Clinical Factors Determining the Occurrence of Impaired Awareness of Hypoglycemia (IAH) in Adult Patients With Type 1 Diabetes

Hypoglycemia defined as a blood glucose level ≤70 mg / dL is the most common acute complication in patients with type 1 diabetes (T1D). Hypoglycemia is accompanied by alarm symptoms caused by neuroglycopenia and stimulation of the autonomic nervous system caused by the response of counterregulatory hormones. Being aware of the symptoms of hypoglycemia helps patients to recognize hypoglycemia and begin self-treatment. In people experiencing recurrent episodes of hypoglycemia, the counter-regulatory hormonal response may be abnormal, reducing the perception of hypoglycemia. This condition is called impaired awareness of hypoglycemia (IAH) and affects up to 40% of T1D patients. IAH is the reduction or loss of the ability to recognize low blood glucose and respond correctly to the onset of hypoglycemia. It is a significant clinical problem among patients with T1D. IAH exposes patients to severe hypoglycemia, which is associated with impaired consciousness and damage to nerve cells. Therefore, patients with T1D with IAH may feel fear of developing hypoglycemia, which often results in a lack of compliance with the rules of insulin therapy, and thus difficulties in achieving good glycemic control. This can result in chronic hyperglycemia and the development of microvascular and macrovascular complications.

Common episodes of hypoglycemia can lead to disturbances in the development and maturation of neurons, resulting in cognitive impairment, structural changes in the central nervous system, lower levels of intellectual abilities, and behavioral disturbances. MRI studies in patients with T1D and IAH showed brain changes including gray matter and white matter. These changes correlate with the frequency of severe hypoglycemia and, in some areas of the brain, with the severity of IAH.

Hypoglycemia unawareness may also be due to the presence of diabetic cardiovascular autonomic neuropathy (CAN). CAN is an established factor associated with severe hypoglycemia. By reducing the catecholamine counter-regulatory response to hypoglycemia as well as the severity of autonomic warning symptoms, CAN may contribute to IAH. The American Diabetes Association (ADA) recommends screening for CAN in patients with impaired hypoglycemia awareness. However, the relationship between CAN and IAH has not been well established. Few data suggested CAN as a possible cause of IAH, however, further studies in patients with T1D ruled out the association of CAN with IAH. Olsen et al. assessed the relationship of IAH with the presence of CAN and peripheral neuropathy in a group of 66 patients with a 31-year history of T1D. The study showed that adults with IAH compared to the control group (adults with T1D without IAH) did not differ in the incidence of CAN and peripheral neuropathy. Paes et al. in the group of 98 patients with a 13-year duration of CT1 also observed no difference in the incidence of CAN among patients with IAH compared to those with T1D without IAH. However, they confirmed the relationship between age, diabetes duration, number of severe hypoglycemic episodes, and creatinine clearance with IAH. Patients with IAH had a longer T1D duration and lower creatinine clearance compared to the control group. Moreover, in people with impaired hypoglycemia awareness, the number of severe hypoglycemia episodes was higher compared to those with normal hypoglycemia.

A simple and widely used method of assessing hypoglycemia awareness is the use of validated questionnaires in which patients report specific situations in their life related to hypoglycemia. Four questionnaires are known to diagnose awareness of hypoglycemia: Gold, Clarke, Pedersen-Bjergaard, and HypoA-Q. The advantage of using the above-mentioned questionnaires as a method of assessing hypoglycemia awareness is non-invasiveness, no / minimal cost, reporting experiences from actual episodes of hypoglycemia, the possibility of use in large patient populations, and the possibility of clinical application.

Identifying the factors that influence IAH could help draw attention to patients at risk of its consequences. Then, they could undergo hypoglycemia training, education to optimize insulin dosing, or stricter control, e.g. thanks to the use of continuous glucose monitoring systems.