INSULIN – Hyperinsulinemic Hypoglycemia
Hyperinsulinemic
hypoglycemia
describes the condition and effects of low blood glucose caused
by excessive insulin.
Hypoglycemia
due to excess insulin is the most common type of serious hypoglycemia. It can
be due to endogenous or injected insulin.
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 who take insulin.- Hypoglycemia
due to endogenous insulin
- Congenital hyperinsulinism
- Transient
neonatal hyperinsulinism (mechanism not known)
- Focal
hyperinsulinism (KATP 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
- KATP
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)
- 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
Signs, symptoms, and potential effects
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)
or (2) to the adrenergic
response of the autonomic nervous system 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 ketones. Brain damage of various types ranging from stroke-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.
Diagnostic evaluation
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 acids,
beta-hydroxybutyrate and ketones, and either high or low levels of C-peptide and proinsulin 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 and may have other features such as enlarged heart and liver. Knowing that someone takes insulin or oral hypoglycemic agents 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 tests, but insulin cannot. Endogenous and exogenous insulin can be distinguished by the presence or absence of C-peptide, a by-product of endogenous insulin secretion which is not present in pharmaceutical insulin. Some of the newer analog insulins are not measured by the usual insulin level assays.
Treatment
Acute hypoglycemia is
reversed by raising the blood glucose. This is usually accomplished by eating
or drinking 10-30 grams of carbohydrate.
Carbohydrate is digested and raises blood sugar most rapidly if it is not eaten
with protein or fat. When hypoglycemia is more severe or
carbohydrate cannot be given by mouth, glucagon can be
injected intramuscularly or intravenously, or dextrose can be
infused intravenously to raise the blood glucose. 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 stroke can occur rarely as a result of
severe hypoglycemia. See hypoglycemia
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 type 1 diabetes. Management of this hypoglycemia is sugar or starch by mouth (or in severe cases, an injection of glucagon or intravenous dextrose). 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 is similar, and the dose of the oral hypoglycemic agent 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 tumor of the pancreas or elsewhere is usually curable by surgical removal. Most of these tumors are benign. Streptozotocin is a specific beta cell toxin and has been used to treat insulin-producing pancreatic carcinoma.
Hyperinsulinism due to diffuse overactivity of beta cells, such as in many of the forms of congenital hyperinsulinism, and more rarely in adults, can often be treated with diazoxide or a somatostatin analog called octreotide. 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 may be needed to prevent continuing hypoglycemia. Even after pancreatectomy, continuous glucose may be needed in the form of gastric infusion of formula or dextrose.
High dose glucocorticoid is an older treatment used for presumptive transient hyperinsulinism but incurs side effects with prolonged use.
