Metabolic derangement and vascular parameters in young individuals with double diabetes

The prevalence of obesity among people living with type 1 diabetes (T1D) has been increasing in the past few decades. This phenomenon has created a new clinical entity, often termed double diabetes (DD), whereby overweight individuals develop features of insulin resistance in conjunction with T1D. Given the initial absence of pragmatic means to measure insulin resistance in people with T1D, family history of type 2 diabetes or the presence of the metabolic syndrome have been proposed as markers of DD. More recently, estimated glucose disposal rate (eGDR), using a simple formula based on data from hyperinsulinaemic-euglycaemic clamp, offered a practical way to assess insulin resistance in T1D. Importantly, several pieces of evidence strongly suggest that insulin resistance, as assessed by eGDR, is contributing to an excess cardiovascular risk in individuals with T1D.
This thesis has further explored the role of insulin resistance as a contributor to vascular complications in T1D, moving away from the concept that glycaemia is the sole factor responsible. Moreover, I describe new potential mechanisms for the adverse effect of insulin resistance in T1D, including changes in the thrombotic milieu early in life, manifesting as altered fibrin network properties and impaired fibrinolysis. My data demonstrate that the adverse vascular effects of insulin resistance occur early in life, thus contributing to excess cardiovascular risk in T1D. In addition, I identify a potential interaction between glycaemic abnormalities and insulin resistance that further increases vascular risk. Given that excessive energy intake leads to weight gain and predisposes to insulin resistance, I also investigate the effects of altered dietary habits on insulin resistance and show that without careful energy balance, high-fat intake can increase insulin resistance, thus predisposing to an adverse vascular profile.
In conclusion, DD should be considered as a distinct high-risk phenotype with eGDR employed as a practical marker to identify this subgroup of individuals. In addition to traditional risk factors associated with insulin resistance, hypofibrinolysis may be another mechanism responsible for the excess vascular risk in T1D. Moreover, increased energy consumption in T1D, particularly from high fat-intake, may contribute to worsening insulin resistance and higher vascular risk in this population.