Estimated glucose disposal rate is associated with retinopathy and kidney disease in young people with type 1 diabetes: a nationwide observational study.

AIMS: The aim of this study was to investigate the association between estimated glucose disposal rate (eGDR), a proxy for insulin resistance, and retinopathy or kidney disease, i.e. micro-, or macroalbuminuria, in young individuals with type 1 diabetes (T1D). MATERIAL AND METHODS: Using data from the Swedish pediatric registry for diabetes (SweDiabKids) and the registry for adults (NDR), all individuals with T1D with a duration of diabetes of less than 10 years between 1998 and 2017 were included. We calculated the crude incidence rates with 95% confidence intervals (CIs) and used multivariable Cox regression to estimate crude and adjusted hazard ratios (HRs) for two cohorts: retinopathy cohort or kidney disease cohort, stratified by eGDR categories: < 4, 4 to 5.99, 6 to 7.99, and ≥ 8 mg/kg/min (reference). RESULTS: A total of 22 146 (10 289 retinopathy cohort, and 11 857 kidney disease cohort with an overlapping of 9575) children and adults with T1D (median age 21 years, female 42% and diabetes duration of 6 and 7 years, respectively for the cohorts) were studied. During a median follow-up of 4.8 years (IQR 2.6-7.7) there were 5040 (24.7%), 1909 (48.1%), 504 (52.3%) and 179 (57.6%) events for retinopathy in individuals with an eGDR ≥ 8, 7.99 to 6, 5.99 to 4, and < 4 mg/kg/min, respectively. Corresponding numbers for kidney disease was 1321 (6.5%), 526 (13.3%), 255 (26.8%) and 145 (46.6%). After multiple adjustments for different covariates, individuals with an eGDR 7.99 to 6, 5.99 to 4 and < 4 mg/kg/min, had an increased risk of retinopathy compared to those with an eGDR ≥ 8 mg/kg/min (adjusted HRs, 95% CIs) 1.29 (1.20 to 1.40); 1.50 (1.31 to 1.71) and 1.74 (1.41 to 2.14). Corresponding numbers for kidney disease was (adjusted HRs, 95% CIs) 1.30 (1.11 to 1.52); 1.58 (1.25 to 1.99) and 1.33 (0.95 to 1.86), respectively. CONCLUSIONS: eGDR, a proxy for insulin resistance, is associated with retinopathy and kidney disease in young adults with T1D. The risk of retinopathy increased with lower eGDR. The risk of kidney disease also increased with lower eGDR; however results show no association between the lowest eGDR and kidney disease. eGDR can be helpful to identify young T1D individuals at risk.

Risk factors for nephropathy in persons with type 1 diabetes: a population-based study.

AIMS: Albuminuria is strongly associated with risk of renal dysfunction, cardiovascular disease and mortality. However, clinical guidelines diverge, and evidence is sparse on what risk factor levels regarding blood pressure, blood lipids and BMI are needed to prevent albuminuria in adolescents and young adults with type 1 diabetes. METHODS: A total of 9347 children and adults with type 1 diabetes [mean age 15.3 years and mean diabetes duration 1.4 years at start of follow-up] from The Swedish National Diabetes Registry were followed from first registration until end of 2017. Levels for risk factors for a risk increase in nephropathy were evaluated, and the gradient of risk per 1 SD (standard deviation) was estimated to compare the impact of each risk factor. RESULTS: During the follow-up period, 8610 (92.1%) remained normoalbuminuric, 737 (7.9%) individuals developed micro- or macroalbuminuria at any time period of whom 132 (17.9% of 737) individuals developed macroalbuminuria. Blood pressure ≥ 140/80 mmHg was associated with increased risk of albuminuria (p ≤ 0.0001), as were triglycerides ≥ 1.0 mmol/L (p = 0.039), total cholesterol ≥ 5.0 mmol/L (p = 0.0003), HDL < 1.0 mmol/L (p = 0.013), LDL 3.5- < 4.0 mmol/L (p = 0.020), and BMI ≥ 30 kg/m2 (p = 0.033). HbA1c was the strongest risk factor for any albuminuria estimated by the measure gradient of risk per 1 SD, followed by diastolic blood pressure, triglycerides, systolic blood pressure, cholesterol and LDL. In patients with HbA1c > 65 mmol/mol (> 8.1%), blood pressure > 140/70 mmHg was associated with increased risk of albuminuria. CONCLUSIONS: Preventing renal complications in adolescents and young adults with type 1 diabetes need avoidance at relatively high levels of blood pressure, blood lipids and BMI, whereas very tight control is not associated with further risk reduction. For patients with long-term poor glycaemic control, stricter blood pressure control is advocated.

Combined Etanercept, GAD-alum and vitamin D treatment: an open pilot trial to preserve beta cell function in recent onset type 1 diabetes.

AIM: We aimed to study the feasibility and tolerability of a combination therapy consisting of glutamic acid decarboxylase (GAD-alum), Etanercept and vitamin D in children and adolescents with newly diagnosed with type 1 diabetes (T1D), and evaluate preservation of beta cell function. MATERIAL AND METHODS: Etanercept Diamyd Combination Regimen is an open-labelled multi-centre study pilot trial which enrolled 20 GAD antibodies positive T1D patients (7 girls and 13 boys), aged (mean ±SD): 12.4 ± 2.3 (8.3-16.1) years, with a diabetes duration of 81.4 ± 22.1 days. Baseline fasting C-peptide was 0.24 ± 0.1 (0.10-0.35) nmol/l. The patients received Day 1-450 Vitamin D (Calciferol) 2000 U/d per os, Etanercept sc Day 1-90 0.8 mg/kg once a week and GAD-alum sc injections (20 µg, Diamyd™) Day 30 and 60. They were followed for 30 months. RESULTS: No treatment related serious adverse events were observed. After 6 months 90-min stimulated C-peptide had improved in 8/20 patients and C-peptide area under the curve (AUC) after Mixed Meal Tolerance Test in 5 patients, but declined thereafter, while HbA1c and insulin requirement remained close to baseline. Administration of Etanercept did not reduce tumour necrosis factor (TNF) spontaneous secretion from peripheral blood mononuclear cells, but rather GAD65-induced TNF-α increased. Spontaneous interleukin-17a secretion increased after the administration of Etanercept, and GAD65-induced cytokines and chemokines were also enhanced following 1 month of Etanercept administration. CONCLUSIONS: Combination therapy with parallel treatment with GAD-alum, Etanercept and vitamin D in children and adolescents with type 1 diabetes was feasible and tolerable but had no beneficial effects on the autoimmune process or beta cell function.

Combined vitamin D, ibuprofen and glutamic acid decarboxylase-alum treatment in recent onset Type I diabetes: lessons from the DIABGAD randomized pilot trial.

AIM: Double-blind placebo-controlled intervention using glutamic acid decarboxylase (GAD)-alum, vitamin D and Ibuprofen in recent onset Type I diabetes (T1D). METHODS: 64 patients (T1D since <4 months, age 10-17.99, fasting sC-peptide ≥0.12 nmol/l, GADA-positive) were randomized into Day(D) 1-90 400 mg/day Ibuprofen, D1-450 vitamin D 2000 IU/day, D15, 45 sc. 20 µg GAD-alum; as A but placebo instead of Ibuprofen; as B but 40 µg GAD-alum D15, 45; placebo. RESULTS: Treatment was safe and tolerable. No C-peptide preservation was observed. We observed a linear correlation of baseline C-peptide, HbA1c and insulin/per kilogram/24 h with change in C-peptide AUC at 15 months (r = -0.776, p < 0.0001). CONCLUSION: Ibuprofen, vitamin D + GAD-alum did not preserve C-peptide. Treatment efficacy was influenced by baseline clinical and immunological factors and vitamin D concentration. Clinical Trial Registration: NCT01785108 (ClinicalTrials.gov).

Treatment satisfaction correlated with glycaemic control and burden of diabetes in Swedish adolescents with type 1 diabetes.

AIM: To assess treatment satisfaction and perceived discomfort or pain from the treatment, and potential associations with glycaemic control, type of treatment, perceived burden of diabetes, sex and age, in adolescents with type 1 diabetes. METHODS: A cross-sectional study was performed at one paediatric and at one adult diabetes clinic in Sweden, preceded by a translation of 'Diabetes Treatment Satisfaction Questionnaire (DTSQ) Teen'. Adolescents with type 1 diabetes (15-20 years) participated. The questionnaires 'DTSQ Teen' and 'Check your health' were used. Data on glycosylated haemoglobin (HbA1c), type of treatment, sex and age were collected. RESULTS: One hundred and thirty-eight adolescents (70 females, mean age 17.3, mean HbA1c 64.0 mmol/mol) participated. Treatment satisfaction correlated inversely with HbA1c (r = -.352, P < .001) and with all types of burden of diabetes (r = -.342 to -0.467, P < .001), but did not differ with type of treatment, sex and age. Perceived pain correlated inversely with burden on physical health (r = -.265, P = .002), mental health (r = -.237, P = .006) and quality of life (r = -.246, P = .004) but not with HbA1c, age or burden on social relations. Females perceived more discomfort or pain. CONCLUSION: In Swedish adolescents with type 1 diabetes, treatment satisfaction correlated with both glycaemic control and perceived burden of diabetes.

Long-term prognosis in patients with type 1 and 2 diabetes mellitus after coronary artery bypass grafting.

BACKGROUND: Patients with diabetes mellitus (DM) have an increased risk of adverse outcomes after coronary artery bypass grafting (CABG). Previous studies have reported prognosis in relation to treatment with or without insulin, and not to the type of diabetes. OBJECTIVES: This study investigated long-term survival in patients with type 1 DM (T1DM) and type 2 DM (T2DM) following CABG. METHODS: We included all patients from the SWEDEHEART (Swedish Web-System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies) register who underwent primary isolated CABG in Sweden during 2003 through 2013. We identified patients with T1DM or T2DM in the Swedish National Diabetes Register. We calculated hazard ratios (HRs) with 95% confidence intervals (CIs) for all-cause mortality in patients with T1DM or T2DM. RESULTS: In total, 39,235 patients were included, of whom 725 (1.8%) had T1DM and 8,208 (21%) had T2DM. Patients with TDM1 were younger (59 vs. 67 years), had reduced kidney function (31% vs. 24%), and had peripheral vascular disease (21% vs. 11%) more often than patients with TDM2 or no diabetes. During a mean follow-up of 5.9±3.2 years (230,085 person-years), 6,765 (17%) patients died. Among patients with T1DM, 152 (21%) died, and among patients with T2DM, 1,549 (19%) died. Adjusted hazard ratio (95% confidence interval) for death in patients with T1DM and T2DM, compared with patients without diabetes, were 2.04 (1.72 to 2.42), and 1.11 (1.05 to 1.18), respectively. CONCLUSIONS: Patients with T1DM had more than double the long-term risk of death after CABG compared with patients without diabetes. The long-term risk of death in patients with T2DM was only slightly increased.

Intensified insulin treatment is associated with improvement in skin microcirculation and ischaemic foot ulcer in patients with type 1 diabetes mellitus: a long-term follow-up study.

AIMS/HYPOTHESIS: We investigated skin microcirculation and its association with HbA1c and the incidence of ischaemic foot ulcer in patients with type 1 diabetes formerly randomised (1982-1984) to intensified conventional treatment (ICT) or standard treatment (ST) with insulin for a mean of 7.5 years. METHODS: We re-determined the skin microcirculation of 72 patients (ICT 35 vs ST 37) from the original Stockholm Diabetes Intervention Study with iontophoresis topically applied with the following vasoactive stimuli: acetylcholine (ACh) (endothelial-dependent vasodilatation), sodium nitroprusside (SNP) (endothelial-independent vasodilatation), and capsaicin (C-nociceptive-dependent vasodilatation). HbA1c levels (mean of 14 values/patient) were prospectively collected between 1990 and 1995 and tested for association with skin microcirculation. The patients were followed until first hospitalisation for an ischaemic foot ulcer or until 2011. RESULTS: During the median 28 years of follow-up, three patients developed ischaemic foot ulcers in the ICT group compared with ten in the ST group (logrank, p = 0.035). At the time of iontophoresis, HbA1c was lower in the ICT group (median 57 mmol/mol [minimum-maximum 40-79 mmol/mol]) compared with the ST group (68 mmol/mol [41-96 mmol/mol], p < 0.01) (DCCT: ICT 7.4% [5.8-9.4%] vs ST 8.4% [5.9-10.9%]). Stimulated blood flow was higher in the ICT vs ST group with significantly increased perfusion units (PU) for: ACh (8.1 PU [4.6-24.7 PU] vs 5.3 PU [1.7-21.4 PU], p < 0.01); SNP (8.1 PU [2.2-20.1 PU] vs 5.6 PU [2.3-19.2 PU], p = 0.03); and capsaicin (5.0 PU [1.7-22.9 PU] vs 3.4 PU [1.5-8.4 PU], p < 0.01). HbA1c was associated with vasodilatation induced by ACh (b = -0.02, p < 0.01) and capsaicin (b = -0.02, p = 0.03). HbA1c was independently associated with ACh (b = -1.48, p < 0.01) and capsaicin-induced vasodilatation (b = -1.45, p < 0.01). CONCLUSIONS/INTERPRETATION: Improved glycaemic control in patients with type 1 diabetes is associated with an improvement in skin microcirculation and with a lower incidence of ischaemic foot ulcers. TRIAL REGISTRATION: ClinicalTrials.gov NCT01957930.

Early signs of atherosclerosis are associated with insulin resistance in non-obese adolescent and young adults with type 1 diabetes.

BACKGROUND: Patients with type 1 diabetes have a substantial risk of developing cardiovascular complications early in life. We aimed to explore the role of insulin sensitivity (Si) as an early factor of atherosclerosis in young type 1 diabetes vs. non-diabetic subjects. METHODS: Forty adolescent and young adult individuals (20 type 1 diabetics and 20 non-diabetics), age 14-20 years, without characteristics of the metabolic syndrome, participated in this cross-sectional study. After an overnight fast, Si was measured by hyperinsulinemic euglycemic clamp (40 mU/m2) and calculated by glucose infusion rate (GIR). Carotid intima-media thickness (cIMT) was measured in the common carotid artery with high-resolution ultrasonography. Risk factors of atherosclerosis (Body mass index [BMI], waist circumference, systolic blood pressure [sBP], triglycerides, low HDL-cholesterol and HbA1c) were also investigated. RESULTS: cIMT was increased (0.52 ± 0.1 vs. 0.47 ± 0.1 mm, P < 0.01), whereas GIR was decreased (5.0 ± 2.1 vs. 7.1 ± 2.2 mg/kg/min, P < 0.01) in type 1 diabetics vs. non-diabetics. The differences in cIMT were negatively associated with Si (r = -0.4, P < 0.01) and positively associated with waist circumference (r = 0.34, P = 0.03), with no such associations between BMI (r = 0.15, P = 0.32), sBP (r = 0.09, P = 0.58), triglycerides (r = 0.07, P = 0.66), HDL-cholesterol (r = 0.10, P = 0.55) and HbA1c (r = 0.24, P = 0.13). In a multivariate regression model, between cIMT (dependent) and group (explanatory), only adjustment for Si affected the significance (ß = 0.08, P = 0.11) vs. (ß = 0.07, P < 0.01) for the whole model. No interaction between cIMT, groups and Si was observed. CONCLUSIONS: cIMT is increased and associated with insulin resistance in adolescent, non-obese type 1 diabetic subjects. Although, no conclusions toward a causal relationship can be drawn from current findings, insulin resistance emerges as an important factor reflecting early signs of atherosclerosis in this small cohort.

GAD65 antigen therapy in recently diagnosed type 1 diabetes mellitus.

BACKGROUND: The 65-kD isoform of glutamic acid decarboxylase (GAD65) is a major autoantigen in type 1 diabetes. We hypothesized that alum-formulated GAD65 (GAD-alum) can preserve beta-cell function in patients with recent-onset type 1 diabetes. METHODS: We studied 334 patients, 10 to 20 years of age, with type 1 diabetes, fasting C-peptide levels of more than 0.3 ng per milliliter (0.1 nmol per liter), and detectable serum GAD65 autoantibodies. Within 3 months after diagnosis, patients were randomly assigned to receive one of three study treatments: four doses of GAD-alum, two doses of GAD-alum followed by two doses of placebo, or four doses of placebo. The primary outcome was the change in the stimulated serum C-peptide level (after a mixed-meal tolerance test) between the baseline visit and the 15-month visit. Secondary outcomes included the glycated hemoglobin level, mean daily insulin dose, rate of hypoglycemia, and fasting and maximum stimulated C-peptide levels. RESULTS: The stimulated C-peptide level declined to a similar degree in all study groups, and the primary outcome at 15 months did not differ significantly between the combined active-drug groups and the placebo group (P=0.10). The use of GAD-alum as compared with placebo did not affect the insulin dose, glycated hemoglobin level, or hypoglycemia rate. Adverse events were infrequent and mild in the three groups, with no significant differences. CONCLUSIONS: Treatment with GAD-alum did not significantly reduce the loss of stimulated C peptide or improve clinical outcomes over a 15-month period. (Funded by Diamyd Medical and the Swedish Child Diabetes Foundation; ClinicalTrials.gov number, NCT00723411.).