Definition of hypoglycemia
The American Diabetes Association Working Group has defined multiple forms of hypoglycemia and defined hypoglycemia as blood glucose below 3.9 mmol/L (70 mg/dl) and, in addition, as biochemical hypoglycemia (biochemical hypoglycaemia) with blood glucose between 3.2 and 3.9 mmol/L (58-70 mg/dl).
However, the clinical significance of blood glucose values in this range, which are frequently seen in the starvation state, is controversial. Because of the different diagnostic criteria for hypoglycemia, it is difficult to obtain uniformity among different epidemiological studies, and this, together with differences in populations and differences in study methods, makes it difficult to summarize existing studies using meta-analysis.
In type 1 diabetes, hypoglycemia occurs on average twice a week, and the incidence of severe hypoglycemia is about ~30%, and the longer the disease duration, the higher the risk of developing it. The risk of severe hypoglycemia in adults with type 2 diabetes is much lower than in type 1 diabetes, but the risk of developing it gradually increases with longer insulin therapy. The frequency of hypoglycemia is related to the degree of blood glucose fluctuations (including the magnitude and frequency of daily blood glucose fluctuations), but glycosylated hemoglobin does not fully reflect the degree of daily blood glucose fluctuations.
Nighttime hypoglycemia is easily overlooked because sleep masks the symptoms of hypoglycemia. 50% of severe hypoglycemia in patients with type 1 diabetes occurs at night. Continuous blood glucose monitoring in adults with type 2 diabetes treated with insulin revealed biochemical hypoglycemia in about 50% of patients, and in up to 80% of immature type 1 diabetics.
Clinical significance of hypoglycemia
Hypoglycemia in patients with diabetes is associated with a variety of clinical conditions. Hypoglycemia can interfere with daily life and can bring about uncomfortable symptoms and negative emotions. Most mild episodes of hypoglycemia are transient and can resolve quickly on their own. However, even mild neuroglycopenia can affect cognitive function.
Transient hypoglycemia symptoms can also affect a person’s ability to perform household chores or work. For example, hypoglycemia while driving can lead to car accidents. Loss of balance, ataxia, impaired vision or impaired consciousness can lead to falls and injuries, resulting in broken bones or dislocated joints. Severe hypoglycemia can also lead to coma, seizures and strokes.
Damage from the short-term effects of hypoglycemia tends to have a better prognosis, while the long-term effects associated with hypoglycemia can lead to more serious consequences. Hypoglycemia at work can be dangerous, and certain hazardous jobs are prohibited for people with diabetes who are receiving insulin therapy. Patients with brucellosis (both type 1 and type 2 diabetics) receiving insulin therapy are not suitable to drive cars, and in many countries people with diabetes are prohibited from obtaining a driver’s license. Hypoglycemia can also interfere with activities such as learning, socializing, and physical activity.
Hypoglycemia can have long-term effects on the behavior and self-control of people with diabetes. There is a widespread fear of diabetes among people with diabetes and their relatives, which affects the patient’s glycemic control and leads to deliberate reductions in insulin dosage and excessive food intake. In addition, severe hypoglycemia can lead to marital and family discord and personal relationships.
Cardiovascular effects of hypoglycemia
Significant autonomic nervous system activation secondary to hypoglycemia is an inverse regulatory mechanism that regulates blood glucose to normal levels, and sympathoadrenal system excitation can also lead to autonomic symptoms associated with hypoglycemia. Sympathetic excitation and the release of large amounts of catecholamines can lead to significant hemodynamic changes and therefore have a significant impact on the cardiovascular system.
The increased cardiac burden can lead to a sudden increase in cardiac burden in patients with pre-existing comorbid cardiovascular disease and lead to myocardial ischemia or heart failure. When hypoglycemia occurs acutely, the patient’s blood vessels dilate to lower central arterial pressure; however, as the duration of diabetes mellitus increases, the elasticity of the vessel walls decreases and the patient’s vascular response becomes poorer when hypoglycemia occurs again.
Myocardial ischemia
Although the clinical evidence is inconclusive, hypoglycemia due to insulin in patients with type 2 diabetes can bring about cardiac ischemia. Continuous glucose monitoring and 24-hour ECG monitoring in patients with type 2 diabetes treated with insulin have shown that patients with hypoglycemia can have a myocardial ischemic response.
Cardiac arrhythmias
Hypoglycemia can affect cardiac repolarization and electrophysiological activity and can lead to electrocardiographic changes, including ST-segment and T-wave changes, as well as prolonged QT intervals. Sympathoadrenal nerve excitation and decreased blood potassium due to catecholamines may be responsible for ECG changes due to hypoglycemia.
Among the arrhythmias caused by hypoglycemia in diabetic patients, atrial fibrillation is the most common. Continuous glucose monitoring in type 2 diabetic patients reveals that asymptomatic hypoglycemia (<3.1 mmol/l) can lead to ventricular arrhythmias, especially at night. A study of diabetic patients receiving insulin therapy also found that hypoglycemia can lead to bradycardia, sometimes accompanied by premature atrial or ventricular beats.
The possible mechanisms by which hypoglycemia causes arrhythmias are as follows.
Possible mechanisms of hypoglycemia leading to arrhythmias. Nocturnal hypoglycemia can lead to a decrease in sympathetic excitability, followed by compensatory excitation of parasympathetic excitability, leading to bradycardia and lethal ventricular arrhythmias. Daytime hypoglycemia can also lead to an increased risk of arrhythmias, but is rarely life-threatening.
Altered hemodynamics and blood rheology function
Hypoglycemia can lead to increased release of hormones, such as catecholamines, and active peptides, such as endothelin, which in turn can cause increased blood viscosity and coagulation activity, as well as leukocyte mobilization and platelet activation, and affect the function of the vascular endothelium. These alterations in circulation can affect blood flow, so that recurrent hypoglycemia can lead to local tissue ischemia, which will worsen if there is existing microvascular disease. It has been demonstrated that repeated hypoglycemia in patients with type 1 diabetes can lead to the development of atherosclerosis.
Persistent pathophysiological changes
The pathophysiological response to hypoglycemia can last for several days, which in turn affects cardiovascular and autonomic function, thereby increasing the risk of cardiovascular events. The release of inflammatory factors due to hypoglycemia can last 24-48 hours. In addition, hypoglycemia can contribute to increased blood clotting and trigger a low-grade inflammatory response, and these effects can persist for up to 1 week. All of these effects are capable of contributing to intravascular thrombosis.
Clinical implications
Although the evidence that hypoglycemia causes cardiovascular dysfunction is inconclusive, many patients with type 2 diabetes have concomitant cardiovascular disease, many of which are asymptomatic. Moreover, cardiac insufficiency occurs at a higher rate in type 2 diabetic patients than in the normal population. The impact of hypoglycemia on cardiovascular function is particularly important in patients with type 2 diabetes combined with cardiovascular disease, and it can exacerbate the patient’s own underlying disease.
Hypoglycemia is even more dangerous at night, when patients are asleep and cardiac symptoms are easily masked. It is important to protect against nocturnal hypoglycemia in patients with type 2 diabetes treated with insulin, so patients with type 2 diabetes with cardiovascular disease should relax their blood glucose control appropriately.
Effects of hypoglycemia on brain function
The brain is most sensitive to hypoglycemia because sugar is the only source of energy for brain tissue, and brain function damage can occur rapidly in hypoglycemia, called neuroglycopenia. Several cognitive functions may be involved at this time, especially attention-demanding tasks, and tasks requiring rapid responses and complex transmission processes. When blood glucose returns to normal, it is possible that full recovery of cognitive function may take longer than 60 minutes.
Most of the acute impairments caused by hypoglycemia are associated with cognitive dysfunction. For example, cognitive dysfunction can bring about unstable and irrational behavior, confusion and affect vision and balance, leading to falls or accidents, or more severe neurological deficits.
Electroencephalographic (EEG) changes
Hypoglycemia primarily causes anterior brain EEG changes. EEG abnormalities, more frequent epileptiform electrical activity, and altered theta waves are also seen in minors with type 1 diabetes who develop hypoglycemia. Some EEG changes due to hypoglycemia, such as alterations in theta waves, persist for some time after blood glucose recovery. Some changes can be permanently irreversible, especially with recurrent severe hypoglycemia. Seizures due to hypoglycemia can trigger cardiac arrhythmias leading to sudden death.
Altered cerebral blood flow and cerebral ischemia
When acute hypoglycemia occurs, blood flow to the prefrontal lobes of the brain increases to increase glucose supply. regional changes in cerebral blood flow become permanently irreversible in patients with type 1 diabetes with recurrent severe hypoglycemia. Transient ischemic attacks and hemiparesis are the main manifestations of hypoglycemia, especially in older patients with cerebrovascular disease.
Cerebral neurological dysfunction
Hypoglycemia may lead to localized cerebral neurological dysfunction with clinical symptoms, cognitive impairment and imaging changes, but the incidence is extremely low. Neuroimaging has shown that hypoglycemia can cause reversible functional changes in the brain. However, the available studies have not established a link between neuroimaging changes and neurobehavioral or cognitive changes.
Cognitive impairment
Whether recurrent severe hypoglycemia can cause permanent and lasting damage depends on the age of the patient. Children who develop type 1 diabetes are very sensitive to neurological hypoglycemia, and the neurological damage caused by hypoglycemia is significantly different from that caused by diabetes itself.
Patients with type 1 diabetes who have experienced severe hypoglycemia at ages younger than 5 years have poorer cognitive function in adulthood than those who have never experienced hypoglycemia. Patients with type 1 diabetes at younger age of onset had lower scores on variable intelligence and executive function than those at older age of onset, and even lower scores for those who had severe hypoglycemia at a young age.
In a cohort study, there were no significant differences in cognitive ability between children with type 1 diabetes and control children at the time of study inclusion, but cognitive ability (verbal IQ [Verbal IQ] and full scale IQ [Full Scale IQ] as measured by the Wechsler scale) was poorer in patients with type 1 diabetes 12 years later, and patients with multiple episodes of hypoglycemia had poorer verbal ability than other patients.
Older patients are more sensitive to hypoglycemia than children, and recurrent hypoglycemia in type 2 diabetic patients can significantly affect cognitive function and may even lead to dementia. In conclusion, the long-term effects of hypoglycemia on cognitive function in patients with diabetes are very complex and have significant age differences.
How to reduce the risk of hypoglycemia?
Current recommendations
A working group of the American Diabetes Association (ADA) outlined measures to prevent the risk of hypoglycemia, with the main principles being.
1. patient education; 2. help patients understand the symptoms of hypoglycemia; 3. treat hypoglycemia effectively; 4. provide patients with detailed information about hypoglycemia at the time of their visit: frequency of occurrence, severity, symptoms and how to detect them, analysis of hypoglycemic events (triggers, time of occurrence, role of alcohol); 5. understand the pharmacokinetics of hypoglycemic drugs: formal training for patients receiving insulin injections, training for Training on hypoglycemic symptoms; 6. Dietary measures; 7. Knowledge of carbohydrate content in food;
8. reasonable meal planning; 9. flexible adjustment of insulin injection dose; 10. carrying carbohydrate foods that can be absorbed quickly; 11. physical exercise; 12. knowledge of potential risk factors (e.g., type, duration, and time of exercise initiation); 13. targeted monitoring of blood glucose according to the amount of exercise; 14. preventive carrying of snacks; 15. adjustment of insulin dose; 16. Monitor; 17. Measure blood glucose regularly, and when necessary, and record accurately: peripheral blood glucose monitoring, real-time continuous dynamic monitoring of blood glucose.
Effective patient (and family) education is fundamental to the prevention of hypoglycemia. Teaching patients the basics of hypoglycemia should be avoided because some patients do not understand it and the primary responsibility for preventing hypoglycemia in different patients lies with the physician. Although formal patient education programs are meaningful, many specialty care centers do not provide intensive training and standard educational measures on dietary modification, physical activity, glucose monitoring, and medication modification.
More targeted treatment measures, such as continuous glucose monitoring and continuous intravenous insulin infusion, are needed for some patients who lack adequate awareness of hypoglycemia. In addition, some new technologies can help patients detect the early signs of hypoglycemia.
Hypoglycemic risks of new diabetes treatment drugs
Insulin therapy in patients with type 2 diabetes is known to increase the risk of diabetes. New short-acting insulin analogs have no benefit for hypoglycemia, but long-acting analogs can reduce the incidence of nocturnal hypoglycemia.
The use of newly marketed oral and injectable glucose-lowering drugs includes: entero-insulin analogs (GLP-1 receptor blockers and DPP-4 inhibitors), and SGLT2 inhibitors are less commonly reported to occur as hypoglycemia. With the increased use of these hypoglycemic agents there is potential to reduce the incidence of hypoglycemia.
The biggest barrier to the application of these treatments is currently the cost, which is far more expensive than sulfonylureas and metformin. Also the safety of these drugs for long-term use has yet to be tested.
New technologies to prevent hypoglycemia
Continuous glucose monitoring can help detect hypoglycemia, but its cost and technical limitations have affected its use in the clinic. A major technical limitation of continuous glucose monitoring is the difficulty of alerting patients at night. However, the significance of real-time continuous glucose monitoring in preventing the occurrence of severe hypoglycemia in populations lacking sufficient awareness of hypoglycemia has been demonstrated, and its use will become more widespread with increased reliability and sensitivity, as well as increased warning features and reduced costs.
The application of continuous subcutaneous insulin injections with an insulin pump can reduce the incidence of severe hypoglycemia, especially in patients who have been treated with insulin injections for a longer period of time and have had multiple episodes of hypoglycemia.
Hypoglycemia in diabetic patients has a detrimental effect on the cardiovascular system and the central nervous system, which can in turn lead to an increased incidence of complications and patient mortality. In order to prevent the emergence of hypoglycemia, the goal of blood glucose control must be different from person to person: the goal of blood glucose control should be moderately relaxed for the elderly with combined cardiovascular disease, young children and frail people. With the deeper understanding of the dangers of hypoglycemia in different populations of patients, many treatment guidelines have been revised, and the concept that glycemic control goals need to be individualized is gaining more and more attention.