Hypoglycemia is a common complication in patients with diabetes treated with insulin or sulfonylureas and can significantly affect daily life, such as driving, work, and leisure activities. In addition to sudden accidents and personal injury, hypoglycemia can lead to cardiovascular disease and central nervous system disorders. The fear of hypoglycemia may lead to failure of self-management and glycemic control in diabetic patients. 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. The short-term effects of hypoglycemia tend to cause damage with 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 The autonomic nervous system activation that is evident 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 thus have a significant impact on the cardiovascular system (Table 3). The increased cardiac burden can lead to a sudden increase in cardiac burden in patients with otherwise comorbid cardiovascular disease and lead to myocardial ischemia or heart failure. When hypoglycemia occurs acutely, patients’ blood vessels dilate to lower central arterial pressure; however, as the duration of diabetes mellitus increases, the elasticity of the vessel wall decreases, and patients’ 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 electrocardiographic monitoring in patients with type 2 diabetes treated with insulin have shown that patients with hypoglycemia 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, and 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, which are particularly pronounced at night. A study of diabetic patients receiving insulin therapy also found that hypoglycemia can lead to bradycardia, sometimes with premature atrial or ventricular beats. Altered Hemodynamics and Hemorheology Hypoglycemia can lead to increased release of hormones, such as catecholamines, and reactive 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 caused by 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 develop 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 who have 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 damage to brain function 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. Electroencephalography (EEG) changes Hypoglycemia mainly causes EEG changes in the anterior part of the brain. 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. Cerebral blood flow changes and cerebral ischemia When acute hypoglycemia occurs, cerebral prefrontal blood flow increases to increase glucose supply. regional cerebral blood flow changes 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 has the potential to cause 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 (fluidintelligence) 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 ability [VerbalIQ] 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 diabetic patients are very complex and have significant age differences. What can be done to reduce the risk of hypoglycemia? A working group of the American Diabetes Association (ADA) has outlined measures to prevent the risk of hypoglycemia, the main principles of which are: 1. patient education; 2. helping patients understand the symptoms of hypoglycemia; 3. effective treatment of hypoglycemia; 4. providing patients with detailed information at the time of their visit about hypoglycemia: how often it occurs, its severity, its symptoms and how to detect it, The frequency, severity, symptoms and how to detect symptoms, analysis of hypoglycemic events (triggers, time of occurrence, role of alcohol); 5. understanding the pharmacokinetics of hypoglycemic drugs: formal training for patients receiving insulin injections, training for hypoglycemic symptoms; 6. dietary measures; 7. understanding the content of carbohydrates in food; 8. developing a reasonable meal plan; 9. flexible adjustment of insulin injection doses; 10. Carbohydrate foods that can be absorbed quickly; 11. physical exercise; 12. understanding potential risk factors (such as type, duration and time of starting exercise); 13. targeted monitoring of blood glucose according to the amount of exercise; 14. preventive carrying of snacks; 15. adjustment of insulin dose; 16. blood glucose monitoring; 17. regular, and when necessary, blood glucose measurement, and accurately recorded: peripheral blood glucose monitoring, real-time continuous monitoring of blood glucose. Effective patient (and family) education is fundamental to the prevention of hypoglycemia. Teaching patients the basics about hypoglycemia should be avoided because some patients do not understand it and the primary responsibility for preventing hypoglycemia in diverse patients lies with the physician. Although formal patient education programs are meaningful, many specialty care centers cannot 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. Risk of hypoglycemia with new drugs for diabetes treatment Patients with type 2 diabetes are now known to be at increased risk for diabetes with insulin therapy. 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 affect 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.