Rudy Bilous, MD, FRCP
Richard Donnelly, MD, PHD, FRCP, FRACP
Hypoglycemia is a common side effect of treatment with insulin and oral antidiabetic drugs, especially sulphonylureas, and is a major factor preventing patients with type 1 and 2 diabetes from achieving near normoglycemia. The brain is dependent on a continuous supply of glucose, and its interruption for more than a few minutes leads to central nervous system dysfunction, impaired cognition and eventually coma. The brain cannot synthesize glucose or store more than 5 minutes supply as glycogen. At normal or high circulating glucose concentrations, blood-to-brain glucose transport exceeds the rate of brain glucose metabolism but as glucose levels fall, blood-to-brain glucose transport becomes limiting to brain glucose utilization. Hypoglycemia is more common in young children and may be responsible for the cognitive impairment and lowered academic achievement in children diagnosed with diabetes under the age of 5 years – the developing brain is especially sensitive to hypoglycemia….
Iatrogenic hypoglycemia often causes physical and psychosocial morbidity and sometimes causes death (the ‘dead-in-bed’ syndrome may be due to cardiac arrhythmias secondary to nocturnal hypoglycemia) (Box 13.1).
|Box 13.1 Some consequences of hypoglycemia in diabetes
• Obstacle to achieving normoglycemia
• Disabling symptoms
• Sudden death syndrome
• Cognitive impairment in children
• Major source of anxiety in patients
In the person without diabetes, hypoglycemia is limited in part by inhibition of insulin release from the pancreatic beta cells and stimulation of glucagon from the alpha cells. The major physiological responses to hypoglycemia occur as a result of activation of neurones in the ventromedial region of the hypothalamus and elsewhere in the brain; these neurones sense the lowered plasma glucose levels, activate the autonomic nervous system and stimulate pituitary counter-regulatory hormone release (Figure 13.1). Glucagon and epinephrine (adrenaline) release are probably the main factors that limit hypoglycemia and ensure glucose recovery in normal subjects.
The physiological responses to a falling plasma glucose level produce a range of symptoms that help individuals to recognize hypoglycemia and take corrective action. Hypoglycemic symptoms can be classified as ‘autonomic,’ caused by activation of the sympathetic or parasympathetic nervous system (e.g. tremor, palpitations or sweating), or ‘neuroglycopenic,’ caused by the effects of glucose deprivation on the brain (e.g. drowsiness, confusion and loss of consciousness) (Table 13.1). Headache and nausea are probably non-specific symptoms of malaise. Autonomic symptoms are prominent in subjects with a short duration of diabetes, but diminish with increasing duration of diabetes.
In patients with type 1 diabetes, episodes of asymptomatic hypoglycemia are common: plasma glucose levels may be in the region of 2.8 – 3.3 mmol/L (50 – 60 mg/dL) 10% of the time. Patients experience an average of two episodes of symptomatic hypoglycemia per week, and one episode of severe disabling hypoglycemia per year; 2 – 4% of deaths among people with type 1 diabetes are attributed to hypo-glycemia. Hypoglycemia causes unpleasant symptoms, e.g. anxiety, palpitations, sweating, and the neurological consequences include behavioral changes, cognitive dysfunction, seizures and coma.
The frequency of iatrogenic hypoglycemia is much lower in patients with type 2 diabetes. For example, published rates of severe hypoglycemia among type 1 diabetic patients treated aggressively with insulin range from 60 to 170 episodes per 100 patient-years. Corresponding rates for insulin-treated type 2 diabetic patients range from 3 to 70 episodes per 100 patient-years. Severe hypoglycemia rates in type 2 diabetes are only 10% of those in type 1 diabetes, even during aggressive insulin therapy. During 6 years of follow-up in the UKPDS, only 2.4% of metformin-treated patients, 3.3% of sulphonylurea-treated patients and 11.2% of those on insulin reported a major hypoglycemia episode (requiring third-party assistance). Modern therapies, including long-acting insulin analogues, third-generation sulphonylureas, and DPP-4 inhibitors are associated with less hypoglycemia (Figure 13.3).