Hyperinsulinemic hypoglycemia describes the condition and effects of low blood

glucose Glucose is a simple sugar with the molecular formula . Glucose is overall the most abundant monosaccharide, a subcategory of carbohydrates. Glucose is mainly made by plants and most algae during photosynthesis from water and carbon dioxide, using ...

caused by excessive

insulin Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the ''INS'' gene. It is considered to be the main anabolic hormone of the body. It regulates the metabolism o ...

Hypoglycemia Hypoglycemia, also called low blood sugar, is a fall in blood sugar to levels below normal, typically below 70 mg/dL (3.9 mmol/L). Whipple's triad is used to properly identify hypoglycemic episodes. It is defined as blood glucose belo ...

due to excess insulin is the most common type of serious hypoglycemia. It can be due to endogenous or injected insulin.

Signs and symptoms

Manifestations of hyperinsulinemic hypoglycemia vary by age and severity of the hypoglycemia. In general, most signs and symptoms can be attributed to (1) the effects on the brain of insufficient glucose (

neuroglycopenia Neuroglycopenia is a shortage of glucose (glycopenia) in the brain, usually due to hypoglycemia. Glycopenia affects the function of neurons, and alters brain function and behavior. Prolonged or recurrent neuroglycopenia can result in loss of consc ...

) or (2) to the

adrenergic Adrenergic means "working on adrenaline (epinephrine) or noradrenaline (norepinephrine)" (or on their receptors). When not further qualified, it is usually used in the sense of enhancing or mimicking the effects of epinephrine and norepinephrine in ...

response of the

autonomic nervous system The autonomic nervous system (ANS), formerly referred to as the vegetative nervous system, is a division of the peripheral nervous system that supplies viscera, internal organs, smooth muscle and glands. The autonomic nervous system is a control ...

to hypoglycemia. A few miscellaneous symptoms are harder to attribute to either of these causes. In most cases, all effects are reversed when normal glucose levels are restored. There are uncommon cases of more persistent harm, and rarely even death due to severe hypoglycemia of this type. One reason hypoglycemia due to excessive insulin can be more dangerous is that insulin lowers the available amounts of most alternate brain fuels, such as

ketone In organic chemistry, a ketone is a functional group with the structure R–C(=O)–R', where R and R' can be a variety of carbon-containing substituents. Ketones contain a carbonyl group –C(=O)– (which contains a carbon-oxygen double bo ...

s. Brain damage of various types ranging from

stroke A stroke is a medical condition in which poor blood flow to the brain causes cell death. There are two main types of stroke: ischemic, due to lack of blood flow, and hemorrhagic, due to bleeding. Both cause parts of the brain to stop functionin ...

-like focal effects to impaired memory and thinking can occur. Children who have prolonged or recurrent hyperinsulinemic hypoglycemia in infancy can suffer harm to their brains and may be developmentally delayed.

Causes

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 Type 1 diabetes (T1D), formerly known as juvenile diabetes, is an autoimmune disease that originates when cells that make insulin (beta cells) are destroyed by the immune system. Insulin is a hormone required for the cells to use blood sugar for ...

who take insulin. * Hypoglycemia due to endogenous insulin **

Congenital hyperinsulinism Congenital hyperinsulinism is a medical term referring to a variety of congenital disorders in which hypoglycemia is caused by excessive insulin secretion.update 2013 Congenital forms of hyperinsulinemic hypoglycemia can be transient or persiste ...

*** Transient neonatal hyperinsulinism (mechanism not known) *** Focal hyperinsulinism (K_ATP channel disorders) **** Paternal SUR1

mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mi ...

with clonal loss of heterozygosity of 11p15 **** Paternal Kir6.2 mutation with clonal loss of heterozygosity of 11p15 *** Diffuse hyperinsulinism **** K_ATP channel disorders ***** SUR1 mutations ***** Kir6.2 mutations ****

Glucokinase Glucokinase () is an enzyme that facilitates phosphorylation of glucose to glucose-6-phosphate. Glucokinase occurs in cells in the liver and pancreas of humans and most other vertebrates. In each of these organs it plays an important role in ...

gain-of-function mutations **** Hyperammonemic hyperinsulinism (glutamate dehydrogenase gain-of-function mutations) **** Short chain acyl coenzyme A dehydrogenase deficiency ****

Carbohydrate-deficient glycoprotein syndrome 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 defect ...

( Jaeken's Disease) **** Beckwith-Wiedemann syndrome(suspected due to hyperinsulinism but pathophysiology uncertain: 11p15 mutation or

IGF2 Insulin-like growth factor 2 (IGF-2) is one of three protein hormones that share structural similarity to insulin. The MeSH definition reads: "A well-characterized neutral peptide believed to be secreted by the liver and to circulate in the bloo ...

excess) ** Acquired forms of hyperinsulinism **

Insulinoma An insulinoma is a tumour of the pancreas that is derived from beta cells and secretes insulin. It is a rare form of a neuroendocrine tumour. Most insulinomas are benign in that they grow exclusively at their origin within the pancreas, but a min ...

s (insulin-secreting

tumor A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...

s) ***

Islet cell adenoma An islet is a very small, often unnamed island. Most definitions are not precise, but some suggest that an islet has little or no vegetation and cannot support human habitation. It may be made of rock, sand and/or hard coral; may be permanent ...

or adenomatosis ***

Islet cell carcinoma An islet is a very small, often unnamed island. Most definitions are not precise, but some suggest that an islet has little or no vegetation and cannot support human habitation. It may be made of rock, sand and/or hard coral; may be permanent ...

** Adult

nesidioblastosis Nesidioblastosis is a controversial medical term for hyperinsulinemic hypoglycemia attributed to excessive insulin production by pancreatic beta cells that have an abnormal microscopic appearance. The term was coined in the first half of the 20th c ...

Autoimmune insulin syndrome In immunology, autoimmunity is the system of immune responses of an organism against its own healthy cells, tissues and other normal body constituents. Any disease resulting from this type of immune response is termed an "autoimmune disease". P ...

** Noninsulinoma pancreatogenous hypoglycemia **

Reactive hypoglycemia Reactive hypoglycemia, postprandial hypoglycemia, or sugar crash is a term describing recurrent episodes of symptomatic hypoglycemia occurring within four hours"Hypoglycemia." It can also be referred to as "sugar crash" or "glucose crash." Nati ...

(also see

idiopathic postprandial syndrome 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 charac ...

) **

Gastric dumping syndrome Dumping syndrome occurs when food, especially sugar, moves too quickly from the stomach to the duodenum—the first part of the small intestine—in the upper gastrointestinal (GI) tract. This condition is also called rapid gastric emptying. It i ...

* Drug induced hyperinsulinism **

Sulfonylurea Sulfonylureas (UK: sulphonylurea) are a class of organic compounds used in medicine and agriculture, for example as antidiabetic drugs widely used in the management of diabetes mellitus type 2. They act by increasing insulin release from the beta ...

Aspirin Aspirin, also known as acetylsalicylic acid (ASA), is a nonsteroidal anti-inflammatory drug (NSAID) used to reduce pain, fever, and/or inflammation, and as an antithrombotic. Specific inflammatory conditions which aspirin is used to treat inc ...

Pentamidine Pentamidine is an antimicrobial medication used to treat African trypanosomiasis, leishmaniasis, ''Balamuthia'' infections, babesiosis, and to prevent and treat pneumocystis pneumonia (PCP) in people with poor immune function. In African trypano ...

Quinine Quinine is a medication used to treat malaria and babesiosis. This includes the treatment of malaria due to ''Plasmodium falciparum'' that is resistant to chloroquine when artesunate is not available. While sometimes used for nocturnal leg cr ...

Disopyramide Disopyramide (INN, trade names Norpace and Rythmodan) is an antiarrhythmic medication used in the treatment of ventricular tachycardia. It is a sodium channel blocker and therefore classified as a Class 1a anti-arrhythmic agent. Disopyramide has ...

Bordetella pertussis ''Bordetella pertussis'' is a Gram-negative, aerobic, pathogenic, encapsulated coccobacillus of the genus ''Bordetella'', and the causative agent of pertussis or whooping cough. Like '' B. bronchiseptica'', ''B. pertussis'' is motile and expres ...

vaccine A vaccine is a biological Dosage form, preparation that provides active acquired immunity to a particular infectious disease, infectious or cancer, malignant disease. The safety and effectiveness of vaccines has been widely studied and verifie ...

or infection ** D-chiro-inositol and myo-inositol * Hypoglycemia due to exogenous (injected) insulin ** Insulin self-injected for treatment of

diabetes Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ap ...

(i.e.,

diabetic hypoglycemia Diabetic hypoglycemia is a low blood glucose level occurring in a person with diabetes mellitus. It is one of the most common types of hypoglycemia seen in emergency departments and hospitals. According to the National Electronic Injury Survei ...

) ** Insulin self-injected surreptitiously (e.g.,

Munchausen syndrome Factitious disorder imposed on self, also known as Munchausen syndrome, is a factitious disorder in which those affected feign or induce disease, illness, injury, abuse, or psychological trauma to draw attention, sympathy, or reassurance to t ...

) ** Insulin self-injected in a suicide attempt or fatality ** Various forms of diagnostic challenge or "tolerance tests" *** Insulin tolerance test for

pituitary In vertebrate anatomy, the pituitary gland, or hypophysis, is an endocrine gland, about the size of a chickpea and weighing, on average, in humans. It is a protrusion off the bottom of the hypothalamus at the base of the brain. The hypop ...

response assessment ***

Protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...

challenge ***

Leucine Leucine (symbol Leu or L) is an essential amino acid that is used in the biosynthesis of proteins. Leucine is an α-amino acid, meaning it contains an α-amino group (which is in the protonated −NH3+ form under biological conditions), an α- ca ...

challenge ***

Tolbutamide Tolbutamide is a first-generation potassium channel blocker, sulfonylurea oral hypoglycemic medication. This drug may be used in the management of type 2 diabetes if diet alone is not effective. Tolbutamide stimulates the secretion of insulin by ...

challenge ** Insulin potentiation therapy ** Insulin-induced coma for depression treatment

Genetics

There are several genetic forms of hyperinsulinemic hypoglycemia:

Diagnosis

When the cause of hypoglycemia is not obvious, the most valuable diagnostic information is obtained from a blood sample (a "critical specimen") drawn during the hypoglycemia. Detectable amounts of insulin are abnormal and indicate that hyperinsulinism is likely to be the cause. Other aspects of the person's metabolic state, especially low levels of

free fatty acid In chemistry, particularly in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated or unsaturated. Most naturally occurring fatty acids have an unbranched chain of an even number of carbon atoms, ...

beta-hydroxybutyrate β-Hydroxybutyric acid, also known as 3-hydroxybutyric acid or BHB, is an organic compound and a beta hydroxy acid with the chemical formula CH3CH(OH)CH2CO2H; its conjugate base is β-hydroxybutyrate, also known as 3-hydroxybutyrate. β-Hydroxyb ...

and

s, and either high or low levels of

C-peptide The connecting peptide, or C-peptide, is a short 31-amino-acid polypeptide that connects insulin, insulin's A-chain to its B-chain in the proinsulin molecule. In the context of diabetes or hypoglycemia, a measurement of C-peptide blood serum lev ...

and

proinsulin Proinsulin is the prohormone precursor to insulin made in the beta cells of the islets of Langerhans, specialized regions of the pancreas. In humans, proinsulin is encoded by the ''INS'' gene. The islets of Langerhans only secrete between 1% and 3 ...

can provide confirmation. Clinical features and circumstances can provide other indirect evidence of hyperinsulinism. For instance, babies with neonatal hyperinsulinism are often

large for gestational age Large for gestational age (LGA) is a term used to describe infants that are born with an abnormally high weight, specifically in the 90th percentile or above, compared to other babies of the same developmental age. Macrosomia is a similar term tha ...

and may have other features such as enlarged heart and liver. Knowing that someone takes insulin or

oral hypoglycemic agent Drugs used in diabetes treat diabetes mellitus by altering the glucose level in the blood. With the exceptions of insulin, most GLP receptor agonists ( liraglutide, exenatide, and others), and pramlintide, all are administered orally and are th ...

s for diabetes obviously makes insulin excess the presumptive cause of any hypoglycemia. Most sulfonylureas and aspirin can be detected on a blood or urine

drug screen A drug is any chemical substance that causes a change in an organism's physiology or psychology when consumed. Drugs are typically distinguished from food and substances that provide nutritional support. Consumption of drugs can be via inhalati ...

tests, but insulin cannot. Endogenous and exogenous insulin can be distinguished by the presence or absence of

, a by-product of endogenous insulin secretion which is not present in pharmaceutical insulin. Some of the newer

analog Analog or analogue may refer to: Computing and electronics * Analog signal, in which information is encoded in a continuous variable ** Analog device, an apparatus that operates on analog signals *** Analog electronics, circuits which use analog ...

insulins are not measured by the usual insulin level assays.

Treatment

Acute hypoglycemia is reversed by raising the blood glucose. Glucagon should be injected intramuscularly or intravenously, or

dextrose Glucose is a simple sugar with the molecular formula . Glucose is overall the most abundant monosaccharide, a subcategory of carbohydrates. Glucose is mainly made by plants and most algae during photosynthesis from water and carbon dioxide, using ...

can be infused intravenously to raise the blood glucose. Oral administration of glucose can worsen the outcome, as more insulin is eventually produced. Most people recover fully even from severe hypoglycemia after the blood glucose is restored to normal. Recovery time varies from minutes to hours depending on the severity and duration of the hypoglycemia. Death or permanent brain damage resembling

can occur rarely as a result of severe hypoglycemia. See

hypoglycemia Hypoglycemia, also called low blood sugar, is a fall in blood sugar to levels below normal, typically below 70 mg/dL (3.9 mmol/L). Whipple's triad is used to properly identify hypoglycemic episodes. It is defined as blood glucose belo ...

for more on effects, recovery, and risks. Further therapy and prevention depends upon the specific cause. Most hypoglycemia due to excessive insulin occurs in people who take insulin for

. Management of this hypoglycemia is sugar or starch by mouth (or in severe cases, an injection of

glucagon Glucagon is a peptide hormone, produced by alpha cells of the pancreas. It raises concentration of glucose and fatty acids in the bloodstream, and is considered to be the main catabolic hormone of the body. It is also used as a Glucagon (medicati ...

or intravenous

). When the glucose has been restored, recovery is usually complete. Prevention of further episodes consists of maintaining balance between insulin, food, and exercise. Management of hypoglycemia due to treatment of

type 2 diabetes Type 2 diabetes, formerly known as adult-onset diabetes, is a form of diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. Common symptoms include increased thirst, frequent urination, ...

is similar, and the dose of the

may need to be reduced. Reversal and prevention of hypoglycemia is a major aspect of the management of type 1 diabetes. Hypoglycemia due to drug overdose or effect is supported with extra glucose until the drugs have been metabolized. The drug doses or combination often needs to be altered. Hypoglycemia due to a

of the pancreas or elsewhere is usually curable by surgical removal. Most of these tumors are benign.

Streptozotocin Streptozotocin or streptozocin (INN, USP) (STZ) is a naturally occurring alkylating antineoplastic agent that is particularly toxic to the insulin-producing beta cells of the pancreas in mammals. It is used in medicine for treating certain canc ...

is a specific

beta cell Beta cells (β-cells) are a type of cell found in pancreatic islets that synthesize and secrete insulin and amylin. Beta cells make up 50–70% of the cells in human islets. In patients with Type 1 diabetes, beta-cell mass and function are dimini ...

toxin and has been used to treat insulin-producing pancreatic

carcinoma Carcinoma is a malignancy that develops from epithelial cells. Specifically, a carcinoma is a cancer that begins in a tissue that lines the inner or outer surfaces of the body, and that arises from cells originating in the endodermal, mesodermal ...

. Hyperinsulinism due to diffuse overactivity of beta cells, such as in many of the forms of

congenital hyperinsulinism Congenital hyperinsulinism is a medical term referring to a variety of congenital disorders in which hypoglycemia is caused by excessive insulin secretion.update 2013 Congenital forms of hyperinsulinemic hypoglycemia can be transient or persiste ...

, and more rarely in adults, can often be treated with

diazoxide Diazoxide, sold under the brand name Proglycem and others, is a medication used to treat low blood sugar due to a number of specific causes. This includes islet cell tumors that cannot be removed and leucine sensitivity. It can also be used in re ...

or a

somatostatin Somatostatin, also known as growth hormone-inhibiting hormone (GHIH) or by several other names, is a peptide hormone that regulates the endocrine system and affects neurotransmission and cell proliferation via interaction with G protein-couple ...

analog called

octreotide Octreotide, sold under the brand name Sandostatin among others, is an octapeptide that mimics natural somatostatin pharmacologically, though it is a more potent inhibitor of growth hormone, glucagon, and insulin than the natural hormone. It was ...

. Diazoxide is given by mouth, octreotide by injection or continuous subcutaneous pump infusion. When congenital hyperinsulinism is due to focal defects of the insulin-secretion mechanism, surgical removal of that part of the pancreas may cure the problem. In more severe cases of persistent congenital hyperinsulinism unresponsive to drugs, a near-total

pancreatectomy In medicine, a pancreatectomy is the surgical removal of all or part of the pancreas. Several types of pancreatectomy exist, including pancreaticoduodenectomy (Whipple procedure), distal pancreatectomy, segmental pancreatectomy, and total pancr ...

may be needed to prevent continuing hypoglycemia. Even after pancreatectomy, continuous glucose may be needed in the form of gastric infusion of

formula In science, a formula is a concise way of expressing information symbolically, as in a mathematical formula or a ''chemical formula''. The informal use of the term ''formula'' in science refers to the general construct of a relationship betwee ...

or dextrose. High dose

glucocorticoid Glucocorticoids (or, less commonly, glucocorticosteroids) are a class of corticosteroids, which are a class of steroid hormones. Glucocorticoids are corticosteroids that bind to the glucocorticoid receptor that is present in almost every vertebr ...

is an older treatment used for presumptive transient hyperinsulinism but incurs side effects with prolonged use.

References