Hypoglycemia is defined as a blood glucose level of less than 70 mg/dL and the start of cognitive alteration [5]. Cognitive impairment is classically observed in patients with functioning autonomic and central nervous systems when blood glucose levels fall to less than 60 mg/dL [8]. Hypoglycemia is generally best diagnosed utilizing the Whipple triad: autonomic and/or central nervous system symptoms, a low plasma glucose concentration, and relief of symptoms with treatment [12,13]. It is important to remember that symptoms of hypoglycemia can instigate anxiety and fear [1].

Hypoglycemia is defined as a blood glucose level of less than 70 mg/dL and the start of cognitive alteration [5]. Cognitive impairment is classically observed in patients with functioning autonomic and central nervous systems when blood glucose levels fall to less than 60 mg/dL [8]. Hypoglycemia is generally best diagnosed utilizing the Whipple triad: autonomic and/or central nervous system symptoms, a low plasma glucose concentration, and relief of symptoms with treatment [12,13]. It is important to remember that symptoms of hypoglycemia can instigate anxiety and fear [1].

The concentration of plasma glucose is dependent on the rate glucose enters the circulation in contrast to the rate it is removed [14]. The fuel homeostasis within the body can be explained in a five-phase approach. Phase 1, or the fed state, occurs immediately and up to 3.9 hours after consumption of food. During this phase, the circulating glucose predominantly comes from an exogenous source. Plasma insulin levels are elevated, glucagon levels are minimal, and triglycerides are synthesized in the liver. Insulin impedes the breakdown of glycogen and triglyceride reservoirs. The brain and other glucose-dependent organs utilize some of the glucose absorbed from the intestinal tract, and the excess glucose is stored in the liver, muscle, adipose tissue, and other tissues for use later.

Hypoglycemia is a result of one of two different issues: hyperinsulinemia (resulting from too much exogenous insulin, an insulin-secreting pancreatic tumor, or excessive oral diabetes medication) or iatrogenic issues (alteration in glucose counter-regulation) [12]. Hypoglycemia can be a complication of insulin therapy in both type 1 and type 2 diabetes or of oral medications that stimulate the pancreatic beta cells in the islets of Langerhans [17]. Symptoms of hypoglycemia tend to have a greater severity when they are the result of hyperinsulinemia due to the prevention in the formation of alternative fuels, such as free fatty acids or ketones [8].

Iatrogenic hypoglycemia is the consequence of the relationship of relative insulin surplus (also referred to as absolute insulin surplus) and compromised physiologic and behavioral responses to falling plasma glucose levels in patients with type 1 diabetes and patients with insulin-deficient type 2 diabetes [4,13]. Normally, a decrease in insulin release is the first physiologic defense. An increase in glucagon production is the second, and the third physiologic defense is epinephrine [15]. Epinephrine limits the clearance of glucose in insulin-sensitive tissues. The result of each of these defenses is a sympathoadrenal response, primarily a sympathetic neural response, to hypoglycemia initiating neurogenic symptoms. As a result, behavioral protections, such as hunger, take effect [1]. In some cases, these natural defenses may be compromised.

Chronic hypoglycemia can result in hypoglycemia-associated autonomic failure (HAAF), a syndrome characterized by both defective glucose counter-regulation and hypoglycemia unawareness. This response is common in patients with type 1 diabetes, but can also occur in patients with advanced type 2 diabetes. In patients with HAAF, the epinephrine response to ensuing hypoglycemia is decreased, with adjustments in insulin and glucagon absent [18]. These patients will also experience fewer symptoms of low blood glucose levels due to a decrease in the sympathoadrenal response, resulting in an unawareness of the condition or the need to correct it [12]. Tight control of blood glucose levels and avoidance of hypoglycemia can reverse HAAF within two to three weeks [18].

Some patients will experience a rebound reaction to hypoglycemia known as the Somogyi phenomenon [21]. This condition almost exclusively occurs in patients who take long-acting insulin and occurs most often following nocturnal hypoglycemia [21]. Untreated hypoglycemia or a rapid decrease in blood glucose triggers a release of counter-regulatory hormones, resulting in an episode of hyperglycemia and a period of insulin resistance that can persist for hours to days. The insulin resistance and hyperglycemia can lead to ketonuria or ketonemia [1].

Women with diabetes who are of child-bearing age should be acutely aware of potential hypoglycemic episodes. Women are at an increased risk of hypoglycemic events at specific points in their lives, such as at the start of each menstrual cycle, as a result of decreased levels of progesterone. After conception and early in the first trimester, the risk of hypoglycemia is amplified as a result of increases in peripheral utilization and storage of glucose. Late in the third trimester, nocturnal hypoglycemia becomes a concern, as a bedtime snack may be insufficient to meet the intensified fetal demands for glucose. Lastly, during the postpartum phase, the risk of hypoglycemia results from the loss of placental hormones [1].

The use of some complementary or alternative therapies can increase the risk of hypoglycemia and may be a concern for many reasons. Some concerns include:

Fenugreek is a member of the Leguminosae family along with chickpeas, green peas, and peanuts. Historically, this herb was used to induce labor, but today it is used for diabetes, loss of appetite, and stimulation of milk production in breastfeeding women [36]. The active compounds of fenugreek include saponins and glycosides, and the seeds contain alkaloids, 4-hydroxyisoleucine, and fenugreekine, which delay gastric emptying, resulting in slow carbohydrate absorption, glucose transport inhibition, increased insulin receptors, improved peripheral glucose utilization, and possible stimulation of insulin secretion [32]. In diabetes patients, these effects may result in hypoglycemia [33].

Milk thistle is related to daisies and other thistles and has been used extensively for various hepatic disorders [43]. The active components are silybin, silychristin, and silydianin. These compounds inhibit the hepatotoxin-binding hepatocyte membrane receptors and decrease glutathione oxidation [32]. The resultant blood glucose-lowering effects and potential for hypoglycemia are being studied [1].

Symptoms of hypoglycemia are categorized by the acute response and progress in severity of the reaction. Initially, symptoms of hypoglycemia are a result of adrenergic effects that occur secondary to the release of catecholamine. These symptoms include sweating, weakness, shakiness, tremors, anxiety, faintness, tachycardia, and palpitations [45].

More than half of all severe hypoglycemia episodes occur during sleep, when symptoms are less likely to be detected or recognized [21]. Nocturnal hypoglycemia most typically is caused by excessive insulin therapy and, with great cause for concern, usually does not awaken the person. Patients should be aware of symptoms that may indicate nocturnal hypoglycemia, such as morning headaches, feeling "foggy" in the morning, difficulty awakening, psychological changes, exhaustion, restlessness while sleeping, night sweats, nightmares, and loud respirations [8]. Additionally, unusually high blood glucose levels after breakfast or lunch or detection of a small amount of ketones but no glucose in the morning urine are signs of nocturnal hypoglycemia [21].

The frequency of hypoglycemia in patients with diabetes is due primarily to abnormalities in glucose counter-regulation. There is a multitude of potential causes of hypoglycemia, including, but not limited to, excessive oral and injectable medications, physical activity, illness, and inappropriate patient practices [1].

The nonsulfonylurea secretagogues, or glinides, are hypoglycemic agents with the potential to reduce blood glucose levels to below normal. Within this classification of hypoglycemic agents there are two medications: repaglinide and nateglinide [47,70]. These agents lower blood glucose levels by stimulating the release of insulin from functioning beta cells in the pancreas. Insulin release is glucose-dependent and diminishes at low glucose concentrations. These agents are most effective when taken just prior to the first intake of a meal [47]. This results in a greater insulin release during the first phase.

Insulin can be divided into two categories: basal and bolus. Healthy pancreatic beta cells release insulin into the blood stream throughout the day. This basal or background insulin enables stored fat and glucose to be released in the correct amounts to enable adequate metabolism during times when a person is not eating. This steady insulin level throughout the day regulates glucose production by the liver, the production and release of fat as fuel, and the entry of particular amino acids into cells for the creation of enzymes and structural proteins. Individuals without diabetes release about half of their total daily insulin requirements as background insulin to fulfill these needs [21]. As food is consumed, it is converted to glucose and other energy precursors by the digestive system. In response to rising blood glucose levels, the beta cells of the pancreas are stimulated to produce and release insulin. This is known as bolus insulin release [1].

Individuals on an insulin therapy regimen should have a clear understanding of the risk of hypoglycemia related to exercise. Strenuous or aerobic exercise raises the blood glucose levels initially, but these levels will decrease as the body re-establishes its stores [57]. Although an initial increase in blood glucose levels will be seen, the potential for hypoglycemia can last up to 72 hours after stopping exercise. This is due to the physiologic reaction of fuel mobilization for energy release. When an individual is exercising at maximal levels, the body's energy level demands increase up to 20-fold in comparison to the resting state. In an attempt to maintain homeostasis and prevent hypoglycemia, several regulatory mechanisms are activated. Initially, skeletal muscles break down their own stores of glycogen, triglycerides, and free fatty acids from adipose tissue. In order to mobilize extramuscular stores, hormonal adjustments are essential. In the early phase of exercise, hepatic glucose production is increased by a reduction of insulin levels and unchanged glucagon levels. In subsequent stages, glucagon and catecholamine levels are elevated. As a result, glucose levels in healthy individuals remain fairly constant during exercise. When individuals with diabetes engage in moderate- or high-intensity exercise on a regular basis, however, the result is a decrease in blood glucose levels and increased insulin sensitivity [57]. Helping patients with diabetes to understand this sophisticated balance of fuel and energy metabolism is vital in the prevention of hypoglycemia [1].

Individuals on an insulin therapy regimen should have a clear understanding of the risk of hypoglycemia related to exercise. Strenuous or aerobic exercise raises the blood glucose levels initially, but these levels will decrease as the body re-establishes its stores [57]. Although an initial increase in blood glucose levels will be seen, the potential for hypoglycemia can last up to 72 hours after stopping exercise. This is due to the physiologic reaction of fuel mobilization for energy release. When an individual is exercising at maximal levels, the body's energy level demands increase up to 20-fold in comparison to the resting state. In an attempt to maintain homeostasis and prevent hypoglycemia, several regulatory mechanisms are activated. Initially, skeletal muscles break down their own stores of glycogen, triglycerides, and free fatty acids from adipose tissue. In order to mobilize extramuscular stores, hormonal adjustments are essential. In the early phase of exercise, hepatic glucose production is increased by a reduction of insulin levels and unchanged glucagon levels. In subsequent stages, glucagon and catecholamine levels are elevated. As a result, glucose levels in healthy individuals remain fairly constant during exercise. When individuals with diabetes engage in moderate- or high-intensity exercise on a regular basis, however, the result is a decrease in blood glucose levels and increased insulin sensitivity [57]. Helping patients with diabetes to understand this sophisticated balance of fuel and energy metabolism is vital in the prevention of hypoglycemia [1].

Treatment of hypoglycemia is fairly straightforward when the cause is known. When symptoms are mild-to-moderate and the patient is able to communicate and swallow, treatment is usually administered via the oral route. In most cases, hypoglycemia may be reversed by adhering to the 15:15 rule [1]. The 15:15 rule is simply defined as utilizing 15 grams of carbohydrate and rechecking the blood glucose in 15 minutes. If the blood glucose level is less than 70 mg/dL, with or without the presence of hypoglycemia symptoms, another 15 grams of carbohydrate should be administered and the blood glucose level should be checked again [58,59]. When the blood glucose level is greater than 70 mg/dL, treatment should be stopped. Examples of foods that provide 15 grams of carbohydrate include three glucose tablets (sold in most pharmacies), one-half can of regular soda, 4 ounces of fruit juice, 2 tablespoons of raisins, 1 tablespoon of sugar, or 8 ounces of non-fat milk [1].

Patients should also receive thorough education related to the signs and symptoms of hypoglycemia [5]: