No sexual predilection is observed because the deficiency of glycogen synthetase activity is inherited as an autosomal recessive trait.

The major morbidity is a risk of fasting hypoglycemia, which can vary in severity and frequency. Major long-term concerns include growth delay, osteopenia, and neurologic damage resulting in developmental delay, intellectual deficits, and personality changes.

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.

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.

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.

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.

Not all of the above manifestations occur in every case of hypoglycemia. There is no consistent order to the appearance of the symptoms. Specific manifestations vary by age and by the severity of the hypoglycemia. In older children and adults, moderately severe hypoglycemia can resemble mania, mental illness, drug intoxication, or drunkenness. In the elderly, hypoglycemia can produce focal stroke-like effects or a hard-to-define malaise. The symptoms of a single person do tend to be similar from episode to episode.

In the large majority of cases, hypoglycemia severe enough to cause seizures or unconsciousness can be reversed without obvious harm to the brain. Cases of death or permanent neurological damage occurring with a single episode have usually involved prolonged, untreated unconsciousness, interference with breathing, severe concurrent disease, or some other type of vulnerability. Nevertheless, brain damage or death has occasionally resulted from severe hypoglycemia.

This list of risk factors for canine diabetes is taken from the genetic breed study that was published in 2007. Their "neutral risk" category should be interpreted as insufficient evidence that the dog breed genetically shows a high, moderate, or a low risk for the disease. All risk information is based only on discovered genetic factors.

High risk

- Cairn Terrier

- Samoyed

Moderate risk

- Bichon Frise

- Border Collie

- Border Terrier

- Collie

- Dachshund

- English Setter

- Poodle

- Schnauzer

- Yorkshire Terrier

Neutral risk

- Cavalier King Charles Spaniel

- Cocker Spaniel

- Doberman

- Jack Russell Terrier

- Labrador Retriever

- Mixed Breed

- Rottweiler

- West Highland Terrier

Low risk

- Boxer

- English Springer Spaniel

- German Shepherd

- Golden Retriever

- Staffordshire Bull Terrier

- Weimaraner

- Welsh Springer Spaniel

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.

A 2001 study followed up on 50 patients. Of these 38% died in childhood while the rest suffered from problems with morbidity.

The exact mechanism in which these diseases cause cachexia is poorly understood, but there is probably a role for inflammatory cytokines, such as tumor necrosis factor-alpha (which is also nicknamed 'cachexin' or 'cachectin'), interferon gamma and interleukin 6, as well as the tumor-secreted proteolysis-inducing factor.

Related syndromes include kwashiorkor and marasmus, although these do not always have an underlying causative illness and are most often symptomatic of severe malnutrition.

Those suffering from the eating disorder anorexia nervosa appear to have high plasma levels of ghrelin. Ghrelin levels are also high in patients who have cancer-induced cachexia.

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.

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

If a metabolic crisis is not treated, a child with VLCADD can develop: breathing problems, seizures, coma, sometimes leading to death.

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.

Idiopathic postprandial syndrome, colloquially but incorrectly known by some as hypoglycemia, describes a collection of clinical signs and symptoms similar to medical hypoglycemia but without the demonstrably low blood glucose levels which characterise said condition.

People with this condition suffer from recurrent episodes of altered mood and cognitive efficiency, often accompanied by weakness and adrenergic symptoms such as shakiness. The episodes typically occur a few hours after a meal, rather than after many hours of fasting. The principal treatments recommended are extra small meals or snacks and avoidance of excessive simple sugars.

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").

A 2011 review of 176 cases found that diagnoses made early in life (within a few days of birth) were associated with more severe disease and a mortality of 33%. Children diagnosed later, and who had milder symptoms, showed a lower mortality rate of ~3%.

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.

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.

Mutations in the "HADHA" gene lead to inadequate levels of an enzyme called long-chain 3-hydroxyacyl-coenzyme A (CoA) dehydrogenase, which is part of a protein complex known as mitochondrial trifunctional protein. Long-chain fatty acids from food and body fat cannot be metabolized and processed without sufficient levels of this enzyme. As a result, these fatty acids are not converted to energy, which can lead to characteristic features of this disorder, such as lethargy and hypoglycemia. Long-chain fatty acids or partially metabolized fatty acids may build up in tissues and damage the liver, heart, retina, and muscles, causing more serious complications.

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.

There are several genetic forms of hyperinsulinemic hypoglycemia:

A 1994 study of the entire population of New South Wales (Australia) found 20 patients. Of these, 5 (25%) had died at or before 30 months of age. Of the survivors, 1 (5%) was severely disabled and the remainder had either suffered mild disability or were making normal progress in school. A 2006 Dutch study followed 155 cases and found that 27 individuals (17%) had died at an early age. Of the survivors, 24 (19%) suffered from some degree of disability, of which most were mild. All the 18 patients diagnosed neonatally were alive at the time of the follow-up.