Elevated risk of developing type 2 diabetes in people with a psychiatric disorder: What is the role of health behaviors and psychotropic medication?

AIMS: Several psychiatric disorders are linked with an increased risk of developing type 2 diabetes (T2D), but the mediating mechanisms are unclear. We aimed to investigate health behaviors, obesity, psychotropic medication use, and comorbidity as potential mediating mechanisms explaining these associations. METHODS: We combined data from a large population-based survey with register-based data and followed a sample of 250,013 Danes (≥16 years) for up to 8.9 years. We conducted mediation analyses investigating 10 potential mediators of the associations between psychiatric disorders and incident T2D. RESULTS: Individuals with a substance use disorder, schizophrenia, mood disorder, neurotic disorder, eating disorder, or a personality disorder had a significantly higher risk of developing T2D. Organic disorders, intellectual disabilities, developmental and behavioral disorders were not associated with T2D-risk. For all psychiatric disorders significantly associated with T2D, the use of antidepressant medication had the largest proportional mediating effect on the association (13-32 %). CONCLUSIONS: Use of antidepressant medication had the largest contribution to the associations between psychiatric disorders and incident T2D. Future epidemiological studies and prevention studies should focus on optimizing the use of antidepressant medication with minimal side effects, and the promotion of health behaviors in individuals with a psychiatric disorder to prevent T2D.

Indicators of quality of diabetes care in persons with type 2 diabetes with and without severe mental illness: a Danish nationwide register-based cohort study.

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.

An LDLR missense variant poses high risk of familial hypercholesterolemia in 30% of Greenlanders and offers potential of early cardiovascular disease intervention.

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.

Risk of Developing Type 2 Diabetes in Individuals With a Psychiatric Disorder: A Nationwide Register-Based Cohort Study.

OBJECTIVE: Previous studies have investigated the incidence of type 2 diabetes in individuals with psychiatric disorders, but most studies have focused on a specific psychiatric disorder or a selected sample. More population-based studies are needed to determine these associations in representative samples. We therefore aimed to determine these associations in a nationwide, register-based dynamic cohort study. RESEARCH DESIGN AND METHODS: We analyzed data from 5,005,612 adults living in Denmark between 1995 and 2018, without prior diabetes. We investigated 10 different categories of psychiatric disorders and a composite group with any psychiatric disorder. Individuals with a psychiatric disorder were compared with individuals without using multivariable-adjusted Poisson regression to estimate incidence rate ratios (IRR) of type 2 diabetes. We modeled age-specific incidence rates (IR) for individuals with and without the specific psychiatric disorder. All models were stratified by sex. RESULTS: In total, 334,739 individuals developed type 2 diabetes during follow-up. For all investigated categories of psychiatric disorders, we found increased IR of type 2 diabetes for individuals with versus those without a psychiatric disorder (IRR: men, 1.47 [95% CI 1.45-1.50]; women, 1.65 [95% CI 1.62-1.68]). When we examined age-specific IR, the largest differences were found in the younger population (<50 years). CONCLUSIONS: We found that the IR of type 2 diabetes was higher in individuals with a psychiatric disorder compared with individuals without a psychiatric disorder and particularly high in the younger people with a psychiatric disorder. New studies into the prevention and early detection of type 2 diabetes in these groups are warranted.

Loss of Sucrase-Isomaltase Function Increases Acetate Levels and Improves Metabolic Health in Greenlandic Cohorts.

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 (ß [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 (ß [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.

Intention and Perceptions of Healthy Eating versus Actual Intake Among Patients with Type 1 and Type 2 Diabetes and the General Population.

PURPOSE: Intention and perceptions of healthy eating may affect diet-related behavior. We assessed the intention and perceptions of eating healthily in patients with type 1 (T1D) and type 2 diabetes (T2D) compared with the general population. Secondly, differences in diet quality were assessed in patients with diabetes perceiving their dietary habits as more or less healthy. MATERIALS AND METHODS: This cross-sectional study included data on socioeconomic status, dietary intake, and questions on healthy eating from adults with T1D (n=426), T2D (n=348) and from the general population (n=2899). RESULTS: Patients with T2D were less likely to perceive their dietary habits as healthy compared with T1D and the general population. Patients with T1D or T2D perceiving their dietary habits as healthy reported higher intake of vegetables, fruit, fish, fibre and protein. In addition, patients with T1D with perceived healthy versus less healthy dietary habits had lower sugar intake and higher alcohol intake. Overall, adherence to dietary guidelines in patients with T1D and T2D was too low both in self-perceived healthy and less healthy eaters. In comparison with T1D patients, patients with T2D were less likely and the general population was more likely to strive to eat a healthy diet. CONCLUSION: Patients with T2D had poorer self-perception of their dietary healthiness and less intention of eating healthily, compared with patients with T1D and the general population. Actual diet quality was higher amongst patients with T1D and T2D perceiving their dietary habits as healthy than those perceiving their dietary habits as less healthy. But inadequate intakes were found in all groups. Health care providers should address and explore the patient's intention and perceptions of healthy eating when discussing dietary changes in diabetes to improve nutritional support.

Effect of Liraglutide on Arterial Inflammation Assessed as [18F]FDG Uptake in Patients With Type 2 Diabetes: A Randomized, Double-Blind, Placebo-Controlled Trial.

BACKGROUND: The mechanism behind the cardiovascular protection observed with human GLP-1 RA (glucagon-like peptide-1 receptor agonists) in type 2 diabetes is unknown. We hypothesized that treatment with the GLP-1 RA liraglutide had a positive effect on vascular inflammation. METHODS: LIRAFLAME (Effect of liraglutide on vascular inflammation in type-2 diabetes: A randomized, placebocontrolled, double-blind, parallel clinical PET/CT trial) was a double-blind, randomized controlled trial performed at a single university hospital clinic in Denmark. Patients with type 2 diabetes were via computer-generated randomization list assigned (1:1) liraglutide up to 1.8 mg or placebo once daily for 26 weeks. The primary end point was change in vascular inflammation over 26 weeks assessed by [18F]-fluorodeoxyglucose positron emission tomography/computed tomography. Analyses were based on intention-to-treat. Key secondary outcomes included change in other indices of atherosclerosis. RESULTS: Between October 26, 2017, and August 16, 2019, 147 patients were screened and 102 were randomly assigned to liraglutide (n=51) or placebo (n=51) and 99 (97%) completed the trial. Change in the [18F]-fluorodeoxyglucose positron emission tomography measure of vascular inflammation (active-segment target-to-background ratio) did not differ between treatment groups: change from baseline to 26 weeks was -0.04 (95% CI, -0.17 to 0.08) in the liraglutide group compared with -0.09 (-0.19 to 0.01) in the placebo group (mean difference, 0.05 [95% CI, -0.11 to 0.21], P=0.53). Secondary analyses restricted to [18F]-fluorodeoxyglucose positron emission tomography of the carotid arteries as well as other indices of atherosclerosis confirmed the primary result. We performed an explorative analysis of interaction between treatment group and history of cardiovascular disease (P=0.052). CONCLUSIONS: In this low to moderate risk population with type 2 diabetes, liraglutide did not change vascular inflammation assessed as [18F]-fluorodeoxyglucose uptake compared with placebo. An explorative analysis indicated a possible effect in persons with history of cardiovascular disease, in line with current guidelines where liraglutide is recommended to patients with history of cardiovascular disease. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03449654.

Omega-3 fatty acids and risk of cardiovascular disease in Inuit: First prospective cohort study.

BACKGROUND AND AIMS: No prospective study have ever assessed if marine n-3 polyunsaturated fatty acids protect Inuit against cardiovascular disease as claimed. It is highly relevant as cardiovascular disease (CVD) incidence rates are rising concurrent with a westernization of diet. We aimed to assess the association between blood cell membrane phospholipid content of eicosapentaenoic acid and docosahexaenoic acid (EPA + DHA) on CVD risk in Inuit. METHODS: We used data from a cohort of adult Greenlanders with follow-up in national registers. The main outcome was fatal and non-fatal CVD incidence among participants without previous CVD. The continuous effect of EPA + DHA was calculated as incidence rate ratios (IRRs) using Poisson regression with age as time scale, adjusting for age, sex, genetic admixture, lifestyle and dietary risk factors. RESULTS: Out of 3095 eligible participants, 2924 were included. During a median follow-up of 9.7 years, 216 had their first CVD event (8.3 events/1000 person years). No association between EPA + DHA and CVD risk was seen, with IRR = 0.99 per percentage point EPA + DHA increase (95% CI: 0.95-1.03, p = 0.59). No association was seen with risk of ischemic heart disease (IHD) (IRR = 1.03, 95% CI: 0.97-1.09) and stroke (IRR = 0.98, 95% CI: 0.93-1.03) as separate outcomes or for intake of EPA and DHA. CONCLUSIONS: We can exclude that the CVD risk reduction is larger than 21% for individuals at the 75% EPA + DHA percentile compared to the 25% percentile. We need a larger sample size and/or longer follow-up to detect smaller effects and associations with IHD and/or stroke.

Effect of dapagliflozin on cardiac function in people with type 2 diabetes and albuminuria - A double blind randomized placebo-controlled crossover trial.

AIMS: Sodium glucose transport inhibitors (SGLT2i) can reduce risk of heart failure (HF) and cardiovascular death in people with type 2 diabetes (T2D) and existing cardiovascular disease. Our aim was to examine the effect of the SGLT2i dapagliflozin on cardiac function in people with T2D and albuminuria. METHODS: A secondary analysis of a double-blind, randomized, cross-over study of 12 weeks treatment with dapagliflozin 10 mg versus placebo. Myocardial function was assessed by echocardiography and biomarkers of cardiac risk were measured. An exploratory diastolic composite of echocardiographic variables was computed. RESULTS: Of the 36 participants completing the study 89% were male, mean age 64 ±â€¯8 years, diabetes duration 16.4 ±â€¯4.7 years and HbA1c 73 ±â€¯15 mmol/mol (8.9 ±â€¯1.4%), 30.6% had former cardiovascular events and 32% had macroalbuminuria. Mean left ventricular ejection fraction (LVEF) was 55.4% after placebo and 54.3% after dapagliflozin (p = 0.15), global longitudinal strain -16.1 vs. -15.9, (p = 0.64), E/e' 7.6 vs. 7.6 (p = 0.082), and tissue Doppler velocity e' 10.0 vs. 10.6 (p = 0.05). The composite score showed diastolic function improvement of 19.8% (p = 0.021). No other significant changes were observed. CONCLUSIONS: Dapagliflozin may have minor effects on diastolic function in people with T2D, albuminuria and preserved LVEF.

Prepregnancy Diabetes and Offspring Risk of Congenital Heart Disease: A Nationwide Cohort Study.

BACKGROUND: Maternal diabetes mellitus is associated with an increased risk of offspring congenital heart defects (CHD); however, the causal mechanism is poorly understood. We further investigated this association in a Danish nationwide cohort. METHODS AND RESULTS: In a national cohort study, we identified 2 025 727 persons born from 1978 to 2011; among them were 7296 (0.36%) persons exposed to maternal pregestational diabetes mellitus. Pregestational diabetes mellitus was identified by using the National Patient Register and individual-level information on all prescriptions filled in Danish pharmacies. Persons with CHD (n=16 325) were assigned to embryologically related cardiac phenotypes. The CHD prevalence in the offspring of mothers with pregestational diabetes mellitus was 318 per 10 000 live births (n=232) in comparison with a baseline risk of 80 per 10 000; the adjusted relative risk for CHD was 4.00 (95% confidence interval, 3.51-4.53). The association was not modified by year of birth, maternal age at diabetes onset, or diabetes duration, and CHD risks associated with type 1 (insulin-dependent) and type 2 (insulin-independent) diabetes mellitus did not differ significantly. Persons born to women with previous acute diabetes complications had a higher CHD risk than those exposed to maternal diabetes mellitus without complications (relative risk, 7.62; 95% confidence interval, 5.23-10.6, and relative risk, 3.49; 95% confidence interval, 2.91-4.13, respectively; P=0.0004). All specific CHD phenotypes were associated with maternal pregestational diabetes mellitus (relative risk range, 2.74-13.8). CONCLUSIONS: The profoundly increased CHD risk conferred by maternal pregestational diabetes mellitus neither changed over time nor differed by diabetes subtype. The association with acute pregestational diabetes complications was particularly strong, suggesting a role for glucose in the causal pathway.

Use of macrolides in mother and child and risk of infantile hypertrophic pyloric stenosis: nationwide cohort study.

OBJECTIVE: To assess the association between use of macrolide antibiotics in mothers and infants from pregnancy onset until 120 days after birth and infantile hypertrophic pyloric stenosis (IHPS). DESIGN: Nationwide register based cohort study. SETTING: Denmark, 1996-2011. PARTICIPANTS: 999,378 liveborn singletons and linked individual level information on macrolide prescriptions (maternal use during pregnancy, n=30,091; maternal use after birth, n=21,557; use in infants, n=6591), surgery for IHPS, and potential confounders. MAIN OUTCOME MEASURES: Surgery for IHPS by three categories of macrolide use: in mothers during pregnancy, in mothers after birth, and in infants after birth. RESULTS: 880 infants developed IHPS (0.9 cases per 1000 births). Compared with infants with no use of macrolides, the adjusted rate ratio for IHPS in infants with use of macrolides during days 0 to 13 after birth was 29.8 (95% confidence interval 16.4 to 54.1) and during days 14 to 120 was 3.24 (1.20 to 8.74); the corresponding absolute risk differences were 24.4 (95% confidence interval 13.0 to 44.1) and 0.65 (0.06 to 2.21) cases per 1000 infants exposed to macrolides, respectively. The rate ratio for maternal use of macrolides for days 0 to 13 after birth was 3.49 (1.92 to 6.34) and for days 14 to 120 was 0.70 (0.26 to 1.90); the corresponding absolute risk differences were 2.15 (0.82 to 4.64) and -0.11 (-0.26 to 0.31). The rate ratios for maternal use of macrolides during pregnancy were 1.02 (0.65 to 1.59) for weeks 0 to 27 and 1.77 (0.95 to 3.31) for weeks 28 to birth; the corresponding absolute risk differences were 0.01 (-0.31 to 0.50) and 0.67 (-0.06 to 2.02). CONCLUSIONS: Treatment of young infants with macrolide antibiotics was strongly associated with IHPS and should therefore only be administered if potential treatment benefits outweigh the risk. Maternal use of macrolides during the first two weeks after birth was also associated with an increased risk of IHPS. A possible association was also found with use during late pregnancy.