Insulin sensitivity estimates and their longitudinal association with coronary artery disease in type 1 diabetes. Does it matter?

BACKGROUND: Insulin resistance and chronic kidney disease are both associated with increased coronary artery disease risk. Many formulae estimating glucose disposal rate in type 1 diabetes infer insulin sensitivity from clinical data. We compare associations and performance relative to traditional risk factors and kidney disease severity between three formulae estimating the glucose disposal rate and coronary artery disease in people with type 1 diabetes. METHODS: The baseline glucose disposal rate was estimated by three (Williams, Duca, and Januszewski) formulae in FinnDiane Study participants and related to subsequent incidence of coronary artery disease, by baseline kidney status. RESULTS: In 3517 adults with type 1 diabetes, during median (IQR) 19.3 (14.6, 21.4) years, 539 (15.3%) experienced a coronary artery disease event, with higher rates with worsening baseline kidney status. Correlations between the three formulae estimating the glucose disposal rate were weak, but the lowest quartile of each formula was associated with higher incidence of coronary artery disease. Importantly, only the glucose disposal rate estimation by Williams showed a linear association with coronary artery disease risk in all analyses. Of the three formulae, Williams was the strongest predictor of coronary artery disease. Only age and diabetes duration were stronger predictors. The strength of associations between estimated glucose disposal rate and CAD incidence varied by formula and kidney status. CONCLUSIONS: In type 1 diabetes, estimated glucose disposal rates are associated with subsequent coronary artery disease, modulated by kidney disease severity. Future research is merited regarding the clinical usefulness of estimating the glucose disposal rate as a coronary artery disease risk factor and potential therapeutic target.

Risk of Thyroid Cancer in People With Type 1 Diabetes by Autoimmune Thyroid Diseases and Tumor Histology.

Context: Thyroid cancer is the most common endocrine cancer, but little is known about it in type 1 diabetes (T1D) and its potential association with autoimmune diseases. Objective: This study aims to assess the risk of thyroid cancer in adults with long-term T1D compared to individuals without diabetes and the proposed association of thyroid autoimmune diseases with thyroid cancer. Methods: The study included 4758 individuals with T1D participating in the Finnish Diabetic Nephropathy Study and 12 710 controls. Thyroid cancers were obtained from the Finnish Care Registers for Health Care. Results: 27 (0.57%) individuals with T1D had thyroid cancer compared to 27 (0.21%) in the controls (standardized incidence ratio 2.43; 95% confidence interval 1.59-3.56). The absolute increase in incidence was modest, with a 0.36%-unit rise. This translates to 17 additional cases among 4710 individuals with T1D. Cancer type was papillary in 81.5% of individuals with T1D and 88.9% of the controls; the rest were follicular. In T1D the distribution of hypothyreosis was similar between those with (n = 5, 18.5%) and without (18.1%) cancer, but hyperthyreosis was diagnosed more often with thyroid cancer (n = 3, 11.1%) than without (2.3%, P = .003). None of the thyroid cancers were invasive or had metastatic characteristics. Conclusion: Although there is an excess risk of thyroid cancer, it is only marginally increased (0.36%-unit) in individuals with T1D compared to control individuals and was not associated with increased morbidity or mortality. An overdiagnosis effect due to regular health care contacts is the most likely explanation for the higher risk.

Stroke incidence increases with diabetic retinopathy severity and macular edema in type 1 diabetes.

BACKGROUND: As the retina is suggested to mirror the brain, we hypothesized that diabetic retinopathy and macular edema are indicative of stroke risk in type 1 diabetes and sought to assess this association in individuals with type 1 diabetes. METHODS: We included 1,268 adult FinnDiane Study participants with type 1 diabetes (age 38.7 ± 11.8 years, 51.7% men vs. 48.3% women, and 31.5% had diabetic kidney disease), data on baseline diabetic retinopathy severity, and first stroke during our observational follow-up. Retinopathy was graded by the Early Treatment Diabetic Retinopathy Study (ETDRS) scale, and macular edema as clinically significant (CSME) or not. Strokes identified from registries were confirmed from medical files. Adjusted hazard ratios (HR) for stroke by retinopathy severity and CSME were calculated by Cox models adjusted for clinical confounders, including diabetic kidney disease. RESULTS: During median 18.0 (14.1-19.3) follow-up years, 130 strokes (96 ischemic, 34 hemorrhagic) occurred. With no-very mild (ETDRS 10-20) retinopathy as reference, the adjusted HR for stroke was 1.79 (95%CI 1.02-3.15) in non-proliferative (ETDRS 35-53), and 1.69 (1.02-2.82) in proliferative (ETDRS 61-85) retinopathy. Corresponding adjusted HR for ischemic stroke was 1.68 (0.91-3.10) in non-proliferative and 1.35 (0.77-2.36) in proliferative retinopathy. The adjusted HR for hemorrhagic stroke was 2.84 (0.66-12.28) in non-proliferative and 4.31 (1.16-16.10) in proliferative retinopathy. CSME did not increase HR for any stroke type after adjustment for clinical confounders (data not shown). CONCLUSIONS: Stroke incidence increases with the severity of diabetic retinopathy independently of comorbid conditions, including diabetic kidney disease.

Incidence and risk factors for cancer in people with type 1 diabetes, stratified by stages of diabetic kidney disease: a nationwide Finnish cohort study.

Background: Individuals with type 1 diabetes (T1D) have been reported to have increased overall risk of cancer. In addition, individuals with a kidney transplant/transplantation (KT) have markedly increased cancer risk due to chronic use of immunosuppressive agents. However, it has not been elucidated whether the observed excess cancer risk is related to KT or whether diabetic kidney disease (DKD) per se is a risk factor for cancer in individuals with T1D. Methods: The study included 5035 individuals from the Finnish Diabetic Nephropathy Study (FinnDiane) and 14,061 control individuals without diabetes. We assessed the standardized incidence ratios (SIRs) for cancers in individuals with T1D compared to controls according to DKD status. Cox regression analyses were used to identify potential risk factors for cancer in individuals with type 1 diabetes. Findings: The SIR for overall cancer for all participants was 1.14 (1.05-1.24), for participants without KT 0.92 (0.83-1.01) and for participants with KT 4.78 (4.02-5.64). Participants without KT had in fact a reduced risk of prostate cancer with a SIR of 0.54 (0.37-0.76), cancer of urinary organs 0.41 (0.21-0.73) and respiratory and intrathoracic organs, 0.62 (0.38-0.97). Participants with KT had on the contrary an increased risk of non-melanoma skin cancer, SIR 14.50 (10.99-18.86), cancer in the lymphoid and hematopoietic tissue 5.38 (2.99-8.96), mouth or pharynx 5.13 (2.08-10.66), melanoma 5.12 [2.38-9.72]) and respiratory and intrathoracic organs 2.77 (1.21-5.49). The risk of thyroid cancer was increased both in participants without KT, SIR 2.14 (1.39-3.16) and with KT 5.30 (1.68-12.78). Interpretation: The excess overall cancer risk in individuals with type 1 diabetes is only seen in KT recipients and in thyroid cancer. The individuals without KT seem to have a decreased risk of some forms of cancer. Funding: Folkhälsan Research Foundation, Academy of Finland [316664], Wilhelm and Else Stockmann Foundation, Liv och Hälsa Society, Novo Nordisk Foundation [NNF OC0013659], Finnish Foundation for Cardiovascular Research, Finnish Diabetes Research Foundation, Medical Society of Finland, Sigrid Jusélius Foundation, and Helsinki University Hospital Research Funds [TYH2018207 and TYH 2020305].

The use of dietary supplements, and the association between supplemental vitamin D and glycaemic control in adult individuals with type 1 diabetes.

AIMS: To assess the dietary supplement use in adult individuals with type 1 diabetes, and to study the association between vitamin D supplementation and glycaemic control in an observational cross-sectional study. METHODS: The study subjects were participants of the Finnish Diabetic Nephropathy Study. Data were included from all individuals with type 1 diabetes with estimated glomerular filtration rate ≥60 mL/min/1.73 m2, who had completed a diet questionnaire. In the questionnaire, the participants reported dietary supplement use for the past 30 days. A thorough investigation with an assessment of the blood panel was conducted at the study visit. RESULTS: Data were available from 1181 individuals (43% men, mean ± SD age 45 ± 13 years). Altogether 62% of the sample reported supplement use; 56% reported some vitamin or mineral and 27% reported non-vitamin and non-mineral supplement use. Supplement use was more frequent among women and those supplementing had better overall health. In the study sample, of the vitamins and minerals, vitamin D (45%) and magnesium (31%), respectively, were the most frequently reported. In the multivariable models, vitamin D supplementation was associated with better glycaemic control. Starting from a daily dose of ≥30 µg, there was evidence of improving glycaemic control with higher doses of supplemental vitamin D (e.g., for 30 µg: B [Wald Confidence Internal], p-value, -2.76 [-5.03 to -0.49], 0.017). CONCLUSIONS: Supplement use was frequent in this sample of adult individuals with type 1 diabetes. Due to potential drug-supplement interactions, the attending physicians should be aware of their patients' supplement use. The causality between vitamin D supplementation and glycaemic control should be assessed in a randomized controlled trial.

Clustering of risk behaviours and associations between risk behaviours and cardio-metabolic risk factors in adult individuals with type 1 diabetes.

AIMS: To assess clustering of risk behaviours and their health determinants. METHODS: Cross-sectional health behaviour and health data were collected from individuals with type 1 diabetes, in the FinnDiane Study. Clustering of risk behaviours was assessed and associations between behaviours and health variables were investigated. RESULTS: Data were available from 956 participants (40 % men, mean age 46 years). Altogether, 4.3 % individuals reported no risk behaviours, while 25.7 %, 37.4 %, 24.7 %, 6.8 %, and 1.0 % reported 1, 2, 3, 4, and 5 risk behaviours, respectively. Reporting ≥4 risk behaviours occurred more frequently than expected by chance. Dietary non-adherence was most frequently reported (84.4 %), followed by low LTPA (54.4 %), poor sleep (41.9 %), high alcohol consumption (15.2 %), and smoking (11.2 %). Adjusted for confounders, relative to ≤1 risk behaviour, reporting ≥2 risk behaviours was associated with higher BMI, waist circumference, and diastolic blood pressure. Having ≥3 risk behaviours was associated with larger waist-hip ratio, and higher HbA1c and triglyceride concentration; ≥4 risk behaviours was associated with higher cholesterol concentration. Of the health behaviours, low LTPA had the highest number of deleterious health associations. CONCLUSIONS: Accumulation of risk behaviors increases negative health outcomes. Exhibiting ≥2 risk behaviours or low LTPA was associated with multiple adverse outcomes.

No correlation between carotid intima-media thickness and long-term glycemic control in individuals with type 1 diabetes.

AIMS: To determine whether carotid intima-media thickness (CIMT), a surrogate marker of cardiovascular disease (CVD), is associated with long-term blood glucose control in individuals with type 1 diabetes (T1D). METHODS: We recruited 508 individuals (43.4% men; median age 46.1, IQR 37.8-55.9 years) with T1D (median diabetes duration of 30.4, IQR 21.2-40.8 years) in a cross-sectional retrospective sub-study, part of the Finnish Diabetic Nephropathy (FinnDiane) Study. Glycated hemoglobin (HbA1c) data were collected retrospectively over the course of ten years (HbA1c-meanoverall) prior to the clinical study visit that included a clinical examination, biochemical sampling, and ultrasound of the common carotid arteries. RESULTS: Individuals with T1D had a median CIMT of 606 µm (IQR 538-683 µm) and HbA1c of 8.0% (7.3-8.8%) during the study visit and HbA1c-meanoverall of 8.0% (IQR 7.3-8.8%). CIMT did not correlate with HbA1c (p = 0.228) at visit or HbA1c-meanoverall (p = 0.063). After controlling for relevant factors in multivariable linear regression analysis, only age was associated with CIMT (p < 0.001). After further dividing CIMT into quartiles, no correlation between long-term glucose control and CIMT (%, 1st 8.1 [IQR 7.2-8.9] vs 4th 7.9 [7.4-8.7], p = 0.730) was found. CONCLUSIONS: We observed no correlation between long-term blood glucose control and CIMT in individuals with T1D. This finding suggests that the development of early signs of macrovascular atherosclerosis is not strongly affected by the glycemic control in people with T1D.

Medication profiling in women with type 1 diabetes highlights the importance of adequate, guideline-based treatment in low-risk groups.

Effective treatment may prevent kidney complications, but women might be underprescribed. Novel, data-driven insights into prescriptions and their relationship with kidney health in women with type 1 diabetes may help to optimize treatment. We identified six medication profiles in 1164 women from the FinnDiane Study with normal albumin excretion rate based on clusters of their baseline prescription data using a self-organizing map. Future rapid kidney function decline was defined as an annual estimated glomerular filtration rate (eGFR) loss > 3 ml/min/1.73 m2 after baseline. Two profiles were associated with future decline: Profile ARB with the highest proportion of angiotensin receptor blockers (odds ratio [OR] 2.75, P = 0.02) and highly medicated women in profile HighMed (OR 2.55, P = 0.03). Compared with profile LowMed (low purchases of all), profile HighMed had worse clinical characteristics, whereas in profile ARB only systolic blood pressure was elevated. Importantly, the younger women in profile ARB with fewer kidney protective treatments developed a rapid decline despite otherwise similar baseline characteristics to profile ACE & Lipids (the highest proportions of ACE inhibitors and lipid-modifying agents) without a future rapid decline. In conclusion, medication profiles identified different future eGFR trajectories in women with type 1 diabetes revealing potential treatment gaps for younger women.

Rate of Kidney Function Decline is Associated With Kidney and Heart Failure in Individuals With Type 1 Diabetes.

Introduction: Diabetes is the most common cause of chronic kidney disease (CKD). Urinary albumin excretion rate (AER) and estimated glomerular filtration rate (eGFR) are commonly used to monitor the onset and progression of diabetic kidney disease (DKD). We studied if the preceding rate of kidney function decline, that is, the eGFR slope, is independently associated with incident clinical cardiorenal events. Methods: This study included longitudinal data for 2498 Finnish individuals with type 1 diabetes (T1D). The eGFR slope was calculated from 5 years preceding the study visit. Data on kidney failure, coronary heart disease (CHD), stroke, 3-point major adverse cardiovascular events (MACE), heart failure, and death were obtained from national registries. The associations between the eGFR slope and incident events were assessed with multivariable competing risk models during the average follow-up of 9.2 years. Results: The eGFR slopes were associated (P ≤ 0.001) with all outcomes when adjusted for age, sex, and HbA1c. However, eGFR slope remained associated only with the composite outcome of kidney failure or death when the albuminuria group and eGFR at the study visit were included in the model (P = 0.041). In addition, eGFR slope was independently associated with kidney failure in individuals without CKD (eGFR > 60 ml/min per 1.73 m2; P = 0.044), and with heart failure in those with CKD (P = 0.033). However, eGFR slope did not markedly improve the model C-index. Conclusion: The eGFR slope was independently associated with kidney failure in those without CKD, and with heart failure in those with CKD. However, it is unlikely to have major relevance for clinical practice when the current eGFR and albuminuria status are known.

Associations between alcohol consumption and body fat distribution in type 1 diabetes.

AIM: To evaluate the associations between alcohol consumption and body fat distribution in type 1 diabetes (T1D). METHODS: DXA assessed the body composition of 548 adults with T1D from the Finnish Diabetic Nephropathy Study. Visceral fat mass (VFM) ≥ 0.7% of body weight for women and ≥ 1.1% for men defined central obesity (CO), whereas body fat mass (BFM) ≥ 40.4% for women and ≥ 31.8% for men defined general obesity (GO). Alcohol consumption data were collected via questionnaires. One standard dose = 12 g of pure alcohol. Participants were classified as abstainers, low-risk, moderate-risk and high-risk alcohol consumers. We used linear and logistic regression models for analyses. RESULTS: The higher the alcohol consumption the higher the VFM% (r2 = 0.23, ß = 0.083, p = 0.04) in both sexes. BFM% presented a similar pattern in men (r2 = 0.12, ß = 0.160, p = 0.01), but not in women. One weekly dose increase of alcohol consumption increases the odds of CO by 3% (OR 1.03, p = 0.037), but not GO. The odds of CO (OR 7.3, p = 0.003) and GO (OR 5.3, p = 0.007) increase with high-risk, but not with low- and moderate-risk consumptions. CONCLUSIONS: In adults with T1D, alcohol consumption is linearly associated with VFM% regardless of sex, whereas the association with BFM% is sex-dependent.

Residual insulin secretion in individuals with type 1 diabetes in Finland: longitudinal and cross-sectional analyses.

BACKGROUND: Contrary to the presumption that type 1 diabetes leads to an absolute insulin deficiency, many individuals with type 1 diabetes have circulating C-peptide years after the diagnosis. We studied factors affecting random serum C-peptide concentration in individuals with type 1 diabetes and the association with diabetic complications. METHODS: Our longitudinal analysis included individuals newly diagnosed with type 1 diabetes from Helsinki University Hospital (Helsinki, Finland) with repeated random serum C-peptide and concomitant glucose measurements from within 3 months of diagnosis and at least once later. The long-term cross-sectional analysis included data from participants from 57 centres in Finland who had type 1 diabetes diagnosed after 5 years of age, initiation of insulin treatment within 1 year from diagnosis, and a C-peptide concentration of less than 1·0 nmol/L (FinnDiane study) and patients with type 1 diabetes from the DIREVA study. We tested the association of random serum C-peptide concentrations and polygenic risk scores with one-way ANOVA, and association of random serum C-peptide concentrations, polygenic risk scores, and clinical factors with logistic regression. FINDINGS: The longitudinal analysis included 847 participants younger than 16 years and 110 aged 16 years or older. In the longitudinal analysis, age at diagnosis strongly correlated with the decline in C-peptide secretion. The cross-sectional analysis included 3984 participants from FinnDiane and 645 from DIREVA. In the cross-sectional analysis, at a median duration of 21·6 years (IQR 12·5-31·2), 776 (19·4%) of 3984 FinnDiane participants had residual random serum C-peptide secretion (>0·02 nmol/L), which was associated with lower type 1 diabetes polygenic risk compared with participants without random serum C-peptide (p<0·0001). Random serum C-peptide was inversely associated with hypertension, HbA1c, and cholesterol, but also independently with microvascular complications (adjusted OR 0·61 [95% CI 0·38-0·96], p=0·033, for nephropathy; 0·55 [0·34-0·89], p=0·014, for retinopathy). INTERPRETATION: Although children with multiple autoantibodies and HLA risk genotypes progressed to absolute insulin deficiency rapidly, many adolescents and adults had residual random serum C-peptide decades after the diagnosis. Polygenic risk of type 1 and type 2 diabetes affected residual random serum C-peptide. Even low residual random serum C-peptide concentrations seemed to be associated with a beneficial complications profile. FUNDING: Folkhälsan Research Foundation; Academy of Finland; University of Helsinki and Helsinki University Hospital; Medical Society of Finland; the Sigrid Juselius Foundation; the "Liv and Hälsa" Society; Novo Nordisk Foundation; and State Research Funding via the Helsinki University Hospital, the Vasa Hospital District, Turku University Hospital, Vasa Central Hospital, Jakobstadsnejdens Heart Foundation, and the Medical Foundation of Vaasa.

The impact of diabetic nephropathy and severe diabetic retinopathy on chronic limb threatening ischemia risk in individuals with type 1 diabetes: a nationwide, population study.

Background: The prevalence, incidence and risk factors and especially the effect of diabetic nephropathy (DN) and diabetic retinopathy on the risk of chronic limb threatening ischemia (CLTI) have been sparsely studied in individuals with type 1 diabetes (T1D). Methods: The prospective cohort study consisted of 4697 individuals with T1D from the nationwide Finnish Diabetic Nephropathy (FinnDiane) Study. Medical records were thoroughly reviewed in order to ascertain all CLTI events. The key risk factors were DN and severe diabetic retinopathy (SDR). Findings: There were 319 events of confirmed CLTI, 102 prevalent events at baseline and 217 incident events during the follow-up of 11.9 (IQR 9.3-13.8) years. The 12-year cumulative incidence of CLTI was 4.6% (95% CI 4.0-5.3). Risk factors included presence of DN, SDR, age, duration of diabetes, HbA1c, systolic blood pressure, triglycerides and current smoking. Sub-hazard ratios (SHRs) according to combinations of DN status and presence (+) or absence (-) of SDR were 4.8 (2.0-11.7) for normoalbuminuria/SDR+, 3.2 (1.1-9.4) for microalbuminuria/SDR-, 11.9 (5.4-26.5) for microalbuminuria/SDR+, 8.7 (3.2-23.2) for macroalbuminuria/SDR-, 15.6 (7.4-33.0) for macroalbuminuria/SDR+ and 37.9 (17.2-78.9) for kidney failure compared with individuals with normal albumin excretion rate and without SDR. Interpretation: Diabetic nephropathy, especially kidney failure, is associated with high risk of limb threatening ischemia in individuals with T1D. The risk of CLTI increases gradually according to the severity of diabetic nephropathy. Also, diabetic retinopathy is independently and additively associated with high risk of CLTI. Funding: This research was funded by grants from Folkhälsan Research Foundation, Academy of Finland (316664), Wilhelm and Else Stockmann Foundation, Liv och Hälsa Society, Novo Nordisk Foundation (NNF OC0013659), Finnish Foundation for Cardiovascular Research, Finnish Diabetes Research Foundation, Medical Society of Finland, Sigrid Jusélius Foundation and Helsinki University Hospital Research Funds.

L-type calcium channel blocker increases VEGF concentrations in retinal cells and human serum.

OBJECTIVE: Vascular endothelial growth factor (VEGF) plays a key role in diabetic retinopathy (DR). Previously, we have reported an association between mutations in a gene coding for the L-type calcium channel subunit, VEGF and DR. L-type calcium channel blockers (LTCCBs) have been widely used as antihypertensive medication (AHM), but their association with VEGF and DR is still unclear. Therefore, we explored the effect of LTCCBs compared to other AHMs on VEGF concentrations in retinal cells and human serum. Furthermore, we evaluated the association between the use of LTCCBs and the risk of severe diabetic eye disease (SDED). RESEARCH DESIGN AND METHODS: Müller cells (MIO-M1) were cultured as per recommended protocol and treated with LTCCBs and other AHMs. VEGF secreted from cells were collected at 24 hours intervals. In an interventional study, 39 individuals received LTCCBs or other AHM for four weeks with a four-week wash-out placebo period between treatments. VEGF was measured during the medication and placebo periods. Finally, we evaluated the risk of SDED associated with LTCCB usage in 192 individuals from the FinnDiane Study in an observational setting. RESULTS: In the cell cultures, the medium VEGF concentration increased time-dependently after amlodipine (P<0.01) treatment, but not after losartan (P>0.01), or lisinopril (P>0.01). Amlodipine, but no other AHM, increased the serum VEGF concentration (P<0.05) during the interventional clinical study. The usage of LTCCB was not associated with the risk of SDED in the observational study. CONCLUSIONS: LTCCB increases VEGF concentrations in retinal cells and human serum. However, the usage of LTCCBs does not appear to be associated with SDED in adults with type 1 diabetes.

Higher HbA1c variability is associated with increased arterial stiffness in individuals with type 1 diabetes.

BACKGROUND: Both long-term glycaemic variability and arterial stiffness have been recognized as cardiovascular risk factors. This study aims to investigate whether an association between these phenomena exists in individuals with type 1 diabetes. METHODS: This cross-sectional study included 673 adults (305 men, 368 women) with type 1 diabetes and combined available retrospective laboratory data on HbA1c from the preceding 10 years with outcome data on arterial stiffness and clinical variables from a comprehensive study visit. HbA1c variability was calculated as adjusted standard deviation (adj-HbA1c-SD), coefficient of variation (HbA1c-CV) and average real variability (HbA1c-ARV). As measures of arterial stiffness, carotid-femoral pulse wave velocity (cfPWV; n = 335) and augmentation index (AIx; n = 653) were assessed using applanation tonometry. RESULTS: The study population had a mean age of 47.1 (± 12.0) years and a median duration of diabetes of 31.2 (21.2-41.3) years. The median number of HbA1c assessments per individual was 17 (12-26). All three indices of HbA1c variability were significantly correlated with both cfPWV and AIx after adjustment for sex and age (p < 0.001). In separate multivariable linear regression models, adj-HbA1c-SD and HbA1c-CV were significantly associated with cfPWV (p = 0.032 and p = 0.046, respectively) and AIx (p = 0.028 and p = 0.049, respectively), even after adjustment for HbA1c-mean. HbA1c-ARV was not associated with cfPWV or AIx in the fully adjusted models. CONCLUSIONS: An association independent of HbA1c-mean was found between HbA1c variability and arterial stiffness, suggesting a need to consider multiple HbA1c metrics in studies assessing cardiovascular risk in type 1 diabetes. Longitudinal and interventional studies are needed to confirm any causal relationship and to find strategies for reducing long-term glycaemic variability.

Prognosis After First-Ever Myocardial Infarction in Type 1 Diabetes Is Strongly Affected by Chronic Kidney Disease.

OBJECTIVE: To study prognosis after a first-ever myocardial infarction (MI) in type 1 diabetes, as well as how different MI- and diabetes-related factors affect the prognosis and risk of secondary cardiovascular events. RESEARCH DESIGN AND METHODS: In this observational follow-up study of 4,217 individuals from the Finnish Diabetic Nephropathy (FinnDiane) Study with no prior MI or coronary revascularization, we verified 253 (6.0%) MIs from medical records or death certificates. Mortality from cardiovascular or diabetes-related cause was our main end point, whereas hospitalization due to heart failure, coronary revascularization, and recurrent MI were secondary end points, while accounting for death as a competing risk. RESULTS: Of the individuals studied, 187 (73.9%) died during the median post-MI follow-up of 3.07 (interquartile range 0.02-8.45) years. Independent risk factors for cardiovascular and diabetes-related mortality were estimated glomerular filtration rate categories grade 3 (G3) (hazard ratio [HR] 3.27 [95% CI 1.76-6.08]), G4 (3.62 [1.69-7.73]), and G5 (4.03 [2.24-7.26]); prior coronary heart disease diagnosis (1.50 [1.03-2.20]); and older age at MI (1.03 [1.00-1.05]). Factors associated with lower mortality were acute revascularization (HR 0.35 [95% CI 0.18-0.72]) and subacute revascularization (0.39 [0.26-0.59]). In Fine and Gray competing risk analyses, kidney failure was associated with a higher risk of recurrent MI (subdistribution HR 3.27 [95% CI 2.01-5.34]), heart failure (3.76 [2.46-5.76]), and coronary revascularization (3.04 [1.89-4.90]). CONCLUSIONS: Individuals with type 1 diabetes have a high cardiovascular and diabetes-related mortality after their first-ever MI. In particular, poor kidney function is associated with high mortality and excessive risk of secondary cardiovascular events.

Haptoglobin Genotype Does Not Confer a Risk of Stroke in Type 1 Diabetes.

The exon copy number variant in the haptoglobin gene is associated with cardiovascular and kidney disease. For stroke, previous research is inconclusive. We aimed to study the relationship between the haptoglobin Hp1/2 genotype and stroke in individuals with type 1 diabetes from the Finnish Diabetic Nephropathy Study. We included two partially overlapping cohorts: one with haptoglobin genotypes determined using genotyping for 179 individuals with stroke and 517 matched control subjects, and the other using haptoglobin genotype imputation for a larger cohort of 500 individuals with stroke and 3,806 individuals without stroke. We observed no difference in the Hp1-1, Hp2-1, and Hp2-2 genotype frequencies between individuals with or without stroke, neither in the genotyping nor the imputation cohorts. Haptoglobin genotypes were also not associated with the ischemic or hemorrhagic stroke subtypes. In our imputed haptoglobin cohort, 61% of individuals with stroke died during follow-up. However, the risk of death was not related to the haptoglobin genotype. Diabetic kidney disease and cardiovascular events were common in the cohort, but the haptoglobin genotypes were not associated with stroke when stratified by these complications. To conclude, the Hp1/2 genotypes did not affect the risk of stroke or survival after stroke in our cohort with type 1 diabetes.

Whole-exome sequencing identifies novel protein-altering variants associated with serum apolipoprotein and lipid concentrations.

BACKGROUND: Dyslipidemia is a major risk factor for cardiovascular disease, and diabetes impacts the lipid metabolism through multiple pathways. In addition to the standard lipid measurements, apolipoprotein concentrations provide added awareness of the burden of circulating lipoproteins. While common genetic variants modestly affect the serum lipid concentrations, rare genetic mutations can cause monogenic forms of hypercholesterolemia and other genetic disorders of lipid metabolism. We aimed to identify low-frequency protein-altering variants (PAVs) affecting lipoprotein and lipid traits. METHODS: We analyzed whole-exome (WES) and whole-genome sequencing (WGS) data of 481 and 474 individuals with type 1 diabetes, respectively. The phenotypic data consisted of 79 serum lipid and apolipoprotein phenotypes obtained with clinical laboratory measurements and nuclear magnetic resonance spectroscopy. RESULTS: The single-variant analysis identified an association between the LIPC p.Thr405Met (rs113298164) and serum apolipoprotein A1 concentrations (p=7.8×10-8). The burden of PAVs was significantly associated with lipid phenotypes in LIPC, RBM47, TRMT5, GTF3C5, MARCHF10, and RYR3 (p<2.9×10-6). The RBM47 gene is required for apolipoprotein B post-translational modifications, and in our data, the association between RBM47 and apolipoprotein C-III concentrations was due to a rare 21 base pair p.Ala496-Ala502 deletion; in replication, the burden of rare deleterious variants in RBM47 was associated with lower triglyceride concentrations in WES of >170,000 individuals from multiple ancestries (p=0.0013). Two PAVs in GTF3C5 were highly enriched in the Finnish population and associated with cardiovascular phenotypes in the general population. In the previously known APOB gene, we identified novel associations at two protein-truncating variants resulting in lower serum non-HDL cholesterol (p=4.8×10-4), apolipoprotein B (p=5.6×10-4), and LDL cholesterol (p=9.5×10-4) concentrations. CONCLUSIONS: We identified lipid and apolipoprotein-associated variants in the previously known LIPC and APOB genes, as well as PAVs in GTF3C5 associated with LDLC, and in RBM47 associated with apolipoprotein C-III concentrations, implicated as an independent CVD risk factor. Identification of rare loss-of-function variants has previously revealed genes that can be targeted to prevent CVD, such as the LDL cholesterol-lowering loss-of-function variants in the PCSK9 gene. Thus, this study suggests novel putative therapeutic targets for the prevention of CVD.

Genome-wide meta-analysis and omics integration identifies novel genes associated with diabetic kidney disease.

AIMS/HYPOTHESIS: Diabetic kidney disease (DKD) is the leading cause of kidney failure and has a substantial genetic component. Our aim was to identify novel genetic factors and genes contributing to DKD by performing meta-analysis of previous genome-wide association studies (GWAS) on DKD and by integrating the results with renal transcriptomics datasets. METHODS: We performed GWAS meta-analyses using ten phenotypic definitions of DKD, including nearly 27,000 individuals with diabetes. Meta-analysis results were integrated with estimated quantitative trait locus data from human glomerular (N=119) and tubular (N=121) samples to perform transcriptome-wide association study. We also performed gene aggregate tests to jointly test all available common genetic markers within a gene, and combined the results with various kidney omics datasets. RESULTS: The meta-analysis identified a novel intronic variant (rs72831309) in the TENM2 gene associated with a lower risk of the combined chronic kidney disease (eGFR<60 ml/min per 1.73 m2) and DKD (microalbuminuria or worse) phenotype (p=9.8×10-9; although not withstanding correction for multiple testing, p>9.3×10-9). Gene-level analysis identified ten genes associated with DKD (COL20A1, DCLK1, EIF4E, PTPRN-RESP18, GPR158, INIP-SNX30, LSM14A and MFF; p<2.7×10-6). Integration of GWAS with human glomerular and tubular expression data demonstrated higher tubular AKIRIN2 gene expression in individuals with vs without DKD (p=1.1×10-6). The lead SNPs within six loci significantly altered DNA methylation of a nearby CpG site in kidneys (p<1.5×10-11). Expression of lead genes in kidney tubules or glomeruli correlated with relevant pathological phenotypes (e.g. TENM2 expression correlated positively with eGFR [p=1.6×10-8] and negatively with tubulointerstitial fibrosis [p=2.0×10-9], tubular DCLK1 expression correlated positively with fibrosis [p=7.4×10-16], and SNX30 expression correlated positively with eGFR [p=5.8×10-14] and negatively with fibrosis [p<2.0×10-16]). CONCLUSIONS/INTERPRETATION: Altogether, the results point to novel genes contributing to the pathogenesis of DKD. DATA AVAILABILITY: The GWAS meta-analysis results can be accessed via the type 1 and type 2 diabetes (T1D and T2D, respectively) and Common Metabolic Diseases (CMD) Knowledge Portals, and downloaded on their respective download pages ( https://t1d.hugeamp.org/downloads.html ; https://t2d.hugeamp.org/downloads.html ; https://hugeamp.org/downloads.html ).