Type 1 Diabetes Cohort Research Articles

Estimated Glucose Disposal Rate as a Predictor of All-Cause Mortality in Type 1 Diabetes—A 10-Year Follow-Up Study

Insulin resistance (IR) was described in type 1 diabetes (T1D) and is related to higher risk of complications. The association of estimated Glucose Disposal Rate (eGDR), a proxy of IR, to all-cause mortality was assessed in 774 T1D (age 40.2±11.7; DD 19.4±12.2 years; HbA1c 7.8±1.2%) in a follow-up of 10.6±2.5 years. Mean eGDR was 7.52±2.28 mg/kg/min (median 8.29; IQR 5.54-9.31). In agreement with the “Swedish National Diabetes Register” eGDR was stratified in 4 categories: C1: ≥8.0 (n. 424, 54.8%); C2: 6.0-7.99 (n. 125, 16.1%); C3: 4.0-5.99 (n. 149, 19.3%) and C4: <4.0 mg/kg/min (n. 76, 9.8%). Compared to C1, C2-4 showed a worse CV risk profile with increase in age, DD, BMI, WHR, BP, HbA1c, total-, LDL-, nonHDL-Ch and triglycerides (TG), with HDL-Ch reduction (p<0.0001). eGFR (CKD-EPI) decreased, albuminuria (ACR) increased steeply (p<0.0001). Percentages of males (p=0.002), CV events (0.7, 4.8, 13.4 and 15.8%; p<0.0001), eGFR <60 ml/min/1.73m2 (p<0.0001), micro- or macroalbuminuria, (p<0.0001), advanced retinopathy (7.5, 13.9, 28.7 and 37.3%; p<0.0001) increased from C1 to C4, as well treatments for CV risk factors (p<0.0001). A total of 52 deaths occurred in the 8,184 person-years of follow-up (6.7%; 6.36x1000 person-years). Death rate increased with eGDR categories: C1 2.6%; C2 6.4% (HR 2.32, 95% CI 0.93-5.77); C3 11.4% (4.54, 2.12-9.69); C4 21.1% (8.07, 3.74-17.40, p<0.0001). Adjusting for age (HR 1.08, 95% CI 1.05-1.10, p<0.0001) and sex, HRs vs. C1 were: C2 1.53 (95% CI 0.60-3.87); C3 1.97 (0.88-4.44); C4 3.38 (1.48-7.73; p=0.004). Adjusting for age (HR 1.06, 95% CI 1.04-1.09, p<0.0001), sex (M, HR 1.98, 1.10-3.59, p=0.023), eGFR (HR 0.97, 0.96-0.99, p<0.0001), as well DD, BMI, LDL, CVD and statin, HRs were: C2 1.22 (95% CI 0.47-3.17); C3 1.76 (0.78-3.95); C4 2.69 (1.17-6.23; p=0.021). Only adjustment for variables strictly related to IR (HDL, TG, ACR) excludes eGDR as an independent covariate of mortality. In our T1D cohort, eGDR is an uncertain independent predictor of death. Disclosure M. Garofolo: None. A. Bertolotto: None. F. Campi: None. D. Lucchesi: None. L. Giusti: None. V. Sancho-Bornez: None. A. Dardano: None. R. Miccoli: None. G. Penno: None. S. Del Prato: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, GlaxoSmithKline plc., Intarcia Therapeutics, Inc., Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Servier, Sanofi, Takeda Pharmaceuticals U.S.A., Inc.. Research Support; Self; Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Boehringer Ingelheim Pharmaceuticals, Inc., AstraZeneca. Speaker's Bureau; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Novartis Pharmaceuticals Corporation, Takeda Pharmaceuticals U.S.A., Inc.. Advisory Panel; Self; Janssen Biotech, Inc., Abbott.

Risk Factors Differ by First Manifestation of Cardiovascular Disease (CVD) in Type 1 Diabetes (T1D)

CVD is a major contributor to T1D morbidity and mortality but presents in a variety of first manifestations. Thus we aimed to assess risk factors for 3 CVD manifestations in a T1D cohort: 1) major atherosclerotic cardiovascular event (MACE, i.e., CVD death, myocardial infarction (MI), stroke), 2) coronary revascularization, no prior MI (REV), 3) soft CVD (SOFT, i.e., ischemic ECG or angina). Data are from the Pittsburgh Epidemiology of Diabetes Complications (EDC) study, an ongoing, prospective cohort study of childhood-onset (<17 years) T1D diagnosed 1950-80 with 25 years of follow-up (n=658, 49% women, mean age 27, T1D duration 18 years at 1986-88 baseline). Follow-up exams occurred biennially for the first 10 years and at 18 and 25 years. MACE and REV were ascertained by death certificate adjudication or self-report, confirmed with medical records. Angina was determined by EDC physician history and ischemia by Minnesota coded ECGs. Prevalent CVD cases (n=54) were excluded. Those experiencing each manifestation were compared to participants not developing any CVD over follow-up. Baseline (BL), time varying updated mean (UM) and time varying most recent (MR) risk factors were assessed in Cox models (HRs per unit). CVD first manifested as n=107 MACE, n=38 REV, and n=91 SOFT. In T1D duration-adjusted multivariable models, MACE was predicted by MR ln (albumin excretion rate (AER)) (HR 1.3 p<.0001), UM systolic blood pressure (SBP) (HR 1.03 p<.0001), BL smoking (HR 1.9 p=0.003), UM LDLc (HR 1.01 p=0.03) and UM HbA1c (HR 1.2 p=0.03). REV was predicted by BL LDLc (HR 1.03, p<.0001), BL estimated glomerular filtration rate (HR 0.98 p=0.002) and MR HbA1c (HR 1.3 p=0.03). SOFT was predicted by MR SBP (HR 1.03 p<.0001), UM ln(triglycerides) (HR 1.8 p=0.01), MR HbA1c (HR 1.2 p=0.01) and MR ln(AER) (HR 1.2 p=0.02). HbA1c was consistently, but modestly, associated with all CVD manifestations. Additionally, BP and AER are important predictors of MACE and SOFT, while REV is most strongly predicted by BL LDLc. Disclosure R.G. Miller: None. T.J. Orchard: None.

The Relationships between Retinopathy and Other Vascular Complications in Adults with Long-Standing Diabetes—Results from the Canadian Study of Longevity in Type 1 Diabetes (T1D)

We aimed to measure the prevalence of retinopathy in a T1D cohort of 75 adults with T1D duration of ≥50 years, and to determine association with other vascular complications. Participants underwent ultra-widefield retinal imaging and optimal coherence tomography. Neuropathy was characterized by electrophysiology and corneal confocal microscopy. Intrarenal hemodynamic function was determined by inulin and para-aminohippurate clearance, and arterial stiffness was measured by applanation tonometry, both at baseline and in responses to intravenous angiotensin II (ANGII). Participants were classified as having no diabetic retinopathy (ⱷDR), non-proliferative (NPDR), or proliferative (PDR), and associations were determined using multivariable linear regression adjusting for age, sex, and HbA1c. Thirty-nine (52%) participants had PDR, 24 (32%) had NPDR, and 12 (16%) had ⱷDR. Those without retinopathy had lower HbA1c vs. those with NDPR and PDR (6.7±0.6% vs. 7.4±0.7% and 7.5±0.9%, p=0.019). PDR was associated with lower corneal nerve fibre density, worse electrophysiology, and a greater number of signs and symptoms of neuropathy, but not with intrarenal hemodynamic function. Retinopathy severity was associated with greater response to ANGII for carotid-radial pulse wave velocity (mean change -4.9±11.4% vs. 8.2±18.5% vs. 12.9±20.2% for ⱷDR, NPDR, and PDR respectively, p=0.043). In longstanding T1D, retinopathy associated strongly with neuropathy and arterial stiffening, but not with renal hemodynamic function. Greater understanding of the co-occurrence of microvascular complications in patients with T1D, and relationships with macrovascular abnormalities such as arterial stiffness, may improve early detection and management of diabetes-related diseases. Disclosure J.A. Lovshin: Other Relationship; Self; AstraZeneca. Consultant; Self; Novo Nordisk Inc.. Research Support; Self; Sanofi, Merck Sharp & Dohme Corp.. Other Relationship; Self; Novo Nordisk Inc.. L. Lovblom: None. P. Bjornstad: Consultant; Self; Boehringer Ingelheim GmbH. Y. Lytvyn: None. G. Boulet: Advisory Panel; Self; Medtronic, Sanofi, Novo Nordisk Inc.. Other Relationship; Self; Janssen Global Services, LLC., Abbott. A. Weisman: None. V.S. Lai: None. J.M. Tse: None. L. Cham: None. A. Orszag: None. H.A. Keenan: Research Support; Self; Sanofi. Employee; Self; Sanofi Genzyme. N. Paul: None. V. Bril: Consultant; Self; Alexion Pharmaceuticals, Inc.. Research Support; Self; CSL Behring, Grifols. Advisory Panel; Self; CSL Behring. Consultant; Self; Grifols. Research Support; Self; Shire. Advisory Panel; Self; Pfizer Inc. M.H. Brent: Research Support; Self; Novartis Canada. Advisory Panel; Self; Novartis Canada. Research Support; Self; Bayer Canada. Advisory Panel; Self; Bayer Canada, Allergan Canada. Research Support; Self; Roche Canada. B.A. Perkins: Advisory Panel; Self; Boehringer Ingelheim GmbH. Research Support; Self; Boehringer Ingelheim GmbH, Novo Nordisk Inc.. Advisory Panel; Self; Novo Nordisk Inc., Abbott. Speaker's Bureau; Self; Abbott, Janssen Pharmaceuticals, Inc.. Advisory Panel; Self; Insulet Corporation. Speaker's Bureau; Self; Insulet Corporation, Dexcom, Inc. D. Cherney: Consultant; Self; AbbVie Inc.. Other Relationship; Self; AstraZeneca, Boehringer Ingelheim GmbH, Eli Lilly and Company. Consultant; Self; Sanofi. Other Relationship; Self; Merck & Co., Inc.. Consultant; Self; Mitsubishi Tanabe Pharma Corporation. Other Relationship; Self; Janssen Pharmaceuticals, Inc..

Contemporary Prevalence of Diabetic Neuropathy in Type 1 Diabetes (T1D)—Findings from the T1D Exchange

Diabetic peripheral neuropathy (DPN) is a major cause of disability, mortality and poor quality of life in patients with T1D, with prior reported prevalence rates of up to 35%. The contemporary prevalence of DPN in T1D patients was evaluated in T1D Exchange Registry centers throughout the United States. The Michigan Neuropathy Screening Instrument (MNSI), a validated 15-item self-administered questionnaire, was used to assess DPN in adults ≥18 years with ≥ 5 years of T1D duration. A score of ≥4 was used to define DPN. Diabetes-related characteristics and laboratory data were obtained through the most recent clinic update. Chi-square and t-tests were used to compare demographic and diabetes-related characteristics between those with and without DPN. Linear regression was used to determine the effect of DPN on HbA1c, adjusted for possible confounders. In preliminary analyses of 5,058 participants across 62 sites (mean age 39±18 years, T1D duration 22±14 years, 56% female, 88% non-hispanic white, mean HbA1c 8.1±1.6%), the prevalence of DPN was 10%. Those with DPN were older (52±17 vs. 37±18 years), more likely to be female (61% vs. 55%), had longer T1D duration (32±16 vs. 21±13 years), lower annual household income (37% vs. 59% earning ≥$75K), and lower education level (55% vs. 69% with college degree) than those without DPN (all p<0.001). They also had higher systolic blood pressure (126±17 vs. 123±14 mmHg), triglycerides (117±89 vs. 95±62 mg/dL), tobacco use (9% vs. 4%) and prevalence of established CVD (26% vs. 6%), despite higher use of CVD-modifying agents such as statins (64% vs. 31%) and ACE-inhibitors/ARBs (45% vs. 23%) (all p<0.001). Participants with DPN had higher HbA1c (8.4±1.7% vs. 8.1±1.6%), even after adjusting for multiple confounders (p <0.01). The prevalence of DPN in this national T1D cohort is lower than prior published reports, reflecting current clinical care practices, and highlighting other non-glycemic risk factors for DPN including CVD risk factors and socioeconomic status. Disclosure K.R. Mizokami-Stout: None. C.T. Boyle: None. V.N. Shah: None. G. Aleppo: Research Support; Self; AstraZeneca, Novo Nordisk Inc.. Consultant; Self; Dexcom, Inc.. Advisory Panel; Self; Novo Nordisk Inc. J.B. McGill: Research Support; Self; AstraZeneca. Consultant; Self; Boehringer Ingelheim GmbH. Speaker's Bureau; Self; Aegerion Pharmaceuticals. Consultant; Self; Bayer AG, Dexcom, Inc., Intarcia Therapeutics, Inc.. Speaker's Bureau; Self; Janssen Pharmaceuticals, Inc., MannKind Corporation. Research Support; Self; Novartis Pharmaceuticals Corporation. Consultant; Self; Novo Nordisk A/S. R. Pratley: Other Relationship; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eisai Inc., GlaxoSmithKline plc., Janssen Pharmaceuticals, Inc., Lexicon Pharmaceuticals, Inc., Ligand Pharmaceuticals, Inc., Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk Inc., Pfizer Inc., Sanofi-Aventis, Takeda Development Center Americas, Inc.. E. Toschi: None. L. Ang: None. R. Pop-Busui: Research Support; Self; AstraZeneca.

Stigmatization of Adults with Type 1 Diabetes in Asia

Background: Type 1 diabetes (T1D) is uncommon in Asia. Limited awareness can lead to stigmatization of those with T1D. Aims: We aimed to evaluate diabetes stigma in adults with T1D in Singapore. Methods: This was a cross-sectional sampling of adults with T1D in a tertiary public hospital, using the Type 1 Diabetes Stigma Assessment Scale (DSAS-1). Higher scores indicate greater levels of stigma. Results: 125 Singaporeans (mean age 31.2 ± 11.2 y), T1D duration 13.8 ± 7.3 y, M/F: 51/74, 107 on insulin injections, 18 on insulin pumps were sampled. Item response patterns (Figure) suggest a greater burden of stigma in the blame and judgment and identity concerns subscales. DSAS-1 scores did not differ by gender, treatment regimen, age, education level or employment. Identity concerns subscale scores were lower in those with T1D for >10y (n=73) than those with shorter T1D duration (18.9 ± 5.6 v 21.7 ± 7.3, p=0.045). Total DSAS-1 and subscale scores were similar to those of an Australian (Oz) cohort (n=900) (Sg-v-Oz: Total score 53.1 ± 12.9 vs. 53.0 ± 15.6, Treated differently 13.6 ± 4.0 v 13.6 ± 5.4, Blame and Judgment 19.9 ± 5.2 v 19.9 ± 6.0, and Identity Concerns: 19.6 ± 6.4 v 19.5 ± 7.2, all p>0.05). Conclusion: This is novel data documenting significant levels of diabetes stigma among adults in Singapore, particularly relating to blame and judgment and identity concerns. Despite the low prevalence of T1D in Asia, levels of stigma appeared similar to that of an Australian T1D cohort. Disclosure A.Y.R. Lam: None. D. Gardner: None. S. Rama Chandran: None. E.P. Teo: None. L. Zhu: None. G. Koh: None. S. Goh: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim GmbH, Amgen Inc., Novo Nordisk A/S, Sanofi-Aventis, Servier.

Frequency, Severity, and Associations of Gastrointestinal Symptoms in Adults and Children with Type 1 Diabetes

Background: Significant variability is reported as to the presence and quality of gastrointestinal (GI) symptoms in patients with type 1 diabetes (T1D). Objective: To assess reported GI symptoms and associated comorbidities in adults and children with T1D. Methods: The Gastrointestinal Symptom Scale (GISS) and a Visual Analog Scale (VAS) were used to assess GI symptom type and severity in 2,370 patients with T1D aged 8-45 years as part the screening phase of the Celiac Disease and Diabetes Dietary Intervention and Evaluation Trial (CD-DIET). Co-morbidities, including diabetes-related complications, were extracted from clinical records. The presence and severity of GI symptoms and relationships with demographic, clinical and other diabetes-related factors were evaluated. Results: Overall, 1368 adults (57.7%) aged 19-45 years and 1002 (42.3%) pediatric patients aged 8-18 years were studied. At least one GI symptom was reported in 34.1% of adults as compared with 21.7% of children (p<0.0001). Common symptoms in children included upper abdominal pain, lower abdominal pain and nausea while adults more frequently reported lower GI symptoms with females describing more severe symptoms. Overall, patients with ≥1 GI symptom were more likely to have diabetes complications when adjusted for age and sex (OR=1.41; 95% CI=1.1-1.7; p=0.002). Conversely, patients who reported diabetes complications such as nephropathy, retinopathy and/or cardiovascular disease were 1.94 (95% CI=1.49-2.52) times more likely to report GI symptoms. No association was observed between autoimmune conditions (including screen-detected celiac disease and reported thyroid disease) and GI symptoms. Conclusions: In this large screening study in a contemporary T1D cohort, significant differences were found between age groups with more frequent GI symptoms in adults. Significant associations were observed between GI symptoms and diabetes complications along with diabetes duration. Disclosure F.H. Mahmud: None. E. Nunes de Melo: None. A.B. Clarke: None. E. Assor: None. A. Parikh: None. A. Advani: Research Support; Self; AstraZeneca, Boehringer Ingelheim GmbH. Other Relationship; Self; Boehringer Ingelheim GmbH. B.A. Perkins: Advisory Panel; Self; Boehringer Ingelheim GmbH. Research Support; Self; Boehringer Ingelheim GmbH, Novo Nordisk Inc.. Advisory Panel; Self; Novo Nordisk Inc., Abbott. Speaker's Bureau; Self; Abbott, Janssen Pharmaceuticals, Inc.. Advisory Panel; Self; Insulet Corporation. Speaker's Bureau; Self; Insulet Corporation, Dexcom, Inc.. B.R. Shah: None. C.S. Zuijdwijk: None. C. McDonald: None. D. Mack: None. D. Koltin: None. E. Hsieh: None. E.M. Szentgyorgyi: None. F. Saibil: None. G. Mukerji: None. H.A. Lochnan: Research Support; Self; Amylin Pharmaceuticals, Boston Therapeutics, Inc., Sanofi. J. Gilbert: Other Relationship; Self; AstraZeneca, Boehringer Ingelheim GmbH, Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk Inc., Janssen Pharmaceuticals, Inc., Sanofi. K. Bax: None. M.L. Lawson: None. M.D. Beaton: Advisory Panel; Self; Takeda Canada Inc., Janssen Pharmaceuticals, Inc., AbbVie Inc.. N.A. Saloojee: None. O. Lou: None. P.H. Gallego: None. R.L. Houlden: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Novo Nordisk Inc., AstraZeneca, Eli Lilly and Company. R. Aronson: Other Relationship; Self; Novo Nordisk Inc., Janssen Pharmaceuticals, Inc., Sanofi, AstraZeneca. Research Support; Self; Eli Lilly and Company, Becton, Dickinson and Company, Merck & Co., Inc., Senseonics, Boehringer Ingelheim Pharmaceuticals, Inc.. S.E. Kirsch: None. W.G. Paterson: None. Z. Punthakee: Research Support; Self; Amgen, Astra Zeneca/Bristol Myers Squibb, Lexicon, Merck, NovoNordisk, Sanofi. Speaker's Bureau; Self; Abbott, Astra Zeneca/Bristol Myers Squibb, Boehringer Ingelheim/Eli Lilly, Janssen, Merck, NovoNordisk, Pfizer, Sanofi. Advisory Panel; Self; Astra Zeneca/Bristol Myers Squibb, Boehringer Ingelheim/Eli Lilly, Dexcom, Janssen, Medtronic, NovoNordisk, Pfizer, Sanofi. M.A. Marcon: None.

Relationship of Serum Fetuin A with Metabolic and Clinical Parameters in German Children and Adolescents with Type 1 Diabetes

Background and Aim: The hepatokine fetuin A is upregulated in the metabolic syndrome and in type 2 diabetes (T2D), while its role in adolescent type 1 diabetes (T1D) is unclear. We assessed the relationship between circulating fetuin A levels and metabolic control, comorbidities, and complications in adolescent T1D patients. Methods: We studied the relationship between serum fetuin A and clinical diabetes-related data from the DPV registry (Diabetes-Pa­tienten-Verlaufsdokumentation) in 172 adolescent T1D patients with early-onset (<5 years) long-standing (>10 years) T1D. Fetuin A levels were further compared between adolescent T1D and T2D patients. Results: Serum fetuin A levels in T1D patients (mean 0.267 ± 0.043 g/L) did not correlate with age, diabetes duration, gender, body mass index (BMI), glycated hemoglobin, serum lipid levels, blood pressure, celiac or thyroid disease, nephropathy, or retinopathy. An association of fetuin A levels with insulin requirements was only evident within the subgroup of overweight T1D patients (r_s = 0.439, p = 0.028, n = 25, BMI >90th percentile), disappearing after adjustment for multiple testing. Adolescent T1D patients showed distinctly lower fetuin A levels than patients with T2D (p ≤ 0.001). Conclusion: Overall, we did not observe a clinically relevant association of fetuin A levels with surrogate parameters for insulin sensitivity in our juvenile T1D cohort. A correlation with insulin requirements was detectable in overweight patients only. We hypothesize that multiple factors, such as obesity, puberty, inadequate metabolic control, and hepatic steatosis, have to add up before a clinically relevant effect of fetuin A on insulin sensitivity becomes evident.

Cumulative Kidney Complication Risk by 50 Years of Type 1 Diabetes: The Effects of Sex, Age, and Calendar Year at Onset.

OBJECTIVEA common belief is that only a minority of patients with type 1 diabetes (T1D) develop advanced kidney disease and that incidence is higher among men and lower in those diagnosed at a younger age. However, because few patients with T1D survived to older ages until recently, long-term risks have been unclear.RESEARCH DESIGN AND METHODSWe examined the 50-year cumulative kidney complication risk in a childhood-onset T1D cohort diagnosed during 1950–80 (n = 932; mean baseline age 29 years, duration 19 years). Participants comprised 144 who died prior to baseline, 130 followed with periodic surveys, and 658 followed with biennial surveys and a maximum of nine examinations for 25 years. Micro- and macroalbuminuria were defined as an albumin excretion rate of 20–199 and ≥200 μg/min, respectively, and end-stage renal disease (ESRD) was defined as dialysis or kidney transplantation. Cumulative incidence was estimated at 10-year intervals between 20 and 50 years, duration and compared by calendar year of diabetes onset.RESULTSBy 50 years, T1D duration, ESRD affected 60% of the cohort; macroalbuminuria, 72%; and microalbuminuria, 88%. Little evidence existed for declines in cumulative incidence in recent cohorts, except for ESRD (microalbuminuria 3% increase, macroalbuminuria no change; ESRD 45% decrease by 40 years of T1D duration). Onset before age 6 years was associated with the lowest risk; incidence generally did not differ by sex.CONCLUSIONSSome degree of kidney disease in T1D is virtually universal at long durations and not declining, which has major implications for formulating health care and research strategies. ESRD has declined, but continues to affect >25% of the population by 40 years, duration.

Persistence of Pancreatic Insulin mRNA Expression and Proinsulin Protein in Type 1 Diabetes Pancreata

The canonical notion that type 1 diabetes (T1D) results following a complete destruction of β cells has recently been questioned as small amounts of C-peptide are detectable in patients with long-standing disease. We analyzed protein and gene expression levels for proinsulin, insulin, C-peptide, and islet amyloid polypeptide within pancreatic tissues from T1D, autoantibody positive (Ab+), and control organs. Insulin and C-peptide levels were low to undetectable in extracts from the T1D cohort; however, proinsulin and INS mRNA were detected in the majority of T1Dpancreata. Interestingly, heterogeneous nuclear RNA (hnRNA) for insulin and INS-IGF2, both originating from the INS promoter, were essentially undetectable in T1D pancreata, arguing for a silent INSpromoter. Expression of PCSK1, a convertase responsible for proinsulin processing, was reduced in T1D pancreata, supportive of persistent proinsulin. These data implicate the existence of β cells enriched for inefficient insulin/C-peptide production in T1D patients, potentially less susceptible to autoimmune destruction.

Decreased expression of miR-150, miR146a and miR424 in type 1 diabetic patients: Association with ongoing islet autoimmunity

BackgroundRecent studies revealed altered miRNAs profiling in patients with autoimmune diseases, including type 1 diabetes (T1D). Here, we conducted an observational study and examined the expression levels of these five miRNAs (miR-150,miR-146a,miR-424,miR-181a and miR-142-3P) in peripheral blood mononuclear cells (PBMCs) from T1D patients. MethodsPBMCs were obtained from T1D cohorts (n = 78), type 2 diabetes (T2D, n = 46) and healthy control subjects (n = 56). Quantitative analysis of five miRNAs were performed using SYBR quantitative real time PCR (qRT-PCR). All values were normalized to endogenous control U6. Then, We compared expression level of five miRNAs in PBMCs from T1DM and age-matched healthy controls, and related the miRNAs expression levels to beta-cell function, autoantibodies and glycaemic control in T1D cohort. ResultsWe identified decreased miR-150, miR-146a and miR-424 in patients with T1D, which can distinguished from non-diabetic patients and T2D patients (p < 0.05). Furthermore, they were significantly decreased in PBMCs from GADA autoantibody-positive (Ab+) patients versus GADA autoantibody-negative (Ab-) patients. However, there was no correlation between characteristics such as age, sex, diabetes duration, C-peptide, and glycaemic, and the expression level of miRNAs (p > 0.05). ConclusionsOur study indicated miR-150, miR-146a and miR-424 may be potential biomarkers of T1DM with applications in the clinical setting as well as provided new insights into the molecular mechanisms involved in this disorder.

Regional Gray Matter Volumes as Related to Psychomotor Slowing in Adults with Type 1 Diabetes.

Psychomotor slowing is a common cognitive complication in type 1 diabetes (T1D), but its neuroanatomical correlates and risk factors are unclear. In nondiabetic adults, smaller gray matter volume (GMV) and presence of white matter hyperintensities are associated with psychomotor slowing. We hypothesize that smaller GMV in prefronto-parietal regions explains T1D-related psychomotor slowing. We also inspect the contribution of microvascular disease and hyperglycemia. GMV, white matter hyperintensities (WMH), and glucose levels were measured concurrently with a test of psychomotor speed (Digit Symbol Substitution Test [DSST]) in 95 adults with childhood-onset T1D (mean age/duration = 49/41 years) and 135 similarly aged non-T1D adults. Linear regression models tested associations between DSST and regional GMV, controlling for T1D, sex, and education; a bootstrapping method tested whether regional GMV explained between-group differences in DSST. For the T1D cohort, voxel-based and a priori regions-of-interest methods further tested associations between GMV and DSST, adjusting for WMH, hyperglycemia, and age. Bilateral putamen, but no other regions examined, significantly attenuated DSST differences between the cohorts (bootstrapped unstandardized indirect effects: -3.49, -3.26; 95% confidence interval = -5.49 to -1.80, -5.29 to -1.44, left and right putamen, respectively). Among T1D, DSST was positively associated with GMV of bilateral putamen and left thalamus. Neither WMH, hyperglycemia, age, nor other factors substantially modified these relationships. For middle-aged adults with T1D and cerebral microvascular disease, GMV of basal ganglia may play a critical role in regulating psychomotor speed, as measured via DSST. Studies to quantify the impact of basal ganglia atrophy concurrent with WMH progression on psychomotor slowing are warranted.

Psychiatric medication use before and after the onset of type 1 diabetes in children and adolescents: A population-based cohort study.

Several studies showed a bidirectional association between type 2 diabetes and psychiatric disorders in adults. Because there is limited information on the association between type 1 diabetes (T1D) and psychiatric disorders (including psychiatric medication use) in children and adolescents, we assessed frequency of use of these medications before and after the onset of T1D. A population-based cohort study was conducted in the Dutch PHARMO Record Linkage System (1999-2009). Children and adolescents (<19 years) with at least 2 insulin dispensings from community pharmacies (T1D cohort, N = 925) were matched by age and sex (reference cohort without insulin use, N = 3591). The 5-year prevalence of psychiatric medication use (psycholeptics [ATC N05] and psychoanaleptics [ATC N06]) before and after onset of T1D were estimated, compared, and stratified by age, sex, and medication subgroup. The mean age of study participants was 10.1 years and 51% were boys. The 5-year prevalence of psychiatric medication use before the index date was significantly higher in the T1D cohort than in the reference cohort (7.2% vs 4.7%, respectively; P = .002) with the same pattern after developing T1D (10.4% vs 7.9%, respectively; P = .015). In both cohorts, adolescents (15-19 years) and boys had higher prevalences of use. This increased prevalence of psychiatric medication use both before and after the index date in T1D cohort was mainly driven by an increased use of psycholeptics (predominantly anxiolytics). Children with T1D were more likely to use psychiatric medication in the years before and after the onset of T1D which was mainly driven by psycholeptic use.

Alteration of B cell subsets and the receptor for B cell activating factor (BAFF) in paediatric patients with type 1 diabetes

BackgroundLately, mounting evidence has shown that B cells play an important role in the pathogenesis of type 1 diabetes (T1D). Here, we present alterations in B cell subsets including BAFF receptor (BAFFR) expression in cohorts of patients with type 1 diabetes (T1D) and their relatives. Patients and methodsB cells were studied in 438 patients with T1D (158 at disease onset and 280 with long-term disease), 136 first-degree relatives and 53 healthy controls. The B cell panel included transitional, naïve, MZ-like, switched memory B cells and plasmablasts. We also measured serum BAFF levels as well as BAFFR expression on both B and T cells. Moreover, the effect of BAFF on T and B lymphocytes was analysed in vitro. ResultsWe observed a significant decrease in the proportion of transitional B cells in the patients with T1D, accompanied by an increased proportion of plasmablasts, especially in recent-onset patients and their relatives. While the BAFF serum levels did not differ in the patients with T1D, BAFFR-expressing B and especially T cell numbers were reduced in the T1D cohort, with the exception of patients with recent-onset disease who exhibited a significant increase in the number of BAFFR-expressing T cells. T cell activation and B cell proliferation were more pronounced after activation with BAFF in the T1D cohort compared to controls. ConclusionThe B cell panel in patients with T1D is characterized by significantly reduced populations of B cells in their early stages of development with a shift towards plasma cells. The dynamics of BAFFR-expressing B and T cells and the more pronounced responsiveness of the T1D T cells to BAFF point to the role of BAFF and T and B cell cooperation in the development of T1D.

Urinary adenosine excretion in type 1 diabetes.

In experimental models of diabetes, augmented sodium-glucose cotransport-2 (SGLT2) activity diminishes sodium (Na+) delivery at the macula densa. As a result, less vasoconstrictive adenosine is generated, leading to afferent arteriolar vasodilatation and hyperfiltration. The measurement and significance of urinary adenosine in humans has not been examined extensively in states of renal hemodynamic impairment like that of diabetes. Our aim was to validate a method for urine adenosine quantification in humans and perform an exploratory post hoc analysis to determine whether urinary adenosine levels change dynamically in response to natriuresis in patients with type 1 diabetes (T1D) before and after treatment with the SGLT2 inhibitor (SGLT2i) empagliflozin. We hypothesized that SGLT2i, which reduces renal hyperfiltration through increased Na+ delivery to the macula densa, would increase urinary adenosine excretion. Urine adenosine corrected for creatinine was measured using our validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method in 40 healthy participants and 40 patients with T1D. In the T1D cohort, measurements were performed during clamped euglycemic and hyperglycemic conditions before and following 8 wk of SGLT2i therapy. Urinary adenosine was detectable in healthy subjects (0.32 ± 0.11 µmol/mmol Cr) and patients with T1D. In response to SGLT2i, urine adenosine increased during clamped hyperglycemia (0.40 ± 0.11 vs. 0.45 ± 0.12 µmol/mmol Cr, P = 0.005). Similar trends were observed during clamped euglycemia (P = 0.08). In conclusion, SGLT2i increases urinary adenosine excretion under clamped hyperglycemic conditions in patients with T1D. The potentially protective role of SGLT2i against glomerular hyperfiltration and its mediation by adenosine in diabetes merits further study.

HLA class II alleles in Norwegian patients with coexisting type 1 diabetes and celiac disease.

Type 1 diabetes (T1D) and celiac disease (CeD) are 2 distinct diseases, but there is an increased risk of developing CeD for T1D patients. Both diseases are associated with HLA-class II alleles, such as DQB1 *02:01 and DQB1 *03:02; however, their risk contribution vary between the diseases. We genotyped HLA-DRB1 and - DQB1 in 215 patients with coexisting T1D and CeD identified from a T1D cohort, and compared them to patients with T1D (N = 487) and CeD (N = 327), as well as healthy controls (N = 368). The patients with coexisting T1D and CeD had an intermediate carrier frequency (72.8%) of the DRB1 *03:01- DQB1 *02:01- DQA1 *05:01 haplotype compared to T1D (64.1%) and CeD (88.7%) patients. The DRB1 *03:01- DQB1 *02:01- DQA1 *05:01/ DRB1 *04- DQB1 *03:02- DQA1 *03 haplotype combination, encoding DQ2.5 and DQ8 molecules, was equally frequent among patients with both T1D and CeD (52.6%) and T1D patients (46.8%) but significantly lower in CeD patients (9.5%). Overall, the patients with coexisting T1D and CeD had an HLA profile more similar to T1D patients than CeD patients.

Psychiatric disorders during early adulthood in those with childhood onset type 1 diabetes: Rates and clinical risk factors from population-based follow-up.

To determine the incidence of and risk factors for psychiatric disorders in early adulthood in patients with childhood onset type 1 diabetes (T1D). In this retrospective-cohort study, we identified a population-based childhood onset T1D cohort and an age and sex matched (5:1) non-diabetic comparison cohort. Data linkage was used to access inpatient hospitalization data, mental health support service data, and mortality data to follow-up both cohorts into early adulthood. The mean age of T1D diagnosis was 9.5 years (SD 4.1), with a mean age at end of follow-up of 26.4 years (SD 5.2, max 37.7). The diagnosis of any psychiatric disorder was observed for 187 of 1302 (14.3%) in the T1D cohort and 400 of 6422 (6.2%) in the comparison cohort [adjusted hazard ratio (HR) 2.3; 95% CI 1.9, 2.7]. Anxiety, eating, mood, and personality and behaviour disorders were observed at higher rates within the T1D cohort. Comorbid psychiatric disorders were more frequent, at the cohort level, within the T1D cohort (2-3 disorders 3.76% vs 1.56%) and service utilization was higher (15+ contacts 6.8% vs 2.8%); though these differences did not remain when restricted to only those individuals diagnosed during follow-up. A history of poor glycaemic control was associated with an increased risk of anxiety, mood, and 'any' disorder (HR ranging from 1.35 to 1.42 for each 1% increase in mean paediatric HbA1c). Our findings highlight the need for access to mental health support services as part of routine patient care for young adults with T1D, and for better predictive tools to facilitate targeting at-risk patients with early intervention programs.

Longitudinal Evaluation of Cognitive Functioning in Young Children with Type 1 Diabetes over 18 Months.

Decrements in cognitive function may already be evident in young children with type 1 diabetes (T1D). Here we report prospectively acquired cognitive results over 18 months in a large cohort of young children with and without T1D. A total of 144 children with T1D (mean HbA1c: 7.9%) and 70 age-matched healthy controls (mean age both groups 8.5 years; median diabetes duration 3.9 years; mean age of onset 4.1 years) underwent neuropsychological testing at baseline and after 18-months of follow-up. We hypothesized that group differences observed at baseline would be more pronounced after 18 months, particularly in those T1D patients with greatest exposure to glycemic extremes. Cognitive domain scores did not differ between groups at the 18 month testing session and did not change differently between groups over the follow-up period. However, within the T1D group, a history of diabetic ketoacidosis (DKA) was correlated with lower Verbal IQ and greater hyperglycemia exposure (HbA1c area under the curve) was inversely correlated to executive functions test performance. In addition, those with a history of both types of exposure performed most poorly on measures of executive function. The subtle cognitive differences between T1D children and nondiabetic controls observed at baseline were not observed 18 months later. Within the T1D group, as at baseline, relationships between cognition (Verbal IQ and executive functions) and glycemic variables (chronic hyperglycemia and DKA history) were evident. Continued longitudinal study of this T1D cohort and their carefully matched healthy comparison group is planned.

Cardiovascular medication use and cardiovascular disease in children and adolescents with type 1 diabetes: a population-based cohort study.

To investigate the 5-yr prevalence and incidence rates of cardiovascular medication and cardiovascular disease before and after onset of type 1 diabetes (T1D) in children and adolescents. Children and adolescents (<19 yr) with T1D (n = 925), defined as those who received at least two insulin prescriptions, and a four times larger reference cohort (n = 3591) with the same age and gender in the Dutch PHARMO Record Linkage System (RLS) were studied in a retrospective cohort study between 1999 and 2009. The date of first insulin dispensing was selected as the index date. The overall prevalence rate of cardiovascular medication use was substantially higher in the T1D cohort before (2.2 vs. 1.0%, p < 0.001) and after (9.2 vs. 3.2%, p < 0.001) the index date. After the index date angiotensin-converting enzyme inhibitors (2.0%) and statins (1.5%) were the most prevalent cardiovascular medications in the T1D cohort. The highest incidence rate of cardiovascular medication use was observed in the first year after the index date [28.1 per 1000 person years (PY)]. Furthermore, three type 1 diabetic patients were hospitalized due to cardiomyopathy (n = 2) and heart failure (n = 1) and one child from the reference group was hospitalized due to cardiomyopathy in the 5 yr after the index date. Children with T1D were more likely to use cardiovascular medications in the years before and after the onset of diabetes. Our study emphasizes the importance of routine screening tests and timely treatment of CVD risk factors in the pediatric population with diabetes.

Quantitative Differences in the Urinary Proteome of Siblings Discordant for Type 1 Diabetes Include Lysosomal Enzymes.

Individuals with type 1 diabetes (T1D) often have higher than normal blood glucose levels, causing advanced glycation end product formation and inflammation and increasing the risk of vascular complications years or decades later. To examine the urinary proteome in juveniles with T1D for signatures indicative of inflammatory consequences of hyperglycemia, we profiled the proteome of 40 T1D patients with an average of 6.3 years after disease onset and normal or elevated HbA1C levels, in comparison with a cohort of 41 healthy siblings. Using shotgun proteomics, 1036 proteins were identified, on average, per experiment, and 50 proteins showed significant abundance differences using a Wilcoxon signed-rank test (FDR q-value ≤ 0.05). Thirteen lysosomal proteins were increased in abundance in the T1D versus control cohort. Fifteen proteins with functional roles in vascular permeability and adhesion were quantitatively changed, including CD166 antigen and angiotensin-converting enzyme 2. α-N-Acetyl-galactosaminidase and α-fucosidase 2, two differentially abundant lysosomal enzymes, were detected in western blots with often elevated quantities in the T1D versus control cohort. Increased release of proteins derived from lysosomes and vascular epithelium into urine may result from hyperglycemia-associated inflammation in the kidney vasculature.

Chronic comorbidities in children with type 1 diabetes: a population-based cohort study

ObjectiveTo determine the incidence of chronic comorbidities among children with type 1 diabetes (T1D) and to compare incidences with a group of children without diabetes.DesignPopulation-based cohort study.SettingDutch PHARMO database (1998–2010).PatientsAll...