in women rose with age and menopause to converge, in the age range of 50-55 years, with concentrations in men. The LDL-C/apoB ratio was generally higher in women than in men. ApoA-I concentrations were highest in postmenopausal women and lowest in men (standardized median (IQR) 144 (130, 158) vs 119 (108, 132) g/l, respectively, P < 0·001). ApoA-II concentrations were also highest in postmenopausal women but were lowest in premenopausal women (40·3 (37·5, 44·5) vs 32·9 (30·5, 35·7) g/l, respectively, P < 0·001). Nevertheless, postmenopausal women had HDL-C/apoA-I and HDL-C/apoA-II ratios approaching the lowest ratios, which were seen in men., Conclusions: Consistent with adverse effects on CVD risk, male gender, ageing in women and menopause were associated with increased apoB concentrations, and menopause and male gender were associated with a decreased cholesterol content of HDL particles., (© 2016 John Wiley & Sons Ltd.)

Background: The objective was to study the ability of the 30-min plasma glucose (30-min PG) during an oral glucose tolerance test to predict the future risk of type 2 diabetes among Asian Indians with impaired glucose tolerance., Methods: For the present analyses, we utilized data from 753 participants from two diabetes primary prevention studies, having complete data at the end of the study periods, including 236 from Indian Diabetes Prevention Programme-1 and 517 from the 2013 study. Baseline 30-min PG values were divided into tertiles: T1 < 9.1 mmol/L (<163.0 mg/dL); T2 9.2-10.4 mmol/L (164.0-187.0 mg/dL) and T3 ≥ 10.4 mmol/L (≥188 mg/dL). The predictive values of tertiles of 30-min PG for incident diabetes were assessed using Cox regression analyses RESULTS: At the end of the studies, 230 (30.5%) participants developed diabetes. Participants with higher levels of 30-min PG were more likely to have increased fasting, 2-h PG and HbA 1c levels, increased prevalence of impaired fasting glucose and decreased beta cell function. The progression rate of diabetes increased with increasing tertiles of 30-min PG. Cox's regression analysis showed that 30-min PG was an independent predictor of incident diabetes after adjustment for an array of covariates [Hazard Ratio (HR):1.44 (1.01-2.06)] CONCLUSIONS: This prospective analysis demonstrates, for the first time, an independent association between an elevated 30-min PG level and incident diabetes among Asian Indians with impaired glucose tolerance. Predictive utility of glycemic thresholds at various time points other than the traditional fasting and 2-h PG values should therefore merit further consideration. Copyright © 2016 John Wiley & Sons, Ltd., (Copyright © 2016 John Wiley & Sons, Ltd.)

Objective: Overweight and obese individuals may be metabolically healthy, but attention needs to be given to long-term persistence of this trait and any associated variation in cardiovascular risk., Design: Cross-sectional and longitudinal variation in metabolic health and associated cardiovascular mortality were analysed in 1099 white European-origin normal-weight and overweight or obese males followed for 20years., Methods: Definitions of metabolic health were based on LDL and HDL cholesterol, triglycerides, blood pressure, fasting glucose and cardiovascular risk. Insulin resistance (e.g. HOMA-IR) and sub-clinical inflammation (ESR and white blood cell count) were explored. Cardiovascular mortality risks and persistence of metabolic health status were evaluated., Results: There were 87 cardiovascular deaths. Insulin resistance was increased in metabolically healthy overweight or obese participants (median HOMA-IR 2.63, 95% CI: 1.79-3.65, P<0.001) relative to normal-weight participants (median HOMA-IR 1.67, 95% CI: 1.08-2.67, P<0.001) as was sub-clinical inflammation but metabolically healthy overweight or obese individuals were not at increased risk of cardiovascular mortality compared with the metabolically healthy normal-weight individuals (hazard ratio 1.13, 95% CI: 0.34-3.72, P=0.8). The proportions of initially metabolically healthy overweight or obese who remained metabolically healthy for visits 2, 3 and 4 were 54, 48 and 39% respectively, and for initially normal-weight individuals, 68, 51 and 41%. A lower proportion of metabolically healthy overweight or obese individuals remained metabolically healthy at visit 2 compared with normal-weight individuals (P=0.007), but proportions converged thereafter., Conclusions: Despite being insulin resistant and having greater sub-clinical inflammation, and despite instability in metabolic health status, metabolically healthy overweight or obese individuals were at no greater risk of cardiovascular mortality than their normal-weight equivalents., (© 2016 European Society of Endocrinology.)

Epithelial barrier function and innate immunity are fundamental to the pathogenesis of inflammatory and infectious disease. Along with plasma membranes, epithelial cells are the primary cellular determinant of epithelial barrier function. The mechanism by which polarized epithelia form a permeability barrier is of fundamental importance to the prevention of many infectious and inflammatory diseases. Moreover, epithelial cells express Toll-like receptors (TLRs) which upon recognition of conserved microbial factors such as lipopolysaccharide (LPS) induce epithelial responses including epithelial cell proliferation, secretion of secretory IgA into the lumen and production mucins and antimicrobial peptides, thereby promoting intestinal barrier function. Understanding gut barrier integrity and regulation of permeability is crucial to increase our understanding of the pathogenesis of intestinal disease. A variety of tests have been developed to assess this barrier, including assessing intestinal epithelial cell proliferation or death, intestinal tight junction status and the consequence of intestinal barrier integrity loss such as increased intestinal permeability and susceptibility to bacterial infection. Using a mouse model, this chapter describes some of the methods to assess the functional integrity of this epithelial barrier and the part played by a TLR signalling pathway.

Aims: We describe a two-step screening approach using non-invasive risk assessment and glycated hemoglobin (HbA1c) to identify participants for a diabetes prevention trial., Methods: A total of 6030 non-diabetic persons of 35-55 years were screened using risk assessment for diabetes. Those with three or more risk factors were screened using point of care HbA1c test. For this study, participants in HbA1c categories of 6.0% (42.1 mmol/mol)-6.4% (46.4 mmol/mol) were selected and their characteristics were analyzed., Results: Among 6030 persons, 2835 (47%) had three or more risk factors for diabetes. Among those screened with HbA1c, 43.2% (1225) had HbA1c values of <6.0% (42.1 mmol/mol), 46.8% (1327) had HbA1c values between 6.0% (42.1 mmol/mol) and ≤ 6.4% (46.4 mmol/mol) and 10% (283) had undiagnosed diabetes with ≥6.5% (47.5 mmol/mol). Positive family history was present in 53.2%, 81.7% were obese and 14.8% were overweight., Conclusions: Opportunistic screening using a two-step approach: diabetes risk profile and HbA1c measurement detected a large percentage of individuals with prediabetes. Prediabetic persons recruited to the trial had higher percentage of obesity and presence of positive family history than those who had lower HbA1c values. Outcomes from this trial will enable comparisons with the previous prevention studies that used blood glucose levels as the screening criteria., (Copyright © 2015. Published by Elsevier Ireland Ltd.)

Background: The Bio-inspired Artificial Pancreas (BiAP) is a closed-loop insulin delivery system based on a mathematical model of beta-cell physiology and implemented in a microchip within a low-powered handheld device. We aimed to evaluate the safety and efficacy of the BiAP over 24 hours, followed by a substudy assessing the safety of the algorithm without and with partial meal announcement. Changes in lactate and 3-hydroxybutyrate concentrations were investigated for the first time during closed-loop., Methods: This is a prospective randomized controlled open-label crossover study. Participants were randomly assigned to attend either a 24-hour closed-loop visit connected to the BiAP system or a 24-hour open-loop visit (standard insulin pump therapy). The primary outcome was percentage time spent in target range (3.9-10 mmol/l) measured by sensor glucose. Secondary outcomes included percentage time in hypoglycemia (<3.9 mmol/l) and hyperglycemia (>10 mmol/l). Participants were invited to attend for an additional visit to assess the BiAP without and with partial meal announcements., Results: A total of 12 adults with type 1 diabetes completed the study (58% female, mean [SD] age 45 [10] years, BMI 25 [4] kg/m(2), duration of diabetes 22 [12] years and HbA1c 7.4 [0.7]% [58 (8) mmol/mol]). The median (IQR) percentage time in target did not differ between closed-loop and open-loop (71% vs 66.9%, P = .9). Closed-loop reduced time spent in hypoglycemia from 17.9% to 3.0% (P < .01), but increased time was spent in hyperglycemia (10% vs 28.9%, P = .01). The percentage time in target was higher when all meals were announced during closed-loop compared to no or partial meal announcement (65.7% [53.6-80.5] vs 45.5% [38.2-68.3], P = .12)., Conclusions: The BiAP is safe and achieved equivalent time in target as measured by sensor glucose, with improvement in hypoglycemia, when compared to standard pump therapy., (© 2015 Diabetes Technology Society.)

Background: There is evidence suggesting that glycemic variability reduces quality of life (QoL) in people with type 2 diabetes, but this association has not been explored in type 1 diabetes. We aimed to assess whether glycemic variability has an impact on QoL in adults with established type 1 diabetes using multiple daily injections (MDI) of insulin or continuous subcutaneous insulin infusion (CSII)., Methods: Participants wore a blinded continuous glucose monitor for up to 5 days and completed the diabetes quality of life (DQOL) questionnaire. Glycemic variability measures were calculated using the EasyGV version 9.0 software. A correlation analysis was performed to assess whether there was a relationship between glycemic variability and measures of QoL., Results: In all, 57 participants with type 1 diabetes (51% male, 65% on CSII, 35% on MDI, mean [SD] age 41 [13] years, duration of diabetes 21 [12] years, HbA1c 63 [12] mmol/mol [7.9% (1.1)], body mass index 25.2 [4.0] kg/m(2)) were included in the analysis. No significant associations between glycemic variability and DQOL total or subscale scores were demonstrated. The glycemic variability was significantly higher for MDI participants compared to CSII participants (P < .05 for all glycemic variability measures), but no significant difference in QoL between the 2 treatment modality groups was observed., Conclusions: Treatment with CSII is associated with lower glycemic variability compared to MDI. Despite this, and contrary to findings in type 2 diabetes, this study did not find an association between glycemic variability and QoL in adults with relatively well-controlled type 1 diabetes, irrespective of whether they are on MDI or CSII., (© 2015 Diabetes Technology Society.)

Aims: The aims of this study were: (1) to assess the association of adiponectin, leptin and interleukin-6 (IL-6) with incidence of type 2 diabetes (T2DM) in Asian Indian men with impaired glucose tolerance (IGT) and (2) to evaluate the additional contribution of these with the well-established glycaemic marker HbA1c., Methods: This is an ancillary analyses of a nested case-control study derived from a prospective, prevention trial in India. All the participants had IGT at baseline. For this subanalysis a total of 147 (T2DM: 71; nondiabetic: 76) participants were selected based on the final glycemic outcomes. Association of these selected adipokines with T2DM were assessed using logistic regression analyses. Clinical usefulness of adding adipokine markers with HbA1c on prediction of T2DM was assessed using the area under the curve (AUC) of the receiver operating characteristics., Results: Baseline levels of adiponectin were lower and the levels of IL-6 were higher in T2DM cases when compared with non-diabetic cases (P<0.05). Levels of leptin were similar in both groups. In fully adjusted models, adiponectin (odds ratio (OR): 0.55 [95%CI: 0.33-0.91]; P=0.019) and IL-6 (OR: 2.27 [95%CI: 1.40-3.691]; P=0.001) were associated with diabetes. Addition of adiponectin to HbA1c improved the AUC (ΔAUC: 0.0619; P=0.0251), whereas addition of IL-6 did not improve the predictive power of HbA1c alone., Conclusions: Adiponectin and IL-6 are independently associated with incident diabetes. However, they are unlikely to serve as simple tools to predict future risk of diabetes but may have a role in understanding the pathogenesis., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Aims: In this analysis, we sought to examine the prospective association of the disposition index (DIo) derived from oral glucose tolerance test with incident diabetes in Asian Indian men with impaired glucose tolerance (IGT)., Methods: These post hoc analyses used data from a 2-year prospective study in primary prevention of diabetes using lifestyle intervention among 517 men with IGT. All the participants received standard lifestyle advice at baseline. The surrogate insulin sensitivity and insulin secretion measures were tested for their hyperbolic relationship. Predictive associations of various surrogate measures with incident diabetes were determined using receiver operating characteristic curves., Results: The combination of total area under the curve of insulin-to-glucose ratio (AUCinsulin/glucose) and Matsuda's insulin sensitivity index was the best equation to depict DIo [β: -0.954 (95 % CI -1.015 to -0.893)] compared to other measures tested in this cohort. There was an inverse association between change in DIo at the final follow-up and development of incident diabetes. Among the surrogate insulin measures studied, DIo [AUC (0.717 (95 % CI 0.675-0.756))] as a composite measure was superior than other surrogate indices., Conclusions: Among the surrogate indices studied, DIo was the best measure associated with incident diabetes.

The association of retinol binding protein-4 (RBP4) with incident type 2 diabetes (T2DM) in Asian Indian middle-aged men with impaired glucose tolerance (IGT) was studied. This was an ancillary analysis of a subsample from a cohort of participants with IGT in a 2 year prospective diabetes prevention program in India. For this analysis, 71 incident T2DM and 76 non-diabetic cases (non-progressors) based on the final glycemic outcome were selected. Baseline serum RBP4 was measured using competitive enzyme immunoassay. Correlations of RBP4 with relevant anthropometric and biochemical variables and also its association with diabetes were assessed using appropriate statistical analyses. Participants who developed T2DM had higher levels of serum RBP4 (21.3 [IQR: 17.7-24.9] µg/mL) compared with non-progressors (17.3 [IQR: 13.1-21.0] µg/mL; P = 0.001). Levels of RBP4 were lower than in Caucasians. Stepwise linear regression analysis showed that body mass index (BMI), systolic blood pressure, triglycerides, and HbA1c had independent associations with RBP4 levels. Multiple logistic regression analyses showed that RBP4 was independently associated with incident diabetes (odds ratio [OR] [95%confidence interval (CI)]: 1.69 [1.18-2.41]; P = 0.004). Adjustment for study group, age, BMI, waist circumference, 2 H plasma glucose, triglycerides, gamma glutamyl transferase, and insulin resistance weakened the significance of its association (OR [95%CI]: 1.65 [1.03-2.66]; P = 0.038).The results of this preliminary analyses showed that baseline serum RBP4 levels were independently associated with incident diabetes in Asian Indian men with IGT. It may be used as an additional predictor of future diabetes., (© 2015 International Union of Biochemistry and Molecular Biology.)

Objective: To distinguish the effects of menopause, gender and age on serum lipid risk markers for vascular disease, including high-density lipoprotein cholesterol (HDL-C) subfractions 2 and 3 (HDL2-C and HDL3-C)., Methods: We undertook a cross-sectional database analysis of apparently healthy Caucasian pre- and postmenopausal women and men (n=515, 518 and 800, respectively) not taking drugs affecting lipid metabolism (including contraceptive or post-menopausal steroids). Measurements of serum total cholesterol (TC), low-density lipoprotein (LDL-C), triglycerides (TG), HDL-C, HDL2-C, HDL3-C and non-HDL-C concentrations and the TC/HDL-C concentration ratio were considered., Results: Men had lower TC than postmenopausal women (p<0.001) and similar LDL-C. Compared with premenopausal women, postmenopausal women had a more atherogenic lipid profile with lower HDL2-C (median 0.67 vs 0.60 mmol/L, p<0.001) but no difference in HDL3-C (0.96 vs 0.96 mmol/L, p=0.8). Compared with either pre or postmenopausal women, men had a more atherogenic profile with lower HDL2-C (0.36 mmol/L) and HDL3-C (0.91 mmol/L, all p<0.001). With standardization for confounding variables, including standardization to age of menopause (50 years), differences apparent in the non-standardized comparisons were generally sustained, although HDL3-C levels were lower at menopause, HDL2-C ceased to differ and LDL-C was lower in postmenopausal women than men., Conclusions: Male gender is associated with a more atherogenic profile than female gender, with appreciably lower levels of the HDL2-C subfraction. Among women, menopause is associated with a more atherogenic lipid profile, but has less effect than male gender., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Macrophages activated by the TLR4 agonist LPS undergo dramatic changes in their metabolic activity. We here show that LPS induces expression of the key metabolic regulator Pyruvate Kinase M2 (PKM2). Activation of PKM2 using two well-characterized small molecules, DASA-58 and TEPP-46, inhibited LPS-induced Hif-1α and IL-1β, as well as the expression of a range of other Hif-1α-dependent genes. Activation of PKM2 attenuated an LPS-induced proinflammatory M1 macrophage phenotype while promoting traits typical of an M2 macrophage. We show that LPS-induced PKM2 enters into a complex with Hif-1α, which can directly bind to the IL-1β promoter, an event that is inhibited by activation of PKM2. Both compounds inhibited LPS-induced glycolytic reprogramming and succinate production. Finally, activation of PKM2 by TEPP-46 in vivo inhibited LPS and Salmonella typhimurium-induced IL-1β production, while boosting production of IL-10. PKM2 is therefore a critical determinant of macrophage activation by LPS, promoting the inflammatory response., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Aim: To determine prospectively the association of baseline hypertriglyceridaemic waist phenotype with incident diabetes in Asian-Indian men with impaired glucose tolerance., Methods: In a randomized 2-year diabetes prevention trial in 517 men with impaired glucose tolerance, 123 (23.8%) developed diabetes. Baseline anthropometric, metabolic and clinical variables were estimated. Associations of hypertriglyceridaemic waist phenotype (waist circumference ≥ 90cm and a serum triglyceride level of ≥ 1.7 mmol/l) with insulin resistance and incident diabetes were assessed using multiple linear regression and Cox's proportional hazard models, respectively., Results: Men with an isolated enlarged waistline and hypertriglyceridaemic waist phenotype had significantly higher BMI and percentage of total body fat compared with the group with normal waistline and triglyceride levels and the group with isolated hypertriglyceridaemia. The men with hypertriglyceridaemic waist phenotype had higher insulin resistance (mean ± sd homeostasis model assessment of insulin resistance value: 3.6 ± 1.5) compared with those in the isolated enlarged waistline, the isolated hypertriglyceridaemia or the normal waistline and triglyceride level groups (3.1 ± 1.4, 2.7 ± 1.0 and 2.5 ± 1.1, respectively, all P < 0.05 compared with hypertriglyceridaemic waist phenotype). Multiple linear regression analyses showed that hypertriglyceridaemic waist phenotype was significantly associated with insulin resistance after adjusting for age, BMI, family history, percentage of total body fat, smoking, alcohol intake, 2-h plasma glucose and HDL cholesterol level. Hypertriglyceridaemic waist phenotype was independently associated with incident diabetes after adjusting for the above confounders and gamma-glutamyl transferase (hazard ratio 1.49, 95% CI 1.01-2.21; P = 0.047). The association of hypertriglyceridaemic waist phenotype with incident diabetes was abolished when insulin resistance was introduced into the model (hazard ratio 1.39, 95% CI 0.092-2.10; P=0.12)., Conclusions: Hypertriglyceridaemic waist phenotype is a simple clinical proxy measurement for insulin resistance and is strongly associated with incident diabetes in Asian-Indian men with impaired glucose tolerance., (© 2014 The Authors. Diabetic Medicine © 2014 Diabetes UK.)

The relative risk for cardiovascular disease (CVD) events and mortality in diabetic women (in comparison with non-diabetic women) is believed to be greater than that in diabetic men. However, the absolute risk for CVD mortality and morbidity does not appear to be higher in women. In general, there is heterogeneity between studies, and whether there is any definite difference in the CVD risk between sexes at any level of glycaemia is not known. The same arguments also apply when comparing the CVD risk factors, such as lipid profiles and systemic inflammation indices, which seem to be worse in women than in men with diabetes mellitus (DM). The same questions emerge at any given glycaemic state: are women at worse risk and do they have a worse risk factor profile than men? These issues have yet to be resolved. Similar, though less extensive, data have been reported for prediabetes. Furthermore, women with DM are suboptimally treated compared with men regarding lipid and blood pressure targets. Large prospective studies representative of the general population are therefore needed to define the differences between sexes regarding CVD events and mortality at a given glucose level and after adjusting for any other confounders., (© 2014 European Society of Endocrinology.)

Aims: To assess the beneficial effects of the components of lifestyle intervention in reducing incidence of diabetes in Asian Indian men with impaired glucose tolerance (IGT) in India., Methods: This analysis was based on a 2 year prospective, randomized controlled primary prevention trial in a cohort of Asian Indian men with IGT (n=537) (Clinical Trial No: NCT00819455). Intervention and control groups were given standard care advice at baseline. Additionally, the intervention group received frequent, mobile phone based text message reminders on healthy lifestyle principles. Dietary intake and physical activity habits were recorded by validated questionnaires. The lifestyle goals were: reductions in consumption of carbohydrates, oil, portion size and body mass index of at least 1 unit (1 kg/m(2)) from baseline and maintenance of good physical activity. The association between diabetes and lifestyle goals achieved was assessed using multiple logistic regression analyses. Changes in insulin sensitivity (Matsuda's insulin sensitivity index) and oral disposition index during the follow-up were assessed., Results: At the end of the study, 123 (23.8%) participants developed diabetes. The mean lifestyle score was higher in the intervention group compared with control (2.59 ± 1.13 vs. 2.28 ± 1.17; P=0.002). Among the 5 lifestyle variables, significant improvements in the 3 dietary goal were seen with intervention. Concomitant improvement in insulin sensitivity and oral disposition index was noted. Higher lifestyle score was associated with lower risk of developing diabetes (odds ratio: 0.54 [95% CI: 0.44-0.70]; P<0.0001)., Conclusions: Beneficial effects of intervention were associated with increased compliance to lifestyle goals. The plausible mechanism is through improvement in insulin sensitivity and beta cell preservation., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Objective: To study the associations of baseline gamma-glutamyltransferase (GGT) and alanine transaminase (ALT) with incident diabetes among Asian Indian men with impaired glucose tolerance (IGT)., Methods: In a 2 year prospective, randomised, controlled primary prevention study of diabetes, among 537 IGT men aged 35-55 years, 123 incident diabetes (DM) cases occurred. Anthropometric {body mass index (BMI), waist circumference (WC)}, and laboratory measurements (fasting, 30 min and 2 hr plasma glucose (2 hr PG), HbA1c and plasma insulin, lipid profile, ALT, GGT) were estimated at baseline (Clinical Trial Identification No: NCT00819455). Predictive associations of baseline GGT and ALT values during the study were assessed using appropriate statistical methods., Results: Baseline GGT but not ALT was significantly higher in incident diabetes cases. Mean (95% CI) GGT decreased in subjects who reverted to normal glucose tolerance (NGT), whereas it increased in subjects who deteriorated to diabetes (NGT:-3.5 (-6.4 to -0.6); IGT:0.3 (-3.0 to 2.4); DM:8.3 (3.6 to 13.0) UL(-1); P < 0.0001). The risk of DM significantly increased with increasing baseline GGT after adjusting for confounders such as BMI, alcohol drinking, 2 hr PG and insulin resistance (2.02[1.35-3.02]; P = 0.001). Receiver operating characteristic curve showed that the model comprising of baseline fasting plasma glucose (FPG) and GGT (area-under-curve(AUC)[95% CI]: 0.668 [0.613-0.722]; P < 0.0001) was equally sensitive in identifying subjects with risk of diabetes as compared to 2 hr PG (AUC [95% CI]: 0.670 [0.614-0.725]; P < 0.0001) and HbA1c (AUC [95% CI]: 0.677 [0.619-0.734]; P < 0.0001) alone., Conclusions: GGT was an independent predictor of incident diabetes. Combination of GGT and FPG offers a simple and sensitive tool to identify subjects at high risk of developing diabetes.