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

There are several genetic forms of hyperinsulinemic hypoglycemia:

Since hyperinsulinemia and obesity are so closely linked it is hard to determine whether hyperinsulinemia causes obesity or obesity causes hyperinsulinemia, or both.

Obesity is characterized by an excess of adipose tissue – insulin increases the synthesis of fatty acids from glucose, facilitates the entry of glucose into adipocytes and inhibits breakdown of fat in adipocytes.

On the other hand, adipose tissue is known to secrete various metabolites, hormones and cytokines that may play a role in causing hyperinsulinemia. Specifically cytokines secreted by adipose tissue directly affect the insulin signalling cascade, and thus insulin secretion. Adiponectins are cytokines that are inversely related to percent body fat; that is people with a low body fat will have higher concentrations of adiponectins where as people with high body fat will have lower concentrations of adiponectins. Weyer "et al." (2011) reported that hyperinsulinemia is strongly associated with low adiponectin concentrations in obese people, though whether low adiponectin has a causal role in hyperinsulinemia remains to be established.

- May lead to hypoglycemia or diabetes

- Increased risk of PCOS

- Increased synthesis of VLDL (hypertriglyceridemia)

- Hypertension (insulin increases sodium retention by the renal tubules)

- Coronary Artery Disease (increased insulin damages endothelial cells)

- Increased risk of cardiovascular disease

- Weight gain and lethargy (possibly connected to an underactive thyroid)

Possible causes include:

- Neoplasm

- Pancreatic cancer

- Polycystic ovary syndrome (PCOS)

- Trans fats

Although many factors influence insulin secretion, the most important control is the amount of glucose moving from the blood into the beta cells of the pancreas. In healthy people, even small rises in blood glucose result in increased insulin secretion. As long as the pancreatic beta cells are able to sense the glucose level and produce insulin, the amount of insulin secreted is usually the amount required to maintain a fasting blood glucose between 70 and 100 mg/dL (3.9-5.6 mmol/L) and a non-fasting glucose level below 140 mg/dL (<7.8 mmol/L).

When liver cells and other cells that remove glucose from the blood become less sensitive (more resistant) to the insulin, the pancreas increases secretion and the level of insulin in the blood rises. This increased secretion can compensate for reduced sensitivity for many years, with maintenance of normal glucose levels. However, if insulin resistance worsens or insulin secretion ability declines, the glucose levels will begin to rise. Persistent elevation of glucose levels is termed diabetes mellitus.

Typical fasting insulin levels found in this type of hyperinsulinism are above 20 μU/mL. When resistance is severe, levels can exceed 100 μU/mL.

In addition to being a risk factor for type 2 diabetes, hyperinsulinism due to insulin resistance may increase blood pressure and contribute to hypertension by direct action on vascular endothelial cells (the cells lining blood vessels). Hyperinsulinism has also been implicated as a contributing factor in the excessive production of androgens in polycystic ovary syndrome.

The principal treatments of hyperinsulinism due to insulin resistance are measures that improve insulin sensitivity, such as weight loss, physical exercise, and drugs such as thiazolidinediones or metformin.

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").

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).

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.

Significant hypoglycemia appears to increase the risk of cardiovascular disease.

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).

Insulinomas are rare neuroendocrine tumors with an incidence estimated at one to four new cases per million persons per year. Insulinoma is one of the most common types of tumors arising from the islets of Langerhans cells (pancreatic endocrine tumors). Estimates of malignancy (metastases) range from 5 to 30%. Over 99% of insulinomas originate in the pancreas, with rare cases from ectopic pancreatic tissue. About 5% of cases are associated with tumors of the parathyroid glands and the pituitary (multiple endocrine neoplasia type 1) and are more likely to be multiple and malignant. Most insulinomas are small, less than 2 cm.

Most patients with benign insulinomas can be cured with surgery. Persistent or recurrent hypoglycemia after surgery tends to occur in patients with multiple tumors. About 2% of patients develop diabetes mellitus after their surgery.

Nesidioblastosis is a controversial medical term for hyperinsulinemic hypoglycemia attributed to excessive function of pancreatic beta cells with an abnormal microscopic appearance. The term was coined in the first half of the 20th century. The abnormal histologic aspects of the tissue included the presence of islet cell enlargement, islet cell dysplasia, beta cells budding from ductal epithelium, and islets in apposition to ducts.

By the 1970s, nesidioblastosis was primarily used to describe the pancreatic dysfunction associated with persistent congenital hyperinsulinism and in most cases from the 1970s until the 1980s, it was used as a synonym for what is now referred to as congenital hyperinsulinism. Most congenital hyperinsulinism is caused by different mechanisms than excessive proliferation of beta cells in a fetal pattern and the term fell into disfavor after it was recognized in the late 1980s that the characteristic tissue features were sometimes seen in pancreatic tissue from normal infants and even adults, and is not consistently associated with hyperinsulinemic hypoglycemia.

However, the term has been resurrected in recent years to describe a form of "acquired" hyperinsulinism with beta cell hyperplasia found in adults, especially after gastrointestinal surgery.

Evidence of physiologic mechanisms purporting that weight loss surgery conveys the ability to induce a more contemporary presentation of nesidioblastosis remains elusive and is of intense interest to diabetes researchers.

Hyperammonemia (or hyperammonaemia) is a metabolic disturbance characterised by an excess of ammonia in the blood. It is a dangerous condition that may lead to brain injury and death. It may be primary or secondary.

Ammonia is a substance that contains nitrogen. It is a product of the catabolism of protein. It is converted to the less toxic substance urea prior to excretion in urine by the kidneys. The metabolic pathways that synthesize urea involve reactions that start in the mitochondria and then move into the cytosol. The process is known as the urea cycle, which comprises several enzymes acting in sequence.

3-hydroxyacyl-coenzyme A dehydrogenase deficiency (HADH deficiency) is a rare condition that prevents the body from converting certain fats to energy, particularly during fasting. Normally, through a process called fatty acid oxidation, several enzymes work in a step-wise fashion to metabolize fats and convert them to energy. People with 3-hydroxyacyl-coenzyme A dehydrogenase deficiency have inadequate levels of an enzyme required for a step that metabolizes groups of fats called medium chain fatty acids and short chain fatty acids; for this reason this disorder is sometimes called medium- and short-chain 3-hydroxyacyl-coenzyme A dehydrogenase (M/SCHAD) deficiency.

Typically, initial signs and symptoms of this disorder occur during infancy or early childhood and can include poor appetite, vomiting, diarrhea, lethargy, hypoglycemia, hypotonia, liver problems, and abnormally high levels of hyperinsulinism. Insulin controls the amount of sugar that moves from the blood into cells for conversion to energy. Individuals with 3-hydroxyacyl-coenzyme A dehydrogenase deficiency are also at risk for complications such as seizures, life-threatening heart and breathing problems, coma, and sudden unexpected death.

Problems related to 3-hydroxyacyl-coenzyme A dehydrogenase deficiency can be triggered by periods of fasting or by illnesses such as viral infections. This disorder is sometimes mistaken for Reye syndrome, a severe disorder that may develop in children while they appear to be recovering from viral infections such as chicken pox or flu. Most cases of Reye syndrome are associated with the use of aspirin during these viral infections.

The following list includes such examples:

- - hyperammonemia due to ornithine transcarbamylase deficiency

- - hyperinsulinism-hyperammonemia syndrome (glutamate dehydrogenase 1)

- - hyperornithinemia-hyperammonemia-homocitrullinuria

- - hyperammonemia due to N-acetylglutamate synthetase deficiency

- - hyperammonemia due to carbamoyl phosphate synthetase I deficiency (carbamoyl phosphate synthetase I)

- - hyperlysinuria with hyperammonemia (genetics unknown)

- Methylmalonic acidemia

- Isovaleric acidemia

- Propionic acidemia

- Carnitine palmitoyltransferase II deficiency

- Transient hyperammonemia of the newborn, specifically in the preterm

A congenital disorder of glycosylation (previously called carbohydrate-deficient glycoprotein syndrome) is one of several rare inborn errors of metabolism in which glycosylation of a variety of tissue proteins and/or lipids is deficient or defective. Congenital disorders of glycosylation are sometimes known as CDG syndromes. They often cause serious, sometimes fatal, malfunction of several different organ systems (especially the nervous system, muscles, and intestines) in affected infants. The most common subtype is CDG-Ia (also referred to as PMM2-CDG) where the genetic defect leads to the loss of phosphomannomutase 2, the enzyme responsible for the conversion of mannose-6-phosphate into mannose-1-phosphate.

No treatment is available for most of these disorders. Mannose supplementation relieves the symptoms in PMI-CDG (CDG-Ib) for the most part, even though the hepatic fibrosis may persist. Fucose supplementation has had a partial effect on some SLC35C1-CDG (CDG-IIc or LAD-II) patients.

The mortality rate ranges from 3–7% in a mean follow up period of 8.5 to 9.7 years. Death is often related to accidents.

Onset is between 3 and 15 years of age with a mean of around 8. Both sexes are equally affected. The disorder accounts for about 2–7% of benign childhood focal seizures.

People with epilepsy are at an increased risk of death. This increase is between 1.6 and 4.1 fold greater than that of the general population and is often related to: the underlying cause of the seizures, status epilepticus, suicide, trauma, and sudden unexpected death in epilepsy (SUDEP). Death from status epilepticus is primarily due to an underlying problem rather than missing doses of medications. The risk of suicide is increased between two and six times in those with epilepsy. The cause of this is unclear. SUDEP appears to be partly related to the frequency of generalized tonic-clonic seizures and accounts for about 15% of epilepsy related deaths. It is unclear how to decrease its risk. The greatest increase in mortality from epilepsy is among the elderly. Those with epilepsy due to an unknown cause have little increased risk. In the United Kingdom, it is estimated that 40–60% of deaths are possibly preventable. In the developing world, many deaths are due to untreated epilepsy leading to falls or status epilepticus.

LGS is seen in approximately 4% of children with epilepsy, and is more common in males than in females. Usual onset is between the ages of three and five. Children can have no neurological problems prior diagnosis, or have other forms of epilepsy. West syndrome is diagnosed in 20% of patients before it evolves into LGS at about 2 years old.

While many cases are not preventable, efforts to reduce head injuries, provide good care around the time of birth, and reduce environmental parasites such as the pork tapeworm may be effective. Efforts in one part of Central America to decrease rates of pork tapeworm resulted in a 50% decrease in new cases of epilepsy.

Both medication and drug overdoses can result in seizures, as may certain medication and drug withdrawal. Common drugs involved include: antidepressants, antipsychotics, cocaine, insulin, and the local anaesthetic lidocaine. Difficulties with withdrawal seizures commonly occurs after prolonged alcohol or sedative use, a condition known as delirium tremens.