A 36-year-old woman with a 25+ year history of type 1 diabetes presents with recurrent severe hypoglycemia, often in the early hours of the morning. She has multiple microangiopathic complications, including proliferative retinopathy (treated by laser photocoagulation), painful neuropathy, microalbuminuria and gastroparesis. HbA1c is 8.4% using a basal-bolus insulin regimen. She has considerable anxiety about hypoglycemia, having embarrassed herself at work with odd behaviour associated with a hypo. She has mostly lost her awareness of hypoglycemic symptoms, and is reluctant to modify her insulin doses (in order to improve HbA1c) because of the risk of hypos. On admission to hospital, she reports at least six severe hypos in the past year requiring third-party assistance.
Comment: Hypoglycemia unawareness is common among patients with long-duration type 1 diabetes, especially when autonomic dysfunction is present. Fear of severe hypoglycemia, associated with behavioral disturbance and altered cognition, is an understandable barrier to improving glycemic control, yet because of advanced microvascular complications, this woman would benefit from lower HbA 1c levels in the long term. This is a complex management problem. She would be a candidate for continuous subcutaneous insulin infusion using a pump.
Hypoglycemia in diabetes is caused by absolute or relative insulin excess, but the integrity of glucose counter-regulatory mechanisms has an important effect on the clinical outcomes. Thus, compromised glucose counter-regulation is well recognized in type 1 diabetes and probably also occurs in advanced type 2 diabetes. Risk factors for compromised glucose counter-regulation include: (1) insulin deficiency states; (2) history of severe hypoglycemia, hypoglycemia unawareness or both; and (3) aggressive antidiabetic therapy, as shown by lower HbA 1c (Table 13.2).
The initial response to hypoglycemia is the acute release of counter-regulatory hormones (in particular, glucagon and epinephrine) which occurs at a plasma glucose concentration of about 3.6 – 3.8 mmol/L (65 – 68 mg/dL). Autonomic symptoms develop at about 3.2 mmol/L (58 mg/ dL), before cognitive function starts to deteriorate at around 3 mmol/L (54 mg/dL) (Figure 13.4). Those patients who retain awareness of hypoglycemia are thus alerted before significant cerebral dysfunction occurs. However, the inability to recognize symptoms of impending hypoglycemia, known as ‘hypoglycemia unawareness,’ is a major clinical problem in those with insulin-treated diabetes. Hypoglycemic unawareness affects about 25% of patients with type 1 diabetes. In these patients, sympathoadrenal activation occurs at a lower plasma glucose level than for cognitive impairment. The risk of a severe episode of hypoglycemia increases 6 – 7-fold in patients with hypoglycemia unawareness.
Nearly all people with insulin-treated diabetes have some defect in the mechanisms that protect them against hypoglycemia, although the impairment is mild in type 2 diabetes. The glucagon response to hypoglycemia begins to fail within 1 – 2 years of type 1 diabetes onset, probably because of disruption to paracrine mechanisms of cross-talk within the islet, as endogenous insulin production declines. A reduced sympathoadrenal response is common in type 1 diabetes of long duration; those who exhibit both glucagon and epinephrine impairment are particularly susceptible to hypoglycemia, because of both impaired glucose counter-regulation and impaired hypoglycemia awareness (Figure 13.5). Autonomic neuropathy is a major cause of hypoglycemia unawareness.