Urinary albumin/creatinine ratio tertiles predict risk of diabetic retinopathy progression: a natural history study from the Adolescent Cardio-Renal Intervention Trial (AdDIT) observational cohort.

AIMS/HYPOTHESIS: We hypothesised that adolescents with type 1 diabetes with a urinary albumin/creatinine ratio (ACR) in the upper tertile of the normal range (high ACR) are at greater risk of three-step diabetic retinopathy progression (3DR) independent of glycaemic control. METHODS: This was a prospective observational study in 710 normoalbuminuric adolescents with type 1 diabetes from the non-intervention cohorts of the Adolescent Cardio-Renal Intervention Trial (AdDIT). Participants were classified as 'high ACR' or 'low ACR' (lowest and middle ACR tertiles) using baseline standardised log10 ACR. The primary outcome, 3DR, was determined from centrally graded, standardised two-field retinal photographs. 3DR risk was determined using multivariable Cox regression for the effect of high ACR, with HbA1c, BP, LDL-cholesterol and BMI as covariates; diabetes duration was the time-dependent variable. RESULTS: At baseline mean ± SD age was 14.3 ± 1.6 years and mean ± SD diabetes duration was 7.2 ± 3.3 years. After a median of 3.2 years, 83/710 (12%) had developed 3DR. In multivariable analysis, high ACR (HR 2.1 [1.3, 3.3], p=0.001), higher mean IFCC HbA1c (HR 1.03 [1.01, 1.04], p=0.001) and higher baseline diastolic BP SD score (HR 1.43 [1.08, 1.89], p=0.01) were independently associated with 3DR risk. CONCLUSIONS/INTERPRETATION: High ACR is associated with greater risk of 3DR in adolescents, providing a target for future intervention studies. TRIAL REGISTRATION: isrctn.org ISRCTN91419926.

Diabetic Ketoacidosis at Onset of Type 1 Diabetes and Long-term HbA1c in 7,961 Children and Young Adults in the Australasian Diabetes Data Network.

OBJECTIVE: The relationship between diabetic ketoacidosis (DKA) at diagnosis of type 1 diabetes and long-term glycemic control varies between studies. We aimed, firstly, to characterize the association of DKA and its severity with long-term HbA1c in a large contemporary cohort, and secondly, to identify other independent determinants of long-term HbA1c. RESEARCH DESIGN AND METHODS: Participants were 7,961 children and young adults diagnosed with type 1 diabetes by age 30 years from 2000 to 2019 and followed prospectively in the Australasian Diabetes Data Network (ADDN) until 31 December 2020. Linear mixed-effect models related variables to HbA1c. RESULTS: DKA at diagnosis was present in 2,647 participants (33.2%). Over a median 5.6 (interquartile range 3.2, 9.4) years of follow-up, participants with severe, but not moderate or mild, DKA at diagnosis had a higher mean HbA1c (+0.23%, 95% CI 0.11,0.28; [+2.5 mmol/mol, 95% CI 1.4,3.6]; P < 0.001) compared with those without DKA. Use of continuous subcutaneous insulin infusion (CSII) was independently associated with a lower HbA1c (-0.28%, 95% CI -0.31, -0.25; [-3.1 mmol/mol, 95% CI -3.4, -2.8]; P < 0.001) than multiple daily injections, and CSII use interacted with severe DKA to lower predicted HbA1c. Indigenous status was associated with higher HbA1c (+1.37%, 95% CI 1.15, 1.59; [+15.0 mmol/mol, 95% CI 12.6, 17.4]; P < 0.001), as was residing in postcodes of lower socioeconomic status (most vs. least disadvantaged quintile +0.43%, 95% CI 0.34, 0.52; [+4.7 mmol/mol, 95% CI 3.4, 5.6]; P < 0.001). CONCLUSIONS: Severe, but not mild or moderate, DKA at diagnosis was associated with a marginally higher HbA1c over time, an effect that was modified by use of CSII. Indigenous status and lower socioeconomic status were independently associated with higher long-term HbA1c.

Determinants of Cardiovascular Risk in 7000 Youth With Type 1 Diabetes in the Australasian Diabetes Data Network.

CONTEXT: Cardiovascular disease occurs prematurely in type 1 diabetes. The additional risk of overweight is not well characterized. OBJECTIVE: The primary aim was to measure the impact of body mass index (BMI) in youth with type 1 diabetes on cardiovascular risk factors. The secondary aim was to identify other determinants of cardiovascular risk. DESIGN: Observational longitudinal study of 7061 youth with type 1 diabetes followed for median 7.3 (interquartile range [IQR] 4-11) years over 41 (IQR 29-56) visits until March 2019. SETTING: 15 tertiary care diabetes centers in the Australasian Diabetes Data Network.Participants were aged 2 to 25 years at baseline, with at least 2 measurements of BMI and blood pressure. MAIN OUTCOME MEASURE: Standardized systolic and diastolic blood pressure scores and non-high-density lipoprotein (HDL) cholesterol were co-primary outcomes. Urinary albumin/creatinine ratio was the secondary outcome. RESULTS: BMI z-score related independently to standardized blood pressure z- scores and non-HDL cholesterol. An increase in 1 BMI z-score related to an average increase in systolic/diastolic blood pressure of 3.8/1.4 mmHg and an increase in non-HDL cholesterol (coefficient + 0.16 mmol/L, 95% confidence interval [CI], 0.13-0.18; P < 0.001) and in low-density lipoprotein (LDL) cholesterol. Females had higher blood pressure z-scores, higher non-HDL and LDL cholesterol, and higher urinary albumin/creatinine than males. Indigenous youth had markedly higher urinary albumin/creatinine (coefficient + 2.15 mg/mmol, 95% CI, 1.27-3.03; P < 0.001) and higher non-HDL cholesterol than non-Indigenous youth. Continuous subcutaneous insulin infusion was associated independently with lower non-HDL cholesterol and lower urinary albumin/creatinine. CONCLUSIONS: BMI had a modest independent effect on cardiovascular risk. Females and Indigenous Australians in particular had a more adverse risk profile.

Gastric Emptying Is More Rapid in Adolescents With Type 1 Diabetes and Impacts on Postprandial Glycemia.

CONTEXT: Gastric emptying is a critical determinant of postprandial glycemic control in health and type 1 diabetes. There are few studies that assess the relationship between gastric emptying and postprandial glycaemia in adolescents with type 1 diabetes. OBJECTIVE: The objectives of the study were to quantify gastric emptying in adolescents with type 1 diabetes and examine its relationship to postprandial glycaemia and autonomic function. DESIGN: This was a case-control study. Gastric half-emptying time of a solid meal was measured by a (13)C-octanoate breath test. Cardio-autonomic function was measured by heart rate variability. Chronic and postprandial gastrointestinal symptoms were evaluated by questionnaire and visual analog scales. Blood glucose concentrations were monitored frequently during the study. SETTING: The study was conducted at a tertiary pediatric hospital in South Australia. PARTICIPANTS: Thirty adolescents (aged 15 ± 2.5 y) with type 1 diabetes and age- and sex-matched controls (gastric emptying, n = 20; heart rate variability, n = 135) participated in the study. MAIN OUTCOME: Gastric half-emptying time was the main outcome in the study. RESULTS: Gastric emptying was more rapid in subjects with type 1 diabetes than controls [median half emptying time 78 (interquartile range 61-99) vs 109 (interquartile range 71-124) min, P = .02]. The postprandial rise in blood glucose at 60 minutes was strongly related to gastric half-emptying time (R = -0.65, P = .0001). Gastric emptying was slower in subjects with fasting hyperglycemia but was not related to heart rate variability. Nausea, bloating, and anxiety were related to fasting glycemia (P = .03). CONCLUSION: Rapid gastric emptying is a major determinant of postprandial glycemia in adolescents with type 1 diabetes. This observation has significant implications for therapy.

Early atherosclerosis relates to urinary albumin excretion and cardiovascular risk factors in adolescents with type 1 diabetes: Adolescent type 1 Diabetes cardio-renal Intervention Trial (AdDIT).

OBJECTIVE: The origins of cardiovascular and renal disease in type 1 diabetes begin during childhood. We aimed to evaluate carotid (cIMT) and aortic intima-media thickness (aIMT) and their relationship with cardiovascular risk factors and urinary albumin excretion in adolescents with type 1 diabetes in the Adolescent Type 1 Diabetes cardio-renal Intervention Trial (AdDIT). RESEARCH DESIGN AND METHODS: A total of 406 adolescents with type 1 diabetes, who were 14.1 ± 1.9 years old with type 1 diabetes duration of 6.7 ± 3.7 years, and 57 age-matched control subjects provided clinical and biochemical data and ultrasound measurements of vascular structure (cIMT and aIMT). Vascular endothelial and smooth muscle function was also measured in 123 of 406 with type 1 diabetes and all control subjects. RESULTS: In type 1 diabetic subjects, mean/maximal aIMT (P < 0.006; <0.008), but not mean/maximal cIMT, was greater than in control subjects. Mean/maximal aIMT related to urinary albumin-to-creatinine ratio (multiple regression coefficient [SE], 0.013 [0.006], P = 0.03; 0.023 [0.007], P = 0.002), LDL cholesterol (0.019 [0.008], P = 0.02; 0.025 [0.011], P = 0.02), and age (0.010 [0.004], P = 0.004; 0.012 [0.005], P = 0.01), independent of other variables. Mean/maximal cIMT was greater in males (0.023 [0.006], P = 0.02; 0.029 [0.007], P < 0.0001), and mean cIMT related independently to systolic blood pressure (0.001 [0.001], P = 0.04). Vascular smooth muscle function related to aIMT and cIMT but not to urinary albumin excretion. CONCLUSIONS: aIMT may be a more sensitive marker of atherosclerosis than cIMT in type 1 diabetes during mid-adolescence. Higher urinary albumin excretion, even within the normal range, is associated with early atherosclerosis and should direct clinical attention to modifiable cardiovascular risk factors.