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Consumption of traditional foods is decreasing amid a lifestyle transition in Greenland as incidence of type 2 diabetes (T2D) increases. In homozygous carriers of a TBC1D4 variant, conferring postprandial insulin resistance, the risk of T2D is markedly higher. We investigated the effects of traditional marine diets on glucose homoeostasis and cardio-metabolic health in Greenlandic Inuit carriers and non-carriers of the variant in a randomised crossover study consisting of two 4-week dietary interventions: Traditional (marine-based, low-carbohydrate) and Western (high in imported meats and carbohydrates). Oral glucose tolerance test (OGTT, 2-h), 14-d continuous glucose and cardio-metabolic markers were assessed to investigate the effect of diet and genotype. Compared with the Western diet, the Traditional diet reduced mean and maximum daily blood glucose by 0·17 mmol/l (95 % CI 0·05, 0·29; P = 0·006) and 0·26 mmol/l (95 % CI 0·06, 0·46; P = 0·010), respectively, with dose-dependency. Furthermore, it gave rise to a weight loss of 0·5 kg (95 % CI; 0·09, 0·90; P = 0·016) relative to the Western diet and 4 % (95 % CI 1, 9; P = 0·018) lower LDL:HDL-cholesterol, which after adjustment for weight loss appeared to be driven by HDL elevation (0·09 mmol/l (0·03, 0·15), P = 0·006). A diet–gene interaction was indicated on insulin sensitivity in the OGTT (p = 0·093), which reflected a non-significant increase of 1·4 (–0·6, 3·5) mmol/l in carrier 2-h glucose. A Traditional diet marginally improved daily glycaemic control and plasma lipid profile compared with a Westernised diet in Greenlandic Inuit. Possible adverse effects on glucose tolerance in carriers of the TBC1D4 variant warrant further studies.

Background: The genetic disease architecture of Inuit includes a large number of common high-impact variants. Identification of such variants contributes to our understanding of the genetic aetiology of diseases and improves global equity in genomic personalised medicine. We aimed to identify and characterise novel variants in genes associated with Maturity Onset Diabetes of the Young (MODY) in the Greenlandic population. Methods: Using combined data from Greenlandic population cohorts of 4497 individuals, including 448 whole genome sequenced individuals, we screened 14 known MODY genes for previously identified and novel variants. We functionally characterised an identified novel variant and assessed its association with diabetes prevalence and cardiometabolic traits and population impact. Findings: We identified a novel variant in the known MODY gene HNF1A with an allele frequency of 1.9% in the Greenlandic Inuit and absent elsewhere. Functional assays indicate that it prevents normal splicing of the gene. The variant caused lower 30-min insulin (β = −232 pmol/L, βSD = −0.695, P = 4.43 × 10−4) and higher 30-min glucose (β = 1.20 mmol/L, βSD = 0.441, P = 0.0271) during an oral glucose tolerance test. Furthermore, the variant was associated with type 2 diabetes (OR 4.35, P = 7.24 × 10−6) and HbA1c (β = 0.113 HbA1c%, βSD = 0.205, P = 7.84 × 10−3). The variant explained 2.5% of diabetes variance in Greenland. Interpretation: The reported variant has the largest population impact of any previously reported variant within a MODY gene. Together with the recessive TBC1D4 variant, we show that close to 1 in 5 cases of diabetes (18%) in Greenland are associated with high-impact genetic variants compared to 1–3% in large populations. Funding: Novo Nordisk Foundation, Independent Research Fund Denmark, and Karen Elise Jensen's Foundation.

Background: This study aims to examine quality of diabetes care in persons with type 2 diabetes with and without severe mental illness (SMI).Methods: In a nationwide prospective register-based study, we followed persons with type 2 diabetes in Denmark with and without SMI including schizophrenia, bipolar disorder, or major depression. Quality of care was measured as receipt of care (hemoglobin A1c, low-density lipoprotein-cholesterol and urine albumin creatinine ratio assessment and eye and foot screening) and achievement of treatment targets between 2015 and 2019. Quality of care was compared in persons with and without SMI using generalized linear mixed models adjusted for key confounders. Findings: We included 216,537 persons with type 2 diabetes. At entry 16,874 (8%) had SMI. SMI was associated with lower odds of receiving care, with the most pronounced difference in urine albumin creatinine ratio assessment and eye screening (OR: 0.55, 95% CI: 0.53-0.58 and OR: 0.37 95% CI: 0.32-0.42, respectively). Among those with an assessment, we found that SMI was associated with higher achievement of recommended hemoglobin A1c levels and lower achievement of recommended low-density lipoprotein-cholesterol levels. Achievement of recommended low-density lipoprotein-cholesterol levels was similar in persons with versus without schizophrenia. Interpretation: Compared to persons without SMI, persons with SMI were less likely to receive process of care, with the most pronounced differences in urine albumin creatinine ratio assessment and eye screening.Funding: This study was funded by Steno Diabetes Center Copenhagen through an unrestricted grant from Novo Nordisk Foundation.

Aims: To estimate the incidence rates of genital warts (GWs) in women and men with type 1 diabetes compared to persons without diabetes. Methods: In this nationwide registry-based cohort study, we included the entire population aged 15 to 49 years living in Denmark between 1996 and 2016. From national registries, we retrieved individual level information on diabetes status, diagnoses and treatment of GWs, and potential confounding variables. We used Poisson regression to model sex- and age-specific incidence rates of GWs in persons with type 1 diabetes and persons without diabetes. Based on the models, we computed sex-specific incidence rate ratios (IRRs) of GWs in persons with type 1 diabetes compared to persons without diabetes, overall and according to age. Results: The analysis included 3,514,824 persons without type 2 diabetes and no GW diagnoses before baseline. The incidence rate of GWs in persons with type 1 diabetes was higher than in those without diabetes, both among women (IRR = 1.59; 95% CI, 1.42–1.78) and men (IRR = 1.36; 95% CI, 1.25–1.48). The pattern of increased incidence rates of GWs in persons with type 1 diabetes was seen at all ages. Conclusions: Persons with type 1 diabetes have higher incidence rates of GWs than persons without diabetes. This supports the importance of HPV vaccination of young girls and boys with type 1 diabetes.

OBJECTIVE: The global rise in type 2 diabetes is associated with a concomitant increase in diabetic complications. Diabetic polyneuropathy is the most frequent type 2 diabetes complication and is associated with poor outcomes. The metabolic syndrome has emerged as a major risk factor for diabetic polyneuropathy; however, the metabolites associated with the metabolic syndrome that correlate with diabetic polyneuropathy are unknown.METHODS: We conducted a global metabolomics analysis on plasma samples from a subcohort of participants from the Danish arm of Anglo-Danish-Dutch study of Intensive Treatment of Diabetes in Primary Care (ADDITION-Denmark) with and without diabetic polyneuropathy versus lean control participants.RESULTS: Compared to lean controls, type 2 diabetes participants had significantly higher HbA1c (p = 0.0028), BMI (p = 0.0004), and waist circumference (p = 0.0001), but lower total cholesterol (p = 0.0001). Out of 991 total metabolites, we identified 15 plasma metabolites that differed in type 2 diabetes participants by diabetic polyneuropathy status, including metabolites belonging to energy, lipid, and xenobiotic pathways, among others. Additionally, these metabolites correlated with alterations in plasma lipid metabolites in type 2 diabetes participants based on neuropathy status. Further evaluating all plasma lipid metabolites identified a shift in abundance, chain length, and saturation of free fatty acids in type 2 diabetes participants. Importantly, the presence of diabetic polyneuropathy impacted the abundance of plasma complex lipids, including acylcarnitines and sphingolipids.INTERPRETATION: Our explorative study suggests that diabetic polyneuropathy in type 2 diabetes is associated with novel alterations in plasma metabolites related to lipid metabolism.

OBJECTIVE Experiencing adversities in childhood may increase the risk of type 1 diabetes through hyperactivation of the stress response system, but the empirical evidence is conflicting. We aim to describe the age-specific incidence of type 1 diabetes for males and females separately in five predefined groups covering the most common trajectories of adversity among Danish children. RESEARCH DESIGN AND METHODS We included all 1,081,993 children without parental type 1 diabetes born in Denmark from 1980 to 1998. We used register data to estimate age-specific incidence rates of type 1 diabetes in five trajectory groups of adversity characterized by 1) low adversity, 2) early life material deprivation, 3) persistent material deprivation, 4) loss or threat of loss in the family, and 5) cumulative high adversity. All analyses were stratified by sex. RESULTS In total, 5,619 people developed type 1 diabetes before 2016. We found only minor differences when comparing the incidence rates of type 1 diabetes between the trajectory groups. The only clear exceptions were in the high versus low adversity group, in which males had a higher incidence of type 1 diabetes in childhood ( CONCLUSIONS Childhood adversities were generally not associated with age-specific incidence of type 1 diabetes except among those exposed to a very high and increasing annual rate of childhood adversities. Differences between highly exposed males and females seem to depend on age at onset of type 1 diabetes.

Background People with type 1 diabetes often live for many years with different combinations of diabetes-related complications. We aimed to quantify how complication duration and total complication burden affect mortality, using data from national registers. Methods This study included 33 396 individuals with type 1 diabetes, registered in the Swedish National Diabetes Register at any time between 2001 and 2012. Each individual was followed and classified according to their time-updated diabetes-related complication status. The main outcomes were all-cause mortality, cardiovascular (CV) mortality and non-CV mortality. Poisson models were used to estimate the rate of these outcomes as a function of the time-updated complication duration. Results Overall, 1748 of the 33 396 individuals died during 198 872 person-years of follow-up. Overall, the time-updated all-cause mortality rate ratio (MRR) was 2.25 [95% confidence interval (CI): 1.99–2.54] for patients with diabetic kidney disease, 0.98 (0.82–1.18) for patients with retinopathy and 4.00 (3.56–4.50) for patients with cardiovascular disease relative to individuals without complications. The excess rate was highest in the first period after a diagnosis of CVD, with an 8-fold higher mortality rate, and stabilized after some 5 years. After diagnosis of diabetic kidney disease, we observed an increase in all-cause mortality with an MRR of around 2 compared with individuals without diabetic kidney disease, which stabilized after few years. Conclusions In this cohort we show that duration of diabetes-related complications is an important determinant of mortality in type 1 diabetes, for example the MRR associated with CVD is highest in the first period after diagnosis of CVD. A stronger focus on time-updated information and thorough consideration of complication duration may improve risk stratification in routine clinical practice.

BACKGROUND & AIMS: The sucrase-isomaltase (SI) c.273_274delAG loss-of-function variant is common in Arctic populations and causes congenital sucrase-isomaltase deficiency, which is an inability to break down and absorb sucrose and isomaltose. Children with this condition experience gastrointestinal symptoms when dietary sucrose is introduced. We aimed to describe the health of adults with sucrase-isomaltase deficiency.METHODS: The association between c.273_274delAG and phenotypes related to metabolic health was assessed in 2 cohorts of Greenlandic adults (n = 4922 and n = 1629). A sucrase-isomaltase knockout (Sis-KO) mouse model was used to further elucidate the findings.RESULTS: Homozygous carriers of the variant had a markedly healthier metabolic profile than the remaining population, including lower body mass index (β [standard error], -2.0 [0.5] kg/m2; P = 3.1 × 10-5), body weight (-4.8 [1.4] kg; P = 5.1 × 10-4), fat percentage (-3.3% [1.0%]; P = 3.7 × 10-4), fasting triglyceride (-0.27 [0.07] mmol/L; P = 2.3 × 10-6), and remnant cholesterol (-0.11 [0.03] mmol/L; P = 4.2 × 10-5). Further analyses suggested that this was likely mediated partly by higher circulating levels of acetate observed in homozygous carriers (β [standard error], 0.056 [0.002] mmol/L; P = 2.1 × 10-26), and partly by reduced sucrose uptake, but not lower caloric intake. These findings were verified in Sis-KO mice, which, compared with wild-type mice, were leaner on a sucrose-containing diet, despite similar caloric intake, had significantly higher plasma acetate levels in response to a sucrose gavage, and had lower plasma glucose level in response to a sucrose-tolerance test.CONCLUSIONS: These results suggest that sucrase-isomaltase constitutes a promising drug target for improvement of metabolic health, and that the health benefits are mediated by reduced dietary sucrose uptake and possibly also by higher levels of circulating acetate.

Background Elevated childhood body mass index (BMI), commonly examined as a “once-only” value, increases the risk of cancer and type 2 diabetes (T2D) in adulthood. Continuous exposure to adiposity during childhood may further increase cancer risk. We examined whether longitudinal childhood BMI trajectories were associated with adult obesity-related cancer and the role of adult-onset T2D in these associations. Methods Five sex-specific latent class BMI trajectories were generated for 301 927 children (149 325 girls) aged 6-15 years from the Copenhagen School Health Records Register. Information on obesity-related cancers and T2D was obtained from national health registers. Incidence rate ratios (IRR), cumulative incidences, and confidence intervals (CI) were estimated using Poisson regressions. Results Compared with the average childhood BMI trajectory (containing approximately 40% of individuals), the rate of obesity-related cancer (excluding breast cancer) increased with higher childhood BMI trajectories among women. The highest rates occurred in the overweight (IRR = 1.27, 95% CI = 1.17 to 1.38) and obesity (IRR = 1.79, 95% CI = 1.53 to 2.08) BMI trajectories. Similar patterns were observed among men. In contrast, women with the obesity childhood BMI trajectory had the lowest rate of pre- and postmenopausal breast cancer (IRR = 0.59, 95% CI = 0.43 to 0.80, and IRR = 0.41, 95% CI = 0.30 to 0.57, respectively). For all trajectories, the cumulative risk of obesity-related cancer increased with adult-onset T2D. Conclusion Consistent childhood overweight or obesity may increase the rates of adult obesity-related cancer and decrease the rates of breast cancer. Adult-onset T2D conferred additional risk for obesity-related cancer, but the effect did not differ across childhood BMI trajectories.

The common Arctic-specific

Aims/hypothesis: We aimed to investigate the short-term efficacy and safety of three glucose-lowering interventions in overweight or obese individuals with prediabetes defined by HbA1c. Methods: The PRE-D Trial was a randomised, controlled, parallel, multi-arm, open-label, non-blinded trial performed at Steno Diabetes Center Copenhagen, Gentofte, Denmark. One hundred and twenty participants with BMI ≥25 kg/m2, 30–70 years of age, and prediabetes (HbA1c 39–47 mmol/mol [5.7–6.4%]) were randomised 1:1:1:1 to dapagliflozin (10 mg once daily), metformin (1700 mg daily), interval-based exercise (5 days/week, 30 min/session) or control (habitual lifestyle). Participants were examined at baseline and at 6, 13 and 26 weeks after randomisation. The primary outcome was the 13 week change in glycaemic variability (calculated as mean amplitude of glycaemic excursions [MAGE]) determined using a continuous glucose monitoring system (pre-specified minimal clinically important difference in MAGE ∼30%). Results: One hundred and twelve participants attended the examination at 13 weeks and 111 attended the follow-up visit at 26 weeks. Compared with the control group, there was a small decrease in MAGE in the dapagliflozin group (17.1% [95% CI 0.7, 30.8], p = 0.042) and a small, non-significant, reduction in the exercise group (15.3% [95% CI −1.2, 29.1], p = 0.067), whereas MAGE was unchanged in the metformin group (0.1% [95% CI −16.1, 19.4], p = 0.991)). Compared with the metformin group, MAGE was 17.2% (95% CI 0.8, 30.9; p = 0.041) lower in the dapagliflozin group and 15.4% (95% CI −1.1, 29.1; p = 0.065) lower in the exercise group after 13 weeks, with no difference between exercise and dapagliflozin (2.2% [95% CI −14.8, 22.5], p = 0.815). One serious adverse event occurred in the control group (lung cancer). Conclusions/interpretation: Treatment with dapagliflozin and interval-based exercise lead to similar but small improvements in glycaemic variability compared with control and metformin therapy. The clinical importance of these findings in prediabetes is uncertain. Trial registration: ClinicalTrials.gov NCT02695810 Funding: The study was funded by the Novo Nordisk Foundation, AstraZeneca AB, the Danish Innovation Foundation, the University of Copenhagen and Ascensia Diabetes Care Denmark ApS [Figure not available: see fulltext.]

BackgroundPrevious studies have indicated an association between childhood adversities and type 1 diabetes but have been underpowered and limited by selection. We aim to quantify the effect of accumulation of childhood adversities on type 1 diabetes risk, and to assess whether the effect differs between males and females in a large and unselected population sample.MethodsWe used register-based data covering all children born in Denmark between 1980 and 2015, totalling >2 million children. We specified a multi-state model to quantify the effect of accumulation of childhood adversities on type 1 diabetes risk. The effects of specific childhood adversities on type 1 diabetes were estimated using proportional hazards models.ResultsAccumulation of childhood adversities had a quantitatively small effect on type 1 diabetes risk among females [adjusted hazard ratio (HR) per adversity increase: 1.07; 95% confidence interval (CI): 1.02–1.11], but not among males (adjusted HR per adversity increase: 0.99; 95% CI: 0.97–1.03). Females exposed to extreme numbers (7+) of adversities had two times higher risk of type 1 diabetes compared with unexposed females (adjusted HR: 2.06; 95% CI: 1.10–3.86).ConclusionsIn an unselected total population sample, we generally find no or negligible effects of childhood adversities on type 1 diabetes risk, which may be reassuring to persons with type 1 diabetes who are concerned that personal trauma contributed to their disease. There is a very small group of females exposed to a high degree of adversity who may have a higher risk of type 1 diabetes and this group needs further attention.

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

Context Individuals with severe mental illness (SMI) are at increased risk of developing type 2 diabetes. Objective This work explores whether individuals with diabetes and SMI are also at increased risk of diabetes complications and the potential age-specific differences in development of these. Methods Using nationwide registry data, we followed the entire Danish population with type 2 diabetes from January 1, 1996 to December 31, 2018. Exposure was SMI (schizophrenia, bipolar, or depression disorders). Outcome was diabetes complications (nephropathy, retinopathy, lower limp amputations, and cardiovascular disease). We applied Poisson regression models to estimate overall incidence rate ratios (IRRs) and age-specific incidence rates (IRs) and IRRs of the first event of each complication in individuals with SMI compared to individuals without SMI. The models were adjusted for sex, age, diabetes duration, calendar year, education, and migration status. Results We followed 371 625 individuals with type 2 diabetes, of whom 30 102 had coexisting diagnosed SMI. Individuals with SMI had a higher IR of nephropathy (IRR: 1.15; 95% CI, 1.12-1.18), amputations (IRR: 1.15; 95% CI, 1.04-1.28), and cardiovascular disease (men: IRR: 1.10; 95% CI, 1.05-1.15, women: IRR: 1.18; 95% CI, 1.13-1.22) but a lower IR of retinopathy (IRR: 0.75; 95% CI, 0.70-0.81) when compared to individuals without SMI, after adjustment for confounders. For all complications except amputations, the difference in IR was highest in the younger age groups. Conclusion Individuals with type 2 diabetes and SMI had a higher risk and an earlier onset of several diabetes complications diagnoses, emphasizing focusing on improving diabetes management in younger age groups with SMI.

To assess the prevalence of diabetic retinopathy (DR) among persons with diabetes and prediabetes participating in the 2018 Population Health Survey in Greenland (B2018), a follow-up survey of three previous health surveys. Participants were invited to a diabetes complication screening. We assessed the prevalence of DR using Optos Daytona Ultra-wide field fundus camera and assessed differences in prevalence according to demographic and clinical characteristics using chi square test and a t-test and assessed DR based on ethnicity. The overall prevalence of DR was 2% (10/483). Among participants with HbA1c ≥48 mmol/mol (6.5%) DR prevalence was 9% (9/91), compared with 1c 1c below the diabetes threshold.

Aim: To assess lipid-lowering drug (LLD) use patterns during 1996-2017 and examine lipid levels in relation to the use of LLDs and prevalent atherosclerotic cardiovascular disease (ASCVD). Methods: Using a nationwide diabetes register, 404 389 individuals with type 2 diabetes living in Denmark during 1996-2017 were identified. Individuals were followed from 1 January 1996 or date of type 2 diabetes diagnosis until date of emigration, death or 1 January 2017. Redemptions of prescribed LLDs were ascertained from the nationwide Register of Medicinal Products Statistics. Data on lipid levels were sourced from the National Laboratory Database since 2010. LLD coverage was calculated at any given time based on the redeemed amount and dose. Trends in lipid levels were estimated using an additive mixed-effect model. Low-density lipoprotein cholesterol (LDL-C) goal attainment was assessed based on recommended targets by the 2011, 2016 and 2019 guidelines for management of dyslipidaemias. Results: LLD use has decreased since 2012 and only 55% of those with type 2 diabetes were LLD users in 2017. A decline in levels of total cholesterol and LDL-C, and an increase in triglycerides, was observed during 2010-2017. Annual mean levels of LDL-C were lower among LLD users compared with non-users (in 2017: 1.84 vs. 2.57 mmol/L). A greater fraction of LLD users achieved the LDL-C goal of less than 1.8 mmol/L compared with non-users (in 2017: 51.7% and 19%, respectively). Among LLD users with prevalent ASCVD, 26.9% and 55% had, as recommended by current 2019 European guidelines, an LDL-C level of less than 1.4 mmol/L and less than 1.8 mmol/L, respectively, in 2017. Conclusions: LLD use and LDL-C levels are far from optimal in the Danish type 2 diabetes population and improvement in LLD use could reduce ASCVD events.

IntroductionDiabetes is increasing among Greenlandic Inuit; however, the prevalence of cardiovascular autonomic neuropathy (CAN) is yet unknown. The assessment of CAN requires an ability to differentiate between normal and abnormal. The aim was to establish normative reference data of cardiovascular autonomic function in Greenlandic Inuit.Research design and methodsIn this cross-sectional study, cardiovascular autonomic function was evaluated in participants without diabetes during the Greenlandic Population Study 2018 and in the town Qasigiannguit in 2020. Assessment included cardiovascular autonomic reflex tests (CARTs) and power spectral analysis of heart rate variability (HRV). Normative reference limits were estimated by applying piecewise linear quantile regression models at the fifth percentile. Models were adjusted for age and sex.ResultsBased on examinations of 472 participants (61.7% females), normative reference data was established for all outcomes. Mean age was 54 years (SD 13.1). Higher age was inversely associated with all outcomes of CARTs and HRV. A linear fall in cardiovascular autonomic function tended to level off beyond age of 60 or 70 years for supine-to-upright position ratio and low frequency power. However, the number of observations in subjects older than 60 or 70 years was limited, which may have caused a flattening of the curve around that age. No other associations were found.ConclusionsThe general level of the CARTs and HRV for all age groups is notably lower than in previous studies from other nationalities. We speculate that sociodemographic and cultural aspects of the Greenlandic Inuit population including body mass index, smoking, physical activity and alcohol consumption may have affected the cardiovascular autonomic function.

Background: Diabetes may increase risk of human papillomavirus (HPV)-related precancer and cancer. We estimated incidence of penile and anal high-grade intraepithelial neoplasia (hgPeIN, hgAIN) and squamous cell carcinoma (SCC) in men with diabetes compared with the entire Danish male population without diabetes. Methods: In this registry-based cohort study, we included all men born 1916-2001 and residing in Denmark (n = 2,528,756). From nationwide registries, we retrieved individual-level information on diabetes, educational level, and diagnoses of hgPeIN, hgAIN, penile SCC, and anal SCC. We used Poisson regression models to estimate incidence of hgPeIN, hgAIN, penile SCC, and anal SCC as a function of diabetes status, attained age, calendar period, and education. We estimated incidence rate ratios (IRRs) of each outcome in men with diabetes compared with nondiabetic men, both for diabetes overall and separately for type 1 (T1D) and type 2 diabetes (T2D). Results: Men with diabetes had increased incidence rate of penile SCC compared with nondiabetic men (IRR = 1.5, 95% CI = 1.2, 1.9). We saw similar trends for anal SCC, hgPeIN, and hgAIN. The combined incidence rate of penile and anal SCC was increased in men with T2D (IRR = 1.5, 95% CI = 1.3, 1.8), but not with T1D (IRR = 0.53, 95% CI = 0.20, 1.4) compared with men without diabetes. Conclusion: The incidence of penile and anal high-grade intraepithelial neoplasia and SCC in men with diabetes was increased compared with men without diabetes. For penile and anal SCCs, this was primarily due to an increased risk in men with T2D.

Discontinuation of diabetes medication in the last years of life has been suggested to improve quality of life while deemed safe to implement. However, the extent, patterns, and secular changes in discontinuation of glucose-lowering medication in older people with type 2 diabetes have been scarcely described. We therefore aimed to describe the trends in the use of glucose-lowering medication during the last 10 years of life of older people and explore how key clinical and socioeconomic covariates are associated with these patterns.In this register-based cohort study, all individuals with type 2 diabetes who died aged 80 years or older between Jan 1, 2006, and Dec 31, 2018, were identified through the Danish Diabetes Register and linked to the Danish National Prescription Registry. We followed the population backwards in time from death to date of last medication intake. To estimate the cumulative proportion of people on glucose-lowering medication, a Poisson regression model for the rate of medication as a function of time before death (0 to 10 years before death) and calendar year of death (2006-18) was fitted. Both single-substance and combination glucose-lowering medications were included and categorised as insulins, sulfonylureas, metformin, DPP-4 inhibitors, GLP-1 analogues, SGLT2 inhibitors, acarbose, and thiazolidinediones. Insulin was further subdivided into four groups: fast-acting, intermediate-acting, long-acting, and mixed insulin. To identify which covariates were associated with discontinuation, estimates were adjusted for sex, age at death, diabetes duration at time of death, the total number of diabetes complications at time of death (from no complications to four or more), level of education, immigrant status, and income quartile.52 523 individuals (28 746 [54·7%] females and 23 777 [45·3%] males) were identified, with a mean age at type 2 diabetes diagnosis of 77 years (SD 8), median age at death of 86 years (IQR 83-90), and median diabetes duration at death of 9 years (IQR 5-14). We found a considerable discontinuation of glucose-lowering medication during the last 10 years of life, with the proportion of people on glucose-lowering medication starting at between 89% (95% CI 87-91) in 2006 and 87% (86-88) in 2018 at 10 years before death and decreasing to between 52% (50-54) in 2006 and 38% (37-39) in 2018 at the time of death. Specifically, we found that the proportion of people on sulfonylureas, at any time before death, decreased substantially from 2006 to 2018, whereas the proportion on metformin and DPP-4 inhibitors increased with calendar year of death. Changes were less pronounced for the remaining medications. The overall discontinuation patterns changed with increasing calendar year of death, such that discontinuation rates increased and occurred earlier (further away from time of death) with increasing calendar year. Discontinuations were generally more pronounced during the last year of life. Proportions of people on medication and patterns of discontinuation, as well as the association with covariates, varied with medication class. Covariates most frequently associated with changes in discontinuation rates were sex, age at death, type 2 diabetes duration at death, and number of complications. For example, females were less likely to receive metformin than males at all years before death (rate ratio 0·91 (95% CI 0·89-0·94, p0·0001), and there was a negative association between the proportion of individuals on metformin and increasing age at death (rate ratio per year increase 0·96 [0·96-0·96], p0·0001) and type 2 diabetes duration (0·95 per year increase [0·94-0·95], p0·0001).Our results suggest that increased focus on and implementation of discontinuation of glucose-lowering medication in recent years might have had an effect on discontinuation patterns, particularly during the last year of life.None.

Muscle strength is an important predictor for function and mortality among older adults. We measured hand grip strength among 1442 participants aged 15+ years and carried out a 30 second chair stand test among 786 participants aged 55+ years. Neither test has been carried out among the Inuit before. We present reference values for men and women as means with standard deviations and medians with 10th, 25th, 75th and 90th percentiles. Hand grip strength was higher among men than among women (means 45.2 kg and 25.8 kg; p

IntroductionLifetime risk and lifetime lost to diabetes are measures of current diabetes burden in a population. We aimed at quantifying these measures in the Danish population.Research design and methodsWe modeled incidence and mortality of type 1 diabetes (T1D) and type 2 diabetes (T2D) and non-diabetes mortality based on complete follow-up of the entire population of Denmark in 1996–2016. A multistate model with these transition rates was used to assess the lifetime risk of diabetes, as well as the difference in expected lifetime between persons with type 1 and T2D and persons without.ResultsIn 2016, the lifetime risk of T1D was 1.1% and that for T2D 24%, the latter a 50% increase from 1996. For 50-year-old persons, the lifetime lost was 6.6 years for T1D and 4.8 years for T2D. These figures have been declining over the study period.At 2016, the total foreseeable lives lost in Denmark among patients with T1D were 182 000 years, and those among patients with T2D were 766 000 years, corresponding to 6.6 and 3.0 years per person, respectively.ConclusionAt the individual level, improvements in the disease burden for both T1D and T2D have occurred. At the population level, the increasing number of patients with T2D has contributed to a large increase in the total loss of lifetime.

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.

The Inuit in Greenland have gone through dramatic lifestyle changes during the last half century. More time is spent being sedentary and imported foods replaces traditional foods like seal and whale. The population has also experienced a rapid growth in obesity and metabolic disturbances and diabetes is today common despite being almost unknown few decades ago. In this paper, we describe and discuss the role of lifestyle changes and genetics for Inuit metabolic health. Novelty: Cardiometabolic disease risk has increased in Greenland. Lifestyle changes and possibly gene-lifestyle interactions play a role.

OBJECTIVES: The overall aim was to describe food reward in an Inuit population in Greenland. More specifically, the objective was to first test the differences in food reward for sweet relative to savory food (taste bias) after four weeks on a traditionally Inuit diet (TID) vs a Westernized diet (WD). If no differences in taste bias were found between diet groups, we aimed to describe food reward in a pooled sample (median [IQR]). We hypothesized that participants would have higher preferences for sweet compared to savory foods. METHODS: After a dietary intervention in Greenland (20% of foods provided), we measured behavioral components of food reward using the Leeds Food Preference Questionnaire. The reward components, explicit liking and implicit wanting, were measured in response to images of Western foods varying in fat content and taste after four weeks on either TID or WD. A positive bias score reflected preference for sweet over savory, and oppositely a negative bias score reflected preference for savory over sweet foods. RESULTS: Participant characteristics were similar in the two diet groups (age (mean (SD): TID = 58.1 (11.5) vs. WD = 55.4 (9.5) years); sex: TID = 50% vs. WD = 54% women; body mass index (mean (SD): TID = 26.6 (5.5) vs. WD = 27.9 (4.7) kg/m(2)). In these preliminary, unadjusted analyses, we found no differences in explicit liking (P = 0.77) or implicit wanting (P = 0.70) bias score for sweet over savory foods after four weeks following either TID (n = 26) or WID (n = 24). Altogether, participants in the two diet groups had a greater explicit liking (−11.5 [−19.9; −2.8]) and implicit wanting (−21.6 [−44.2; −5.2]) for savory compared to sweet foods. CONCLUSIONS: This is the first study to examine explicit and implicit aspects of food reward in an Inuit population. Contrary to our hypothesis, this population did not prefer sweet over savory Western foods. FUNDING SOURCES: The study was supported by unrestricted grants from The Novo Nordisk Foundation. Royal Greenland and the supermarket chains Kalaallit Nunaanni Brugseni & Pilersuisoq supported the study with foods and food logistics.

In the Greenlandic Inuit population a common nonsense TBC1D4 p.Arg684Ter variant in muscle is found with an allele frequency of 17%. Homozygous carriers of this variant have impaired glucose tolerance, and a 10-fold increased risk of type 2 diabetes. Here we investigate whether the TBC1D4 p.Arg684Ter affects regulation of skeletal muscle glucose uptake during exercise and during insulin stimulation in the post exercise period. Inuits carrying zero (n=8) or two (n=8) alleles of TBC1D4 p.Arg684Ter were recruited from population surveys in Greenland. Glucose tolerance was measured during a 6 hour oral glucose tolerance test (OGTT). Skeletal muscle glucose uptake was measured by applying arterial-venous balance technique across the legs during one-legged exercise and during subsequent euglycemic hyperinsulinemic clamp. Glucose uptake was measured in both the rested and the exercised leg. During the OGTT blood glucose was similar at fasting but markedly elevated (by 4.4 mM) in TBC1D4 p.Arg684Ter carriers compared to matched controls at 2 hours, and variants became hypoglycemic at 4 hours (3.3 vs. 4.7 mM) and similar to controls at 6 hours. During exercise, TBC1D4 variant carriers and controls displayed similar glucose uptake in skeletal muscle. During insulin clamp, glucose uptake in the previously rested leg was lower (~50%) in TBC1D4 variant carriers compared to controls. In the prior exercised leg, glucose uptake during the insulin clamp was higher in both groups compared to the rested leg. However, glucose uptake in the previously exercised leg from TBC1D4 variant carriers was comparable to the previously rested leg in controls and thus still markedly lower than controls. In conclusion: TBC1D4 p.Arg684Ter carriers have impaired insulin stimulated but normal exercise stimulated glucose uptake in skeletal muscle. A single bout of exercise improves muscle glucose uptake in carriers to levels seen in non-exercise muscle of controls. Disclosure J. M. Kristensen: None. T. Hansen: None. M. E. Jørgensen: Research Support; Self; Boehringer Ingelheim International GmbH, Sanofi-Aventis, Stock/Shareholder; Self; Novo Nordisk A/S. J. F. P. Wojtaszewski: None. T. L. J. Larsen: None. C. S. Carl: None. A. Thorup: None. J. Hingst: None. J. Onslev: None. J. S. Olesen: None. M. L. Pedersen: None. E. A. Richter: None. Funding Novo Nordisk Foundation (NNF14OC0013057, NNF17OC0028136); Independent Research Fund Denmark (FSS802000288B5855628)

In the elderly population with type 2 diabetes (T2D), decisions about discontinuation of medication is important, as it may lead to improved outcomes and reduced polypharmacy-associated adverse events. However, the extent, patterns and secular changes of discontinuation of cardioprotective medication during the last years of life have been scarcely described. All individuals with T2D that died at age ≥ 80, between 2006-2018 were identified through the Danish Diabetes Register and linked to the Register of Medicinal Products Statistics. The population was followed backward in time, from death to date of last intake of cardioprotective medication. To estimate the cumulative proportion on different medication classes, we fitted a crude Poisson regression model for the rate of medication with time before death. A total of 52,523 persons (55% female) were identified, with a mean (SD) age at T2D diagnosis of 77 (8) years, a median (Q1-Q3) age at death of 86 (83-90) years and a median (Q1-Q3) diabetes duration at death of 9 (5-14) years. From year of death in 2006 to 2018, we found an increased utilization of antihypertensive and lipid-lowering medication, during the last 10 years of life, while the opposite was true for aspirin (ASA) (Figure 1). We also found a simultaneous increase in discontinuation rates during the last years of life, which was particularly pronounced during the last year of life. Disclosure V. Kosjerina: None. B. Carstensen: Stock/Shareholder; Self; Novo Nordisk. M. E. Jorgensen: Research Support; Self; Boehringer Ingelheim International GmbH, Sanofi-Aventis, Stock/Shareholder; Self; Novo Nordisk A/S. B. Brock: None. H. Christensen: None. J. Rungby: None. G. S. Andersen: Stock/Shareholder; Self; Novo Nordisk A/S.

Hundreds of thousands of genetic variants have been reported to cause severe monogenic diseases, but the probability that a variant carrier develops the disease (termed penetrance) is unknown for virtually all of them. Additionally, the clinical utility of common polygenetic variation remains uncertain. Using exome sequencing from 77,184 adult individuals (38,618 multi-ancestral individuals from a type 2 diabetes case-control study and 38,566 participants from the UK Biobank, for whom genotype array data were also available), we apply clinical standard-of-care gene variant curation for eight monogenic metabolic conditions. Rare variants causing monogenic diabetes and dyslipidemias display effect sizes significantly larger than the top 1% of the corresponding polygenic scores. Nevertheless, penetrance estimates for monogenic variant carriers average 60% or lower for most conditions. We assess epidemiologic and genetic factors contributing to risk prediction in monogenic variant carriers, demonstrating that inclusion of polygenic variation significantly improves biomarker estimation for two monogenic dyslipidemias., Penetrance of variants in monogenic disease and clinical utility of common polygenic variation has not been well explored on a large-scale. Here, the authors use exome sequencing data from 77,184 individuals to generate penetrance estimates and assess the utility of polygenic variation in risk prediction of monogenic variants.

OBJECTIVE Symptoms indicative of diabetic polyneuropathy (DPN) early in type 2 diabetes may act as a marker for cardiovascular disease (CVD) and death. RESEARCH DESIGN AND METHODS We linked data from two Danish type 2 diabetes cohorts, the Anglo-Danish-Dutch Study of Intensive Treatment in People With Screen-Detected Diabetes in Primary Care (ADDITION-Denmark) and the Danish Centre for Strategic Research in Type 2 Diabetes (DD2), to national health care registers. The Michigan Neuropathy Screening Instrument questionnaire (MNSIq) was completed at diabetes diagnosis in ADDITION-Denmark and at a median of 4.6 years after diagnosis of diabetes in DD2. An MNSIq score ≥4 was considered as indicative of DPN. Using Poisson regressions, we computed incidence rate ratios (IRRs) of CVD and all-cause mortality comparing MNSIq scores ≥4 with scores RESULTS In total, 1,445 (ADDITION-Denmark) and 5,028 (DD2) individuals were included in the study. Compared with MNSIq scores CONCLUSIONS The MNSIq may be a tool to identify a subgroup within individuals with newly diagnosed type 2 diabetes with a high incidence rate of subsequent CVD. MNSIq scores ≥4, indicating DPN, were associated with a markedly higher incidence rate of CVD, beyond that conferred by established CVD risk factors.

Background: Severe mental illness (SMI) is linked with a higher incidence of type 2 diabetes (T2D); however, it is unclear whether persons with SMI and T2D have a higher incidence of diabetes complications compared to persons with T2D only. We calculated incidence rate ratios (IRR) and incidence rates (IR) of micro- and macrovascular diabetes complications among persons with T2D and SMI compared to those with T2D only. Methods: We used Danish nationwide registers to follow all persons with T2D from 1996 to 2018. IRR and age-specific IR of first event of each diabetes complication was estimated using Poisson regression models with risk time as offset comparing persons with T2D with and without SMI, while adjusting for sex, age, diabetes duration, calendar year, substance abuse and Charlson’s Comorbidity Index. Results: A total of 371,625 persons with T2D were on average followed for 6.9 - 7.6 year depending on the complication outcome. Persons with T2D and SMI (n=29,249) were younger at T2D diagnosis than persons with T2D only (mean [SD], 59 [15] vs. 63 [14] year). In total, 73,598 (27%) developed cardiovascular disease (CVD), 25,846 (7%) developed retinopathy, 20,191 (5%) developed nephropathy, and 6,796 (2%) underwent an amputation during follow-up. Persons with T2D and SMI had an increased risk of CVD (IRR: 1.14 (95% CI: 1.11-1.18)) and nephropathy (IRR: 1.11 (95% CI: 1.03-1.16)), and a decreased risk of retinopathy (IRR: 0.83 (95% CI: 0.78-0.86)) compared to persons with T2D only when adjusting for confounders. The risk for amputations were similar in persons with T2D with and without SMI (IRR: 1.00 (95% CI: 0.90-1.12)). The increased risk of CVD and nephropathy in persons with SMI were persistent in all ages except for the ages 80-95 year. Conclusion: Persons with T2D and SMI have a slightly higher risk of CVD and nephropathy and a lower risk of retinopathy compared to persons with T2D only. Disclosure S. H. Scheuer: None. V. Kosjerina: None. N. Lindekilde: None. F. Pouwer: None. B. Carstensen: Stock/Shareholder; Self; Novo Nordisk. M. E. Jørgensen: Research Support; Self; Boehringer Ingelheim International GmbH, Sanofi-Aventis, Stock/Shareholder; Self; Novo Nordisk A/S. M. E. Benros: None. G. S. Andersen: Stock/Shareholder; Self; Novo Nordisk A/S.

Objective Symptoms indicative of diabetic polyneuropathy (DPN) early in type 2 diabetes may act as a marker for cardiovascular disease (CVD) and death. Research Design and Methods We linked data from two Danish type 2 diabetes cohorts, ADDITION-Denmark and DD2, to national healthcare registers. The Michigan Neuropathy Screening Instrument questionnaire (MNSIq) was completed at diabetes diagnosis in ADDITION-Denmark and at a median of 4.6 years after diagnosis of diabetes in DD2. An MNSIq score ≥ 4 was considered as indicative of DPN. Using Poisson regressions, we computed incidence rate ratios of CVD and all-cause mortality comparing MNSIq scores ≥ 4 with scores < 4. Analyses were adjusted for a range of established CVD risk factors. Results In total, 1,445 (ADDITION-Denmark) and 5,028 (DD2) individuals were included in the study. Compared with MNSIq scores < 4, MNSIq scores ≥ 4 were associated with higher incidence rate of CVD, with incidence rate ratios (IRRs) of 1.79 [95% confidence interval (CI) 1.38-2.31] in ADDITION-Denmark, 1.57 (CI: 1.27-1.94) in the DD2, and a combined IRR of 1.65 (CI: 1.41-1.95) in a fixed-effect meta-analysis. MNSIq scores ≥ 4 did not associate with mortality; combined mortality rate ratio 1.11 (CI: 0.83-1.48). Conclusions The MNSIq may be a tool to identify a subgroup within individuals with newly diagnosed type 2 diabetes who has a high incidence rate of subsequent CVD. MNSIq scores ≥ 4, indicating DPN, were associated with a markedly higher incidence rate of CVD, beyond that conferred by established CVD risk factors.

We would like to thank Ostergaard et al. (1) for their perspective on our article (2), which includes a suggestion for using lifetime prediction models to estimate disease-free life expectancy. The lifetime prediction models previously published are primarily based on Cox proportional hazards models including age as timescale (3). We have used Poisson models that facilitate the inclusion of multiple timescales such as age and diabetes duration. Both modeling approaches estimate a hazard function for the event of interest as well as for the competing event of death, and with both approaches these hazard functions can be used to estimate lifetime risk and disease-free life expectancy. As pointed out by Ostergaard et al., risk prediction should ideally cover a long time horizon, and in that sense estimating lifetime risk may seem attractive. Models predicting diseases …

Novel crop improvement methodologies, including the exploitation of natural genetic variation, are urgently required to feed our rapidly growing human population in the context of global climate change. Here we describe a ‘Fast Identification of Nucleotide variants by DigITal PCR’ (FIND-IT) method for the rapid identification of pre-targeted genetic variants or rare alleles in large genomic populations. Libraries of 500,000 individuals can be screened and desired variants isolated within two weeks. FIND-IT is widely applicable for mining valuable diversity in any genomic population, including elite breeding and wild germplasm collections. The method provides single nucleotide resolution that has been validated by identifying and isolating knockout lines, non-synonymous codon changes and variants of miRNA and transcription factor binding sites in the agronomically important crop barley. In contrast to existing methods, FIND-IT does not require transformation, cloning or enzymatic steps, and is exempt from GMO regulations. Thus, FIND-IT can be applied immediately to elite crop cultivars and can be tailored to minimize or eliminate time-consuming backcrossing requirements.

In this register-based cohort study, we estimated the incidence of human papillomavirus (HPV)-related anogenital precancer and cancer in women with diabetes compared with women without diabetes. We followed all women living in Denmark born 1916 to 2001 (n = 2 508 321) for individual-level information on diabetes (Type 1 or 2 [T1D or T2D]), diagnoses of cervical, vaginal, vulvar and anal intraepithelial neoplasia Grade 2 or 3 (IN2/3) and cancer and other covariates from nationwide registries. We used Poisson regression to model the incidence rates of anogenital IN2/3 and cancer as a function of diabetes status, age, HPV vaccination, education, calendar year, and cervical cancer screening status. Incidence rate ratios (IRRs) were estimated for diabetes overall, and separately for T1D and T2D, compared with women without diabetes. Women with diabetes had higher rates of vulvar IN2/3 (IRR = 1.63; 95% confidence interval [CI]: 1.41-1.88), vulvar cancer (IRR = 1.61; 95% CI: 1.36-1.91) and vaginal cancer (IRR = 1.79; 95% CI: 1.27-1.91) than women without diabetes. Similar patterns were observed for anal IN2/3, anal cancer and cervical cancer, although not statistically significant. In contrast, women with diabetes had lower rates of cervical IN2/3 (IRR = 0.74; 95% CI: 0.69-0.79) than women without diabetes. Patterns were generally similar in women with T1D and T2D, although cancer rates were higher in women with T2D. In conclusion, the incidence of most anogenital precancers and cancers were increased in women with diabetes. However, women with diabetes had lower incidence of cervical precancer. Our findings could be explained by biological mechanisms and/or behavioral factors, such as smoking and less frequent cervical screening participation.

OBJECTIVE Autonomic nervous system dysfunction is associated with impaired glucose metabolism, but the temporality of this association remains unclear in individuals without diabetes. We investigated the association of autonomic function with 5-year changes in glucose metabolism in individuals without diabetes. RESEARCH DESIGN AND METHODS Analyses were based on 9,000 person-examinations for 3,631 participants without diabetes in the Whitehall II cohort. Measures of autonomic function included 5-min resting heart rate and six heart rate variability (HRV) indices. Associations between baseline autonomic function measures and 5-year changes in fasting and 2-h plasma glucose, serum insulin concentrations, insulin sensitivity (insulin sensitivity index [ISI0–120] and HOMA of insulin sensitivity), and β-cell function (HOMA of β-cell function) were estimated in models adjusting for age, sex, ethnicity, metabolic factors, and medication. RESULTS A 10-bpm higher resting heart rate was associated with 5-year changes in fasting and 2-h insulin and ISI0–120 of 3.3% change (95% CI 1.8; 4.8), P < 0.001; 3.3% change (1.3; 5.3), P = 0.001; and −1.4% change (−2.4; −0.3), P = 0.009, respectively. In models adjusted for age, sex, and ethnicity, higher baseline values of several HRV indices were associated with a 5-year decrease in fasting and 2-h insulin and ISI0–120. However, significance was lost by full adjustment. A majority of HRV indices exhibited a trend toward higher values being associated with lower insulin levels and higher insulin sensitivity. CONCLUSIONS Higher resting heart rate in individuals without diabetes is associated with future unfavorable changes in insulin levels and insulin sensitivity. Associations may be mediated via autonomic function; however, results are inconclusive. Resting heart rate may be a risk marker for future pathophysiological changes in glucose metabolism.