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Purpose: To review our institutional experience with the surgical management of prolactinomas through the endoscopic endonasal approach with specific focus on cavernous sinus invasion., Methods: Clinical and radiographic data were collected retrospectively from the electronic medical record of 78 consecutive patients with prolactinomas undergoing endoscopic endonasal resection from 2002 to 2019. Immediate and late post-operative remission were defined as prolactin < 20 ng/mL within 14 days and 1-year of surgery without adjuvant therapy, respectively. Cavernous sinus invasion was quantified by Knosp score., Results: A total of 78 patients with prolactinoma, 59% being male, underwent surgical resection with a mean age of 37 ± 13 years. Indications for surgery were medication resistance in 38 patients (48.7%), medication intolerance in 11 (14.1%), and patient preference in 29 (37.2%). Patients with Knosp 0-2 achieved higher immediate remission rates (83.8%) compared to patients with Knosp 3 (58.8%) and Knosp 4 (41.7%) patients (p = 0.003). Long-term remission rates were 48.7% and increased to 71.8% when combined with adjuvant treatments. Knosp 4 prolactinomas had significantly higher tumor volumes, higher preoperative prolactin levels, higher recurrence rates, higher rates of adjuvant therapy utilization, and were more likely to have failed dopamine agonist therapy compared to other tumor grades (p < 0.05). We encountered 18 complications in our series, and no cerebrospinal fluid leaks., Conclusion: The endoscopic endonasal approach is a safe and effective modality that can be employed in properly selected patients with invasive prolactinomas. It is associated with improved control and remission rates despite cavernous sinus invasion, though at a lower rate than without invasion., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Older adults receive treatment for fall injuries in both inpatient and outpatient settings. The effect of persistent polypharmacy (i.e. using multiple medications over a long period) on fall injuries is understudied, particularly for outpatient injuries. We examined the association between persistent polypharmacy and treated fall injury risk from inpatient and outpatient settings in community-dwelling older adults., Methods: The Health, Aging and Body Composition Study included 1764 community-dwelling adults (age 73.6 ± 2.9 years; 52% women; 38% black) with Medicare Fee-For-Service (FFS) claims at or within 6 months after 1998/99 clinic visit. Incident fall injuries (N = 545 in 4.6 ± 2.9 years) were defined as the initial claim with an ICD-9 fall E-code and non-fracture injury, or fracture code with/without a fall code from 1998/99 clinic visit to 12/31/08. Those without fall injury (N = 1219) were followed for 8.1 ± 2.6 years. Stepwise Cox models of fall injury risk with a time-varying variable for persistent polypharmacy (defined as ≥6 prescription medications at the two most recent consecutive clinic visits) were adjusted for demographics, lifestyle characteristics, chronic conditions, and functional ability. Sensitivity analyses explored if persistent polypharmacy both with and without fall risk increasing drugs (FRID) use were similarly associated with fall injury risk., Results: Among 1764 participants, 636 (36%) had persistent polypharmacy over the follow-up period, and 1128 (64%) did not. Fall injury incidence was 38 per 1000 person-years. Persistent polypharmacy increased fall injury risk (hazard ratio [HR]: 1.31 [1.06, 1.63]) after adjusting for covariates. Persistent polypharmacy with FRID use was associated with a 48% increase in fall injury risk (95%CI: 1.10, 2.00) vs. those who had non-persistent polypharmacy without FRID use. Risks for persistent polypharmacy without FRID use (HR: 1.22 [0.93, 1.60]) and non-persistent polypharmacy with FRID use (HR: 1.08 [0.77, 1.51]) did not significantly increase compared to non-persistent polypharmacy without FRID use., Conclusions: Persistent polypharmacy, particularly combined with FRID use, was associated with increased risk for treated fall injuries from inpatient and outpatient settings. Clinicians may need to consider medication management for FRID and other fall prevention strategies in community-dwelling older adults with persistent polypharmacy to reduce fall injury risk., (© 2021. The Author(s).)

Background: Skin intrinsic fluorescent (SIF) scores are indirect measures of advanced glycation end-products (AGEs). SIF scores are cross-sectionally associated with type 1 diabetes (T1D) complications such as increased albumin excretion rate (AER), coronary artery calcification (CAC) and neuropathy. We assessed predictors of SIF score change in those with T1D., Methods: Data from the 30-year longitudinal Epidemiology of Diabetes Complications (EDC) study of childhood-onset T1D were used to assess AGEs measured with a SIF score produced by the SCOUT DS® device. SIF scores were assessed twice in 83 participants: between 2007-08 and again between 2010-14. Regression analyses were used to assess independent predictors of SIF score change., Results: At baseline, mean age was 47.9 ± 6.9 years, diabetes duration was 36.7 ± 6.4 years, and median glycosylated hemoglobin (HbA1c) was 7.1 (interquartile range: 6.5, 8.5). During a mean follow-up of 5.2 ± 0.9 years, mean change in SIF score was 2.9 ± 2.8 arbitrary units. In multivariable linear regression models, log HbA1c ( P < 0.001), log estimated glomerular filtration rate (eGFR) ( P < 0.001), overt nephropathy (defined as AER ≥ 200 µg/min, P = 0.06), and multiple daily insulin shots/pump use (MDI) exposure years ( P = 0.02) were independent predictors of SIF score change., Conclusions: Increases in SIF score over 5 years were related to increased glycemic levels and decreased kidney function (eGFR). MDI and glomerular damage were related to a decreased SIF score. This is one of the first studies with repeated SIF assessments in T1D and provides unique, albeit preliminary, insight about these associations.

Background: Rare variants in gene coding regions likely have a greater impact on disease-related phenotypes than common variants through disruption of their encoded protein. We searched for rare variants associated with onset of ESKD in individuals with type 1 diabetes at advanced kidney disease stage., Methods: Gene-based exome array analyses of 15,449 genes in five large incidence cohorts of individuals with type 1 diabetes and proteinuria were analyzed for survival time to ESKD, testing the top gene in a sixth cohort ( n =2372/1115 events all cohorts) and replicating in two retrospective case-control studies ( n =1072 cases, 752 controls). Deep resequencing of the top associated gene in five cohorts confirmed the findings. We performed immunohistochemistry and gene expression experiments in human control and diseased cells, and in mouse ischemia reperfusion and aristolochic acid nephropathy models., Results: Protein coding variants in the hydroxysteroid 17- β dehydrogenase 14 gene ( HSD17B14 ), predicted to affect protein structure, had a net protective effect against development of ESKD at exome-wide significance ( n =4196; P value=3.3 × 10 -7 ). The HSD17B14 gene and encoded enzyme were robustly expressed in healthy human kidney, maximally in proximal tubular cells. Paradoxically, gene and protein expression were attenuated in human diabetic proximal tubules and in mouse kidney injury models. Expressed HSD17B14 gene and protein levels remained low without recovery after 21 days in a murine ischemic reperfusion injury model. Decreased gene expression was found in other CKD-associated renal pathologies., Conclusions: HSD17B14 gene is mechanistically involved in diabetic kidney disease. The encoded sex steroid enzyme is a druggable target, potentially opening a new avenue for therapeutic development., (Copyright © 2021 by the American Society of Nephrology.)

Objective: Women with type 1 diabetes (T1D) are thought to experience menopause earlier than women without diabetes, although not all studies agree. We assessed metabolic predictors of the age at which natural menopause occurs among women with T1D participating in the Epidemiology of Diabetes Complications study., Methods: Women with childhood-onset (<17 y) of T1D who underwent natural menopause without use of hormone therapy during their menopausal transition were included in the analysis (n = 105; mean baseline age, 29.5 and diabetes duration, 20.2 y). Self-reported reproductive history and the Women's Ischemia Syndrome Evaluation hormonal algorithms were used to determine menopause status. Linear regression was used to ascertain whether time-weighted metabolic factors (eg, BMI, lipids, HbA1c, insulin dose, albumin excretion rate [AER]) were associated with age at natural menopause., Results: Univariately, only insulin dose (β = -4.87, P = 0.04) and log (AER) (β = -0.62, P = 0.02) were associated (negatively) with age at natural menopause. Adjusting for BMI, smoking status, lipids, HbA1c, number of pregnancies, and oral contraceptive use, each 0.1 unit increase in the daily dose of insulin per kilogram body weight was associated with 0.64 years younger age at natural menopause (P = 0.01), while for every 30% increase in AER, age at natural menopause decreased by 0.18 years (P = 0.03)., Conclusion: Higher average levels of insulin dose and AER over time were significantly associated with a younger age at which natural menopause occurred among women with T1D. The biologic mechanisms underlying the observed associations between exogenous insulin dose and AER on reproductive health should be investigated among women with T1D., Competing Interests: Financial disclosures/conflicts of interest: R.G.M. receives funding from the American Diabetes Association. The other authors have nothing to disclose., (Copyright © 2021 by The North American Menopause Society.)

Aims/hypothesis: Type 1 diabetes increases CHD risk. We examined the use of the American Heart Association's cardiovascular health metrics (blood pressure, total cholesterol, glucose/HbA 1c , BMI, physical activity, diet, smoking) to predict incidence of CHD among individuals with type 1 diabetes, with the hypothesis that a better American Heart Association health metric profile would be associated with lower incident CHD., Methods: Prevalence of the seven cardiovascular health metrics was determined using first and second visits from adult participants (mean age 28.6 years) in the Epidemiology of Diabetes Complications prospective cohort study of childhood-onset type 1 diabetes. An ideal metric score (0-7) was defined as the sum of all metrics within the ideal range, and a total metric score (0-14) was calculated based on poor, intermediate and ideal categories for each metric. Incident CHD development (medical record-confirmed CHD death, myocardial infarction, revascularisation, ischaemic electrocardiogram changes or Epidemiology of Diabetes Complications physician-determined angina) over 25 years of follow-up was examined by metric scores., Results: Among 435 participants, BMI, blood pressure, total cholesterol and smoking demonstrated the highest prevalence within the ideal range, while diet and HbA 1c demonstrated the lowest. During 25 years of follow-up, 177 participants developed CHD. In Cox models, each additional metric within the ideal range was associated with a 19% lower risk (p = 0.01), and each unit increase in total metric score was associated with a 17% lower risk (p < 0.01) of CHD, adjusting for diabetes duration, estimated glomerular filtration rate, albumin excretion rate, triacylglycerols, depression and white blood cell count., Conclusions/interpretation: Among individuals with type 1 diabetes, higher cardiovascular health metric scores were associated with lower risk of incident CHD. The American Heart Association-defined cardiovascular health metrics provide straightforward goals for health promotion that may reduce CHD risk in the type 1 diabetes population. Graphical abstract.

Objective: Evidence suggests that insulin deficiency and hyperglycemia may disrupt the female reproductive system's normal function, leading to delayed menarche and premature ovarian aging. We thus compared the length of the reproductive period of women with type 1 diabetes (T1D) to women without diabetes., Methods: Women with childhood-onset T1D (diagnosed in 1950-80) from the prospective Epidemiology of Diabetes Complications (EDC) study and nondiabetic women from the Pittsburgh site of the Study of Women's Health Across the Nation (SWAN) were studied. Exclusion criteria comprised not having reached natural menopause, hysterectomy/oophorectomy before menopause, and sex hormone therapy during the menopausal transition. Reproductive history was self-reported. The historical and Women's Ischemia Syndrome Evaluation hormonal algorithms were also used to assess menopause status., Results: Women in the T1D cohort (n = 105) were younger, more likely to be White, never smokers, with lower BMI and higher high-density lipoprotein cholesterol levels (all P values < 0.05) compared with women without diabetes (n = 178). After covariate adjustment, T1D women were also older at menarche (0.5-y delay, P = 0.002) but younger at natural menopause (-2.0 y, P < 0.0001). Women with T1D thus experienced 2.5 fewer reproductive years compared to those without diabetes (P < 0.0001). These findings were restricted to the subgroup of women who were diagnosed with T1D before reaching menarche (n = 80)., Conclusion: Women with T1D onset before menarche have a shorter reproductive period compared with nondiabetic women, exhibiting delayed menarche and earlier natural menopause. Factors that may be related to a shorter reproductive period in T1D should be investigated., Competing Interests: Financial disclosure/conflicts of interest: R.G.M. receives funding from the American Diabetes Association. The other authors have nothing to disclose., (Copyright © 2021 by The North American Menopause Society.)

Aims: We evaluated the relationship between the timing of insulin initiation and cardiovascular diseases (CVD) risk in Pennsylvania Medicaid enrollees with type 2 diabetes (T2D)., Methods: We included 17,873 enrollees (age 47.4 ± 10.3 years; range 18-64 years) initially treated with non-insulin glucose-lowering agents (GLAs) in 2008-2016. Based on clinical guidelines, we identified early (N = 1,158; 6%; insulin initiation ≤ 6 months after first-line GLAs), in-time (N = 569; 3%; 6-12 months), delayed (N = 2,761; 15%; >12 months), and non-insulin users (N = 13,385; 75%). The Prentice-Williams-Peterson (PWP) models with inverse probability weighting estimated CVD risk across the four groups and the change in risk after insulin initiation., Results: Regardless of time to insulin initiation, insulin users had higher CVD risks after first-line GLAs than non-insulin users (aHR: early: 2.0 [1.5-2.5], in-time: 1.8 [1.2-2.6], delayed: 1.9 [1.6-2.3]). However, we found only a borderline increase in CVD risk after insulin initiation vs. before in early (aHR: 1.4 [1.1-1.8]) and delayed users (aHR: 1.3 [1.0-1.7]), and no increase in in-time users (aHR: 1.3 [0.9-2.0])., Conclusions: We observed no gains in CVD benefits from insulin initiation in the early stages of pharmacotherapy possibly because CVD developed before insulin initiation. Additional management of hypertension and dyslipidemia may be important to reduce CVD risk in this young and middle-aged T2D cohort., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2020 The Authors.)

Background: Individuals with type 1 diabetes (T1D) demonstrate varied trajectories of estimated glomerular filtration rate (eGFR) decline. The molecular pathways underlying rapid eGFR decline in T1D are poorly understood, and individual-level risk of rapid eGFR decline is difficult to predict., Methods: We designed a case-control study with multiple exposure measurements nested within 4 well-characterized T1D cohorts (FinnDiane, Steno, EDC, and CACTI) to identify biomarkers associated with rapid eGFR decline. Here, we report the rationale for and design of these studies as well as results of models testing associations of clinical characteristics with rapid eGFR decline in the study population, upon which "omics" studies will be built. Cases (n = 535) and controls (n = 895) were defined as having an annual eGFR decline of ≥3 and <1 mL/min/1.73 m2, respectively. Associations of demographic and clinical variables with rapid eGFR decline were tested using logistic regression, and prediction was evaluated using area under the curve (AUC) statistics. Targeted metabolomics, lipidomics, and proteomics are being performed using high-resolution mass-spectrometry techniques., Results: At baseline, the mean age was 43 years, diabetes duration was 27 years, eGFR was 94 mL/min/1.73 m2, and 62% of participants were normoalbuminuric. Over 7.6-year median follow-up, the mean annual change in eGFR in cases and controls was -5.7 and 0.6 mL/min/1.73 m2, respectively. Younger age, longer diabetes duration, and higher baseline HbA1c, urine albumin-creatinine ratio, and eGFR were significantly associated with rapid eGFR decline. The cross-validated AUC for the predictive model incorporating these variables plus sex and mean arterial blood pressure was 0.74 (95% CI: 0.68-0.79; p < 0.001)., Conclusion: Known risk factors provide moderate discrimination of rapid eGFR decline. Identification of blood and urine biomarkers associated with rapid eGFR decline in T1D using targeted omics strategies may provide insight into disease mechanisms and improve upon clinical predictive models using traditional risk factors., (© 2020 S. Karger AG, Basel.)

Purpose of Review: The protection against CVD observed in women compared to men in the general population is essentially erased in type 1 diabetes. This review will discuss evidence regarding the role of glucose management on CVD risk by sex, with a particular focus on studies of long-duration type 1 diabetes of > 20 years., Recent Findings: Across studies, women with type 1 diabetes have similar or worse glycemic control compared to men, despite higher rates of intensive insulin therapy. The association between HbA1c and CVD risk does not seem to differ by sex, but few studies have reported on sex-specific analyses. Beyond HbA1c, there is a lack of published data regarding the relationship between other aspects of glucose management and CVD risk by sex in type 1 diabetes. Glucose management factors do not seem to directly account for the increased CVD risk in women with type 1 diabetes, but may influence other risk factors that play a more direct role.

Background: Although diabetic kidney disease demonstrates both familial clustering and single nucleotide polymorphism heritability, the specific genetic factors influencing risk remain largely unknown., Methods: To identify genetic variants predisposing to diabetic kidney disease, we performed genome-wide association study (GWAS) analyses. Through collaboration with the Diabetes Nephropathy Collaborative Research Initiative, we assembled a large collection of type 1 diabetes cohorts with harmonized diabetic kidney disease phenotypes. We used a spectrum of ten diabetic kidney disease definitions based on albuminuria and renal function., Results: Our GWAS meta-analysis included association results for up to 19,406 individuals of European descent with type 1 diabetes. We identified 16 genome-wide significant risk loci. The variant with the strongest association (rs55703767) is a common missense mutation in the collagen type IV alpha 3 chain ( COL4A3) gene, which encodes a major structural component of the glomerular basement membrane (GBM). Mutations in COL4A3 are implicated in heritable nephropathies, including the progressive inherited nephropathy Alport syndrome. The rs55703767 minor allele (Asp326Tyr) is protective against several definitions of diabetic kidney disease, including albuminuria and ESKD, and demonstrated a significant association with GBM width; protective allele carriers had thinner GBM before any signs of kidney disease, and its effect was dependent on glycemia. Three other loci are in or near genes with known or suggestive involvement in this condition ( BMP7) or renal biology ( COLEC11 and DDR1 )., Conclusions: The 16 diabetic kidney disease-associated loci may provide novel insights into the pathogenesis of this condition and help identify potential biologic targets for prevention and treatment., (Copyright © 2019 by the American Society of Nephrology.)

Aims: To evaluate recent trends, by diagnosis year, in the cumulative incidence of vascular type 1 diabetes (T1D) complications and their risk factors up to 35 years duration., Methods: Participants from the Epidemiology of Diabetes Complications study of childhood-onset T1D were categorized into three calendar year onset cohorts: 1965-69, 1970-74, and 1975-80. All-cause, cardiovascular and renal mortality were determined both on the complete cohort (n=440) as well as in the subset with clinical examinations (n=363). Coronary artery disease (CAD, CAD death, myocardial infarction, revascularization, angina and ischemic ECG abnormalities); lower extremity arterial disease (LEAD, abnormal Ankle Brachial Index/amputation/intermittent claudication); distal symmetric polyneuropathy (DSP, clinical exam); cardiac autonomic neuropathy (CAN, abnormal heart rate response to deep breathing); overt nephropathy (ON, albumin excretion rate>200 μg/min) and proliferative retinopathy (PR, fundus photography) were assessed on the subset with clinical examinations., Results: While all-cause, cardiovascular and renal mortality improved with a more recent diagnosis in the overall cohort, no univariate differences were observed for complications requiring examination (CAD, DSP, CAN, ON), although a borderline trend toward improved complication-free survival with a more recent onset was observed for PR (p=0.06). LEAD incidence showed an anomalous pattern, being highest in the 1975-80 and lowest in the 1970-74 cohort (p=0.009). Allowing for risk factors over time did not materially change these results., Conclusions: Despite declines in all-cause, cardiovascular and renal mortality in the total cohort, no improvements were observed in either mortality or complication incidence with a more recent onset in the examined cohort.

Objectives  This study is to examine the association between different diagnostic criteria for gestational diabetes mellitus (GDM) and adverse birth outcomes. Study Design  A retrospective cohort study of 5,937 women with a singleton pregnancy was conducted, who completed GDM screening between 24 to 32 weeks gestational age. Four nonoverlapping groups of women defined as: 1) Normal: glucose challenge test (GCT) <130 mg/dL, 2) elevated GCT + normal oral glucose tolerance test (OGTT): abnormal 1 hour GCT + normal 3 hour OGTT, 3) GDM/International Association of Diabetes in Pregnancy Study Group (IADPSG): abnormal 3 hour OGTT by the IADPSG criteria, and 4) GDM/Carpenter-Coustan (CC): diagnosis per CC criteria. We used logistic regression to examine the association between GDM group classification and main outcome of macrosomia and secondary birth outcomes. Results  Prevalences were GDM/CC 4.6%, GDM/IADPSG 3.0, and 7.6% overall. GDM/IADPSG group was associated with increased macrosomia (adj OR [odd ratio] 1.87; 95% CI [confidence interval]: 1.08-3.25; p  = 0.02), while GDM/CC group was associated with increased preterm birth (adj OR 1.75; 95% CI: 1.05-2.80; p  = 0.03). Conclusion  Little difference in birth outcomes was found between the two criteria, GDM/CC and GDM/IADPSG. Randomized controlled trials are needed to clarify the risks and benefits of these screening paradigms before their incorporation into clinical practice.

Introduction: Plasmin and its precursor, plasminogen, are detectable in urine from patients with glomerular disease. Urinary plasmin(ogen) levels correlate with blood pressure (BP) and may contribute to renal Na + retention by activating the epithelial Na + channel (ENaC). In a longitudinal nested-cohort study, we asked whether urinary plasmin(ogen) levels predict subsequent increase in BP, incident hypertension, or mortality in subjects with type I diabetes, who often develop proteinuria., Methods: The Pittsburgh Epidemiology of Diabetes Complications (EDC) study followed up type I diabetic subjects for 25 years. Urine specimens from 70 subjects with a spectrum of baseline urinary albumin levels were examined. Outcomes included increased BP after 2 years (≥1 SD over baseline systolic or diastolic BP, examined via logistic regression), 25-year incident hypertension (≥140/90 mm Hg or initiating BP-lowering medications), and all-cause or cardiovascular mortality, examined using Cox regression., Results: Subjects experiencing a 2-year increase in BP had higher baseline urinary plasmin(ogen)/creatinine levels (uPl/Cr) than other subjects ( P  = 0.04); the difference in baseline urinary albumin/creatinine levels (uAlb/Cr) was similar ( P  = 0.07). Baseline uPl/Cr was associated with increased 25-year hypertension incidence (hazard ratio = 2.05, P  = 0.001), all-cause mortality (HR = 2.05, P  = 0.01) and cardiovascular mortality (HR = 3.30, P  = 0.005), although not independent of uAlb/Cr., Conclusion: This is the first long-term prospective study addressing clinical outcomes associated with increased urinary plasmin(ogen). Findings are consistent with a role for plasmin(ogen) in promoting increased BP, but also demonstrate the difficulty in distinguishing effects due to plasmin(ogen) from those of albuminuria.

Aims/hypothesis: The aim of this study was to identify genetic variants associated with beta cell function in type 1 diabetes, as measured by serum C-peptide levels, through meta-genome-wide association studies (meta-GWAS)., Methods: We performed a meta-GWAS to combine the results from five studies in type 1 diabetes with cross-sectionally measured stimulated, fasting or random C-peptide levels, including 3479 European participants. The p values across studies were combined, taking into account sample size and direction of effect. We also performed separate meta-GWAS for stimulated (n = 1303), fasting (n = 2019) and random (n = 1497) C-peptide levels., Results: In the meta-GWAS for stimulated/fasting/random C-peptide levels, a SNP on chromosome 1, rs559047 (Chr1:238753916, T>A, minor allele frequency [MAF] 0.24-0.26), was associated with C-peptide (p = 4.13 × 10 -8 ), meeting the genome-wide significance threshold (p < 5 × 10 -8 ). In the same meta-GWAS, a locus in the MHC region (rs9260151) was close to the genome-wide significance threshold (Chr6:29911030, C>T, MAF 0.07-0.10, p = 8.43 × 10 -8 ). In the stimulated C-peptide meta-GWAS, rs61211515 (Chr6:30100975, T/-, MAF 0.17-0.19) in the MHC region was associated with stimulated C-peptide (β [SE] = - 0.39 [0.07], p = 9.72 × 10 -8 ). rs61211515 was also associated with the rate of stimulated C-peptide decline over time in a subset of individuals (n = 258) with annual repeated measures for up to 6 years (p = 0.02). In the meta-GWAS of random C-peptide, another MHC region, SNP rs3135002 (Chr6:32668439, C>A, MAF 0.02-0.06), was associated with C-peptide (p = 3.49 × 10 -8 ). Conditional analyses suggested that the three identified variants in the MHC region were independent of each other. rs9260151 and rs3135002 have been associated with type 1 diabetes, whereas rs559047 and rs61211515 have not been associated with a risk of developing type 1 diabetes., Conclusions/interpretation: We identified a locus on chromosome 1 and multiple variants in the MHC region, at least some of which were distinct from type 1 diabetes risk loci, that were associated with C-peptide, suggesting partly non-overlapping mechanisms for the development and progression of type 1 diabetes. These associations need to be validated in independent populations. Further investigations could provide insights into mechanisms of beta cell loss and opportunities to preserve beta cell function.

Aims: Despite recent findings of increased life expectancy among individuals with type 1 diabetes, mortality remains greatly increased compared to the general population. As this is largely the result of cardiovascular and renal complications, we aimed to review recent findings surrounding these diseases in type 1 diabetes., Methods: We reviewed published findings concerning the cardiovascular complications of type 1 diabetes, with a particular focus on links with renal disease., Results: The cardiovascular and renal complications of type 1 diabetes share many features including insulin resistance, oxidative damage, and genetic associations with the Haptoglobin genotype, and both are strongly affected by glycemic control., Conclusions: Although current knowledge on predictors of type 1 diabetes cardiovascular and renal complications has increased, further investigation is required to understand the mechanisms leading to cardio-renal complications in this population.

Aims: Haptoglobin (Hp) genotype 2-2 increases cardiovascular diabetes complications. In type 2 diabetes, α-tocopherol was shown to lower cardiovascular risk in Hp 2-2, potentially through HDL function improvements. Similar type 1 diabetes data are lacking. We conducted a randomized crossover pilot of α-tocopherol supplementation on HDL function [i.e., cholesterol efflux (CE) and HDL-associated lipid peroxides (LP)] and lipoprotein subfractions in type 1 diabetes., Methods: Hp genotype was assessed in members of two Allegheny County, PA, type 1 diabetes registries and the CACTI cohort; 30 were randomly selected within Hp genotype, and 28 Hp 1-1, 31 Hp 2-1 and 30 Hp 2-2 were allocated to daily α-tocopherol or placebo for 8 weeks with a 4-week washout., Results: Baseline CE decreased with the number of Hp 2 alleles (p-trend = 0.003). There were no differences in LP or lipoprotein subfractions. In intention-to-treat analysis stratified by Hp, α-tocopherol increased CE in Hp 2-2 (β = 0.79, p = 0.03) and LP in Hp 1 allele carriers (β Hp 1-1 = 0.18, p = 0.05; β Hp 2-1 = 0.21, p = 0.07); reduced HDL particle size (β = -0.07, p = 0.03) in Hp 1-1 carriers; increased LDL particle concentration in Hp 1-1; and decreased it in Hp 2-2 carriers. However, no significant interactions were observed by Hp., Conclusions: In this type 1 diabetes study, HDL function worsened with the number of Hp 2 alleles. α-Tocopherol improved HDL function in Hp 2-2 carriers and appeared to adversely affect lipid peroxides and lipoprotein subfractions among Hp 1 allele carriers. As no significant interactions were observed, findings require replication in larger studies.

Aims: The Haptoglobin (HP) 2-2 genotype increases cardiovascular diabetes complication incidence. In type 1 diabetes, HP 2-2 also predicts declining kidney function and end-stage renal disease. We investigated whether HP 2-2 predisposes to cardio-renal mortality, while considering other causes of death as competing risks., Methods: Individuals with type 1 diabetes and HP data available (n=486; mean baseline age, 27 and duration, 19 years) were selected for study. Vital status was assessed as of 8/31/2014. The underlying cause of death was determined and classified based on standardized procedures., Results: During 25 years of follow-up, 79 (16.3%) cardio-renal deaths and 43 (8.8%) deaths related to other causes occurred. Although total mortality did not differ by HP (25.4% with HP 1 versus 24.6% with HP 2-2, p=0.84), a greater proportion of HP 2-2 carriers exhibited a cardio-renal death (19.0 versus 14.2, p=0.05). In time-to-event analyses, HP 2-2 was associated with a statistically significant increase of the sub-distribution hazard ratio for cardio-renal mortality (HR=1.64, p=0.03), although this effect was somewhat attenuated after multivariable adjustment (HR=1.58, p=0.05)., Conclusions: Our results suggest that in addition to predicting the incidence of cardio-renal complications, HP 2-2 also increases susceptibility for cardio-renal mortality in type 1 diabetes. These findings require validation in other cohorts., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Over the past decade, several longitudinal epidemiological studies have brought attention to the haptoglobin genotype and its importance in determining diabetic vascular disease risk. This manuscript presents an overview of the biology of the haptoglobin genotype and reviews the literature concerning its role in the development of cardiovascular disease among individuals with diabetes mellitus.

Given the paucity of data in type 1 diabetes concerning lipoprotein-associated phospholipase A( 2) (Lp-PLA(2)), we examined its prospective relationship with coronary artery disease (CAD), as well as the effect of modification by C-reactive protein (CRP) and haptoglobin genotype, in individuals with type 1 diabetes who are at an increased risk for CAD due to also having macroalbuminuria (n=96). Although Lp-PLA(2) activity was univariately predictive of CAD (HR=1.54 per SD, p=0.009), this relationship was not significant after covariate adjustment (p=0.59). There was a significant interaction between Lp-PLA(2) and CRP (p=0.02), i.e. those with both markers greater than the median level were more likely to have a CAD event than those persons with low levels of both (HR=2.89, p=0.06). When stratified by haptoglobin genotype, Lp-PLA(2) was predictive of CAD in persons with the 2/1 (HR=2.40, p=0.05), but not 2/2 (HR=0.66, p=0.27), genotype. The association between Lp-PLA(2) activity and CAD differs by CRP and haptoglobin genotype in this group of persons with type 1 diabetes and macroalbuminuria.

Background: The sensitivity of albuminuria in predicting loss of kidney function has been questioned. We determined the sequence of kidney disease stages (microalbuminuria, macroalbuminuria, low estimated glomerular filtration rate [eGFR], and end-stage renal disease [ESRD]) and characterized those without albuminuria before a low eGFR., Study Design: The Pittsburgh Epidemiology of Diabetes Complications Study is a prospective cohort investigation of childhood-onset type 1 diabetes., Setting & Participants: 480 study participants with eGFR greater than 60 mL/min/1.73 m(2) (mean age, 27 years; diabetes duration, 19 years at study entry) were prospectively followed up for 16 years., Outcomes & Measurements: Low eGFR was defined as creatinine clearance less than 60 mL/min/1.73 m(2) from timed urine collections; microalbuminuria, as albumin excretion rate between 20 to 200 microg/min (30 to 300 mg/24 h); macroalbuminuria, as albumin excretion rate greater than 200 microg/min (>300 mg/24 h); and ESRD, as dialysis or renal transplantation., Results: The 33 of 480 individuals (7%) who developed ESRD had prior albuminuria. 71 of 480 (15%) individuals developed low eGFR. 66 of 71 (93%) had prior/concurrent albuminuria, and 5 of 71 (7%) did not. Incident low eGFR values in the 5 patients were: (1) 54, (2) 58, (3) 59, (4) 59.7, and (5) 59.8 mL/min/1.73 m(2). 3 of 5 (60%; patients 1, 4, and 5) subsequently developed albuminuria. Final eGFRs in the 5 patients were: (1) 94, (2) 86, (3) 60, (4) 65, and (5) 54 mL/min/1.73 m(2), respectively., Limitations: GFR and insulin sensitivity were not measured, but estimated. Incident decreased eGFR in patients without preceding/concurrent albuminuria may be caused by misclassification or a temporary eGFR decrease., Conclusions: Moderately decreased eGFR may occur rarely in patients with type 1 diabetes without preceding albuminuria.