Hypoglycemia in Type 1 Diabetes Mellitus

Abstract

Hypoglycemia is a common problem in patients with type 1 diabetes and can be asymptomatic, mild, and severe. Despite therapeutic approaches and technological advances, hypoglycemia continues to be an important cause of morbidity and mortality in patients. Impairment in counterregulatory defense mechanisms and unawareness of hypoglycemia are the main risk factors for hypoglycemia. Recurrent episodes of hypoglycemia cause an awareness of hypoglycemia and defective counter-regulation, resulting in hypoglycemia-associated autonomic deficiency (HAAF) syndrome. Efforts are needed to prevent hypoglycemia, and approaches include glucose monitoring, patient education, and medication adjustment. Advances in technology, such as insulin pumps and devices that allow continuous glucose monitoring, can significantly reduce the risk of hypoglycemia in patients when used appropriately.

1. Introduction

Type 1 diabetes mellitus (T1DM) is a disease that occurs as a result of the destruction of pancreatic beta-cells due to autoimmunity or different reasons and is characterized by absolute insulin deficiency and hyperglycemia. It is mostly prevalent in children between the ages of 7–15 and can also occur in adulthood. The fact that the disease can occur at any age and the annual rate of increase of 3% leads to a rise in the number of individuals with T1DM.

All individuals diagnosed with T1DM should undergo an intensive diabetes management regimen, which has emerged as the prevailing standard for the majority of patients. Intensive diabetes treatment involves the implementation of an insulin regimen closely mirroring physiological release patterns strategically integrated with lifestyle modifications, dietary considerations, and regular physical exercise. Vigilant blood sugar monitoring is strongly advised. Customized glycemic targets should be discerned individually, taking into account the dual objective of averting both macrovascular and microvascular complications, all while judiciously considering the potential risks associated with hypoglycemia.

Vigorous management of hyperglycemia holds significant significance, particularly in light of recent findings indicating an elevated risk of cardiovascular morbidity among individuals with elevated but still within normal range HbA1C values. Consequently, the prevailing objective of care for individuals with diabetes is the achievement of normalized or near-normalized blood glucose levels. While lifestyle modifications retain their value in managing individuals with T1DM, it is imperative to acknowledge that optimal glycemic control is unattainable without the incorporation of insulin therapy. The administration of insulin, however, is not without its challenges, as iatrogenic hypoglycemia emerges as a complicating factor, posing limitations on the feasibility of achieving intensive glycemic control.

1.1 Epidemiology of type 1 diabetes mellitus

The incidence of T1DM shows variability across age groups, with a peak typically observed around 10–14 years. Nevertheless, T1DM can manifest at any age. According to recent studies, the global incidence of T1DM has risen over the past few decades, with an average annual increase of approximately 3–4%. In China and other Asian and South American countries, the annual incidence ranges from 1 to 3 per 100,000. Meanwhile, South European countries and the USA demonstrate rates of approximately 10–20 per 100,000. In Scandinavia, the incidence is higher, ranging from 30 to 60 per 100,000 [1, 2].

1.2 Pathophysiology of type 1 diabetes mellitus

T1DM is characterized by the persistent immune-mediated destruction of pancreatic beta-cells, resulting in a complete deficiency of insulin. The exact mechanisms triggering autoimmunity remain elusive; however, it is widely acknowledged that various environmental factors, within the context of genetic susceptibility, likely play a role. The destruction of beta-cells occurs at a variable pace and becomes clinically evident when at least 70% of beta-cells are either inactive or destroyed [3, 4]. The evolving risk of T1DM associated with migration underscores the significant influence of environmental factors in the pathogenesis of T1DM. This phenomenon has been observed in certain countries but not universally across all regions. Genetic susceptibility to T1DM is intricate, with approximately 40–50% of familial clustering attributed to polymorphisms in class II HLA genes encoding DQ and DR. The most high-risk haplotypes, DR3 and DR4, are present in 90–95% of young children with T1DM. However, less than 5% of individuals with HLA-conferred genetic susceptibility actually develop T1DM. Furthermore, there exists a diverse array of other genes that contribute to the overall risk. Children with a sibling affected by T1DM face a 5% probability of developing T1DM by the age of 20 years, compared to the 0.3% risk observed in the general population. Identical twins exhibit a 65% concordance rate when followed by 60 years of age. The risk for children of fathers with T1DM is higher (6%) than when the mother has T1DM, particularly if she gives birth before the age of 25 (4%), decreasing to 1% after that, akin to the general population. Remarkably, over 90% of individuals with T1DM have no discernible family history of the condition, although there might be a prevalence of other autoimmune diseases within the family, such as coeliac disease or autoimmune thyroid disease. The influence of genetic risk is more pronounced in individuals diagnosed at a young age and diminishes as the age of diagnosis increases. Conversely, patients with adolescent- and adult-onset T1DM exhibit lower twin concordance and decreased genetic risk scores [2, 5].

Childhood infections have demonstrated an association with an increased risk of islet autoimmunity and T1DM. In the TEDDY study, the incidence of respiratory infections and islet autoimmunity displayed a correlation in children under 4 years of age, reaching a peak between 6 and 9 months [6]. Enteroviruses, primarily, have been implicated as the predominant pathogens, and a meta-analysis revealed significant associations between infection and T1DM [7].

Moreover, some studies suggest that parental obesity, vitamin D deficiency, and dietary factors may increase the risk of T1DM [8, 9, 10]; however, the evidence is insufficient or weakly associated with the risk.

2. Hypoglycemia in type 1 diabetes

From a clinical perspective, hypoglycemia is categorized into mild or severe episodes. Mild occurrences of hypoglycemia do not induce alterations in mentation and can be readily rectified with straightforward measures. Conversely, severe hypoglycemia (SH) results in altered mental status, seizure, or coma and often requires external intervention (e.g., intravenous dextrose and glucagon injection).

In individuals with diabetes, pinpointing a precise plasma glucose concentration for diagnosing hypoglycemia poses a challenge, as the threshold for symptom onset varies among patients. Recurrent hypoglycemic episodes lower this threshold, while uncontrolled diabetes elevates it.

The contemporary classification of hypoglycemic episodes in diabetes encompasses three severity levels [11]:

Level 1 hypoglycemia is characterized by a plasma glucose concentration < 70 mg/dL but >54 mg/dL. The threshold concentration of 70 mg/dL is significant because it is below this level that neuroendocrine responses to hypoglycemia typically manifest in individuals without diabetes. In the context of individuals with diabetes, a significant number may exhibit compromised defense mechanisms against hypoglycemia or a lack of awareness regarding it. Consequently, plasma glucose concentrations below 70 mg/dL are deemed clinically significant in diabetes, mandating intervention irrespective of the severity of accompanying symptoms.

Level 2 hypoglycemia is characterized by a plasma glucose concentration below 54 mg/dL, necessitating immediate action to correct the hypoglycemia.

Level 3 hypoglycemia is characterized by a significant event characterized by alterations in mental status or a decline in the individual’s physical capacity to perform tasks. This degree of hypoglycemia necessitates external intervention by another person to rectify the glucose concentration.

2.1 Clinical significance of hypoglycemia

Hypoglycemia poses a challenge to achieving optimal glycemic control in individuals with diabetes. Although the ADA Standards of Care [12] emphasize a patient-centered approach to glycemic targets, the overall recommendations lean toward rigorous, intensive glycemic control, aiming for an HbA1C level below 7% when the risk of hypoglycemia is low. This is due to the extensive literature [13] that tight glycemic control is associated with significantly reduced rates of microvascular complications. However, the goal of intensive control has also led to an increase in hypoglycemia rates, contributing to morbidity and mortality in certain patients [14]. Severe hypoglycemia is a common problem during intensive insulin therapy in patients with T1DM. The annual incidence of severe hypoglycemia among patients with type 1DM has been reported to range from 3.3 to 13.5% [15]. Severe hypoglycemia is reported to be the cause of death in 4–10% of the patients [16]. Because of the apprehension associated with acute hypoglycemia, individuals with diabetes might prioritize averting immediate risks over contemplating the long-term consequences of chronic hyperglycemia. Consequently, many diabetes patients may tolerate elevated glycemic levels as a strategy to prevent episodes of acute hypoglycemia.

The Diabetes Control and Complications Trial (DCCT) in 1997 revealed a substantial prevalence of severe hypoglycemia. Specifically, the incidence of hypoglycemia requiring treatment assistance was documented at 61.2 per 100 patient-years among individuals undergoing intensive treatment, compared to 18.7 per 100 patient-years in those subjected to conventional treatment [17]. Nevertheless, the incidence of severe hypoglycemia has exhibited a declining trend over time. An Italian study conducted in 29 diabetes centers during 2011–2012 reported a lower incidence of 7.7 per 100 patient-years [18]. Similar decreasing trends were observed in children and adolescents in Germany, Australia, and Japan [19, 20]. In contrast, the HAT study in 2016, which included 24 countries, showed a high incidence of hypoglycemia in T1DM patients. Rates of any, nocturnal and severe hypoglycemia were 73.3, 11.3, and 4.9 events/patient-year for T1DM, respectively. The highest rates of hypoglycemia were observed in Latin America for T1DM [21]. Although advancements in treatment regimens may contribute to the decrease in severe hypoglycemia incidence, it remains a pertinent risk and ongoing threat for individuals with type 1 diabetes and their families.

Hypoglycemia may be associated with permanent brain damage and abnormalities in brain structure, particularly in young children with T1DM. Many studies conducted among children, adolescents, and older adults with T1DM have consistently demonstrated an association between severe hypoglycemia and a decline in cognitive function, particularly affecting tasks related to executive function and memory [22].

Hypoglycemia is associated with increased cardiovascular morbidity in patients with T2DM and T1DM [23]. The counter-regulatory release of epinephrine triggered by hypoglycemia increases heart rate and cardiac output. This response is also associated with hypokalemia, which has the potential to cause QT prolongation and other cardiac arrhythmias. Additionally, counter-regulatory hormones induce platelet coagulation and the release of proinflammatory cytokines, both of which impact vascular flow. When combined with the pre-existing vascular disease often observed in patients with diabetes, these factors create significant stress on the heart and contribute to cardiac morbidity.

Studies have shown that hypoglycemia is associated with an increased risk of fracture in patients with T1DM [24]. Compared to the general population, people with T1DM have more than twice the risk of fracture. Episodes of hypoglycemia increase fracture risk by more than 50%. Insulin treatment does not change the risk of fracture [25].

Hypoglycemia has a profound negative effect on the quality of life for individuals with diabetes. Patients who experience frequent episodes of symptomatic hypoglycemia within a year reported making significant lifestyle adjustments. These adjustments include avoiding social settings and structuring daily activities around meal and medication schedules [26]. Consequently, individuals with a history of severe hypoglycemia demonstrate lower scores on assessments of overall health and well-being, including the EQ-5D Visual Analog Scale, World Health Organization Five Well-Being Index, Problem Areas in Diabetes Scale, and Food Habits Questionnaire. Additionally, the fear of hypoglycemia becomes a self-perpetuating concern. Experiencing one or more severe hypoglycemic episodes within a year doubles the likelihood of scoring within the highest tertile of the Fear of Hypoglycemia Questionnaire [27].

2.2 Pathophysiology of hypoglycemia

2.2.1 Risk factors for hypoglycemia

Hypoglycemia may arise from an excess of therapeutic insulin or a failure in defense mechanisms against a decrease in plasma glucose concentration. Common risk factors for iatrogenic hypoglycemia (Table 1) include missed or insufficient meals in relation to insulin therapy, unaccustomed physical exertion without additional caloric intake, overall improvements in fitness and insulin sensitivity without adjusting the insulin dosage, and other instances of inadvertent or misguided insulin overdosage. Other contributing factors comprise alcohol consumption, which inhibits gluconeogenesis; drug interactions; systemic illnesses linked to malnutrition or poor food intake; chronic liver disease (resulting in impaired glucose production); and renal failure (accompanied by decreases in renal gluconeogenesis and insulin clearance).

Inadequate caloric consumption	Increased insulin sensitivity	Impaired glucose production
Skipped meals; Delayed meals; Malnutrition; Intercurrent illness	Weight loss; Exercise; Improved fitness; Medications	Alcohol intake; Liver disease; Renal failure

Table 1.

Common risk factors for hypoglycemia in T1DM [28].

In individuals without diabetes, a decrease in plasma glucose prompts a swift reduction in insulin secretion. This diminished insulin secretion limits peripheral glucose disposal, initiates lipolysis (thus providing gluconeogenic substrates), and enables two essential hepatic processes: glycogenolysis and gluconeogenesis. The reduction in insulin secretion is a crucial physiological response designed to elevate plasma glucose back to the normal range. However, individuals with T1DM, lacking the capacity for autoregulation of insulin secretion, experience unavoidable fluctuations in exogenous insulin administration and caloric intake. Those with insulin deficiency (C-peptide negative) lack endogenous insulin that can be suppressed in reaction to declining plasma glucose levels. Paradoxically, the insulin deficiency that underlies hyperglycemia in T1DM patients becomes a primary risk factor for iatrogenic hypoglycemia [28].

In individuals with T1DM who are incapable of suppressing circulating (exogenous) insulin levels, pharmacokinetic factors serve as the sole mechanism for eliminating administered insulin during evolving hypoglycemia. To put it succinctly, there are presently no strategies to directly hinder the action or expedite the removal of injected insulin. Furthermore, conditions that impair insulin clearance (such as renal failure) increase the risk of prolonged hypoglycemia.

2.2.2 Other risk factors for hypoglycemia

Additional risk factors for hypoglycemia in individuals with T1DM encompass a history of severe hypoglycemia, the pursuit of intensive glycemic control, hypoglycemia unawareness, and low levels of HbA1C. Deficiencies in glucocorticoids, such as those seen in Addison’s disease, heighten insulin sensitivity, escalating the risk of severe or recurrent insulin-induced hypoglycemia. Furthermore, polymorphisms in the angiotensin-converting enzyme (ACE) gene have been proposed as potential contributors to the risk of severe hypoglycemia in individuals with T1DM [29]. Genotypes at two variants of ADRB2 (Adrenoceptor Beta 2) are associated with impaired awareness of hypoglycemia [30].

2.2.3 Impairment in counter-regulatory responses to hypoglycemia

A reduction in plasma glucose concentration typically elicits two primary responses in the body under normal circumstances: [1] Elevated endogenous glucose production through processes such as glycogenolysis and gluconeogenesis and [2] Behavioral changes, including sensations of hunger and a tendency to seek food.

In individuals without diabetes, the initial response to a decline in glucose concentration involves a reduction in insulin secretion, occurring while the glucose concentration is still within the lower physiological range. As the glucose concentration approaches or falls just below the physiological range, other counter-regulatory hormones are released. Glucagon, discharged by pancreatic alpha cells into the hepatic portal circulation, experiences an approximate increase within 15 minutes once the glycemic threshold is reached. Its hyperglycemic effects are realized through the stimulation of glycogenolysis, gluconeogenesis, and lipolysis, resulting in an augmentation of hepatic glucose production. Glucagon is released at a glucose threshold of around 68 mg/dl (3.7 mmol/L) and plays a pivotal role in promptly rectifying hypoglycemia. It is indispensable for achieving complete restoration of normoglycemia subsequent to insulin administration.

When plasma glucose levels reach approximately 69–70 mg/dl (3.8 mmol/L), the release of epinephrine can occur, typically increasing around 20 minutes after reaching this threshold. Epinephrine exerts its effects by stimulating hepatic glycogenolysis and gluconeogenesis, enhancing glycolysis in muscles, and promoting lipolysis in adipose tissue. Additionally, it restricts glucose utilization by reducing insulin secretion and diminishing glucose uptake.

The function of secondary counterregulatory hormones, such as cortisol and growth hormone, is relatively modest and not crucial. Interestingly, hypercortisolemia appears to weaken symptomatic, autonomic, and neuroendocrine responses to subsequent hypoglycemia. Due to the underlying destruction of pancreatic β-cells in patients with T1DM, autoregulation of insulin secretion is not feasible during decreasing plasma glucose levels. However, the other counterregulatory responses occur to varying extents. Counterregulatory responses, especially sympathetic activation, are accountable for the autonomic warning symptoms of impending hypoglycemia. In this context, counter-regulation and awareness are physiologically intertwined in the earliest stages of defense against emerging hypoglycemia. Patients with impaired glucose counter-regulation may experience a decrease in counterregulatory hormone secretion during hypoglycemia, resulting in the absence of typical warning symptoms that accompany milder degrees of hypoglycemia.

The mentioned defense mechanisms are often compromised in patients with diabetes, and significant beta-cell failure is associated with the absence of an initial response to a decline in insulin. This leads to a delay in glucose secretion from the liver during hypoglycemia. The frequency of hypoglycemic episodes increases with the duration of diabetes, possibly due to the gradual decline in endogenous insulin. This decline occurs more rapidly in patients with T1DM and at a slower pace in those with T2DM. Additionally, although it is normal in the initial stages of diabetes, the glucagon reaction to hypoglycemia deteriorates over time in T1DM and more slowly in T2DM. For unclear reasons, glucagon-releasing responses to hypoglycemia disappear within approximately 5 years of T1DM diagnosis, leaving epinephrine responses as the only early defense against hypoglycemia. Interestingly, epinephrine responses to hypoglycemia are attenuated by ~50% in patients with T1DM compared with healthy subjects. Epinephrine and other counterregulatory responses can be blunted by a single episode of hypoglycemia, worsened by recurrent episodes of hypoglycemia, and reversed by rigorous avoidance of iatrogenic hypoglycemia.

Essentially, iatrogenic hypoglycemia is the outcome of the interaction between insulin excess and impaired glucose counter-regulation in patients with T1DM.

2.2.4 Hypoglycemia unawareness

Hypoglycemia unawareness in diabetes is characterized by the inability to recognize the symptoms of impending hypoglycemia by a patient. This condition is particularly associated with effective glycemic control.

Recurrent hypoglycemia may arise due to a diminished autonomic response to hypoglycemia, leading to a reduction in autonomic warning symptoms. The impaired brain response is marked by increased GLUT1 activity, aiming to preserve brain function and modifying glucose sensing in the ventromedial hypothalamus through elevated levels of gamma-aminobutyric acid.

Partial or complete hypoglycemia unawareness is observed in 25–50% of patients with T1DM and is strongly correlated with a prolonged duration of diabetes, typically exceeding 20 years. This state has been defined by Cryer as hypoglycemia-associated autonomic failure (HAAF) [31].

HAAF and impaired awareness of hypoglycemia (IAH) are clinical concepts that describe frequent and recent exposure to iatrogenic hypoglycemia in patients with T1DM. This exposure leads to a defective counter-regulatory hormonal response, especially the epinephrine response, as well as hypoglycemia unawareness. Intensive glycemic therapy with tight glycemic control has been associated with an increased risk of developing HAAF [32]. Moreover, individuals with HAAF face a sixfold elevated risk of iatrogenic hypoglycemia [33]. Additionally, both exercise and sleep can enhance the diminished autonomic response [34].

Multiple theories have been postulated, including: [1] the systemic–mediator hypothesis, suggesting that elevated circulating cortisol during hypoglycemia diminishes the sympathoadrenal and symptomatic response to subsequent hypoglycemia; [2] the brain fuel–transport hypothesis, proposing that recent hypoglycemia leads to increased blood-to-brain transport of glucose or alternative fuels, thereby attenuating sympathoadrenal and symptomatic responses to subsequent hypoglycemia; [3] the brain–metabolism hypothesis, stating that recent hypoglycemia alters CNS metabolic regulation, resulting in subdued sympathoadrenal responses; and [4] the cerebral network hypothesis, which posits that recent hypoglycemia acts through a network of interconnected brain regions mediated through the thalamus to inhibit hypothalamic activation, thus attenuating the sympatho-adrenal and symptomatic responses to subsequent hypoglycemia [35]. Hence, a complex interplay exists between central and peripheral mechanisms to sense and respond appropriately to declining blood glucose levels. Figure 1 shows the mechanisms associated with HAAF in patients with T1DM.

Figure 1.

Mechanisms associated with HAAF in patients with T1DM.

The hyperinsulinemic hypoglycemic clamp technique is considered the gold standard for evaluating impaired awareness of hypoglycemia (IAH). This method involves measuring hypoglycemic symptoms at specified intervals during the clamp procedure as plasma glucose levels are systematically lowered. Individuals who do not exhibit significant hypoglycemic symptoms, even around glucose levels of 50–54 mg/dl, are classified as having IAH. While this technique is an objective and well-established approach for assessing hypoglycemia and counter-regulation mechanisms, its application is primarily confined to research studies.

Numerous questionnaires have been formulated and extensively employed, primarily for research endeavors, to evaluate IAH. These include the Gold, Clarke, Pedersen-Bjergaard, Hypo or Ryan, DAFNE IAH, and HypoA-Q scores [36]. Self-reported hypoglycemia awareness questionnaires are relatively inexpensive and easy to administer. However, they are susceptible to recall and reporting biases, and their incorporation into research studies or clinical care has not been standardized. Combining clinical questionnaires with continuous glucose monitoring (CGM) data in diabetes mellitus management has demonstrated an improved specificity for identifying individuals with longstanding T1DM and a lack of autonomic symptom recognition in response to insulin-induced hypoglycemia [36, 37].

2.3 Clinical manifestations of hypoglycemia

The clinical manifestations of hypoglycemia include asymptomatic, mild, and severe episodes. Asymptomatic episodes of hypoglycemia manifest in patients with IAH and are most effectively diagnosed through self-blood glucose monitoring (SMBG) data. Unreported incidents of mild and severe hypoglycemia commonly occur during sleep in individuals with T1DM [28]. Nocturnal hypoglycemia is prevalent due to the fact that individuals in a sleep state are typically in a post-absorptive or fasting condition and are often deprived of calories [28].

Mild episodes of hypoglycemia respond promptly to appropriate measures and seem not to leave clinically detectable sequelae. However, even milder degrees of hypoglycemia have been reported to induce measurable impairments in brain stem function. Severe hypoglycemia has the potential to induce seizures, physical harm, or coma. Depending on the context (e.g., in traffic or while operating machinery), secondary damage may also occur. Recurrent, severe, or prolonged hypoglycemia can lead to permanent cognitive impairment or death. To mitigate the risk of nocturnal hypoglycemia, it is advisable for individuals undergoing intensive therapy to incorporate occasional nocturnal time points (between 2 and 5 am) into their SMBG protocol. Other predictable periods characterized by an elevated frequency of iatrogenic hypoglycemia include interprandial intervals and the post-exercise period [28].

2.3.1 Symptoms of hypoglycemia

Symptoms of hypoglycemia encompass autonomic symptoms and neuroglycopenic symptoms, exhibiting variation among patients based on age and diabetes duration. In the case of children, emotional and behavioral changes may manifest alongside classic autonomic and neuroglycopenic symptoms. Autonomic symptoms entail sweating, palpitations, tremulousness, hunger, and nervousness, while neuroglycopenic symptoms comprise impaired concentration, tiredness, dizziness/faintness, confusion, convulsions, seizures, tingling, and blurred vision [28]. Neuroglycopenic symptoms arise from the deprivation of glucose to brain neurons. The glycemic threshold for the onset of neuroglycopenic symptoms is typically around 54 mg/dL. [11, 38].

3. The management of hypoglycemia in type 1 diabetes mellitus

Previous experience of hypoglycemia and fear of hypoglycemia are the key barriers that prevent patients with T1DM from using their medical treatment properly in the optimization of glycemic control. For minimizing the risk of hypoglycemia, patient education, reducing the conventional risk factors for hypoglycemia, and minimizing the risk factors indicative of HAAF are the main steps.

3.1 Patient education

The anticipation, recognition, and treatment of hypoglycemia by patients with T1DM is fundamentally important. They should recognize their most commonly encountered symptoms of hypoglycemia, learn how to manage hypoglycemia and learn the predisposing risk factors for hypoglycemia. The patient should be educated about SMBG (including nocturnal testing) and counting carbohydrates to permit a flexible diet. There are many studies in the literature evaluating the effect of patient education on hypoglycemia [39, 40, 41, 42]. In some studies, participation in the diabetes teaching and treatment program (DTTP) improved HbA1C while reducing severe hypoglycemia by approximately 50% [39, 40, 41]. Hopkins et al. reported improved awareness of hypoglycemia in up to 43% of participants at 1 year follow-up with DTTP [41], and the rate of IAH decreased from 39.9–33%, with improvement in psychological distress and well-being up to 1 year following DTTP [41]. In the HypoCOMPaSS trial, a half-day education about reducing episodes of hypoglycemia was given to all participants [42]. At 6 months, all groups reached great improvement in IAH, and rates of severe hypoglycemia fell from 77–20% at the end of the 6-month trial (8.9 ± 13.4 vs. 0.8 ± 1.8 episodes per person per year; p = 0.0001) [42]. All these studies show that structured education (defined as insulin self-management and/or specific training for the avoidance of hypoglycemia) is effective in decreasing the rates of severe hypoglycemia in T1DM with improvement in glycemic control. In every documented hypoglycemia, the conditions of the event should be evaluated together with the patient to try to find out the etiology of hypoglycemia, for example, a skipped meal/prolonged fasting, physical exertion, alcohol consumption, and injection of a high insulin dose. Patient support should be provided by a team including professionals trained in glycemic management, and caregivers should work with each individual patient over time to find the best methods to prevent hypoglycemia.

3.2 Dietary intervention

Dietary intervention includes information about the amount of carbohydrates at meals and their influence on blood glucose levels and forming an individualized regular meal plan. The patients using insulin should be educated about the appropriate dosage and time of insulin in relation to meals. Patients at risk of hypoglycemia should be notified always to keep glucose or foods containing carbohydrates at hand.

3.3 Frequent SMBG

Patients should be educated about how to apply SMBG in their daily practice. Patients with T1DM should perform SMBG regularly and whenever they suspect hypoglycemia. Especially before performing a critical task such as driving, it is crucial to check their glucose level. SMBG documents hypo/hyperglycemia and allows patients to correlate their symptoms and glucose levels. Moreover, patients adjust their regimen according to the provided data from SMBG to prevent hypoglycemia. Paired glucose testing before and 2 hours after meals should be measured during SMBG. Normally, the difference between the premeal and 2-hour postprandial glucose should be <50 mg/dL. If the difference between these values is negative at 2 hours, the patient is likely to become hypoglycemic by 3 hours after eating, so the patient should be advised to check their blood glucose level again.

3.4 Individualized glycemic goals

To achieve a target a HbA1C level of 6.5%, fasting plasma glucose (FPG) should be kept at <110 mg/dL and 2-hour postprandial glucose (PPG) <140 mg/dL [43]. It is not always possible to achieve that level without hypoglycemia. If a patient has limited life expectancy, a history of severe hypoglycemia and/or hypoglycemia unawareness, advanced renal disease or other severe comorbid conditions with a high risk for CVD events and prohibitive cognitive and/or psychological status, it is not necessary to control strictly blood glucose levels. Instead, a less stringent A1C target (e.g., 7–8%) becomes reasonable [43].

3.5 Newer insulins

The use of a long-acting basal insulin analog (glargine, detemir) rather than NPH insulin in an MDI regimen is reported to reduce hypoglycemia including nocturnal hypoglycemia in patients with T1DM [44, 45]. Rapid-acting analogs (lispro, aspart, and glulisine) with faster onset and shortened duration of action are found to be associated with a 20% reduction in the risk of severe hypoglycemia and nocturnal hypoglycemia compared to regular insulin in patients with T1DM [44, 45]. A randomized trial including patients with IAH demonstrated a 29% reduction in the number of episodes of severe hypoglycemia per person-year with an insulin analog-based regimen when compared to a regimen of regular insulin and NPH [46]. Recently introduced ultra-fast-acting analogs may reduce this risk further [47]. They have faster onset of action and shorter exposure times. The PRONTO-T1D study compared the ultra-rapid lispro (URLi) with lispro in 269 patients with T1DM and found that both mealtime URLi and URLi given after the meal were associated with significant reductions in nocturnal hypoglycemia and decreased time spent in hypoglycemia compared with mealtime lispro [48]. Moreover, longer-acting basal insulins with less day-to-day variability (insulin degludec four times↓ day-to-day variability vs. U-100 glargine) and reduced nocturnal peak action (insulin degludec and U-300 glargine) have been associated with a reduced risk of nocturnal and severe hypoglycemia [49, 50].

3.6 Minimizing the conventional risk factors for hypoglycemia

Ill-timed insulin is a major problem in the glycemic control management. Patients should be educated about the proper timing of insulin dosing in relation to meals. Insulin analogs should be injected 5–15 minutes prior to meal time. If the preprandial glucose is <80 mg/dL, the injection should be done at the beginning of the meal. Patients with T1DM should be aware of “insulin stacking,” a condition whereby patients inject bolus insulin prior to complete absorption of prior insulin dose. The general rule for insulin analogs is that 90, 60, and 40% of the insulin remain on board after 1, 2, and 3 hours following a bolus of the insulin, respectively.

3.7 Reducing the risk factors indicative of HAAF

Patients with HAAF should have higher targeted fasting and postprandial glucose values as well as HbA1C levels >7%. With a history of HA, a 2- to 3-week trial of scrupulous avoidance of hypoglycemia is advised to restore awareness. These patients should also be initiated on glucose sensors, notifying them with an alarm system.

3.8 Insulin pump therapy

Continuous subcutaneous insulin infusion (CSII) via an insulin pump allows insulin delivery, supplying variable doses according to the time of the day. Insulin pumps comprise four parts: [1] the infusion site, [2] the reservoir, [3] the pump, and [4] the control and interface (with sensor-augmented pump and hybrid closed-loop pumps). There is controversial data about the benefit of CSII in the prevention of hypoglycemia in the literature. In a meta-analysis including 19 studies comparing MDI with CSII, comparable rates of severe hypoglycemia between the groups were reported [51]. On the other hand, another meta-analysis demonstrated a 4.2-fold reduction in SH incidence in CSII users rather than MDI users [52]. The Relative Effectiveness of Pumps Over MDI and Structured Education (REPOSE) trial, which is the largest and the longest randomized controlled trial (RCT) of CSII in T1DM, compared the patients receiving insulin by either CSII or MDI after structured education [53]. In both groups, improvement in HbA1C and severe hypoglycemia (50%↓) was achieved, and structured education is advocated in flexible insulin self-management before progression to CSII for hypoglycemia [53].

3.9 CGM

Continuous glucose monitoring (CGM) has provided a major advance in the treatment of persons with all forms of DM to reach goals safely. The first CGM system was released by Medtronic in 1999 [CGMS Gold, Medtronic, Inc., North-ridge, CA [54]]. These systems measure the glucose levels in interstitial fluid space in 1- or 5-minute increments with a lag of 4–10 min. The device has three components: a disposable sensor measuring the current glucose, a transmitter attached to the sensor, and a receiver displaying and storing glucose information. A sensor wire (size: 21G to 26G) is inserted under the skin using an applicator or insertion device. The transmitter sends a radio frequency signal to the receiver, where it is translated into a glucose value. The accuracy of the sensor is checked by periodic calibration using capillary blood glucose obtained from a fingerstick in 3-, 5-, or 7-day intervals, depending on the system.

CGM can be categorized into two classes: blinded retrospective CGM and real-time CGM. In blinded type CGM, glucose measurement is done intermittently to collect data on glucose excursion and facilitate changes in therapy, while real-time CGM displays current glucose value with alerts and alarms to intervene and manage their diabetes in response to impending hypo/hyperglycemia. In many countries, CGM is approved for use in all persons with DM on multiple-dose insulin (3 injections/day) or an insulin pump as well as those who have frequent or severe hypoglycemia, nocturnal hypoglycemia, or hypoglycemia unawareness. At present, three types of CGM systems are available: retrospective CGM (r-CGM), real-time glucose monitoring (rt-CGM), and intermittent scanning CGM (isCGM). Rt-CGM devices in which readers, either stand-alone devices or integrated into insulin pumps or mobile phones, show transmitted interstitial glucose readings in real-time, whereas isCGM devices demonstrate glucose values on demand when the sensor is scanned with a reading device. Rt-CGM or isCGM including alarms or alerts is recommended particularly for persons with hypoglycemia who would benefit from these warnings. Table 2 summarizes the main characteristics of currently available CGM sensor devices.

CGM system	Manufacturer	Accuracy (MARD)%	Calibrations	Sensor lifetime, day	Smart features	Limitations
Enlite-Sensor	Medtronic	13.6	Every 12 hr	6	Trend arrows, rate-of-change alerts, hypo/hyperglycemic alarms	Acetaminophen interference
Guardian Sensor 3	Medtronic	10.6 (abdomen) 9.1 (arm)	Every 12 hr	7	Trend arrows, rate-of-change alerts, hypo/hyperglycemic alarms	Acetaminophen interference
Freestyle Navigator II	Abbott	14.5	2, 10, 24, 72 hr. after insertion	5	Trend arrows, rate-of-change alerts, hypo/hyperglycemic alarms
Freestyle Libre	Abbott	11.4	No	14	Trend arrows	Sensor need to be scanned to get a glucose reading, not recommended for patients with IHA
Freestyle Libre 2	Abbott	NA	No	14	Trend arrows, rate-of-change alerts, hypo/hyperglycemic alarms, remote monitoring	Sensor need to be scanned to get a glucose reading, not recommended for patients with IHA
G4 Platinum	Dexcom	9	Every 12 hr	7	Trend arrows, rate-of-change alerts, hypo/hyperglycemic alarms, remote monitoring
G5 Mobile	Dexcom	9	Every 12 hr	7	Trend arrows, rate-of-change alerts, hypo/hyperglycemic alarms, remote monitoring, wireless communication up to five devices	Acetaminophen interference
G6	Dexcom	10	Every 12 hr	10	Trend arrows, rate-of-change alerts, hypo/hyperglycemic alarms, remote monitoring, wireless communication up to five devices
Eversense	Senseonics	11.4	No	90	Trend arrows, rate-of-change alerts, hypo/hyperglycemic alarms	The sensor should be inserted and removed in doctor’s office

Table 2.

Summary of the main characteristics of the CGM sensor devices.

CGM can be used independently to guide therapy or integrated with an insulin pump called sensor-augmented pump (SAP) therapy. SAP therapy with a glucose suspend (LGS) property automatically stops insulin delivery in response to hypoglycemia for up to 2 hr. and restarts it upon recovery (e.g., MiniMed 640G SAP system, Medtronic. Inc.). The Food and Drug Administration approved using the first closed-loop system, the MiniMed 670G System (Medtronic), for patients 14 years or older in the United States in 2016.

A hybrid closed-loop system (HCL) is like an artificial pancreas. It manages an insulin delivery automatically without patient intervention. The system calculates insulin dosages continually related to CGM levels by using a proprietary proportional-integral-derivative controller. Many studies evaluating the effect of closed-loop systems on glycemic control have shown that the rate of hypoglycemia and severe hypoglycemia is decreased in both adults and children, especially at nighttime [55, 56]. In an open-label, randomized, crossover study, the use of a closed-loop system significantly increased the time in range (TIR), whereas the time spent in hypoglycemic range significantly decreased during both daytime and nighttime in adolescents with T1DM [56]. It is one of the most promising technologies to attain optimal glycemic control, minimizing the episodes of hypoglycemia and severe hypoglycemia, particularly at nighttime. Although the majority of the systems include single-hormone insulin, dual-hormone systems, which infuse both insulin and glucagon, have also been in the research phase [57, 58].

There are many randomized controlled trials (RCTs) evaluating the potential benefit of CGM in the management of T1DM and the prevention of problematic hypoglycemia. Table 3 shows the summary of these RCTs.

Study	Intervention	Participants (N)	Impact on hypoglycemia	HbA1C change	Duration of follow-up	Adherence to CGM (%)
JDRF study [59]	CGM vs. SMBG	322 participants; Children 8–14 yrs.; Young adults 15–24 yrs.; Adults>25 yrs	No difference in SH events	0.5%↓-Adults; No change in the young group	26 weeks	The young group-50%↓
Battelino et al. [60]	CGM vs. SMBG	120 patients (HbA1C <7.5%)	↓Time spent in hypoglycemia (0.48–0.57 vs. 0.97–1.55 h/day) (p = 0.03)	0.21%↓ (p: 0.008)	26 weeks
GOLD study [61]	CGM vs. SMBG (Dexcom G4 Platinum)	161 patients (HbA1C ≥7.5% on MDI)	↓Hypoglycemia (2.79 vs. 4.79%). ↓ SH events (5 vs. 1)	7.92% (7.79 to 8.05) vs. 8.35% (8.19 to 8.51) (p < 0.001)	26 weeks	87.8%
DIAMOND study [62]	CGM vs. SMBG (Dexcom G4 Platinum)	158 patients (HbA1C 7.5–9.9% on MDI)	↓Time spent in hypoglycemia (43 min/day vs. 80 min/day) (p = 0.002) No difference in SH events (2 vs. 2)	1.1% vs.0.5↓- 12 wks 1.0% vs. 0.4↓- 24 wks (p < 0.01)	24 weeks	93%
IMPACT study [63]	FGM vs. SMBG	328 patients (HbA1C ≤ 7.5%)	38% ↓ in time in hypoglycemia	No difference in HbA1C	6 months
JDRF<7 study [64]	CGM vs. SMBG	129 adults and children (age range 8–69 years) HbA1C < 7.0%	Median time with a glucose level ≤ 60 mg/dl; (18 vs. 35 min/day, p = 0.05); Time out of range; (377 vs. 491 min/day, p = 0.003); No difference in SH events; (p = 1.0)	6.4 ± 0.5 vs.6.8 ± 0.5 (p < 0.001)	26 weeks	67%↓ in final 4 weeks
IN CONTROL study [65]	CGM vs. SMBG	52 patients with IAH (Gold score > 4)	↓Time spent in hypoglycemia; (6.8% vs. 11.4%); ↓SH events; (14 vs. 34 events, P = 0.033)	−0·1% vs. -0.1% (p: 0.449)	16 wks -CGM 12 wks -wash-out
The Real Trend study [66]	rt-CGM (SAP) vs. SMBG	132 adults and children (HbA1C ≥8%)	No difference in hypoglycemia	In fully compliant patients; CGM group -↓0.96%– 0.93%; CSII group - ↓0.55%– 0.93%,; (P < 0.004)	6 months	>25 yrs.; 74.9%; 5–14 yrs. 68.4%; 15–25 yrs. 52.4%
SMILE study [67]	rt-CGM (SAP) vs. SMBG	153 patients; (HbA1C 5·8–10·0% and Gold score > 4)	↓Hypoglycemic events per week; (−2·9 [95% CI -3·5 to −2·3]); (p < 0·0001); ↓SH events; (3 vs. 18; p = 0·0036)	No difference in HbA1C	24 wks
HypoDE study [68]	rt-CGM (SAP) vs. SMBG	148 patients with IAH	↓Hypoglycemic events; (10·8 to 3·5 /28 days); 72%↓ in hypoglycemic events	No difference in HbA1C	26 wks
Jensen et al. [69]	P-CGM vs. SMBG	472 patients	↓Symptomatic hypoglycemia; (0.82; 95% CI: 0.69–0.97); ↓Asymptomatic hypoglycemia; (0.72; 95% CI: 0.53–0.97); ↓Time spent in hypoglycemia; (p: 0.0070)	Less glycemic variability; (p: 0.0043); No difference in HbA1C; (0.06%, p: 0.2028)	16 wks
Laffel et al. [70]	rt-CGM vs. SMBG	153 patients (age range 14-24 years) (HbA1C 7.5%–10.9%)	↓Mean time in hypoglycemia; −0.7% [95% CI, −1.5% to −0.1%]; (p: 0.002); No difference in SH; (3 vs. 2)	Adjusted between-group difference; −0.37%; [95% CI, −0.66% to −0.08%]; (p: 0.01)	26 wks
Pratley et al. [71]	rt-CGM vs. SMBG	203 patients	↓Mean time in hypoglycemia; −1.9% (−27 minutes per day); (p < 0.001)	Adjusted group difference,; −0.3%; (95% CI, −0.4% to −0.1%); p < 0.001	24 wks
Zhang et al. [72]	FGM vs. SMBG	146 patients	↓The duration of hypoglycemia; (p < 0.05); ↑TIR; [(49.39 ± 17.54)% vs. (42.44 ± 15.49)%]; (p: 0.012)	8.16 ± 1.03 vs. 8.68 ± 1.01; (p: 0.003)	48 wks
HypoCOMPaSS study [42]	rt-CGM vs. SMBG	96 patients	↓The duration of hypoglycemia; (53 ± 63 to 24 ± 56 min/24 h; (p: 0.004); ↑Hypoglycemia awareness; (5.1 ± 1.1 to 4.1 ± 1.6; p: 0.0001); ↓SH; (8.9 ± 13.4 to 0.8 ± 1.8 episodes/patient-year); (p: 0.0001)	↓0.3%-No difference in HbA1C	24 wks
STAR3 study [73]	rt-CGM (SAP) vs. SMBG	485 patients (329 adults and 156 children)	No change in the rate of SH	↓ HbA1C; (7.4% vs. 8.0%, P < 0.001)	24 wks
SWITCH study [74]	CGM (SAP) vs. SMBG	153 patients (adults and children) (HbA1C 7.5% - 9.5%)	↓time spent in hypoglycemia; (19 vs. 31 min/day; p = 0.009); No difference in SH events; (4 vs. 2; p = 0·4)	↓-0.43% in HbA1C; (8.04% vs. 8.47%); (p < 0.001)	24 wks
ASPIRE study [75]	rt-CGM (SAP with LGS) vs. SMBG	247 patients	↓37.5% in mean AUC for nocturnal hypoglycemic events; ↓ 31.8% nocturnal hypoglycemic events	No difference in HbA1C	3 months
Ly et al. [76]	rt-CGM (SAP with LGS) vs. SMBG	95 patients Mean age 18.6 yrs	↓ Hypoglycemic events (175 to 35 vs. 28 to 16)	No difference in HbA1C	24 wks
APCam11 study Jasleen [56]	HCL vs. SAP	86 patients (11–36 yrs)	↓time spent in hypoglycemia (p:0.013)	↓ 0.36% in HbA1C (p < 0.001)	12 wks
iDCL study Jasleen [55]	CL (SAP with LGS) vs. SAP	168 patients (14–71 yrs)	time spent in hypoglycemia (p < 0.001)	↓ 0.33% in HbA1C (p < 0.001)	26 wks

Table 3.

RCTs about the benefits of CGM in the management of hypoglycemia in T1DM.

These studies showed that continuous use and high compliance are very necessary to achieve maximum glucose-lowering effect with CGM. Moreover, the DIAMOND and GOLD studies show that CGM is also beneficial for patients on conventional MDI treatment [61, 62]. A recent meta-analysis evaluating the effectiveness of GCM in the regulation of diabetes mellitus included 21 studies involving 2149 individuals [77]. In this meta-analysis, it is found that CGM significantly decreased HbA1C levels compared with SMBG (mean difference −2.46 mmol/mol, p: 0.0005) and is especially effective in Type 1 diabetic patients with uncontrolled glycemia (HbA1C > 8%) [77]. On the other hand, CGM was reported to have no influence on the number of severe hypoglycemia cases (p: 0.13) in this meta-analysis [77]. Maiorino et al. reported a meta-analysis of 15 RCTs, including 2461 patients, comparing CGM with usual care in both type 1 and type 2 diabetes mellitus on the effect of glycemic control [78]. In this study, it is shown that CGM was associated with a modest reduction in HbA1C (−0.17%, 95% CI -0.29 to −0.06, I²: 96.2%), increase in TIR (70.74 min, 95% CI 46.73–94.76, I²: 66.3%), and lower time above range (TIR) and time below range (TBR) with heterogeneity between studies [78]. In subgroup analyses, rt-CGM led to a higher improvement in mean HbA1C (−0.23%, 95% CI -0.36 to −0.10, p < 0.001), TIR (83.49 min, 95% CI 52.68–114.30, P < 0.001), and TAR, whereas both is-CGM and SAP were associated with the greater decline in TBR [78]. In another meta-analysis by Wang et al., 10 RCTs and 5 crossover design trials, with a total of 2071 patients were included [79]. In this meta-analysis, it is demonstrated that CGM is effective in reducing HbA1C levels (−2.69%, 95% CI (−4.25 to −1.14), p < 0.001) and decreasing the incidence of SH events (RR: 0.52, 95% CI 0.35–0.77; p: 0:001) [79].

The impact of CGM on quality of life is studied in many studies in the literature. The GOLD study reported a significant improvement in QoL in CGM-treated patients when compared to controls [61]. In this study, a significant improvement in patient well-being assessed using the WHO-5 questionnaire (66.1 vs. 62.7, p: 0.02) and in treatment satisfaction assessed using the Diabetes Treatment Satisfaction Questionnaire (DTSQ) (30.21 vs. 26.62, P < 0.001) with less hypoglycemia fear assessed using the Hypoglycemia Confidence Questionnaire (HCQ) scale (3.40 vs. 3.27, p < 0.001) was shown with CGM use [61]. Klak et al. compared the emotional well-being of adults with T1DM between CGM users and SMBG users in a meta-analysis including 11 studies involving 1228 patients with T1DM [80]. This meta-analysis showed that CGM systems reduced fear of hypoglycemia (Cohen d = −0.24; 95% CI, −0.41 to −0.07; p: 0.005) and increased patient satisfaction with improved quality of life [80].

In many studies, it has been emphasized that >80% compliance is needed to reach optimum benefit with CGM [61, 62, 63, 81]. However, compliance is a great problem while using CGM. A major problem is discomfort while wearing the CGM (42%), followed by problems with CGM insertion (33%), problems with adhesion to skin (30%), poor performance (28%), alarms (27%), accuracy (25%) interference with sports and activities (18%), and skin reactions from the CGM sensor (18%). Flash glucose monitoring (FGM) is associated with less discomfort and side effects (less pain, less bleeding on sensor insertion, less itching, and less erythema). Some of the features of FGM differ from the existing sensor technology. FGM measures interstitial glucose levels for up to 14 days without calibration by fingerstick blood glucose measurements, and the wireless handheld reader scans the sensor every 15 minutes for up to 8 hr. to receive the glucose values. Along with factory calibration and no alarm system, FGM may be an attractive option with higher rates of compliance.

The accuracy of the CGM is a great concern for CGM users. It is measured using the mean absolute relative differences (MARDs) between CGM readings and blood glucose readings. The physiological lag time between interstitial and blood glucose, which is usually between 4 and 10 min, can be longer when glucose concentrations are changing rapidly. Also, when the decrease in glucose levels is rapid on approaching hypoglycemic levels, the sensor can show falsely higher values. While early CGM devices had a high error rate with MARDs of around 20%, these error rates are now between 9 and 14% with advances in sensor technology. The MARD of the flash glucose monitoring system (FGS) system is 11.4%, whereas the latest Dexcom G5 system is just under 10%.

3.10 Islet cell transplantation

For patients with resistant hypoglycemia despite all the therapies mentioned above, islet cell transplantation may be an option. In a phase 3 study by the Clinical Islet Transplantation Consortium in North America, including 48 adults with T1DM and IAH, improvement in glycemic control and a significant decrease in SH events (2 events, p < 0.0003) was achieved after islet cell transplantation [82].

4. Treatment of hypoglycemia in type 1 DM

4.1 Oral self-treatment

In case of hypoglycemia, glucose tablets, juice, soft drinks, or candy, containing 15–20 g glucose should be taken by the patient with T1DM. After 15–20 minutes, blood glucose should be checked, and if it is still <80 mg/dl, 15–20 g glucose should be repeated until the blood glucose level is over>80 mg/dl. Since the glycemic response is transient, the patient should be given a subsequent more substantial snack or meal.

4.2 Parenteral treatment

When a hypoglycemic patient is unable to take carbohydrates orally because of loss of consciousness, parenteral therapy is needed. Glucagon is usually injected subcutaneously or intramuscularly by a partner of the patient who has learned to treat it with glucagon. 1 mg glucagon dose in adults may cause nausea or even vomiting with substantial, transient hyperglycemia. It has been shown that smaller doses (e.g., 150 mcg), repeated if necessary, were found to be effective in adolescents with T1DM without side effects [83]. The crystallized glucagon is diluted with the provided diluent to 1 mg/ml according to pharmaceutical instructions for the mini-dose regimen, and a U-100 insulin syringe is used to administer the dose [83]. Each unit on the U-100 insulin syringe represents ~10 μg of glucagon. For the dosing regimen, 2 “units” (20 μg) for children ≤2 years and 1 unit/year for children ≥3–15 years (with a maximum dose of 150 μg or “15 units”) are advised to use. Older patients (young adults over 15 years of age) receive a maximum dose of 15 units (150 μg). If this dose does not increase blood glucose levels over the first 30 minutes, a repeat injection twice the initial dose should be done. An increase of 3.3–5 mmol/l in glucose levels is expected within 30 minutes of administration of the mini-dose glucagon regimen. The regimen is a safe and reliable tool to treat both mild and impending hypoglycemia in the out-of-hospital setting [83]. Liquid form and intranasal powder form of glucagon are other alternatives; however, there is limited data on the efficacy and safety of these glucagon preparations in treating hypoglycemia in the literature. A recent study by Suico et al. reported that nasal glucagon (3 mg) was as efficacious and well tolerated as intramuscular glucagon (1 mg) for the treatment of insulin-induced hypoglycemia in adults and will be as useful as intramuscular glucagon as a rescue treatment for SH [84]. Also, soluble glucagon and a glucagon analog, dasiglucagon, are available for immediate injection.

Patients with diabetes at increased risk of hypoglycemia are suggested to always carry glucagon with them. The relatives of patients should be educated about the administration of glucagon and the storage conditions of the agent. Apart from preventing severe hypoglycemia, it reduces emotional stress by means of empowering the patient’s family and caregivers to take direct action and reduces medical care costs by avoiding the expensive use of emergency medical sources.

In glycogen-depleted individuals (e.g., following a binge of alcohol ingestion), glucagon may not be sufficient to increase glucose levels; 15–25 g intravenous glucose is the standard parenteral therapy initially. Because the response is transient, a subsequent intravenous glucose infusion may be needed, and a meal should be given to the patient as soon as the patient can eat.

4.3 Specific conditions

4.3.1 Management of nocturnal hypoglycemia

Apart from using insulin analogs to prevent nocturnal hypoglycemia, other approaches include bedtime snacks and bedtime administration of uncooked cornstarch for the sustained delivery of exogenous carbohydrates throughout the night. Bedtime oral administration of the epinephrine-stimulating ß2-adrenergic agonist terbutaline and overnight glucagon infusion may be other alternative treatments by providing sustained endogenous glucose throughout the night.

4.3.2 Management of exercise-induced hypoglycemia

Glucose consumption by the tissues increases during exercise with the risk of hypoglycemia. Strenuous, prolonged physical exercise with a lack of energy source is a great risk for hypoglycemia. To prevent hypoglycemia, blood glucose before and after physical exercise should be monitored. Patients should avoid injecting insulin to the part of the body that will be used during exercise because of increased blood flow to these body parts, resulting in faster insulin absorption during exercise, leading to hypoglycemia (e.g., injection insulin to the legs for running or cycling exercise). Moreover, time of exercise is important to prevent hypoglycemia. The consensus is to exercise in the postprandial period, but some studies show that exercising <45 min. When fasted, it results in stable blood glucose concentrations without the risk of hypoglycemia over the 24-hour post-exercise period [85]. Also, exercising in the morning is associated with a lower risk of hypoglycemia than exercising in the afternoon because of the high cortisol levels in the morning and low cortisol levels due to the circadian rhythm of cortisol. SH within the previous 24 hr. is a contraindication to do exercise, and if a self-treated hypoglycemic episode has occurred in the previous 24 hr., extra precautions should be taken before exercise, or it is better to avoid exercise alone. Prior to exercising, the blood glucose target should be >100 mg/dL. To minimize the hypoglycemia risk during and immediately following the exercise, additional carbohydrates (CHOs) prior to exercise may be needed. Patients are recommended to equip themselves with rapid-acting CHOs during physical exercise. This is called “ExCarb.” A simple regimen is to take 30 g CHO every 60 min of exercise [86], or a more accurate method is to take CHO according to the body weight (0.5 gr/kg/h CHO for moderate-intensity activity and 1 gr/kg/h for high-intensity activity) [87]. Adjusting the insulin doses is also important to avoid hypoglycemia during exercise. Insulin pump therapy provides more flexibility for insulin adjustment. If an exercise is planned within 90 min after a meal, a 50% reduction should be made in the pre-meal insulin dosage. For insulin pump therapy users, the basal insulin dose should be reduced by 80% of the daily dose during the exercise period, starting 40 min before exercise and finishing at the end of the exercise. Late post-exercise hypoglycemia in T1DM typically occurs 6–15 hours after strenuous exercise and is usually nocturnal. A 50% reduction in the bolus dose given with the meal after the exercise and 20% reduction in the basal insulin at night reduces the risk of hypoglycemia. For patients with a history of recurrent hypoglycemia, the blood glucose should be checked at 02.00 h. In a recent study, a mini dose (150 μg) of glucagon was found to be more effective than reducing insulin dose to prevent exercise-induced hypoglycemia [88]. rt-CGM and flash glucose monitors are suggested to be used in case of exercise-induced hypoglycemia.

5. Conclusion

In summary, hypoglycemia in diabetes mellitus may result in anxiety and fear of subsequent events, leading to resistance to diabetes management. Severe hypoglycemia may cause cognitive dysfunction and seizures with an increased risk of cardiovascular disease and mortality. Taking measures to minimize the risk factors for the development of hypoglycemia and structured patient training is an important objective to prevent the occurrence of hypoglycemia in patients with T1DM. Advanced diabetes technologies such as CGMs, hybrid closed-loop pumps, and new insulins can be utilized. In contrast, widespread use of these systems is being hindered by cost-effectiveness, access, and education.