If known causes for ketotic hypoglycemia such as the ketotic Glycogen Storage Disease subtypes can be ruled out, it has been proposed that this condition simply represents the extreme edge of the normal population in terms of tolerance for fasting and ability to maintain normoglycemia. It is also possible that some children given this diagnosis have still-undiscovered defects of metabolism which will eventually be identified.

The most common cause of hypoglycemia is medications used to treat diabetes mellitus such as insulin, sulfonylureas, and biguanides. Risk is greater in diabetics who have eaten less than usual, exercised more than usual, or drunk alcohol. Other causes of hypoglycemia include kidney failure, certain tumors, liver disease, hypothyroidism, starvation, inborn errors of metabolism, severe infections, reactive hypoglycemia, and a number of drugs including alcohol. Low blood sugar may occur in babies who are otherwise healthy who have not eaten for a few hours. Inborn errors of metabolism may include the lack of an enzyme to make glycogen (glycogen storage type 0).

Significant hypoglycemia appears to increase the risk of cardiovascular disease.

There are several genetic forms of hyperinsulinemic hypoglycemia:

Hypoglycemia due to endogenous insulin can be congenital or acquired, apparent in the newborn period, or many years later. The hypoglycemia can be severe and life-threatening or a minor, occasional nuisance. By far the most common type of severe but transient hyperinsulinemic hypoglycemia occurs accidentally in persons with type 1 diabetes who take insulin.

- Hypoglycemia due to endogenous insulin

- Congenital hyperinsulinism

- Transient neonatal hyperinsulinism (mechanism not known)

- Focal hyperinsulinism (K channel disorders)

- Paternal SUR1 mutation with clonal loss of heterozygosity of 11p15

- Paternal Kir6.2 mutation with clonal loss of heterozygosity of 11p15

- Diffuse hyperinsulinism

- K channel disorders

- SUR1 mutations

- Kir6.2 mutations

- Glucokinase gain-of-function mutations

- Hyperammonemic hyperinsulinism (glutamate dehydrogenase gain-of-function mutations)

- Short chain acyl coenzyme A dehydrogenase deficiency

- Carbohydrate-deficient glycoprotein syndrome (Jaeken's Disease)

- Beckwith-Wiedemann syndrome(suspected due to hyperinsulinism but pathophysiology uncertain: 11p15 mutation or IGF2 excess)

- Acquired forms of hyperinsulinism

- Insulinomas (insulin-secreting tumors)

- Islet cell adenoma or adenomatosis

- Islet cell carcinoma

- Adult nesidioblastosis

- Autoimmune insulin syndrome

- Noninsulinoma pancreatogenous hypoglycemia

- Reactive hypoglycemia (also see idiopathic postprandial syndrome)

- Gastric dumping syndrome

- Drug induced hyperinsulinism

- Sulfonylurea

- Aspirin

- Pentamidine

- Quinine

- Disopyramide

- Bordetella pertussis vaccine or infection

- D-chiro-inositol and myo-inositol

- Hypoglycemia due to exogenous (injected) insulin

- Insulin self-injected for treatment of diabetes (i.e., diabetic hypoglycemia)

- Insulin self-injected surreptitiously (e.g., Munchausen syndrome)

- Insulin self-injected in a suicide attempt or successful suicide

- Various forms of diagnostic challenge or "tolerance tests"

- Insulin tolerance test for pituitary or adrenergic response assessment

- Protein challenge

- Leucine challenge

- Tolbutamide challenge

- Insulin potentiation therapy

- Insulin-induced coma for depression treatment

The NIH states: "The causes of most cases of reactive hypoglycemia are still open to debate. Some researchers suggest that certain people may be more sensitive to the body’s normal release of the hormone epinephrine, which causes many of the symptoms of hypoglycemia. Others believe deficiencies in glucagon secretion might lead to reactive hypoglycemia.

Stomach surgery or hereditary fructose intolerance are believed to be causes, albeit uncommon, of reactive hypoglycemia. myo-Inositol or D-chiro-inositol withdrawal can cause temporary reactive hypoglycemia.

There are different kinds of reactive hypoglycemia:

1. Alimentary hypoglycemia (consequence of dumping syndrome; it occurs in about 15% of people who have had stomach surgery)

2. Hormonal hypoglycemia (e.g., hypothyroidism)

3. Helicobacter pylori-induced gastritis (some reports suggest this bacteria may contribute to the occurrence of reactive hypoglycemia)

4. Congenital enzyme deficiencies (hereditary fructose intolerance, galactosemia, and leucine sensitivity of childhood)

5. Late hypoglycemia (occult diabetes; characterized by a delay in early insulin release from pancreatic β-cells, resulting in initial exaggeration of hyperglycemia during a glucose tolerance test)

"Idiopathic reactive hypoglycemia" is a term no longer used because researchers now know the underlying causes of reactive hypoglycemia and have the tools to perform the diagnosis and the pathophysiological data explaining the mechanisms.

To check if there is real hypoglycemia when symptoms occur, neither an oral glucose tolerance test nor a breakfast test is effective; instead, a hyperglucidic breakfast test or ambulatory glucose testing is the current standard.

The body requires a relatively constant input of glucose, a sugar produced upon digestion of carbohydrates, for normal functioning. Glucagon and insulin are among the hormones that ensure a normal range of glucose in the human body. Upon consumption of a meal, blood sugar normally rises, which triggers pancreatic cells to produce insulin. This hormone initiates the absorption of the just-digested blood glucose as glycogen into the liver for metabolism or storage, thereby lowering glucose levels in the blood. In contrast, the hormone glucagon is released by the pancreas as a response to lower than normal blood sugar levels. Glucagon initiates uptake of the stored glycogen in the liver into the bloodstream so as to increase glucose levels in the blood.

Sporadic, high-carbohydrate snacks and meals are deemed the specific causes of sugar crashes. The “crash” one feels is due to the rapid increase and subsequent decline of blood sugar in the body system as one begins and ceases consumption of high-sugar foods. More insulin than is actually needed is produced in response to the large, rapid ingestion of sugary foods.

Diabetic hypoglycemia can occur in any person with diabetes who takes any medicine to lower their blood glucose, but severe hypoglycemia occurs most often in people with type 1 diabetes who must take insulin for survival. In type 1 diabetes, iatrogenic hypoglycemia is more appropriately viewed as the result of the interplay of insulin excess and compromised glucose counterregulation rather than as absolute or relative insulin excess alone. Hypoglycemia can also be caused by sulfonylureas in people with type 2 diabetes, although it is far less common because glucose counterregulation generally remains intact in people with type 2 diabetes. Severe hypoglycemia rarely, if ever, occurs in people with diabetes treated only with diet, exercise, or insulin sensitizers.

For people with insulin-requiring diabetes, hypoglycemia is one of the recurrent hazards of treatment. It limits the achievability of normal glucoses with current treatment methods. Hypoglycemia is a true medical emergency, which requires prompt recognition and treatment to prevent organ and brain damage.

Children "outgrow" ketotic hypoglycemia, presumably because fasting tolerance improves as body mass increases. In most the episodes become milder and more infrequent by 4 to 5 years of age and rarely occur after age 9. Onset of hypoglycemia with ketosis after age 5 or persistence after age 7 should elicit referral and an intensive search for a more specific disease.

If there is no hypoglycemia at the time of the symptoms, this condition is called "postprandial syndrome." It might be an "adrenergic postprandial syndrome" — blood glucose levels are normal, but the symptoms are caused through autonomic adrenergic counterregulation. Often, this syndrome is associated with emotional distress and anxious behaviour of the patient. This is often seen in dysautonomic disorders as well. Dietary recommendations for reactive hypoglycemia can help to relieve symptoms of postprandial syndrome.

Oxyhyperglycemia is most commonly caused by early dumping syndrome, but it can rarely caused by other conditions like Graves' disease. It was first described by Lawrence et al. in 1936 as often happening after gastroenterostomy. It is seen in most forms of gastrectomy, gastric bypass and gastrostomy procedures, all of which are surgical causes of dumping syndrome.

Oxyhyperglycemia is a special type of impaired glucose tolerance characterized by a rapid and transient hyperglycemia (i.e. rise in blood glucose) spike after an oral intake of glucose, the peak of this spike being high enough to cause transient, symptom free glycosuria (i.e. detectable glucose in urine), but this hyperglycemia reverses rapidly and may even go to hypoglycemia in the later phase. This sharp downstroke overshooting towards hypoglycemia distinguishes this pathologic phenomenon from the artificial hyperglycemia inducible by an intravenous bolus dose of a large amount of glucose solution. Early dumping syndrome patients usually have oxyhyperglycemia associated with any meal or OGTT.

The Greek root "oxy" means "sharp" or "pointy". The OGTT curve in this condition appears sharp and somewhat pointy (at least relative to the other forms of hyperglycemia)- hence this name.

Dorlands dictionary defines oxyhyperglycemia as:

A blood level of approximately 180 mg/dL is the renal glucose threshold below which all glucose is reabsorbed from glomerular filtrate. But at blood concentrations above the renal threshold sugar starts appearing in the urine.

Oxyhyperglycemia, like other forms of Impaired glucose tolerance has also been suggested to be a prediabetic condition

Although one expects hypoglycemic episodes to be accompanied by the typical symptoms (e.g., tremor, sweating, palpitations, etc.), this is not always the case. When hypoglycemia occurs in the absence of such symptoms it is called "hypoglycemic unawareness". Especially in people with long-standing type 1 diabetes and those who attempt to maintain glucose levels which are closer to normal, hypoglycemic unawareness is common.

In patients with type 1 diabetes mellitus, as plasma glucose levels fall, insulin levels do not decrease - they are simply a passive reflection of the absorption of exogenous insulin. Also, glucagon levels do not increase. Therefore, the first and second defenses against hypoglycemia are already lost in established type 1 diabetes mellitus. Further, the epinephrine response is typically attenuated, i.e., the glycemic threshold for the epinephrine response is shifted to lower plasma glucose concentrations, which can be aggravated by previous incidents of hypoglycemia.

The following factors contribute to hypoglycemic unawareness:

- There may be autonomic neuropathy

- The brain may have become desensitized to hypoglycemia

- The person may be using medicines which mask the hypoglycemic symptoms

Although this hypothesis is well known among clinicians and individuals with diabetes, there is little scientific evidence to support it. Clinical studies indicate that a high fasting glucose in the morning is more likely because the insulin given on the previous evening fails to last long enough. Studies from 2007 onwards using continuous glucose monitoring show that a high glucose in the morning is not preceded by a low glucose during the night. Furthermore, many individuals with hypoglycemic episodes during the night don't wake due to a failure of release of epinephrine during nocturnal hypoglycemia. Thus, Somogyi's theory is not assured and may be refuted.

A rare metabolic disease of the blood-brain glucose transport system has been described in which severe neuroglycopenic effects occurred despite normal blood glucose levels. Low levels of glucose were discovered in the cerebrospinal fluid (CSF), a condition referred to as "hypoglycorrhachia" [or hypoglycorrhacia].

Hypoglycorrhachia is associated with Glucose transporter type 1 GLUT1 deficiency syndrome (GLUT1DS).

Perhaps a much more common example of the same phenomenon occurs in the people with poorly controlled type 1 diabetes who develop symptoms of hypoglycemia at levels of blood glucose which are normal for most people.

A person with type 1 diabetes should balance insulin delivery to manage their blood glucose level. Occasionally, insufficient insulin can result in hyperglycemia. The appropriate response is to take a correction dose of insulin to reduce the blood sugar level and to consider adjusting the insulin regimen to deliver additional insulin in the future to prevent hyperglycemia. Conversely, excessive insulin delivery may result in hypoglycemia. The appropriate response is to treat the hypoglycemia and to consider adjusting the regimen to reduce insulin in the future.

Somogyi and others have claimed that if prolonged hypoglycemia is untreated, then stress due to low blood sugar can result in a high blood glucose rebound. The physiological mechanisms driving the rebound are defensive. When the blood glucose level falls below normal, the body responds by releasing the endocrine hormone glucagon as well as the stress hormones epinephrine, cortisol and growth hormone. Glucagon facilitates release of glucose from the liver that raises the blood glucose immediately, and the stress hormones cause insulin resistance for several hours, sustaining the elevated blood sugar.

Most neurons have the ability to use other fuels besides glucose (e.g. lactic acid, ketones). Knowledge of the "switchover" process is incomplete. The most severe neuroglycopenic symptoms occur with hypoglycemia caused by excess insulin because insulin reduces the availability of other fuels by suppressing ketogenesis and gluconeogenesis.

A few types of specialized neurons, especially in the hypothalamus, act as glucose sensors, responding to changing levels of glucose by increasing or decreasing their firing rates. They can elicit a variety of hormonal, autonomic, and behavioral responses to neuroglycopenia. The hormonal and autonomic responses include release of counterregulatory hormones. There is some evidence that the autonomic nervous system can alter liver glucose metabolism independently of the counterregulatory hormones.

Adjustment of efficiency of transfer of glucose from blood across the blood–brain barrier into the central nervous system represents a third form of compensation which occurs more gradually. Levels of glucose within the central nervous system are normally lower than the blood, regulated by an incompletely understood transfer process. Chronic hypoglycemia or hyperglycemia seems to result in an increase or decrease in efficiency of transfer to maintain CNS levels of glucose within an optimal range.

In both young and old individuals, the brain may habituate to low glucose levels with a reduction of noticeable symptoms, sometimes despite neuroglycopenic impairment. In insulin-dependent diabetic patients this phenomenon is termed "hypoglycemia unawareness" and is a significant clinical problem when improved glycemic control is attempted. Another aspect of this phenomenon occurs in type I glycogenosis, when chronic hypoglycemia before diagnosis may be better tolerated than acute hypoglycemia after treatment is underway.

Developmental delay is a potential secondary effect of chronic or recurrent hypoglycemia, but is at least theoretically preventable. Normal neuronal and muscle cells do not express glucose-6-phosphatase, so GSD I causes no other neuromuscular effects.

Neutropenia is a manifestation of this disease. Granulocyte colony-stimulating factor (G-CSF, e.g. filgrastim) therapy can reduce the risk of infection.

Diabetic coma is a reversible form of coma found in people with diabetes mellitus. It is a medical emergency.

Three different types of diabetic coma are identified:

1. Severe low blood sugar in a diabetic person

2. Diabetic ketoacidosis (usually type 1) advanced enough to result in unconsciousness from a combination of a severely increased blood sugar level, dehydration and shock, and exhaustion

3. Hyperosmolar nonketotic coma (usually type 2) in which an extremely high blood sugar level and dehydration alone are sufficient to cause unconsciousness.

In most medical contexts, the term diabetic coma refers to the diagnostical dilemma posed when a physician is confronted with an unconscious patient about whom nothing is known except that they have diabetes. An example might be a physician working in an emergency department who receives an unconscious patient wearing a medical identification tag saying DIABETIC. Paramedics may be called to rescue an unconscious person by friends who identify them as diabetic. Brief descriptions of the three major conditions are followed by a discussion of the diagnostic process used to distinguish among them, as well as a few other conditions which must be considered.

An estimated 2 to 15 percent of diabetics will suffer from at least one episode of diabetic coma in their lifetimes as a result of severe hypoglycemia.

Hyperinsulinism refers to an above normal level of insulin in the blood of a person or animal. Normal insulin secretion and blood levels are closely related to the level of glucose in the blood, so that a given level of insulin can be normal for one blood glucose level but low or high for another. Hyperinsulinism can be associated with several types of medical problems, which can be roughly divided into two broad and largely non-overlapping categories: those tending toward reduced sensitivity to insulin and high blood glucose levels (hyperglycemia), and those tending toward excessive insulin secretion and low glucose levels (hypoglycemia).

Idiopathic hypoglycemia is, literally, a medical condition in which the glucose level in the blood (blood glucose) is abnormally low due to an undeterminable cause. This is considered an incomplete and unsatisfactory diagnosis by physicians and is rarely used by endocrinologists, as it implies an unfinished diagnostic evaluation. In general, the more severe the hypoglycemia and the more clearly it is proven, the less likely it is to remain "idiopathic".

"Idiopathic hypoglycemia" can also be a synonym for reactive hypoglycemia or for hypoglycemia that is not diagnosed by a physician and does not fulfill the Whipple triad criteria. A more precise term for that condition is idiopathic postprandial syndrome.

Hyperinsulinism due to reduced insulin sensitivity is usually asymptomatic. In contrast, hyperinsulinemic hypoglycemia can produce any of the entire range of hypoglycemic symptoms, from shakiness and weakness, to seizures or coma.

The cause of congenital hyperinsulinism has been linked to anomalies in nine different genes. The diffuse form of this condition is inherited via the autosomal recessive manner(though sometimes in "autosomal dominant").

Some infants are treated with 40% dextrose (a form of sugar) gel applied directly to the infant's mouth.

In terms of the mechanism of congenital hyperinsulinism one sees that channel trafficking requires K channels need the shielding of ER retention signal.E282K prevents the K channel surface expression, the C-terminus (SUR1 subunit) is needed in K channel mechanism.R1215Q mutations (ABCC8 gene) affect ADP gating which in turn inhibits K channel.