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Aim: Dysglycaemia accelerates cognitive decline. Intensive glucose control may help delay or prevent cognitive function decline (CFD). We aimed to determine how patient characteristics influence the effect of intensive glucose control [glycated haemoglobin (HbA1c) <6.0%] on delaying CFD in people with type 2 diabetes., Research Design and Methods: In this post-hoc analysis of 2977 type 2 diabetes participants from the ACCORD MIND trial, we applied the causal forest and causal tree algorithms to identify the effect modifier of intensive glucose control in delaying CFD from 68 variables (demographics, disease history, medications, vitals and baseline biomarkers). The exposure was intensive versus standard glucose control (HbA1c <6.0% vs. 7.0%-7.9%). The main outcome was cognitive function changes from baseline to the 40th month follow-up, which were evaluated using the digit symbol substitution test, Rey auditory verbal learning test, mini-mental state examination and Stroop test. We used Cohen's d, a measure of standardized difference, to quantify the effect size of intensive glucose control on delaying CFD., Results: Among all the baseline characteristics, renal function was the most significant effect modifier. Participants with urinary albumin levels <0.4 mg/dl [absolute function change (AFC): 0.51 in mini-mental state examination, 95% confidence interval (CI): 0.04, 0.98, Cohen's d: 0.25] had slower CFD with intensive glucose control. Patients with preserved renal function (estimated glomerular filtration rate between 60 and 90 ml/min/1.73 m 2 ) were associated with small benefits (AFC: 1.28 in Stroop, 95% CI: 0.28, 2.27, Cohen's d: 0.12) when undergoing intensive glucose control. Conversely, participants with an estimated glomerular filtration rate <60 ml/min/1.73 m 2 (AFC: -0.57 in the Rey auditory verbal learning test, 95% CI: -1.09, -0.05, Cohen's d: -0.30) exhibited faster CFD when undergoing intensive glucose control. Participants who were <60 years old showed a significant benefit from intensive glucose control in delaying CFD (AFC: 1.08 in the digit symbol substitution test, 95% CI: 0.06, 2.10, Cohen's d: 0.13). All p < .05., Conclusions: Our findings linked renal function with the benefits of intensive glucose control in delaying CFD, informing personalized HbA1c goals for those with diabetes and at risk of CFD., (© 2024 John Wiley & Sons Ltd.)

Introduction: People with diabetes are at risk of developing chronic kidney disease. However, limited data are available to quantify their risk of kidney function decline in South Asia. This study evaluates the rate and predictors of kidney function decline among people with type 2 diabetes in South Asia., Research Design and Methods: We analyzed data from the Centre for Cardiometabolic Risk Reduction in South Asia (CARRS) Trial to quantify the rate of decline in estimated glomerular filtration rate (eGFR) in people with type 2 diabetes (n=1146) over 2.5 years of follow-up. The CARRS Trial evaluated a multicomponent intervention of decision-supported electronic health records and non-physician care coordinator to improve diabetes management at 10 diabetes clinics in India and Pakistan. We used linear mixed models to estimate eGFR slope among all participants and tested the association of eGFR slope with demographic, disease-related, and self-care parameters, accounting for randomization and site., Results: The mean age of participants was 54.2 years, with a median duration of diabetes of 7.0 years (IQR: 3.0 - 12.0) and median CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) eGFR of 83.6 (IQR: 67.7 to 97.9) mL/min/1.73 m 2 . The overall mean eGFR slope was -1.33/mL/min/1.73 m 2 /year. There were no differences in the eGFR slope by treatment assignment to intervention versus usual care. In the adjusted regression model, pre-existing diabetic retinopathy (slope difference: -2.11; 95% CI: -3.45 to -0.77), previous cardiovascular disease (-1.93; 95% CI: -3.45 to -0.40), and statins use (-0.87; 95% CI: -1.65 to -0.10) were associated with faster eGFR decline., Conclusions: People with diabetes receiving care at urban diabetes clinics in South Asia experienced annual eGFR decline at two times higher rate than that reported from other contemporary international diabetes cohorts. Risk factors for faster decline were similar to those previously established, and thus care delivery models must put an additional emphasis on kidney protective therapies among subgroups with microvascular and macrovascular diabetes complications., Trial Registration Number: NCT01212328., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Background: Diabetes control is poor globally and leads to burdensome microvascular and macrovascular complications. We aimed to assess post hoc between-group differences in sustained risk factor control and macrovascular and microvascular endpoints at 6.5 years in the Center for cArdiovascular Risk Reduction in South Asia (CARRS) randomized trial., Methods and Findings: This parallel group individual randomized clinical trial was performed at 10 outpatient diabetes clinics in India and Pakistan from January 2011 through September 2019. A total of 1,146 patients with poorly controlled type 2 diabetes (HbA1c ≥8% and systolic BP ≥140 mm Hg and/or LDL-cholesterol ≥130 mg/dL) were randomized to a multicomponent quality improvement (QI) strategy (trained nonphysician care coordinator to facilitate care for patients and clinical decision support system for physicians) or usual care. At 2.5 years, compared to usual care, those receiving the QI strategy were significantly more likely to achieve multiple risk factor control. Six clinics continued, while 4 clinics discontinued implementing the QI strategy for an additional 4-year follow-up (overall median 6.5 years follow-up). In this post hoc analysis, using intention-to-treat, we examined between-group differences in multiple risk factor control (HbA1c <7% plus BP <130/80 mm Hg and/or LDL-cholesterol <100 mg/dL) and first macrovascular endpoints (nonfatal myocardial infarction, nonfatal stroke, death, revascularization [angioplasty or coronary artery bypass graft]), which were co-primary outcomes. We also examined secondary outcomes, namely, single risk factor control, first microvascular endpoints (retinopathy, nephropathy, neuropathy), and composite first macrovascular plus microvascular events (which also included amputation and all-cause mortality) by treatment group and whether QI strategy implementation was continued over 6.5 years. At 6.5 years, assessment data were available for 854 participants (74.5%; n = 417 [intervention]; n = 437 [usual care]). In terms of sociodemographic and clinical characteristics, participants in the intervention and usual care groups were similar and participants at sites that continued were no different to participants at sites that discontinued intervention implementation. Patients in the intervention arm were more likely to exhibit sustained multiple risk factor control than usual care (relative risk: 1.77; 95% confidence interval [CI], 1.45, 2.16), p < 0.001. Cumulatively, there were 233 (40.5%) first microvascular and macrovascular events in intervention and 274 (48.0%) in usual care patients (absolute risk reduction: 7.5% [95% CI: -13.2, -1.7], p = 0.01; hazard ratio [HR] = 0.72 [95% CI: 0.61, 0.86]), p < 0.001. Patients in the intervention arm experienced lower incidence of first microvascular endpoints (HR = 0.68 [95% CI: 0.56, 0.83), p < 0.001, but there was no evidence of between-group differences in first macrovascular events. Beneficial effects on microvascular and composite vascular outcomes were observed in sites that continued, but not sites that discontinued the intervention., Conclusions: In urban South Asian clinics, a multicomponent QI strategy led to sustained multiple risk factor control and between-group differences in microvascular, but not macrovascular, endpoints. Between-group reductions in vascular outcomes at 6.5 years were observed only at sites that continued the QI intervention, suggesting that practice change needs to be maintained for better population health of people with diabetes., Trial Registration: ClinicalTrials.gov NCT01212328., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: MKA has received research support (to Emory University) from Merck and consulting fees from Bayer and Eli Lilly, all outside the scope of this work. SP received research funding in the area of CVD implementation sciences. All other authors have declared that no competing interests exist., (Copyright: © 2024 Ali et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The term prediabetes describes blood glucose levels above the normal range but below the threshold to diagnose type 2 diabetes. Several population health initiatives encourage a test and treat approach for prediabetes. In this approach, screening and identification of individuals with prediabetes should be followed by prompt referral to structured lifestyle modification programs or pharmacologic interventions that have been shown to prevent or delay the progression to type 2 diabetes in clinical trials. Here we provide a critical review of evidence for this test and treat approach by examining health outcomes associated with prediabetes and the availability and effectiveness of lifestyle modification approaches that target prediabetes. We also describe current limitations to the reach and uptake of evidence-based treatment options for prediabetes. Finally, we highlight lessons learned from identifying and labeling other preconditions to consider challenges and opportunities that may arise with increasing awareness of prediabetes as part of routine preventive care.

Objective: To describe the natural history of diabetes in Indians., Research Design and Methods: Data are from participants older than 20 years in the Centre for Cardiometabolic Risk Reduction in South Asia longitudinal study. Glycemic states were defined per American Diabetes Association criteria. Markov models were used to estimate annual transition probabilities and sojourn time through states., Results: Among 2,714 diabetes-free participants, 641 had isolated impaired fasting glucose (iIFG), and 341 had impaired glucose tolerance (IGT). The annual transition to diabetes for those with IGT was 13.9% (95% CI 12.0, 15.9) versus 8.6% (7.3, 9.8) for iIFG. In the normoglycemia ↔ iIFG → diabetes model, mean sojourn time in normoglycemia was 40.3 (34.6, 48.2) years, and sojourn time in iIFG was 9.7 (8.4, 11.4) years. For the normoglycemia ↔ IGT → diabetes model, mean sojourn time in normoglycemia was 34.5 (29.5, 40.8) years, and sojourn time in IGT was 6.1 (5.3, 7.1) years., Conclusions: Individuals reside in normoglycemia for 35-40 years; however, progression from prediabetes to diabetes is rapid., (© 2024 by the American Diabetes Association.)

Objective: To examine whether the effect of conventional lifestyle interventions on type 2 diabetes incidence differs by glucose-defined prediabetes phenotype., Research Design and Methods: We searched multiple databases until 1 April 2023 for randomized controlled trials that recruited people with isolated impaired fasting glucose (i-IFG), isolated impaired glucose tolerance (i-IGT), and impaired fasting glucose plus impaired glucose tolerance (IFG+IGT). Individual participant data were pooled from relevant trials and analyzed through random-effects models with use of the within-trial interactions approach., Results: Four trials with 2,794 participants (mean age 53.0 years, 60.7% men) were included: 1,240 (44.4%), 796 (28.5%), and 758 (27.1%) had i-IFG, i-IGT, and IFG+IGT, respectively. After a median of 2.5 years, the pooled hazard ratio for diabetes incidence in i-IFG was 0.97 (95% CI 0.66, 1.44), i-IGT 0.65 (0.44, 0.96), and IFG+IGT 0.51 (0.38, 0.68; Pinteraction = 0.01)., Conclusions: Conventional lifestyle interventions reduced diabetes incidence in people with IGT (with or without IFG) but not in those with i-IFG., (© 2023 by the American Diabetes Association.)

Introduction: Exposure to fine particulate matter has been associated with several cardiovascular and cardiometabolic diseases. However, such evidence mostly originates from low-pollution settings or cross-sectional studies, thus necessitating evidence from regions with high air pollution levels, such as India, where the burden of non-communicable diseases is high., Research Design and Methods: We studied the associations between ambient PM 2.5 levels and fasting plasma glucose (FPG), glycosylated hemoglobin (HbA1c) and incident type 2 diabetes mellitus (T2DM) among 12 064 participants in an adult cohort from urban Chennai and Delhi, India. A meta-analytic approach was used to combine estimates, obtained from mixed-effects models and proportional hazards models, from the two cities., Results: We observed that 10 μg/m 3 differences in monthly average exposure to PM 2.5 was associated with a 0.40 mg/dL increase in FPG (95% CI 0.22 to 0.58) and 0.021 unit increase in HbA1c (95% CI 0.009 to 0.032). Further, 10 μg/m 3 differences in annual average PM 2.5 was associated with 1.22 (95% CI 1.09 to 1.36) times increased risk of incident T2DM, with non-linear exposure response., Conclusions: We observed evidence of temporal association between PM 2.5 exposure, and higher FPG and incident T2DM in two urban environments in India, thus highlighting the potential for population-based mitigation policies to reduce the growing burden of diabetes., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: To assess the cost-effectiveness of a multicomponent strategy versus usual care in people with type 2 diabetes in South Asia., Design: Economic evaluation from healthcare system and societal perspectives., Setting: Ten diverse urban clinics in India and Pakistan., Participants: 1146 people with type 2 diabetes (575 in the intervention group and 571 in the usual care group) with mean age of 54.2 years, median diabetes duration: 7 years and mean HbA1c: 9.9% (85 mmol/mol) at baseline., Intervention: Multicomponent strategy comprising decision-supported electronic health records and non-physician care coordinator. Control group received usual care., Outcome Measures: Incremental cost-effectiveness ratios (ICERs) per unit achievement in multiple risk factor control (HbA1c <7% (53 mmol/mol) and SBP <130/80 mmHg or LDLc <2.58 mmol/L (100 mg/dL)), ICERs per unit reduction in HbA1c, 5-mmHg unit reductions in systolic BP, 10-unit reductions in LDLc (mg/dl) (considered as clinically relevant) and ICER per quality-adjusted life years (QALYs) gained. ICERs were reported in 2020 purchasing power parity-adjusted international dollars (INT$). The probability of ICERs being cost-effective was considered depending on the willingness to pay (WTP) values as a share of GDP per capita for India (Int$ 7041.4) and Pakistan (Int$ 4847.6)., Results: Compared to usual care, the annual incremental costs per person for intervention group were Int$ 1061.9 from a health system perspective and Int$ 1093.6 from a societal perspective. The ICER was Int$ 10,874.6 per increase in multiple risk factor control, $2588.1 per one percentage point reduction in the HbA1c, and $1744.6 per 5 unit reduction in SBP (mmHg), and $1271 per 10 unit reduction in LDLc (mg/dl). The ICER per QALY gained was $33,399.6 from a societal perspective., Conclusions: In a trial setting in South Asia, a multicomponent strategy for diabetes care resulted in better multiple risk factor control at higher costs and may be cost-effective depending on the willingness to pay threshold with substantial uncertainty around cost-effectiveness for QALYs gained in the short term (2.5 years). Future research needs to confirm the long-term cost-effectiveness of intensive multifactorial intervention for diabetes care in diverse healthcare settings in LMICs., (© 2023 The Authors. Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK.)

Competing Interests: KMVN reports receiving grants from the National Institutes of Health and Robert Wood Johnson Foundation. MR owns stock in AstraZeneca, Eli Lilly, Johnson & Johnson, Novo Nordisk, and UnitedHealth Group. RJ declares no competing interests.

Type 2 diabetes disparities in the USA persist in both the prevalence of disease and diabetes-related complications. We conducted a literature review related to diabetes prevention, management, and complications across racial and ethnic groups in the USA. The objective of this review is to summarise the current understanding of diabetes disparities by examining differences between and within racial and ethnic groups and among young people (aged <18 years). We also examine the pathophysiology of diabetes as it relates to race and ethnic differences. We use a conceptual framework built on the socioecological model to categorise the causes of diabetes disparities across the lifespan looking at factors in five domains of health behaviours and social norms, public awareness, structural racism, economic development, and access to high-quality care. The range of disparities in diabetes prevalence and management in the USA calls for a community-engaged and multidisciplinary approach that must involve community partners, researchers, practitioners, health system administrators, and policy makers. We offer recommendations for each of these groups to help to promote equity in diabetes prevention and care in the USA., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objective: To assess the cost-effectiveness of collaborative versus usual care in adults with poorly controlled type 2 diabetes and depression in India., Research Design and Methods: We performed a within-trial cost-effectiveness analysis of a 24-month parallel, open-label, pragmatic randomized clinical trial at four urban clinics in India from multipayer and societal perspectives. The trial randomly assigned 404 patients with poorly controlled type 2 diabetes (HbA1c ≥8.0%, systolic blood pressure ≥140 mmHg, or LDL cholesterol ≥130 mg/dL) and depressive symptoms (9-item Patient Health Questionnaire score ≥10) to collaborative care (support from nonphysician care coordinators, electronic registers, and specialist-supported case review) for 12 months, followed by 12 months of usual care or 24 months of usual care. We calculated incremental cost-effectiveness ratios (ICERs) in Indian rupees (INR) and international dollars (Int'l-$) and the probability of cost-effectiveness using quality-adjusted life-years (QALYs) and depression-free days (DFDs)., Results: From a multipayer perspective, collaborative care costed an additional INR309,558 (Int'l-$15,344) per QALY and an additional INR290.2 (Int'l-$14.4) per DFD gained compared with usual care. The probability of cost-effectiveness was 56.4% using a willingness to pay of INR336,000 (Int'l-$16,654) per QALY (approximately three times per-capita gross domestic product). The willingness to pay per DFD to achieve a probability of cost-effectiveness >95% was INR401.6 (Int'l-$19.9). From a societal perspective, cost-effectiveness was marginally lower. In sensitivity analyses, integrating collaborative care in clinical workflows reduced incremental costs by ∼47% (ICER 162,689 per QALY, cost-effectiveness probability 89.4%), but cost-effectiveness decreased when adjusting for baseline values., Conclusions: Collaborative care for patients with type 2 diabetes and depression in urban India can be cost-effective, especially when integrated in clinical workflows. Long-term cost-effectiveness might be more favorable. Scalability across lower- and middle-income country settings depends on heterogeneous contextual factors., (© 2022 by the American Diabetes Association.)

Several international studies have stratified people with diabetes into phenotypical clusters. However, there has not been a systematic examination of the variation in these clusters across ethnic groups. For example, some clusters appear more frequent among Asians and may have lower weight, age at diagnosis and poorer beta cell function., (Copyright © 2022 Primary Care Diabetes Europe. Published by Elsevier Ltd. All rights reserved.)

Introduction: Diabetic peripheral neuropathy (DPN) causes morbidity and affects the quality of life. Before diabetes diagnosis, neuropathic damage may be present. Sudoscan provides accurate measurement of the sudomotor function. This study aimed to assess the abnormalities detected by Sudoscan, offered estimates of DPN prevalence, and investigated the relationship between metabolic and clinical parameters. Additionally, we evaluated the diagnostic accuracy of the Sudoscan compared with monofilament and tuning fork tests for detecting DPN., Research Design and Methods: Cross-sectional descriptive study including patients with type 2 diabetes for <5 years since diagnosis. We investigated the presence of DPN using a 128 Hz tuning fork test, the 10 g monofilament, and the sudomotor dysfunction in feet using Sudoscan. We compared patients with and without alterations in the Sudoscan. A logistic regression model analyzed variables independently associated with sudomotor dysfunction., Results: From 2013 to 2020, 2243 patients were included, 55.1% women, age 51.8 years, and 17.1% with normal weight. Monofilament tests and/or tuning fork examination were abnormal in 29% (95% CI 0.23% to 0.27%) and 619 patients (27.6%, 0.25% to 0.29%) had sudomotor alterations. In logistic regression analysis, age (β=1.01, 0.005-1.02), diastolic blood pressure (β=0.98, 0.96-0.99), heart rate (β=1.01, 1.00-1.02), glucose (β=1.00, 1.00-1.03), albuminuria (β=1.001, 1.000-1.001), beta-blockers=1.98, 1.21-3.24) and fibrate use=0.61, 0.43-0.87) were associated with sudomotor dysfunction. The AUC (area under the curve) for Sudoscan was 0.495 (0.469-0.522), with sensitivity and specificity of 24% and 71%, respectively., Conclusion: The Sudoscan identified an important proportion of patients with dysfunction, allowing prompt intervention to decrease the risk for complications., Trial Registration Number: NCT02836808., Competing Interests: Competing interests: CAA-S is part of the Editorial Board of BMJ Open Diabetes Research and Care., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Aims: To determine whether obesity-associated metabolites are associated with type 2 diabetes (T2DM) risk among South Asians., Materials and Methods: Serum-based nuclear magnetic resonance imaging metabolomics data were generated from two South Asian population-based prospective cohorts from Karachi, Pakistan: CARRS1 (N = 4017) and CARRS2 (N = 4802). Participants in both cohorts were followed up for 5 years and incident T2DM was ascertained. A nested case-control study approach was developed to select participants from CARRS1 (N cases  = 197 and N controls  = 195) and CARRS2 (N cases  = 194 and N controls  = 200), respectively. First, we investigated the association of 224 metabolites with general obesity based on body mass index and with central obesity based on waist-hip ratio, and then the top obesity-associated metabolites were studied in relation to incident T2DM., Results: In a combined sample of the CARRS1 and CARRS2 cohorts, out of 224 metabolites, 12 were associated with general obesity and, of these, one was associated with incident T2DM. Fifteen out of 224 metabolites were associated with central obesity and, of these, 10 were associated with incident T2DM. The higher level of total cholesterol in high-density lipoprotein (HDL) was associated with reduced T2DM risk (odds ratio [OR] 0.68, 95% confidence interval [CI] 0.53, 0.86; P = 1.2 × 10 -3 ), while higher cholesterol esters in large very-low-density lipoprotein (VLDL) particles were associated with increased T2DM risk (OR 1.90, 95% CI 1.40, 2.58; P = 3.5 × 10 -5 )., Conclusion: Total cholesterol in HDL and cholesterol esters in large VLDL particles may be an important biomarker in the identification of early development of obesity-associated T2DM risk among South Asian adults., (© 2022 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Nearly half of all adults with type 2 diabetes mellitus (T2DM) live in India and China. These populations have an underlying predisposition to deficient insulin secretion, which has a key role in the pathogenesis of T2DM. Indian and Chinese people might be more susceptible to hepatic or skeletal muscle insulin resistance, respectively, than other populations, resulting in specific forms of insulin deficiency. Cluster-based phenotypic analyses demonstrate a higher frequency of severe insulin-deficient diabetes mellitus and younger ages at diagnosis, lower β-cell function, lower insulin resistance and lower BMI among Indian and Chinese people compared with European people. Individuals diagnosed earliest in life have the most aggressive course of disease and the highest risk of complications. These characteristics might contribute to distinctive responses to glucose-lowering medications. Incretin-based agents are particularly effective for lowering glucose levels in these populations; they enhance incretin-augmented insulin secretion and suppress glucagon secretion. Sodium-glucose cotransporter 2 inhibitors might also lower blood levels of glucose especially effectively among Asian people, while α-glucosidase inhibitors are better tolerated in east Asian populations versus other populations. Further research is needed to better characterize and address the pathophysiology and phenotypes of T2DM in Indian and Chinese populations, and to further develop individualized treatment strategies., (© 2022. Springer Nature Limited.)

Objective: To analyze national and state-specific trends in diabetes-related hospital admissions and determine whether disparities in rates of admission exist between demographic groups and geographically dispersed states., Research Design and Methods: We conducted serial cross-sectional analyses of the National Inpatient Sample (2008, 2011, 2014, and 2016) and State Inpatient Databases for Arizona, Florida, Kentucky, Iowa, Maryland, Nebraska, New Jersey, New York, North Carolina, Utah, and Vermont for 2008, 2011, 2014, and 2016/2017 among adult patients with type 1 and type 2 diabetes-related ICD codes (ICD-9 [250.XX] or ICD-10 [E10.XXX, E11.XXX, and E13.XXX]. We measured hospitalization rates for people with diabetes (all-cause hospitalizations) and for admissions with a primary diagnosis of diabetes or diabetes-related complications (diabetes-specific hospitalizations) per 10,000 people per year., Results: Nationally, all-cause and diabetes-specific hospitalizations declined by 3.1% (95% CI -5.5, -0.7) and 19.1% (95% CI -21.6, -16.6), respectively, over 2008 to 2016. The analysis of individual states showed that diabetes-specific admissions in individuals ≥65 years old declined during this time (16.3-48.8% decrease) but increased among patients 18-29 years old (10.5-81.5% increase) and that rural diabetes-specific admissions decreased in just over half of the included states (15.2-69.2% decrease). There were no differences in changes in admission rates among different racial/ethnic groups., Conclusions: Overall, rates of diabetes-related hospitalizations decreased over 2008 to 2016/2017, but there were large state-level differences across subgroups of patients. The rise in diabetes hospitalizations among young adults is a cause for concern. These state- and subpopulation-level differences highlight the need for state-level policies and interventions to address disparities in diabetes health care use., (© 2022 by the American Diabetes Association.)

Objective: We assessed the impact of a collaborative care intervention on anxiety symptoms among participants in India with comorbid depression, poorly controlled diabetes, and moderate to severe anxiety symptoms., Method: We analyzed data from a randomized controlled trial conducted at four diabetes clinics in India. Participants received either collaborative care or usual care. We included only participants who scored ⩾10 on the Generalized Anxiety Disorder-7 (GAD-7) at baseline. We estimated the effect of the intervention on clinically significant reduction in anxiety symptoms; we considered several potential baseline moderators and mediation by anti-depressant use., Results: One hundred and seventy-two participants scored 10 or above on the GAD-7 at baseline. Collaborative care participants were more likely than control participants to achieve a clinically significant reduction in anxiety symptoms at 6 and 12 months (65.7% vs. 41.4% at 12 months, p = 0.002); these differences were not sustained at 18 or 24 months. There was little evidence of moderation by participant characteristics at baseline, and effects were not mediated by anti-depressant use., Conclusions: Collaborative care for the treatment of depression and type 2 diabetes can lead to clinically significant reductions in anxiety symptoms among patients with anxiety. Effects were notable during the active intervention period but not over the year post-intervention., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Obesity is associated with widespread differential DNA methylation (DNAm) patterns, though there have been limited overlap in the obesity-associated cytosine-guanine nucleotide pair (CpG) sites that have been identified in the literature. We systematically searched four databases for studies published until January 2020. Eligible studies included cross-sectional, longitudinal, or intervention studies examining adiposity and genome-wide DNAm in non-pregnant adults aged 18-75 in all tissue types. Study design and results were extracted in the descriptive review. Blood-based DNAm results in body mass index (BMI) and waist circumference (WC) were meta-analyzed using weighted sum of Z-score meta-analysis. Of the 10,548 studies identified, 46 studies were included in the systematic review with 18 and nine studies included in the meta-analysis of BMI and WC, respectively. In the blood, 77 and four CpG sites were significant in three or more studies of BMI and WC, respectively. Using a genome-wide threshold for significance, 52 blood-based CpG sites were significantly associated with BMI. These sites have previously been associated with many obesity-related diseases including type 2 diabetes, cardiovascular disease, Crohn's disease, and depression. Our study shows that DNAm at 52 CpG sites represent potential mediators of obesity-associated chronic diseases and may be novel intervention or therapeutic targets to protect against obesity-associated chronic diseases., (© 2021 World Obesity Federation.)

Aims: To identify profiles of type 2 diabetes from continuous glucose monitoring (CGM) data using ambulatory glucose profile (AGP) indicators and examine the association with prevalent complications. Methods: Two weeks of CGM data, collected between 2015 and 2019, from 5901 adult type 2 diabetes patients were retrieved from a clinical database in Chennai, India. Non-negative matrix factorization was used to identify profiles as per AGP indicators. The association of profiles with existing complications was examined using multinomial and logistic regressions adjusted for glycated hemoglobin (HbA1c; %), sex, age at onset, and duration of diabetes. Results: Three profiles of glycemic variability (GV) were identified based on CGM data-Profile 1 ["TIR Profile"] ( n  = 2271), Profile 2 ["Hypo"] ( n  = 1471), and Profile 3 ["Hyper"] ( n  = 2159). Compared with time in range (TIR) profile, those belonging to Hyper had higher mean fasting plasma glucose (202.9 vs. 167.1, mg/dL), 2-h postprandial plasma glucose (302.1 vs. 255.6, mg/dL), and HbA1c (9.7 vs. 8.6; %). Both "Hypo profile" and "Hyper profile" had higher odds of nonproliferative diabetic retinopathy ("Hypo": 1.44, 1.20-1.73; "Hyper": 1.33, 1.11-1.58), macroalbuminuria ("Hypo": 1.58, 1.25-1.98; "Hyper": 1.37, 1.10-1.71), and diabetic kidney disease (DKD; "Hypo": 1.65, 1.18-2.31; "Hyper": 1.88, 1.37-2.58), compared with "TIR profile." Those in "Hypo profile" (vs. "TIR profile") had higher odds of proliferative diabetic retinopathy (PDR; 2.84, 1.65-2.88). Conclusions: We have identified three profiles of GV from CGM data. While both "Hypo profile" and "Hyper profile" had higher odds of prevalent DKD compared with "TIR profile," "Hypo profile" had higher odds of PDR. Our study emphasizes the clinical importance of recognizing and treating hypoglycemia (which is often unrecognized without CGM) in patients with type 2 Diabetes Mellitus.

Aim: Achievement of treatment targets among individuals with diabetes remains suboptimal in many parts of the globe. We aimed to assess changes in diabetes prevalence and achievement of diabetes care goals in South Asia using two consecutive cross-sectional population-based surveys., Methods: Two representative samples of South Asian adults were recruited using identical methods from Chennai, Delhi, and Karachi in 2010-11 (n = 16,288; response rate-94.7%) and 2015-16 (n = 14,587; response rate-94.0%) through the Center for Cardio-metabolic Risk Reduction in South Asia (CARRS) Study. Quality of care goals were defined as HbA 1c <53 mmol/mol (7.0%), blood pressure (BP) control: <140/90 mmHg, lipid control: LDL cholesterol <2.56 mmol/l (100 mg/dl), and self-reported non-smoking., Results: Weighted prevalence of self-reported diabetes increased by 9.0% [13% (95%CI: 13-14) to 15% (14-15)] while that of newly diagnosed diabetes decreased by 16% [6.1% (5.7-6.6) to 5.1% (4.6-5.6)]. There were improvements in achieving glycaemic (25% to 30%, p = 0.002) and lipid (34% to 45%, p < 0.001) goals, but no notable improvements in BP control or smoking status. The proportion of individuals with self-reported diabetes meeting more than one target also increased., Conclusions: Diabetes prevalence continues to grow among urban South Asians and large gaps still exist in the attainment of treatment targets. Concerted policy, systemic, clinical and individual efforts are needed to close these care gaps., (© 2020 Diabetes UK.)

Introduction: Lipid control is essential in type 2 diabetes mellitus (T2DM). The aim of this study is to investigate factors associated with lipid therapy adherence and achievement of goals in real-life setting among patients with recently diagnosed T2DM., Research Design and Methods: This is a longitudinal analysis in a center of comprehensive care for patients with diabetes. We include patients with T2DM, <5 years of diagnosis, without disabling complications (eg, amputation, myocardial infarct, stroke, proliferative retinopathy, glomerular filtration rate <60 mL/min/m 2 ) and completed 2-year follow-up. The comprehensive diabetes care model includes 9 interventions in 4 initial visits and annual evaluations. Endocrinologists follow the clinic's guideline and adapt therapy to reach risk-based treatment goal. The main outcome measures were the proportion of patients meeting low-density lipoprotein cholesterol (c-LDL) (<100 mg/dL) and triglycerides (<150 mg/dL) and proportion of patients taking statin, fibrate or combination at baseline, 3 months and annual evaluations., Results: We included 288 consecutive patients (54±9 years, 53.8% women), time since T2DM diagnosis 1 (0-5) year. Baseline, 10.8% patients were receiving statin therapy (46.5% moderate-intensity therapy and 4.6% high-intensity therapy), 8.3% fibrates and 4.2% combined treatment. The proportion of patients with combined treatment increased to 41.6% at 3 months, decreased to 20.8% at 1 year and increased to 38.9% at 2 years of evaluation. Patients receiving treatment met LDL and triglycerides goals at 3 months (17% vs 59.7%, relative ratio (RR)=0.89, 95% CI 0.71 to 1.12), at 1 year (17% vs 26.7%, RR=0.62, 95% CI 0.41 to 0.95) and at 2 years (17% vs 29.9%, RR=0.63, 95% CI 0.43 to 0.93). Main reasons for medication suspension: patient considered treatment was not important (37.5%) and other physician suspended treatment (31.3%)., Conclusion: 88.2% of patients with T2DM required lipid-lowering drugs. Education for patients and physicians is critical to achieve and maintain diabetes goals., Trial Registration Number: NCT02836808., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To assess the predictors of achieving and maintaining guideline-recommended glycemic control in people with poorly controlled type 2 diabetes., Methods: We analyzed data from the Centre for Cardiometabolic Risk Reduction in South Asia (CARRS) Trial (n = 1146), to identify groups that achieved guideline-recommended glycemic control (HbA1c < 7%) and those that remained persistently poorly controlled (HbA1c > 9%) over a median of 28 months of follow-up. We used generalized estimation equations (GEE) analysis for each outcome i.e. achieving guideline-recommended control and persistently poorly controlled and constructed four regression models (demographics, disease-related, self-care, and other risk factors) separately to identify predictors of HbA1c < 7% and HbA1c > 9% at the end of the trial, adjusting for trial group assignment and site., Results: In the final multivariate model, adherence to prescribed medications (RR: 1.46, 95%CI: 1.09, 1.95), adherence to diet plans (RR: 1.79, 95% CI: 1.43, 2.23) and middle-aged: 50-64 years (RR: 1.32; 95% CI: 1.02-1.71) were associated with achieving guideline-recommended control (HbA1c < 7%). Presence of microvascular complications (RR: 0.70; 95%CI: 0.53-0.92) reduced the probability of achieving guideline-recommended glycemic control (HbA1c 7%). Further, longer duration of diabetes (>15 years), RR: 1.41; 95% CI: 1.15, 1.72, hyperlipidemia, RR: 1.19; 95% CI: 1.06, 1.34 and younger age group (35-49 years vs. >64 years: RR: 0.61; 95% CI: 0.47-0.79) were associated with persistently poor glycemic control (HbA1c > 9%)., Conclusion: To achieve and maintain guideline-recommended glycemic control, care delivery models must put additional emphasis and effort on patients with longer disease duration, younger people and those having microvascular complications and hyperlipidemia., Competing Interests: Declaration of Competing Interest None of the authors have any potential conflict of interest to declare., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Aims: To evaluate whether and what combinations of diabetes quality metrics were achieved in a multicentre trial in South Asia evaluating a multicomponent quality improvement intervention that included non-physician care coordinators to promote adherence and clinical decision-support software to enhance physician practices, in comparision with usual care., Methods: Using data from the Centre for Cardiometabolic Risk Reduction in South Asia (CARRS) trial, we evaluated the proportions of trial participants achieving specific and combinations of five diabetes care targets (HbA 1c <53 mmol/mol [7%], blood pressure <130/80 mmHg, LDL cholesterol <2.6 mmol/L, non-smoking status, and aspirin use). Additionally, we examined the proportions of participants achieving the following risk factor improvements from baseline: ≥11-mmol/mol (1%) reduction in HbA 1c , ≥10-mmHg reduction in systolic blood pressure, and/or ≥0.26-mmol/l reduction in LDL cholesterol., Results: Baseline characteristics were similar in the intervention and usual care arms. Overall, 12.3%, 29.4%, 36.5%, 19.5% and 2.2% of participants in the intervention group and 16.2%, 38.3%, 31.6%, 11.3% and 0.8% of participants in the usual care group achieved any one, two, three, four or five targets, respectively. We noted sizeable improvements in HbA 1c , blood pressure and cholesterol, and found that participants in the intervention group were twice as likely to achieve improvements in all three indices at 12 months that were sustained over 28 months of the study [relative risk 2.1 (95% CI 1.5,2.8) and 1.8 (95% CI 1.5,2.3), respectively]., Conclusions: The intervention was associated with significantly higher achievement of and greater improvements in composite diabetes quality care goals. However, among these higher-risk participants, very small proportions achieved the complete group of targets, which suggests that achievement of multiple quality-of-care goals is challenging and that other methods may be needed in closing care gaps., (© 2019 Diabetes UK.)

Importance: Mental health comorbidities are increasing worldwide and worsen outcomes for people with diabetes, especially when care is fragmented., Objective: To assess whether collaborative care vs usual care lowers depressive symptoms and improves cardiometabolic indices among adults with diabetes and depression., Design, Setting, and Participants: Parallel, open-label, pragmatic randomized clinical trial conducted at 4 socioeconomically diverse clinics in India that recruited patients with type 2 diabetes; a Patient Health Questionnaire-9 score of at least 10 (range, 0-27); and hemoglobin A1c (HbA1c) of at least 8%, systolic blood pressure (SBP) of at least 140 mm Hg, or low-density lipoprotein (LDL) cholesterol of at least 130 mg/dL. The first patient was enrolled on March 9, 2015, and the last was enrolled on May 31, 2016; the final follow-up visit was July 14, 2018., Interventions: Patients randomized to the intervention group (n = 196) received 12 months of self-management support from nonphysician care coordinators, decision support electronic health records facilitating physician treatment adjustments, and specialist case reviews; they were followed up for an additional 12 months without intervention. Patients in the control group (n = 208) received usual care over 24 months., Main Outcomes and Measures: The primary outcome was the between-group difference in the percentage of patients at 24 months who had at least a 50% reduction in Symptom Checklist Depression Scale (SCL-20) scores (range, 0-4; higher scores indicate worse symptoms) and a reduction of at least 0.5 percentage points in HbA1c, 5 mm Hg in SBP, or 10 mg/dL in LDL cholesterol. Prespecified secondary outcomes were percentage of patients at 12 and 24 months who met treatment targets (HbA1c <7.0%, SBP <130 mm Hg, LDL cholesterol <100 mg/dL [<70 mg/dL if prior cardiovascular disease]) or had improvements in individual outcomes (≥50% reduction in SCL-20 score, ≥0.5-percentage point reduction in HbA1c, ≥5-mm Hg reduction in SBP, ≥10-mg/dL reduction in LDL cholesterol); percentage of patients who met all HbA1c, SBP, and LDL cholesterol targets; and mean reductions in SCL-20 score, Patient Health Questionnaire-9 score, HbA1c, SBP, and LDL cholesterol., Results: Among 404 patients randomized (mean [SD] age, 53 [8.6] years; 165 [40.8%] men), 378 (93.5%) completed the trial. A significantly greater percentage of patients in the intervention group vs the usual care group met the primary outcome (71.6% vs 57.4%; risk difference, 16.9% [95% CI, 8.5%-25.2%]). Of 16 prespecified secondary outcomes, there were no statistically significant between-group differences in improvements in 10 outcomes at 12 months and in 13 outcomes at 24 months. Serious adverse events in the intervention and usual care groups included cardiovascular events or hospitalizations (4 [2.0%] vs 7 [3.4%]), stroke (0 vs 3 [1.4%]), death (2 [1.0%] vs 7 [3.4%]), and severe hypoglycemia (8 [4.1%] vs 0)., Conclusions and Relevance: Among patients with diabetes and depression in India, a 12-month collaborative care intervention, compared with usual care, resulted in statistically significant improvements in a composite measure of depressive symptoms and cardiometabolic indices at 24 months. Further research is needed to understand the generalizability of the findings to other low- and middle-income health care settings., Trial Registration: ClinicalTrials.gov Identifier: NCT02022111.

Introduction: South Asians have a high prevalence of type 2 diabetes mellitus (T2DM). This may be associated with high rates of conversion through the natural history of disease. However, there is a paucity of data on prediabetes and T2DM incidence and related predictors in South Asians in the USA., Research Design and Methods: We estimated prediabetes and T2DM incidence after 5 years of follow-up in the Mediators of Atherosclerosis in South Asians Living in America study (n=481) and examined the associated correlates. We defined T2DM and prediabetes using the American Diabetes Association criteria. Prediabetes included isolated impaired fasting glucose (iIFG), isolated impaired glucose tolerance (iIGT) and combined IFG and IGT., Results: Overall, 152 (32%, 95% CI: 27.6 to 35.9) individuals progressed either from normal glucose tolerance to prediabetes or T2DM, or from prediabetes to T2DM. In standardised logistic regression models controlling for age and sex, only hepatic fat attenuation (increased hepatic fat) (OR: 0.67 (95% CI: 0.55 to 0.87) per SD, visceral fat area (OR: 1.36 (95% CI: 1.06 to 1.74) per SD and hypertension (OR: 2.21 (95% CI: 1.44 to 3.40) were associated with any glycemic progression., Conclusions: South Asians in the USA have a high incidence of dysglycemia. Hepatic and visceral fat may be factors in glycemic progression, and prevention efforts should target ectopic fat reduction., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Importance: A stepwise approach that includes screening and lifestyle modification followed by the addition of metformin for individuals with high risk of diabetes is recommended to delay progression to diabetes; however, there is scant evidence regarding whether this approach is cost-effective., Objective: To estimate the cost-effectiveness of a stepwise approach in the Diabetes Community Lifestyle Improvement Program., Design, Setting, and Participants: This economic evaluation study included 578 adults with impaired glucose tolerance, impaired fasting glucose, or both. Participants were enrolled in the Diabetes Community Lifestyle Improvement Program, a randomized clinical trial with 3-year follow-up conducted at a diabetes care and research center in Chennai, India., Interventions: The intervention group underwent a 6-month lifestyle modification curriculum plus stepwise addition of metformin; the control group received standard lifestyle advice., Main Outcomes and Measures: Cost, health benefits, and incremental cost-effectiveness ratios (ICERs) were estimated from multipayer (including direct medical costs) and societal (including direct medical and nonmedical costs) perspectives. Costs and ICERs were reported in 2019 Indian rupees (INR) and purchasing power parity-adjusted international dollars (INT $)., Results: The mean (SD) age of the 578 participants was 44.4 (9.3) years, and 364 (63.2%) were men. Mean (SD) body mass index was 27.9 (3.7), and the mean (SD) glycated hemoglobin level was 6.0% (0.5). Implementing lifestyle modification and metformin was associated with INR 10 549 (95% CI, INR 10 134-10 964) (INT $803 [95% CI, INT $771-834]) higher direct costs; INR 5194 (95% CI, INR 3187-INR 7201) (INT $395; 95% CI, INT $65-147) higher direct nonmedical costs, an absolute diabetes risk reduction of 10.2% (95% CI, 1.9% to 18.5%), and an incremental gain of 0.099 (95% CI, 0.018 to 0.179) quality-adjusted life-years per participant. From a multipayer perspective (including screening costs), mean ICERs were INR 1912 (INT $145) per 1 percentage point diabetes risk reduction, INR 191 090 (INT $14 539) per diabetes case prevented and/or delayed, and INR 196 960 (INT $14 986) per quality-adjusted life-year gained. In the scenario of a 50% increase or decrease in screening and intervention costs, the mean ICERs varied from INR 855 (INT $65) to INR 2968 (INT $226) per 1 percentage point diabetes risk reduction, from INR 85 495 (INT $6505) to INR 296 681 (INT $22 574) per diabetes case prevented, and from INR 88 121 (INT $6705) to INR 305 798 (INT $23 267) per quality-adjusted life-year gained., Conclusions and Relevance: The findings of this study suggest that a stepwise approach for diabetes prevention is likely to be cost-effective, even if screening costs for identifying high-risk individuals are added.

South Asians have a high prevalence of type 2 diabetes, even at a lower BMI. This review sets out our perspective and hypothesis on the reasons for this. Emerging data from epidemiological studies indicate that South Asians may have a lower ability to secrete insulin, and thus may have less compensatory reserves when challenged with unhealthy lifestyles. Thus, insulin resistance may not be the primary driver of type 2 diabetes in this population. Furthermore, data also suggest that South Asians, on average, have lower muscle mass, and may have a specific propensity to ectopic hepatic fat accumulation and for intramyocellular fat deposition, which cause further disruption in insulin action. We hypothesise that the high diabetes susceptibility in South Asians is evolutionarily set through dual parallel and/or interacting mechanisms: reduced beta cell function and impaired insulin action owing to low lean mass, which is further accentuated by ectopic fat deposition in the liver and muscle. These areas warrant further research.

Objective: The purpose of this study was to develop and test the feasibility of a culturally tailored Diabetes Prevention Programme (DPP) for US South Asians, a large population with high diabetes risk., Design: The South Asian Health and Prevention Education (SHAPE) study included: (1) focus group discussions with South Asian adults to understand views of lifestyle behaviours and diabetes prevention; (2) modification of the US DPP for South Asians and (3) a pilot, pre-post study to test the feasibility and impact of delivering the culturally tailored programme., Setting: The study was conducted in Atlanta, Georgia, USA. Focus group discussions and intervention classes were held at locations within the community (eg, South Asian restaurants, a public library, university classrooms, a South Asian owned physical therapy studio)., Participants: The focus group discussions (n=17 with 109 individuals) included adults aged 25 years of older who self-identified as South Asian. Groups were stratified by age (25-40 years or older than 40 years) and sex. The SHAPE pilot study included 17 (76.5% male with a mean age of 46.9±12 years) South Asian adults aged 25 years or older with pre-diabetes and body mass index (BMI) >22 kg/m 2 ., Results: Formative data from 17 focus group discussions and a community board guided the modification of the DPP curriculum to reflect cultural food preferences and include tools to leverage social support, create a stronger foundation in exercise and overcome culturally specific barriers. The SHAPE pilot study included 17 South Asian adults with pre-diabetes and BMI >22 kg/m 2 . There were positive changes in participants' weight, waist circumference, blood pressure, plasma lipids, HbA1c and other cardiometabolic markers postintervention and 55% of participants regressed to normoglycaemia., Conclusion: These results provide important information on the barriers faced by US South Asians in participating in 'standard' lifestyle change programs, indicate the feasibility of culturally tailored programmes and show positive impact of a culturally tailored programme for diabetes prevention in the South Asian population., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Aims: To examine the clinical utility of 30-min plasma glucose (30-min-PG) measurement during an oral glucose tolerance (OGTT) in predicting type 2 diabetes (T2DM)., Research Design and Methods: Data from a 3-year, randomized, controlled, primary prevention trial among 548 Asian Indians with prediabetes were analyzed. Participants underwent OGTT with PG measurements at fasting, 30-min, and 2-h at baseline and annually until the end of the study. Multivariable Cox regression models were constructed to calculate the risk of developing diabetes based on 30-min-PG levels. Improvement in prediction performance gained by adding an elevated level of 30-min-PG over prediabetic categories was calculated using the area-under-curve (AUC), net-reclassification (NRI), and integrated discrimination improvement (IDI) statistics., Results: At the end of follow-up, 30.4% of individuals had been diagnosed with T2DM by ADA criteria. Based on the maximally selected log-rank statistics, the optimal 30-min-PG cut point for predicting incident T2DM was >182 mg/dl. Multivariable-adjusted Cox regression models showed an independent association between elevated 30-min-PG (>182 mg/dl) and incident diabetes (hazard ratio (95% CI): 1.85 [1.32, 2.59]; D xy  = 0.353, c-statistic = 0.676). The addition of an elevated 30-min-PG (>182 mg/dl) model significantly improved the prediction of diabetes (Δdeviance: -15.4; ΔAUC: 0.11; NRI continuous : 0.51; IDI: 0.08) compared with IFG model alone) in individuals with prediabetes., Conclusion: In prediabetic individuals, baseline 30-min-PG independently predicted T2DM and significantly improved reclassification and discrimination. Therefore, 30-min-PG should be considered as part of the routine testing in addition to FPG and 2-h-PG for better risk stratification., Competing Interests: Declaration of Competing Interest The authors declared that there is no conflict of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Previous epidemiological studies, largely conducted in high-income countries and cross-sectional, have suggested a relatively strong association between exposure to dichlorodiphenyldichloroethylene (DDE), a metabolite of the pesticide dichlorodiphenyltrichloroethane (DDT), and type 2 diabetes. DDT is widely used in India and the prevalence of type 2 diabetes there is increasing, but the association between these factors has not been explored to date., Objective: The objective was to estimate the association of the p,p' isomer of DDE with incident type 2 diabetes in India., Methods: A nested case-control study was conducted in a representative prospective cohort of adults from two cities in India. Participants were enrolled in 2010-11 (n = 12,271) and followed for annual assessment of chronic diseases including type 2 diabetes. Baseline plasma samples from incident cases of diabetes (n = 193) and sex-city-matched controls (n = 323) were selected for analysis of p,p-DDE. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using conditional logistic regression., Results: At baseline, cases had higher p,p-DDE concentrations: geometric mean (95% CI) 330 (273-399) ng/g lipid compared to 223 (189-262) ng/g lipid among controls. Delhi participants had higher p,p-DDE concentrations: 579 (521-643) ng/g lipid compared to 122 (102-145) ng/g lipid in Chennai. In unadjusted models, being in the highest versus lowest quartile of p,p-DDE was associated with a more than doubling of the odds of diabetes: unadjusted OR (95% CI), 2.30 (1.19, 4.43). However, this effect was no longer significant after adjustment for age: adjusted (95% CI), 0.97 (0.46, 2.06)., Discussion: Results suggest that levels of p,p'-DDE in Delhi are exceptionally high, but we did not observe a significant association between p,p-DDE and incident type 2 diabetes. As this is the first study to evaluate this association in India, more studies are needed to inform our understanding of the association in this context, including potential routes of exposure., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Aims: Type 2 diabetes is a heterogeneous disease and may manifest from multiple disease pathways. We examined insulin secretion and insulin resistance across two ethnicities with particularly high risk for diabetes yet with widely different distributions of weight class., Materials and Methods: In this population-based, cross-sectional study, Pima Indians from Southwestern United States (n = 865) and Asian Indians from Chennai, India (n = 2374) had a 75-g oral glucose tolerance test. We analysed differences in plasma glucose, plasma insulin, insulin resistance (HOMA-IR), and insulin secretion (ΔI 0-30 /ΔG 0-30 ) across categories of body mass index (BMI) and glycemic status per American Diabetes Association criteria., Results: Pima Indians were younger (mean 27.4 ± SD 6.6, Asian: 33.9 ± 6.7 years) and had higher BMI (33.6 ± 8.1, Asian: 25.7 ± 4.9 kg/m 2 ). Among normal weight participants (mean BMI: Pima 22.4 SE 0.2; Asian 22.2 SE 0.06 kg/m 2 ), fasting glucose was higher in Asian Indians (5.2 vs Pima: 4.8 mmol/L, P = .003), adjusted for age and sex. Pima Indians were three times as insulin resistant as Asian Indians (HOMA-IR: 7.7 SE 0.1, Asian: 2.5 SE 0.07), while Asian Indians had three times less insulin secretion (Pima: 2.8 SE 1.0 vs Asian: 0.9 SE 1.0 pmol/mmol), a pattern evident across age, BMI, and glycemic strata., Conclusions: Metabolic differences between Pima and Asian Indians suggest heterogeneous pathways of type 2 diabetes in the early natural history of disease, with emphasis of insulin resistance in Pima Indians and emphasis of poor insulin secretion in Asian Indians., (© 2019 John Wiley & Sons, Ltd.)

Introduction: Strong evidence shows that lifestyle change and weight loss stimulated by counseling improve glycemic control and lower comorbidities for patients with diabetes, but it is unclear whether diet or physical activity counseling for patients with diabetes in ambulatory settings has actually been responsive to this evidence., Methods: Data from the 2005-2015 National Ambulatory Medical Care Surveys were used to assess trends in provider-reported diet or exercise counseling during ambulatory care visits. The data were pooled and multivariate logistic regression models were built, adjusting for patient-, provider-, and practice-level characteristics to examine whether the provision of counseling varied by these characteristics. Data were analyzed from September 2018 to December 2018., Results: There were 42,234 adults with diabetes and 272,094 adults without diabetes. The proportions of patients with provider-reported Type 2 diabetes who received any diet or exercise counseling were no different over time, 30% in 2005 (95% CI=25%, 35%) and 25% in 2015 (95% CI=18%, 31%). Lower proportions of those without diabetes received any counseling, 17% in 2005 (95% CI=14%, 19%) and 15% in 2015 (95% CI=11%, 18%). Adjusted models showed that Hispanic patients had a higher likelihood of receiving diet or exercise counseling, compared with whites (OR=1.38, 95% CI=1.09, 1.75). Those aged 30-49 years were more likely to receive diet or exercise counseling than those aged >75 years (OR=1.51, 95% CI=1.27, 1.80). Compared with rural areas and other providers, visits in a metropolitan area (OR=1.27, 95% CI=1.09, 1.47) or with an advanced practice provider (OR=1.66, 95% CI=1.00, 2.75) had a higher likelihood of any diet or exercise counseling delivery., Conclusions: Less than 30% of Americans with diabetes receive diet or exercise counseling in ambulatory visits, and this proportion has not changed significantly in a decade. Future interventions should focus on addressing this gap in counseling., (Copyright © 2019 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.)

Aims: Guidelines recommend hemoglobin A1c (HbA1c) as a diagnostic test for type 2 diabetes, but its accuracy may differ in certain ethnic groups., Methods: The prevalence of type 2 diabetes by HbA1c, fasting glucose, and 2 h glucose was compared in 3016 participants from Chennai and Delhi, India from the CARRS-2 Study to 757 Indians in the U.S. from the MASALA Study. Type 2 diabetes was defined as fasting glucose ≥ 7.0 mmol/L, 2-h glucose ≥ 11.1 mmol/L, or HbA1c ≥ 6.5%. Isolated HbA1c diabetes was defined as HbA1c ≥ 6.5% with fasting glucose < 7.0 mmol/L and 2 h glucose < 11.1 mmol/L., Results: The age, sex, and BMI adjusted prevalence of diabetes by isolated HbA1c was 2.9% (95% CI: 2.2-4.0), 3.1% (95% CI: 2.3-4.1), and 0.8% (95% CI: 0.4-1.8) in CARRS-Chennai, CARRS-Delhi, and MASALA, respectively. The proportion of diabetes diagnosed by isolated HbA1c was 19.4%, 26.8%, and 10.8% in CARRS-Chennai, CARRS-Delhi, and MASALA respectively. In CARRS-2, individuals with type 2 diabetes by isolated HbA1c milder cardio-metabolic risk than those diagnosed by fasting or 2-h measures., Conclusions: In Asian Indians, the use of HbA1c for type 2 diabetes diagnosis could result in a higher prevalence. HbA1c may identify a subset of individuals with milder glucose intolerance., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Purpose of Review: Overweight and obesity are well-established risk factors for type 2 diabetes. However, a substantial number of individuals develop the disease at underweight or normal weight. In this review, we discuss the epidemiology of type 2 diabetes in non-overweight adults; pose questions about etiology, pathophysiology, diagnosis, and prognosis; and examine implications for prevention and treatment., Recent Findings: In population-based studies, the prevalence of type 2 diabetes ranged from 1.4-10.9%. However, the prevalence of type 2 diabetes in individuals with BMI < 25 kg/m 2 ranged from 1.4-8.8%. In countries from Asia and Africa, the proportion of individuals with diabetes who were underweight or normal weight ranged from 24 to 66%, which is considerably higher than the US proportion of 10%. Impairments in insulin secretion, in utero undernutrition, and epigenetic alterations to the genome may play a role in diabetes development in this subgroup. A substantial number of individuals with type 2 diabetes, particularly those with recent ancestry from Asia or Africa, are underweight or normal weight. Future research should consist of comprehensive studies of the prevalence of type 2 diabetes in non-overweight individuals; studies aimed at understanding gaps in the mechanisms, etiology, and pathophysiology of diabetes development in underweight or normal weight individuals; and trials assessing the effectiveness of interventions in this population.

Objective: Understanding the real-world impacts of lifestyle modification (LSM) for diabetes prevention is imperative to inform resource allocation. The purpose of this study was to synthetize global evidence on the impact of LSM strategies on diabetes incidence and risk factors in one parsimonious model., Research Design and Methods: PubMed, Embase, Cochrane Library, and ClinicalTrials.gov were searched for studies published between January 1990 and April 2015. Effectiveness/translation studies of any design testing LSM strategies, targeting high-risk populations (with prediabetes or diabetes risk factors), and reporting diabetes incidence, weight, or glucose outcomes were included. We extracted number of diabetes cases/incidence rates and mean changes in weight (kg), fasting blood glucose (FBG, mmol/L), 2-h postload glucose (mmol/L), and hemoglobin A 1c (%). Pairwise random-effects and frequentist random-effects network meta-analyses were used to obtain pooled effects., Results: Sixty-three studies were pooled in the meta-analysis ( n = 17,272, mean age 49.7 years, 28.8% male, 60.8% white/European). In analyses restricted to controlled studies ( n = 7), diabetes cumulative incidence was 9% among intervention participants and 12% among control participants (absolute risk reduction 3%; relative risk 0.71 [95% CI 0.58, 0.88]). In analyses combining controlled and uncontrolled studies ( n = 14), participants receiving group education by health care professionals had 33% lower diabetes odds than control participants (odds ratio 0.67 [0.49, 0.92]). Intervention participants lost 1.5 kg more weight [-2.2, -0.8] and achieved a 0.09 mmol/L greater FBG decrease [-0.15, -0.03] than control participants. Every additional kilogram lost by participants was associated with 43% lower diabetes odds (β = 0.57 [0.41, 0.78])., Conclusions: Real-world LSM strategies can reduce diabetes risk, even with small weight reductions., (© 2018 by the American Diabetes Association.)

Background: Vitamin D deficiency (VDD) is a condition that has been associated with diabetic retinopathy (DR) in various populations, but has not been studied in Asian Indians., Aims: To evaluate the association of serum 25-hydroxyvitamin D (25(OH)D) levels with presence and severity of DR among Asian Indians with type 2 diabetes., Methods: We collected information on individuals with type 2 diabetes that received care at a tertiary diabetes centre in India, between 2012 and 2015. Patients were 18 years of age or older, underwent retinal examinations with DR severity grading and had serum 25(OH)D measurements., Results: Serum 25(OH)D levels were lower in patients with retinopathy compared to those without (11.9 ± 2.2 ng/ml vs. 13.7 ± 2.1 ng/ml, p < 0.001). Stratifying patients by DR grade, reduced geometric means of 25(OH)D levels were associated with increased retinopathy severity. After adjusting for six key covariates, VDD was associated with increased rates of proliferative DR (OR 2.05; 95% CI 1.35-3.11; p = 0.001)., Conclusions: In Asian Indians with type 2 diabetes, lower serum 25(OH)D was associated with increased severity of DR and the presence of VDD was associated with a two-fold increased risk for proliferative DR., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background and Objectives: To determine how frequently diabetic diets are recommended to individuals with diabetes in South Asia, whether they are followed, and if they are associated with healthier dietary choices and clinical benefits., Methods and Study Design: Data are from the Centre for cArdiometabolic Risk Reduction in South-Asia Cohort Study. Participants with self-reported physician-diagnosed diabetes (n=1849) were divided into four groups based on whether they reported being prescribed and/or were following a diabetic diet. Linear regression was used to estimate associations between these groups and outcomes., Results: 53% of participants with self-reported diabetes reported not being prescribed or following a diabetic diet. Among those prescribed and following a diet, mean whole grain consumption was 1.18 times/day and refined grain consumption was 0.75 times/day compared to 0.88 times/day and 1.74 times/day, respectively, among those neither prescribed nor following a diet (both p<0.0001). Following a diet despite not being prescribed a diet was not associated with glycemic control, blood pressure, or body mass index, but was associated with a -8.54 mg/dL (95% confidence interval: -15.5, -1.58) lower low-density lipoprotein cholesterol compared to not following and not being prescribed a diet after adjustment for confounders., Conclusion: Though participants who were prescribed diabetic diets and followed them exhibited healthier dietary choices, the majority of participants with diabetes in urban South Asia was neither prescribed nor followed such diets. Moreover, there was no statistically significant clinical benefit, thus indicating that current dietary modifications may not be large enough or consistent enough to produce meaningful changes in health outcomes in this population.

Importance: Diabetes prevention is imperative to slow worldwide growth of diabetes-related morbidity and mortality. Yet the long-term efficacy of prevention strategies remains unknown., Objective: To estimate aggregate long-term effects of different diabetes prevention strategies on diabetes incidence., Data Sources: Systematic searches of MEDLINE, EMBASE, Cochrane Library, and Web of Science databases. The initial search was conducted on January 14, 2014, and was updated on February 20, 2015. Search terms included prediabetes, primary prevention, and risk reduction., Study Selection: Eligible randomized clinical trials evaluated lifestyle modification (LSM) and medication interventions (>6 months) for diabetes prevention in adults (age ≥18 years) at risk for diabetes, reporting between-group differences in diabetes incidence, published between January 1, 1990, and January 1, 2015. Studies testing alternative therapies and bariatric surgery, as well as those involving participants with gestational diabetes, type 1 or 2 diabetes, and metabolic syndrome, were excluded., Data Extraction and Synthesis: Reviewers extracted the number of diabetes cases at the end of active intervention in treatment and control groups. Random-effects meta-analyses were used to obtain pooled relative risks (RRs), and reported incidence rates were used to compute pooled risk differences (RDs)., Main Outcomes and Measures: The main outcome was aggregate RRs of diabetes in treatment vs control participants. Treatment subtypes (ie, LSM components, medication classes) were stratified. To estimate sustainability, post-washout and follow-up RRs for medications and LSM interventions, respectively, were examined., Results: Forty-three studies were included and pooled in meta-analysis (49 029 participants; mean [SD] age, 57.3 [8.7] years; 48.0% [n = 23 549] men): 19 tested medications; 19 evaluated LSM, and 5 tested combined medications and LSM. At the end of the active intervention (range, 0.5-6.3 years), LSM was associated with an RR reduction of 39% (RR, 0.61; 95% CI, 0.54-0.68), and medications were associated with an RR reduction of 36% (RR, 0.64; 95% CI, 0.54-0.76). The observed RD for LSM and medication studies was 4.0 (95% CI, 1.8-6.3) cases per 100 person-years or a number-needed-to-treat of 25. At the end of the washout or follow-up periods, LSM studies (mean follow-up, 7.2 years; range, 5.7-9.4 years) achieved an RR reduction of 28% (RR, 0.72; 95% CI, 0.60-0.86); medication studies (mean follow-up, 17 weeks; range, 2-52 weeks) showed no sustained RR reduction (RR, 0.95; 95% CI, 0.79-1.14)., Conclusions and Relevance: In adults at risk for diabetes, LSM and medications (weight loss and insulin-sensitizing agents) successfully reduced diabetes incidence. Medication effects were short lived. The LSM interventions were sustained for several years; however, their effects declined with time, suggesting that interventions to preserve effects are needed.

Introduction: Depression and diabetes are highly prevalent worldwide and often co-exist, worsening outcomes for each condition. Barriers to diagnosis and treatment are exacerbated in low and middle-income countries with limited health infrastructure and access to mental health treatment. The INtegrating DEPrEssioN and Diabetes treatmENT (INDEPENDENT) study tests the sustained effectiveness and cost-effectiveness of a multi-component care model for individuals with poorly-controlled diabetes and depression in diabetes clinics in India., Materials and Methods: Adults with diabetes, depressive symptoms (Patient Health Questionnaire-9 score≥10), and ≥1 poorly-controlled cardiometabolic indicator (either HbA1c≥8.0%, SBP≥140mmHg, and/or LDL≥130mg/dl) were enrolled and randomized to the intervention or usual care. The intervention combined collaborative care, decision-support, and population health management. The primary outcome is the between-arm difference in the proportion of participants achieving combined depression response (≥50% reduction in Symptom Checklist score from baseline) AND one or more of: ≥0.5% reduction in HbA1c, ≥5mmHg reduction in SBP, or ≥10mg/dl reduction in LDL-c at 24months (12-month intervention; 12-month observational follow-up). Other outcomes include control of individual parameters, patient-centered measures (i.e. treatment satisfaction), and cost-effectiveness., Results: The study trained seven care coordinators. Participant recruitment is complete - 940 adults were screened, with 483 eligible, and 404 randomized (196 to intervention; 208 to usual care). Randomization was balanced across clinic sites., Conclusions: The INDEPENDENT model aims to increase access to mental health care and improve depression and cardiometabolic disease outcomes among complex patients with diabetes by leveraging the care provided in diabetes clinics in India (clinicaltrials.gov number: NCT02022111)., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Aims: To compare the clinical profile and complications between younger and older onset type 2 diabetes (T2DM) patients at a tertiary care diabetes center in south India., Methods: We compared individuals with T2DM detected at age ≤25years (n=267) and at age≥50years (n=267), matched for gender and duration of diabetes. We reviewed electronic patient charts and extracted data on biochemical parameters (plasma glucose, serum lipids and glycated hemoglobin). We estimated prevalence of complications (retinopathy, nephropathy, neuropathy, and peripheral vascular disease). We examined odds of having each complication, after adjusting for clinical differences between younger- and older-onset T2DM., Results: Individuals with younger-onset T2DM had significantly greater glycated hemoglobin (8.7 vs. 7.5%), serum cholesterol (160 vs. 148mg/dl), serum triglycerides (147 vs. 128mg/dl), LDL cholesterol (92 vs. 82mg/dl) and lower HDL cholesterol levels (39 vs. 42mg/dl). However, waist circumference (90.4 vs. 92.6cm) and systolic blood pressure (125 vs. 133mmHg) were significantly higher in older onset T2DM. Prevalence of retinopathy (47.6 vs. 31.0%) was higher in younger onset T2DM while neuropathy (41.8 vs. 9.2%) and peripheral vascular disease (6.2 vs. 1.2%) were higher in older onset T2DM. In multiple logistic regression analysis, after adjusting for glycated hemoglobin, hypertension, and hypercholesterolemia, younger onset T2DM had a higher odds of developing retinopathy [Odds Ratio: 2.19; Confidence Intervals: 1.42-3.38] when compared to older onset T2DM., Conclusions: Younger onset T2DM patients have worse glycemic and lipid control, and higher prevalence of retinopathy compared to older onset T2DM patients. This underscores the need for more aggressive metabolic control in young-onset T2DM., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Aims: To test the hypothesis that a 50-g oral glucose challenge test with 1-h glucose measurement would have superior performance compared with other opportunistic screening methods., Methods: In this prospective study in a Veterans Health Administration primary care clinic, the following test performances, measured by area under receiver-operating characteristic curves, were compared: 50-g oral glucose challenge test; random glucose; and HbA 1c level, using a 75-g oral glucose tolerance test as the 'gold standard'., Results: The study population was comprised of 1535 people (mean age 56 years, BMI 30.3 kg/m 2 , 94% men, 74% black). By oral glucose tolerance test criteria, diabetes was present in 10% and high-risk prediabetes was present in 22% of participants. The plasma glucose challenge test provided area under receiver-operating characteristic curves of 0.85 (95% CI 0.78-0.91) to detect diabetes and 0.76 (95% CI 0.72-0.80) to detect high-risk dysglycaemia (diabetes or high-risk prediabetes), while area under receiver-operating characteristic curves for the capillary glucose challenge test were 0.82 (95% CI 0.75-0.89) and 0.73 (95% CI 0.69-0.77) for diabetes and high-risk dysglycaemia, respectively. Random glucose performed less well [plasma: 0.76 (95% CI 0.69-0.82) and 0.66 (95% CI 0.62-0.71), respectively; capillary: 0.72 (95% CI 0.65-0.80) and 0.64 (95% CI 0.59-0.68), respectively], and HbA 1c performed even less well [0.67 (95% CI 0.57-0.76) and 0.63 (95% CI 0.58-0.68), respectively]. The cost of identifying one case of high-risk dysglycaemia with a plasma glucose challenge test would be $42 from a Veterans Health Administration perspective, and $55 from a US Medicare perspective., Conclusions: Glucose challenge test screening, followed, if abnormal, by an oral glucose tolerance test, would be convenient and more accurate than other opportunistic tests. Use of glucose challenge test screening could improve management by permitting earlier therapy., (© 2016 Diabetes UK.)

Aims: Traditionally, fasting and 2-hour post challenge plasma glucose have been used to diagnose diabetes. However, evidence indicates that clinically relevant pathophysiological information can be obtained by adding intermediate time-points to a standard oral glucose tolerance test (OGTT)., Methods: We studied a population-based sample of 3666 Asian Indians without diabetes from the CARRS-Chennai Study, India. Participants underwent a three-point (fasting, 30-min, and 2-h) OGTT at baseline. Patterns of glycemic response during OGTT were identified using latent class mixed-effects models. After a median follow-up of two years, participants had a second OGTT. Logistic regression adjusted for diabetes risk factors was used to compare risk of incident diabetes among participants in different latent classes., Results: We identified four latent classes with different glucose patterns (Classes 1-4). Glucose values for Classes 1, 2, and 4 ranked consistently at all three time-points, but at gradually higher levels. However, Class 3 represented a distinct pattern, characterized by high 30-min (30minPG), normal fasting (FPG) and 2-h (2hPG) plasma glucose, moderately high insulin sensitivity, and low acute insulin response. Approximately 22% of participants were categorized as Class 3, and had a 10-fold risk of diabetes compared to the group with the most favorable glucose response, despite 92.5% of Class 3 participants having normal glucose tolerance (NGT) at baseline., Conclusions: Elevated 30minPG is associated with high risk of incident diabetes, even in individuals classified as NGT by a traditional OGTT. Assessing 30minPG may identify a subgroup of high-risk individuals who remained unidentified by traditional measures., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: There is little data on the incidence of diabetes complications in young onset type 1 diabetes (T1DM) and type 2 diabetes (T2DM) in non European populations., Methods: From a tertiary diabetes centre, Chennai, India, we recruited 108 T1DM (defined by abrupt onset of symptoms or diabetic ketoacidosis, absent insulin reserve requiring insulin treatment) and 90 T2DM participants (defined by absence of ketosis, good beta-cell reserve, and good response to oral agents) who were diagnosed between the ages of 10 and 25years, and without any evidence of diabetes complications at diagnosis. We estimated the incidence of various complications (median follow up of five years); retinopathy was defined by presence of at least one definite microaneurysm by retinal photography, nephropathy by urinary albumin excretion ⩾30μg/mg of creatinine, neuropathy by vibration perception threshold ⩾20V on biothesiometry, peripheral vascular disease by an ankle-brachial index <0.9, and ischemic heart disease (IHD) by history of myocardial infarction or coronary revascularization or Q waves on ECG or on drug treatment for IHD., Results: The mean ages at diagnosis of T1DM and T2DM participants were 17.1±4.2vs. 21.6±3.6years respectively. The incidence of various complications reported in numbers/1000 person years of follow up of T1DM and T2DM were: retinopathy 77.4vs. 78.0/1000 person years, nephropathy, 62.0vs. 58.8, neuropathy 7.8 vs. 13.9 and ischemic heart disease 1.2vs. 5.4. In Cox regression analysis, after adjustment for age, glycated hemoglobin, systolic blood pressure and serum cholesterol, T2DM participants had 2.11 times (95%CI: 1.27-3.51) higher risk of developing any diabetes complication, compared to T1DM., Conclusions: Young-onset T2DM have a more aggressive disease course than T1DM., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Aim: To describe recruitment challenges in a randomized controlled translational trial (RCTT) of diabetes prevention in India., Methods: The Diabetes Community Lifestyle Improvement Program (D-CLIP) is a RCTT, comparing standard of care to a step-wise model of diabetes prevention. Overweight adults with prediabetes were identified through a two-step screening process (1) field-based screening: minimal testing with a random capillary glucose measurement and (2) clinic-based screening including an Oral Glucose Tolerance Test (OGTT)., Results: Individuals from the community (n=19377) were screened at residential locations, offices, educational institutions, places of worship, parks and beaches. Of these, 3535 (18.2%) 'high-risk' participants based on capillary glucose values were eligible for step 2 screening with OGTT. However, only 21.5% participated. An additional 521 participants directly entered step 2 via direct referrals from our clinical/research databases, study participant referrals and targeted advertisements. Of the 1285 individuals who underwent an OGTT, 710 (55.3%) were eligible for randomization, and 602 (84.8%) were randomized into the trial. The ratio of participants entering from step 1 to step 2 was 25:1 (3.9%) and from step 2 to randomization 2:1 (47%). Average staff time for recruitment was 350 h per week for an 11-person team., Conclusions: Nearly 55 people needed to be screened with a questionnaire plus capillary glucose test to randomize one participant with prediabetes. Using a 2-step strategy requires additional staff time, but considerably reduces the need for OGTT's, thereby minimizing participant burden and study costs., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)