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

Sedentary lifestyle increases the likelihood of development of insulin resistance. It has been estimated that each 500 kcal/week increment in physical activity related energy expenditure, reduces the lifetime risk of type 2 diabetes by 9%. A different study found that vigorous exercise at least once a week reduced the risk of type 2 diabetes in women by 33%.

Several associated risk factors include the following:

- Genetic factors (inherited component):

- Family history of type 2 diabetes

- Insulin receptor mutations (Donohue syndrome)

- LMNA mutations (familial partial lipodystrophy)

- Cultural variables, such as diet varying with race and class; factors related to stress, socio-economic status and history have been shown to activate the stress response, which increases the production of glucose and insulin resistance, as well as inhibiting pancreatic function and thus might be of importance, although it is not fully corroborated by the scientific evidence.

- Particular physiological conditions and environmental factors:

- Age 40–45 years or older

- Obesity

- The tendency to store fat preferentially in the abdomen (also known as "abdominal obesity)", as opposed to storing it in hips and thighs

- Sedentary lifestyle, lack of physical exercise

- Hypertension

- High triglyceride level (hypertriglyceridemia)

- Low level of high-density lipoprotein (also known as HDL cholesterol or "good cholesterol")

- Prediabetes, blood glucose levels have been too high in the past, i.e. the patient's body has previously shown slight problems with its production and usage of insulin ("previous evidence of impaired glucose homeostasis")

- Having developed gestational diabetes during past pregnancies

- Giving birth to a baby weighing more than 9 pounds (a bit over 4 kilograms)

- Pathology:

- Obesity and overweight (BMI > 25)

- Metabolic syndrome (hyperlipidemia + HDL cholesterol level 2.82 mmol/L), hypertension (> 140/90 mmHg), or arteriosclerosis

- Liver pathologies

- Infection (Hepatitis C)

- Hemochromatosis

- Gastroparesis

- Polycystic ovary syndrome (PCOS)

- Hypercortisolism (e.g., Cushing's syndrome, glucocorticoid therapy)

- Medications (e.g., glucosamine, rifampicin, isoniazid, olanzapine, risperidone, progestogens, glucocorticoids, methadone, many antiretrovirals)

There are several genetic forms of hyperinsulinemic hypoglycemia:

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 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").

At present, there is no international standard classification of diabetes in dogs. Commonly used terms are:

- Insulin deficiency diabetes or primary diabetes, which refers to the destruction of the beta cells of the pancreas and their inability to produce insulin.

- Insulin resistance diabetes or secondary diabetes, which describes the resistance to insulin caused by other medical conditions or by hormonal drugs.

While the occurrence of beta cell destruction is known, all of the processes behind it are not. Canine primary diabetes mirrors Type 1 human diabetes in the inability to produce insulin and the need for exogenous replacement of it, but the target of canine diabetes autoantibodies has yet to be identified. Breed and treatment studies have been able to provide some evidence of a genetic connection. Studies have furnished evidence that canine diabetes has a seasonal connection not unlike its human Type 1 diabetes counterpart, and a "lifestyle" factor, with pancreatitis being a clear cause. This evidence suggests that the disease in dogs has some environmental and dietary factors involved.

Secondary diabetes may be caused by use of steroid medications, the hormones of estrus, acromegaly, (spaying can resolve the diabetes), pregnancy, or other medical conditions such as Cushing's disease. In such cases, it may be possible to treat the primary medical problem and revert the animal to non-diabetic status. Returning to non-diabetic status depends on the amount of damage the pancreatic insulin-producing beta cells have sustained.

It happens rarely, but it is possible for a pancreatitis attack to activate the endocrine portion of the organ back into being capable of producing insulin once again in dogs. It is possible for acute pancreatitis to cause a temporary, or transient diabetes, most likely due to damage to the endocrine portion's beta cells. Insulin resistance that can follow a pancreatitis attack may last for some time thereafter. Pancreatitis can damage the endocrine pancreas to the point where the diabetes is permanent.

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.

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.

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.

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.

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.

Hyperinsulinism may also refer to forms of hypoglycemia caused by excessive insulin secretion. In normal children and adults, insulin secretion should be minimal when blood glucose levels fall below 70 mg/dL (3.9 mM). There are many forms of hyperinsulinemic hypoglycemia caused by various types of insulin excess. Some of those that occur in infants and young children are termed congenital hyperinsulinism. In adults, severe hyperinsulinemic hypoglycemia is often due to an insulinoma, an insulin-secreting tumor of the pancreas.

Insulin levels above 3 μU/mL are inappropriate when the glucose level is below 50 mg/dL (2.8 mM), and may indicate hyperinsulinism as the cause of the hypoglycemia. The treatment of this form of hyperinsulinism depends on the cause and the severity of the hyperinsulinism, and may include surgical removal of the source of insulin, or a drug such as diazoxide or octreotide that reduces insulin secretion.

That spontaneous hyperinsulinism might be a cause of symptomatic hypoglycemia was first proposed by Seale Harris, MD, 1924, in "Journal of the American Medical Association".

Dr. Seale Harris first diagnosed hyperinsulinism in 1924 and also is credited with the recognition of spontaneous hypoglycemia.

In February 2013 scientists successfully cured type 1 diabetes in dogs using a pioneering gene therapy.

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.

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.

In early dumping syndrome, pancreatic glucagon is augmented in the early postprandial period, probably through stimulation the catecholamines involved in the generalized autonomic surge induced by the osmotic load, but at 120 min, when most of the hypoglycemias are encountered, pancreatic glucagon is no longer detectable, likely through inhibition by GLP-1. Incretins including GLP1 and GIP also bring in the late dumping effects including the insulin rise and the reactive hypoglycemia.

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.

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.

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

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

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).

A 1988 study over 41 months found that improved glucose control led to initial "worsening of complications" but was not followed by the expected improvement in complications. In 1993 it was discovered that the serum of diabetics with neuropathy is toxic to nerves, even if its blood sugar content is normal.

Research from 1995 also challenged the theory of hyperglycemia as the cause of diabetic complications. The fact that 40% of diabetics who carefully controlled their blood sugar nevertheless developed neuropathy made clear other factors were involved.

In a 2013 meta-analysis of 6 randomized controlled trials involving 27,654 patients, tight blood glucose control reduced the risk for some macrovascular and microvascular events but without effect on all-cause mortality and cardiovascular mortality.

Research from 2007 suggested that in type 1 diabetics, the continuing autoimmune disease which initially destroyed the beta cells of the pancreas may also cause retinopathy, neuropathy, and nephropathy.

In 2008 it was even suggested to treat retinopathy with drugs to suppress the abnormal immune response rather than by blood sugar control.