Higher frequency of cardiovascular autonomic neuropathy in youth with type 2 compared to type 1 diabetes : Role of cardiometabolic risk factors

Objective Cardiovascular autonomic neuropathy (CAN) is an overlooked but common and serious diabetes complication. We examined CAN in youth with diabetes and associations with cardiovascular risk factors. Research Design and Methods This was a prospective cohort of youth aged <20 years with type 2 or type 1 diabetes (n = 66/1153, median age 15.4/16.5 years, duration 1.7/8.0 years), assessed between 2009 and 2020. CAN was defined as ≥2 abnormal heart rate variability measures across time, geometric, and frequency domains. Obesity was defined as BMI ≥ 95th percentile and severe obesity as ≥120% of 95th percentile. Multivariable generalized estimating equations (GEE) were used to examine putative risk factors for CAN, including diabetes type, obesity, and HbA1c. Results At most recent assessment, youth with type 2 versus type 1 diabetes had median: HbA1c 7.1% (54 mmol/mol) versus 8.7% (72 mmol/mol) and BMI SDS (2.0 vs. 0.7); frequency of CAN (47% vs. 27%), peripheral nerve abnormality (47% vs. 25%), hypertension (29% vs. 12%), albuminuria (21% vs. 3%), and severe obesity (35% vs. 2%). In multivariable GEE, CAN was associated with type 2 diabetes: Odds Ratio 2.53, 95% CI 1.46, 4.38, p = 0.001, higher BMI SDS: 1.49, 95% CI 1.29, 1.73, p < 0.0001, and obesity: 2.09, 95% CI 1.57, 2.78, p < 0.0001. Conclusions Youth with type 2 diabetes have a higher frequency of CAN, peripheral nerve abnormality, hypertension, albuminuria and severe obesity despite shorter diabetes duration and younger age. Our findings highlight the importance of targeting modifiable risk factors to prevent cardiovascular disease in youth with diabetes

New insights into pathophysiology of early complications in adolescents with type 1 diabetes mellitus

Adolescence is an important period for determining the risk of vascular dysfunction later in adulthood. With the increasing rate of obesity in the type 1 diabetes population, there is an increased risk of metabolic syndrome and dyslipidemia. Increased prevalence of obesity leads to a greater risk of cardiovascular disease and microvascular complications. Other contributors to microvascular disease may be autonomic nerve dysfunction and metabolic dysfunction, independently of other known risk factors. Much interest has focused on retinal vascular calibres as predictors of a systemic disease, but to date, retinal calibres have not predicted non-retinal complications during adolescence. This thesis explores retinal vascular calibres (arterioles and venules): “extended zone” mean retinal calibres (MWa and MWv) within two-disc diameters in addition to traditionally reported CRAE and CRVE within one disc diameter from the optic disc. A second focus is the role of autonomic neuropathy in the development of microvascular complications. Finally, the third focus is the interaction of retinal vessel calibres and liver transaminases (a measure of metabolic dysfunction) and autonomic nerve dysfunction. Study 1 was a cross-sectional analysis of retinal vessel calibres in 736 adolescents aged 12-20yrs with a minimum T1D duration of 2 years without retinopathy. Glycaemic control was significant for the extended zone calibres (arterioles and venules) but not the central vessel equivalents. Study 2 was a longitudinal study of the development of moderate retinopathy in 904 adolescents with a median follow-up of 3 years. Wider baseline extended zone calibres (upper three quartiles vs lowest quartile) predicted moderate retinopathy after adjusting for HbA1c and blood pressure: MWa; OR, 3.6 (2.06-6.1), and MWv; OR, 4.2 (2.2-7.5). CRAE and CRVE were not associated with retinopathy. Study 3 was a longitudinal study of albuminuria in 441 adolescents with normal albumin secretion at baseline with a median follow-up of 3 years. Wider MWa and MWv (quartile 2-4 vs quartile 1) predicted early renal dysfunction: MWa OR 2.0 (1.41, 2.90); MWv 1.63(1.16, 2.29) after adjusting for covariates (A1C, diabetes duration, gender, height and blood pressure). Study 4 was a longitudinal study of sensory nerve abnormalities (thermal and vibration discrimination) in 889 adolescents with a median follow-up of 6.2 years. Narrower extended zone calibre quartiles but not CRAE or CRVE quartiles were independently associated with sensory nerve abnormality: MWa (Q1 vs Q2-4: OR 1.35 (95%CI 1.02, 1.61) and MWv (Q1 vs Q2-4: 1.31 (1.03, 1.7)), after adjusting for HbA1C, duration and blood pressure. Study 5 was a longitudinal study of early cardiac autonomic dysfunction as a predictor of incident retinopathy and albuminuria in 725 adolescents with T1 diabetes free of retinopathy or albuminuria at baseline. Over a median follow-up of 3.8 [interquartile range 2.2-7.5] years, complications rates were retinopathy at 27%, early kidney dysfunction at 16%, and albuminuria at 3%. In addition, cardiac autonomic nerve dysfunction predicted incident retinopathy: OR 2.0 (CI: 1.4, 2.9) and early kidney dysfunction 1.4 (1.0, 2.0) independent of HbA1C and duration. Study 6 was a longitudinal study of repeated measures of retinal vascular calibre and liver dysfunction (transaminase elevation) in 102 adolescents. Retinal vessel calibre and transaminase ALT increased and predicted cardiac autonomic neuropathy independently of each other and other known variables. In conclusion, assessment of extended zone retinal vessel calibres provides insight into early microvascular changes associated with diabetes and its complications. Progressive retinal vascular changes predate autonomic nerve dysfunction, which itself predates retinopathy and albuminuria. Chronic hyperglycemia leads to a maladaptive inflammatory reaction in retinal endothelial cells and systemic inflammation. Additionally leads to structural and functional endothelial dysfunction resulting in retinal vascular changes. Systemic inflammation and metabolic syndrome lead to alterations in liver enzymes followed by autonomic microvascular dysregulation and, subsequently, microvascular complications