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Background: Cardiovascular outcome trials have shown cardiovascular benefit with sodium-glucose co-transporter-2 (SGLT2) inhibitors in patients with type 2 diabetes, whereas dipeptidyl peptidase-4 (DPP-4) inhibitors have not shown an effect. We aimed to address knowledge gaps regarding the comparative effectiveness of SGLT2 inhibitor use in clinical practice (with DPP-4 inhibitor use as an active comparator) across a range of cardiovascular risks and in diverse geographical settings. Methods: In this comparative cohort study, we used data from clinical practice from 13 countries in the Asia-Pacific, Middle East, European, and North American regions to assess the risk of cardiovascular events and death in adult patients with type 2 diabetes newly initiated on SGLT2 inhibitors compared with those newly initiated on DPP-4 inhibitors. De-identified health records were used to select patients who were initiated on these drug classes between Dec 1, 2012, and May 1, 2016, with follow-up until Dec 31, 2014, to Nov 30, 2017 (full range; dates varied by country). Non-parsimonious propensity scores for SGLT2 inhibitor initiation were developed for each country and patients who were initiated on an SGLT2 inhibitor were matched with those who were initiated on a DPP-4 inhibitor in a 1:1 ratio. Outcomes assessed were hospitalisation for heart failure, all-cause death, myocardial infarction, and stroke. Hazard ratios (HRs) were estimated by country and then pooled in a weighted meta-analysis. Findings: Following propensity score matching, 193 124 new users of SGLT2 inhibitors and 193 124 new users of DPP-4 inhibitors were included in the study population. Participants had a mean age of 58 years (SD 12·2), 170 335 (44·1%) of 386 248 were women, and 111 933 (30·1%) of 372 262 had established cardiovascular disease. Initiation of an SGLT2 inhibitor versus a DPP-4 inhibitor was associated with substantially lower risks of hospitalisation for heart failure (HR 0·69, 95% CI 0·61–0·77; p

The common Arctic-specific LDLR p.G137S variant was recently shown to be associated with elevated lipid levels. Motivated by this, we aimed to investigate the effect of p.G137S on metabolic health and cardiovascular disease risk among Greenlanders to quantify its impact on the population. In a population-based Greenlandic cohort (n = 5,063), we tested for associations between the p.G137S variant and metabolic health traits as well as cardiovascular disease risk based on registry data. In addition, we explored the variant's impact on plasma NMR measured lipoprotein concentration and composition in another Greenlandic cohort (n = 1,629); 29.5% of the individuals in the cohort carried at least one copy of the p.G137S risk allele. Furthermore, 25.4% of the heterozygous and 54.7% of the homozygous carriers had high levels (>4.9 mmol/L) of serum LDL cholesterol, which is above the diagnostic level for familial hypercholesterolemia (FH). Moreover, p.G137S was associated with an overall atherosclerotic lipid profile, and increased risk of ischemic heart disease (HR [95% CI], 1.51 [1.18–1.92], p = 0.00096), peripheral artery disease (1.69 [1.01–2.82], p = 0.046), and coronary operations (1.78 [1.21–2.62], p = 0.0035). Due to its high frequency and large effect sizes, p.G137S has a marked population-level impact, increasing the risk of FH and cardiovascular disease for up to 30% of the Greenlandic population. Thus, p.G137S is a potential marker for early intervention in Arctic populations.

AIMS: To examine the association between birth weight and glucose intolerance in adult Greenlandic Inuit.METHODS: We examined 1429 participants aged 18-56 years from two population-based, cross-sectional studies in Greenland with information on birth weight. Oral glucose tolerance tests, anthropometric measures and ultrasound of abdominal tissue were performed. Associations of birth weight with glucose markers were analysed using linear or logistic regressions. Spline analyses were conducted to examine u-shaped associations. Adjustments were done for age, sex, birth place, family history of diabetes, genetic admixture, TBC1D4 p.Arg684Ter carrier status, BMI and visceral adipose tissue.RESULTS: The median birthweight was 3300 g and 3.9% had type 2 diabetes, T2DM. Spline analyses indicated overall linear associations. In fully adjusted analyses, an increase in birth weight of 1 kg was associated with a change in fasting plasma glucose of -0.06 mmol/L (95%CI: -0.11, -0.01), 2-h plasma glucose of -0.16 mmol/L (95%CI: -0.35, 0.02), HOMA-IR of -5.45% (95%CI: -10.34, -0.29), insulin sensitivity index of 7.04% (95%CI: 1.88, 12.45) and a trend towards a reduced risk of hyperglycaemia and T2DM, although statistically insignificant.CONCLUSIONS: Birth weight was inversely associated with hepatic and peripheral insulin resistance independently of adult adiposity. Thus, the findings support low birth weight as a contributing factor for glucose intolerance in adult Inuit in Greenland.

Aims To examine the incidence rates of any and referable diabetic retinopathy (DR) among migrants in Denmark. Methods Nationwide clinical data on diabetes patients followed since 2005 were analysed. Patients were classified according to country of origin into six groups: Denmark, other Europe, Sub Saharan Africa, Middle East/North Africa, Asia, and America/Oceania. A total of 93,780 or 110,897 patients without any (including unspecific diagnoses) or referable (proliferative) DR at baseline were analyzed. We estimated event rates and hazard ratios (HRs) for incidence of any and referable DR according to country of origin. Results After an average follow-up of 3.59 years 6727 had incident any DR and 4747 patients had referable DR. Compared to people of Danish origin, migrants from the Middle East/North Africa and Asia had a higher risk of any and referable DR after adjustment for age, sex, body mass index, smoking status, types and duration of diabetes, clinic type (general practice vs outpatient clinic), HbA1c, blood pressure and lipid levels. The associations remained significant after further adjustment for frequency of eye screening. Conclusions Migrants from the Middle East/North Africa and Asia were at increased risk of developing any and referable DR compared to native Danes, and these differences were not fully explained by differences in underlying clinical, diabetic and cardiometabolic risk factors.

SUMMARY The Inuit ancestors of the Greenlandic people arrived in Greenland close to 1,000 years ago.1 Since then, Europeans from many different countries have been present in Greenland. Consequently, the present-day Greenlandic population has ~25% of its genetic ancestry from Europe.2 In this study, we investigated to what extent different European countries have contributed to this genetic ancestry. We combined dense SNP chip data from 3,972 Greenlanders and 8,275 Europeans from 14 countries and inferred the ancestry contribution from each of these 14 countries using haplotype-based methods. Due to the rapid increase in population size in Greenland over the past ~100 years, we hypothesized that earlier European interactions, such as pre-colonial Dutch whalers and early German and Danish-Norwegian missionaries, as well as the later Danish colonists and post-colonial immigrants, all contributed European genetic ancestry. However, we found that the European ancestry is almost entirely Danish and that a substantial fraction is from admixture that took place within the last few generations., In brief The Greenlandic Inuit have had extensive historical contact with Europeans, and the present-day Greenlandic population has substantial amounts of European ancestry. Waples et al. use genetic data to investigate the origin of this ancestry. They show that much of it is Danish and find little evidence of it being from pre-colonial European contact.

Aim Diabetic foot ulcer (DFU) is a serious complication to diabetes. The aim was to study the incidence of first DFU among patients with type 1 (T1DM) and type 2 diabetes (T2DM), stratified according to etiology: neuropathic, neuro-ischemic or ischemic, over a period of 14 years (2001–2014). Methods DFU incidence rates were calculated from electronic patient record data from patients with T1DM and complicated T2DM from a large specialized diabetes hospital with a multidisciplinary foot clinic in Denmark. Poisson regression was used to model incidence of first DFU according to calendar year, diabetes type and etiology. Results Among 5640 patients with T1DM 255 developed a DFU, corresponding to an incidence of 5.8 (95% confidence interval (95%CI) 5.1–6.5) per 1000 patient years; this incidence dropped from 8.1 (95%CI 5.4–11.9) per 1000 patient years in 2002 to 2.6 (95%CI 1.3–5.3) in 2014 (p = 0.0059). Among 6953 patients with T2DM 310 developed a DFU, corresponding to an incidence of 11.3 (95%CI 10.1–12.6) per 1000 patient years; this incidence dropped from 17.0 (95%CI 12.2–23.8) per 1000 patient years in 2002 to 8.7 (95%CI 5.3–14.1) per 1000 patient year (p = 0.0260) in 2014. Conclusion The incidence of DFU has decreased substantially in T1DM as well as in T2DM. This change was driven by a decrease in incidence of neuropathic ulcers.

AIMS: Vitamin B12 deficiency could be associated with cardiovascular autonomic neuropathy (CAN) in diabetes patients. We aim to investigate the association between serum levels of vitamin B12 and CAN in type 2 diabetes patients.METHODS: 469 ambulatory type 2 diabetes patients (mean diabetes duration 10.0years (IQR 5.0;17.0), mean age 59.0years (SD 11.6), 63% men, mean B12 289.0pmol/l (IQR 217;390)) were screened for CAN using three cardiovascular reflex tests, five minute resting heart rate (5min RHR) and heart rate variability indices.RESULTS: Serum levels of vitamin B12 were significantly lower in patients treated with metformin and/or proton pump inhibitors (PPIs) compared with patients not treated (pCONCLUSION: Vitamin B12 may be inversely associated with CAN in patients with type 2 diabetes. Confirmatory studies investigating a causal role of vitamin B12 for the development of diabetic CAN are warranted.

Objective Studies of diabetes in migrant populations have shown a higher prevalence compared to their respective countries of origin and to people natively born in the host country, but there is little population-based data on diabetes incidence and mortality in migrant populations. The aim of the current study was (1) to describe the incidence rates and prevalence of diabetes among first generation migrants in Denmark compared to the Danish background population, and (2) to compare standardised mortality rates (SMRs) for individuals with and without diabetes according to country of origin. Research design and methods Information was obtained from linkage of the National Diabetes Register with mortality statistics and information from the Central Personal Register on country of origin. Age- and sex-specific estimates of prevalence, incidence rates, mortality rates and SMRs relative to the part of the population without diabetes were calculated based on follow up of the entire Danish population. Results Compared with native born Danes, the incidence of diabetes was about 2.5 times higher among migrants from Africa, Asia, and the Middle East, and these migrant groups also showed significantly higher prevalence. The standardised mortality rates (SMR) were higher particularly above 50 years of age among most migrant groups compared with native born Danes, and with a higher annual increase. Conclusions The highest diabetes incidence rates and prevalence estimates were observed among migrants from Africa, Asia, and the Middle East, and the annual increase in SMRs was higher in these groups compared to native born Danes. © 2016 Elsevier Ireland Ltd

SummaryMetabolic dysregulation in multiple tissues alters glucose homeostasis and influences risk for type 2 diabetes (T2D). To identify pathways and tissues influencing T2D-relevant glycemic traits (fasting glucose [FG], fasting insulin [FI], two-hour glucose [2hGlu] and glycated hemoglobin [HbA1c]), we investigated associations of exome-array variants in up to 144,060 individuals without diabetes of multiple ancestries. Single-variant analyses identified novel associations at 21 coding variants in 18 novel loci, whilst gene-based tests revealed signals at two genes, TF (HbA1c) and G6PC (FG, FI). Pathway and tissue enrichment analyses of trait-associated transcripts confirmed the importance of liver and kidney for FI and pancreatic islets for FG regulation, implicated adipose tissue in FI and the gut in 2hGlu, and suggested a role for the non-endocrine pancreas in glucose homeostasis. Functional studies demonstrated that a novel FG/FI association at the liver-enriched G6PC transcript was driven by multiple rare loss-of-function variants. The FG/HbA1c-associated, islet-specific G6PC2 transcript also contained multiple rare functional variants, including two alleles within the same codon with divergent effects on glucose levels. Our findings highlight the value of integrating genomic and functional data to maximize biological inference.Highlights23 novel coding variant associations (single-point and gene-based) for glycemic traits51 effector transcripts highlighted different pathway/tissue signatures for each traitThe exocrine pancreas and gut influence fasting and 2h glucose, respectivelyMultiple variants in liver-enriched G6PC and islet-specific G6PC2 influence glycemia

Introduction The lifestyle of Inuit in Greenland and worldwide is undergoing a transition from a fisher-hunter to a westernized society and meanwhile the prevalence of type-2 diabetes (T2D) has increased dramatically. Studies have shown that a common nonsense p.Arg684Ter variant in TBC1D4, which is frequent in Greenland, confers genetic susceptibility towards high risk of T2D. The aim of the study is to investigate whether a traditional marine diet, with high fat and low carbohydrate, will improve glycemic control in Greenland Inuit compared to a western diet. Moreover, we want to examine if the response is more pronounced in carriers of the p.Arg684Ter variant. Materials and methods We will conduct a randomized, clinical cross-over trial with two dietary intervention periods of four weeks duration. The diet intervention comprise provision of >20E% and instruction for the remaining part of the diet. We expect to include 30 homozygous carriers and 30 homozygous non-carriers of the p.Arg684Ter variant, aged 18–80 years, across three Greenlandic towns. The primary outcome is plasma (p)-glucose 2 h post an oral glucose tolerance test and we aim to have 80% power, at α = 0.05, to detect a difference of 1.1 mmol/L. We will also include supporting measures of glucose homeostasis, assess other markers of the metabolic syndrome and perform metabolome and microbiome profiling. The statistical analysis will be performed as complete case analyses using linear mixed models. Ethics and dissemination The study received approval by the Ethics Committee of Greenland (KVUG 2018-26) and will be disseminated via international peer-reviewed journal articles and conferences. Trial registration number Clinicaltrials.gov identifier no. NCT04011904., Strengths and limitations of this study • This study is the first dietary intervention study targeting a gene polymorphism with very high effect on T2D risk. • The study design ensure high statistical power for a genetically heterogeneous indigenous population. • Extensive clinical phenotyping including multiple measurements of glucose metabolism. • The traditional diet only reflect the current traditional diet to some extent and thus, not in perfect coherence to the original Inuit diet. • Compliance might be affected by not providing the full diet to the participants.

Objective Weight loss is important for prevention of type 2 diabetes and an accurate self-perceived body image can promote weight reduction. We evaluated the association of self-perceived body image with body mass index (BMI) and type 2 diabetes. Methods Data from the Danish ADDITION-PRO cohort study (2009–2011) were used. A total of 2082 men and women attended a health examination including assessment of BMI, waist circumference, the Stunkard scale of self-perceived obesity and an oral glucose tolerance test for assessment of diabetes risk. Results Mean (SD) age was 66.2 (6.9) years and 24% were obese (BMI ≥ 30 kg/m 2 ). However, only 7% of obese men and 11% of obese women perceived themselves as obese. Among obese women, for a given level of BMI and waist circumference, one unit higher self-perceived body image was associated with 52% (95% CI: 14–73) lower risk of having type 2 diabetes and 45% (95% CI: 12–65) lower risk of having pre-diabetes. Overweight, but not obese, men had a 35% (95% CI: 36–56) lower risk of type 2 diabetes per unit increase in body image. Conclusions Obese individuals seem to underestimate their body shape. However, having a realistic body image (higher self-perceived obesity) is independently associated with lower diabetes risk. Self-perceived body image might serve as a valuable tool for type 2 diabetes risk assessment.

OBJECTIVES: Traditional foods of the Greenlandic Inuit are mainly fish and marine mammals. Hence, the high fat content and unique dietary fatty acid (FA) profile may affect circulating FA profiles. Moreover, it is shown that the rs80356779 variant of the carnitine palmitoyl-transferase 1A (CPT1A) gene, involved in FA transportation, underwent positive selection in Inuit ancestors. The variant is associated with circulating FA profiles in Inuit, and selection may be a result of diet adaptation. While the variant may modify the dietary effect on FA metabolism, the gene-diet interaction has not been tested. Therefore, we aimed to assess if an interaction exists between the CPT1A variant and intake of traditional diet on erythrocyte membrane levels of very-long-chain n-3 PUFAs and the FAs previously found to be associated with the variant in Greenlandic Inuit. METHODS: We included 3005 individuals (mean age = 45 years) living in Greenland, who were genotyped and had erythrocyte membranes measured for the content of 40 FA. Food intake was estimated from a 68-item semi-quantitative food-frequency questionnaire. Consumption of 25 food items typical of the traditional diet was expressed as percentage of total energy intake. Linear mixed models were fitted, regressing a normalized FA variable on genotype, the Inuit diet variable, and their cross-product term, adjusting for population structure, relatedness, age, and sex. P-values were corrected by genomic control. Subsequent QQ-plots based on genome wide markers showed no indication of confounding. RESULTS: Sixty % of participants were homozygous for the derived CPT1A allele; 33% were heterozygous. Median % (interquartile range) of energy from traditional diet was 17% (8.8–30.5%). Of the 10 FAs that CPT1A had a main effect on (P

Background Exposure to persistent organic pollutants (POPs) is of concern in Arctic populations since these contaminants accumulate in fish and marine mammals, which is an important part of the traditional diet of these populations. Epidemiological and experimental studies have reported significant associations between POPs and increased blood pressure (BP) in populations with different degrees of exposure. Objective We aimed to assess the risk of hypertension related to increasing levels of polychlorinated biphenyls (PCBs) and organochlorine (OC) pesticides. Methods Fifteen PCBs and 11 OC pesticides or their metabolites were determined in plasma of 1614 Inuit adults ≥18 years living in 9 towns and 13 villages in Greenland. BP was measured using a standardized protocol. The risk of hypertension was estimated through logistic regression using POPs as continuous variables (log-transformed). Hypertension was defined as systolic BP ≥140 mm Hg, diastolic BP ≥90 mm Hg and/or antihypertensive treatment. Results Overall, the odd ratios (ORs) of hypertension were not statistically significant for dioxin-like PCBs, non-dioxin-like PCBs and OC pesticides after adjusting for confounders. Once the analyses were stratified by age category (18–39 and ≥40 years), increased risk of hypertension was observed for total dioxin-like PCBs among the youngest [OR: 1.34 (95% CI: 1.03–1.74)] while a borderline protective effect was observed for total non-dioxin-like PCBs [OR: 0.81 (95% CI: 0.66–0.99)] among the oldest. Higher risk of hypertension was also associated with increasing p , p ′-dichlorodiphenyltrichloroethane (DDT) concentrations among the youngest [OR: 1.42 (95% CI: 1.08–1.85)]. Conclusion Overall, no significant associations were observed between PCBs, OC pesticides and blood pressure in this highly exposed population although the associations differed by age category.

Elevated blood pressure is a risk factor for cardiovascular disease and may be detected by left ventricular hypertrophy (LVH) in electrocardiogram (ECG). Pre-western Inuit had frequent signs of LVH in ECG predominantly in the 3rd decade while a low occurrence of ischemic heart disease.We evaluated the association between blood pressures and ECG signs of LVH, cardiac auscultation, and symptoms related to heart disease in the recently recovered data from the survey of 1851 Inuit conducted in 1962-1964 in East Greenland.The participation rate was 97%. Among the 812 Inuit aged 18 years or above blood pressure was unaltered until the age of 39 years (systolic, p=76; diastolic, p=0.36) and increased subsequently (both, p0.001). Systolic blood pressure140 mmHg was more frequent when aged40 years (p0.001) and diastolic blood pressure90 mmHg was more common in men (p0.001) and in men and women aged40 years (p0.001). ECG signs of LVH were more frequent in men (p0.01) but the occurrence decreased from the age of 40 years (p0.01), and were not influenced by systolic (p=0.97), diastolic (p=0.87) or pulse pressure (p=0.69).Blood pressure rose only after the age of 40 years in pre-western Inuit. Left ventricular hypertrophy peaked among 30-year olds and was independent of elevated blood pressure. It may be speculated that the common left ventricular hypertrophy was due to marked physical activity that contributed to the low occurrence of ischemic heart disease among pre-western Inuit.

BACKGROUND: The reputed low prevalence of cardiovascular disease among the Inuit has recently been challenged. Studies have shown total cholesterol among the Inuit to differ little from that of western populations and the association between cholesterol and atherosclerosis to be inconsistent.METHODS: We studied serum lipids in a population survey among 2114 Inuit living in Denmark or in West Greenland. Blood tests were supplemented by structured interviews, anthropometry and measurements of blood pressure.FINDINGS: Compared with the general population of Denmark, total cholesterol was higher among Inuit women, while HDL-cholesterol was higher among Inuit men. Triglyceride was lower among Inuit of both sexes. Cholesterol and triglyceride varied according to westernisation, diet, alcohol consumption and smoking. In a multivariate analysis, serum lipids also differed significantly between pure and genetically mixed Inuit: HDL-cholesterol was higher among the genetically pure Inuit, while among men triglyceride was lower and among women total and LDL-cholesterol were higher.INTERPRETATION: Among the Inuit, serum lipids are significantly associated with westernisation and genetic heritage. The effect of westernisation is to some extent due to dietary changes. From a cardiovascular health point of view, westernisation within Greenland is associated with unfavourable lipid changes while migration to Denmark is associated with favourable lipid changes.

The coadsorption of CO 2 and K on Cu(110) has been studied for K coverages in the range 0–2 monolayers. Both physisorbed and reacted states of CO 2 are observed in the thermally programmed desorption spectra when the adsorption takes place at 117 K. Photon irradiation over a broad energy range, 2–1486 eV, gives rise to a photochemical process where physisorbed CO 2 is transformed to chemisorbed CO 2 . The mechanism of the process is generation of secondary electrons that are captured by weakly bounded CO 2 molecules. Afterwards the CO 2 anions decay by dissociation.