eMedicine Specialties > Pediatrics: General Medicine > Endocrinology
Hyperinsulinemia: Treatment & Medication
Updated: Jul 9, 2008
- Overview
- Differential Diagnoses & Workup
- Treatment & Medication
- Follow-up
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Treatment
Medical Care
- Maintaining normoglycemia is essential to prevent neurologic sequelae. Infants with hyperinsulinism are at higher risk of neurologic sequelae than infants with hypoglycemia from other causes. Because insulin inhibits lipolysis and ketogenesis, hyperinsulinism results in the paucity of alternative fuel used by the brain.
- The glucose output from the liver is 2-3 mg/kg/min in adults. Infants and children have a greater need for glucose and have a maximal output estimated at 5-7 mg/kg/min. Patients with hyperinsulinism may require very high glucose infusion rates (20-30 mg/kg/min) to maintain normoglycemia. Attempts should be made to keep blood glucose levels at 60 mg/dL or higher at all times.
- Healthy neonates and infants can fast for 6 hours without experiencing hypoglycemia. This equates to skipping one feeding in the infant who is fed ad libitum.
- Medications should be administered to suppress insulin secretion or stimulate glucose release.
Surgical Care
- Gastrostomy tube: Gastrostomy tube placement may be indicated in extreme cases to administer food if the infant is unable to handle the increased glucose requirements.
- Partial or near-total pancreatectomy
- Pancreatectomy is reserved for infants who fail to establish adequate control on medical therapy.
- Although most surgeons initially remove 95% of the pancreas, a near-total (98%) pancreatectomy appears to be most effective in preventing hypoglycemia in the newborn period for those with diffuse potassium channel disease (SUR1 or Kir6.2 mutations). Remarkably, the elevated lifelong risk of diabetes mellitus is more closely related to the intrinsic error in regulated insulin release, rather than to the extent of pancreatectomy.
- Close monitoring of blood glucose levels is indicated to ensure glycemic control and to minimize hypoglycemia. If hypoglycemia persists, medical therapy should be reattempted. If medical therapy is unsuccessful, a second pancreatectomy may be indicated. The authors' experience indicates that clinically significant pancreatic regrowth can occur in infants after near-total pancreatectomy. A Whipple procedure is unwarranted because it cannot guarantee remission of diffuse disease.
- Limited pancreatectomy is indicated for patients with focal disease.
- Complications include pancreatic exocrine insufficiency, diabetes mellitus, and injury to the common bile duct.
Consultations
- Pediatric endocrinologist
- Pediatric surgeon
- Neonatologist
- Geneticist (if family history is present or suspected)
- Closest tertiary referral center (academic children's hospital) for possible enrollment in clinical research protocols
Diet
- Frequent feedings by gastrostomy help maintain euglycemia but do not prevent the need for intravenous dextrose administration before surgery.
Medication
Medical therapy is the treatment of choice. Patients with hyperinsulinism often require multiple medications to maintain normoglycemia. Patients with severe hyperinsulinism may be refractory to medical therapy and may require excision of a portion of or the entire pancreas. In general, maintenance of normoglycemia should be attempted before pancreatectomy is considered. At the same time, because hypoglycemia can result in irreversible brain damage, surgical excision should not be delayed in patients with severe hypoglycemia.
Insulin secretion inhibiting agents
Insulin secretion may be altered by various mechanisms. Oral diazoxide inhibits pancreatic secretion of insulin, stimulates glucose release from the liver, and stimulates catecholamine release, which elevates blood glucose levels. Octreotide is a peptide with pharmacologic action similar to that of somatostatin, which inhibits insulin secretion. KATPs (ATP–sensitive potassium-dependent channels, composed of the SUR1 and Kir6.2) are inactive in diffuse disease. These channels initiate depolarization of the beta-cell membrane and opening of calcium channels. The resultant increase in intracellular calcium triggers insulin secretion. Calcium channel blockers block the activation of these calcium channels, decreasing insulin secretion. Nifedipine is the only calcium channel blocker that has been used for the treatment of hyperinsulinism in humans and appears to be clinically ineffective.
Diazoxide (Proglycem)
First-line treatment. PO diazoxide (Proglycem) opens KATP channels and inhibits insulin secretion. The IV preparation (Hyperstat) is not used in hyperinsulinism.
Adult
3-5 mg/kg/d PO divided q8h; titrate to effect
Pediatric
5-15 mg/kg/d PO divided q8h; titrate to effect; doses above 15 mg/kg/d are not more effective and may increase risk of adverse effects; half-life is >24 h, so full effect may take 4-5 d to be seen
Diazoxide is highly bound to serum protein and displaces other protein-bound substances, such as bilirubin or coumarin, increasing their serum levels; may decrease serum hydantoins, possibly resulting in decreased anticonvulsant effects; thiazide diuretics may potentiate hyperuricemic effects of diazoxide
Documented hypersensitivity; diabetes mellitus
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Adverse effects of PO diazoxide include fluid retention, hypertension, hyperglycemia, hyperuricemia, hypertrichosis, facial changes, leukopenia (rare), and thrombocytopenia (rare); caution in patients hypersensitive to other thiazides or sulfonamide-derived drugs because cross-reactivity may occur; closely monitor blood glucose levels during use because severe hyperglycemia may occur; half-life may be prolonged in patients with renal impairment; causes sodium and water retention (caution in CHF or poor cardiac reserve)
Octreotide (Sandostatin)
Somatostatin analogue, activates G-protein K channel. Hyperpolarization of beta cell results in inhibition of calcium influx and insulin release. Octreotide also used for acromegaly, carcinoid tumors, and VIPomas.
Adult
50 mcg SC q12-24h initially; may gradually titrate upward while monitoring blood glucose levels; alternatively, may administer daily dose as a continuous SC infusion
Pediatric
5-40 mcg/kg/d SC divided q4-6h or administered as continuous SC infusion; titrate to effect
Precipitates or sludges when mixed with glucagon; octreotide must be given as intermittent SC injection when coadministered with continuous SC glucagon infusion
May decrease absorption of orally administered drugs; may decrease blood levels of cyclosporine; patients may require dose adjustments of insulin, beta blockers, calcium channel blockers, or agents to control fluid and electrolyte balances while on this drug
Documented hypersensitivity
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
May cause GI toxicity (eg, steatorrhea, diarrhea, vomiting, abdominal distention, biliary sludge); cholelithiasis may occur; hyperglycemia; hypothyroidism; bradycardia, cardiac conduction abnormalities, and arrhythmias have been reported; caution in renal impairment (decrease dose)
Nifedipine (Adalat, Procardia)
Blocks calcium channels and insulin release. Also used to treat hypertension and angina.
Adult
10 mg PO tid initially; may gradually titrate upward to 80 mg PO tid as determined by blood glucose
Pediatric
0.25-0.7 mg/kg/d PO divided q8h
Caution with coadministration of any agent that can lower BP, including beta blockers and opioids; H2 blockers (eg, cimetidine) may increase toxicity; may increase serum levels of digoxin or quinidine; nifedipine levels may be affected by CYP3A4 inhibitors (eg, erythromycin, itraconazole) or inducers (eg, carbamazepine, rifampin)
Documented hypersensitivity
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
May cause lower extremity edema or hypotension; allergic hepatitis has occurred but is rare
Dextrose and glucose release stimulators
Emergent blood glucose elevation requires intravenous dextrose. Glucagon enhances release of hepatic glycogen as glucose.
Dextrose (D-glucose)
IV glucose is used to elevate serum glucose levels promptly. PO glucose is rapidly absorbed from intestine and stored or used by the tissues. Parenterally injected dextrose is used in patients unable to sustain adequate PO intake. Direct PO absorption results in a rapid increase in blood glucose concentrations. Dextrose is effective in small doses, and no evidence exists that it may cause toxicity. Concentrated dextrose infusions provide higher amounts of glucose in a small volume of fluid but require central venous access for concentrations above 12.5% to reduce hyperosmolar damage to smaller peripheral blood vessels.
Adult
10-25 g IV bolus; may follow with continuous IV infusion according to patient requirements
Pediatric
250-500 mg/kg IV (1-2 mL of 25% dextrose per kg); may follow with continuous IV infusion of 10% dextrose according to patient requirements
Caution when coadministered with drugs that may increase blood glucose levels
No contraindications to judicious use of IV dextrose in patients with hypoglycemia; PO glucose is contraindicated in patients with glucose-galactose malabsorption
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
May cause nausea, which also may occur with hypoglycemia; IV dextrose solutions may result in dilution of serum electrolyte concentrations or in overhydration when there is fluid overload; caution in patients with congestion or pulmonary edema; hypertonic dextrose given peripherally may cause thrombosis (administer through central venous catheter instead); rapid administration associated with increased risk of inducing significant hyperglycemia or hyperosmolar syndrome, especially in patients with chronic uremia; concentrated solutions should not be administered SC or IM; rates of dextrose infusion higher than 0.5 g/kg/h may produce glycosuria; at infusion rates of 0.8 g/kg/h, incidence of glycosuria is 5%; closely monitor fluid balance, electrolyte concentrations and acid-base balance; dextrose administration may produce vitamin B-complex deficiency
Glucagon
Stimulates hepatic glycogenolysis and gluconeogenesis.
Adult
1 mg (1 unit) IV/IM/SC
Pediatric
2-10 mcg/kg/h IV; alternatively, 0.2 mg/kg IV/IM/SC bolus; not to exceed 1 mg/dose
Effects of anticoagulants may be enhanced by glucagon (although onset may be delayed); monitor prothrombin activity and for signs of bleeding in patients receiving anticoagulants; adjust dose accordingly
Documented hypersensitivity; pheochromocytoma
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Useful only if liver glycogen stores are adequate; may lead to elevated blood pressure from stimulation of catecholamine release; may result in nausea and vomiting
Drugs inhibiting insulin effect
In refractory cases, cortisol and growth hormone have been used with variable rates of success to inhibit insulin effects. Both diminish the hypoglycemic effects of insulin. They may also enhance ketogenesis and increase the availability of alternative fuels.
Hydrocortisone (Hydrocortone, Cortef, Solu-Cortef)
Possesses glucocorticoid activity and weak mineralocorticoid effects. Causes peripheral insulin resistance, gluconeogenesis, and, with prolonged therapy, increased pancreatic release of glucagon (which promotes glycogenolysis).
Adult
25-50 mg/m2/d PO divided q8h; alternatively, administer daily dose as a continuous IV infusion
Pediatric
Administer as in adults
May increase digitalis toxicity secondary to hypokalemia
Documented hypersensitivity; severe bacterial, viral, fungal, or tubercular infections
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Caution in infections and other severe disorders; may exacerbate hypertension; may cause fluid retention and weight gain
Growth hormone, human (Genotropin, Humatrope, Nutropin)
Recombinant hGH. Some patients demonstrate reduced glucose requirement and improved glycemic control. Stimulates growth of linear bone, skeletal muscle, and organs. Stimulates erythropoietin, which increases red blood cell mass. Should not be considered an alternative to continuous SC glucagon, intermittent octreotide, or pancreatectomy.
Adult
Pediatric
0.05-0.06 mg/kg/d SC as single daily injection
Glucocorticoids may decrease growth-promoting effects
Documented hypersensitivity; actively growing intracranial tumor
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Reconstitute with sterile water for injection if administering to newborns
More on Hyperinsulinemia |
| Overview: Hyperinsulinemia |
| Differential Diagnoses & Workup: Hyperinsulinemia |
 Treatment & Medication: Hyperinsulinemia |
| Follow-up: Hyperinsulinemia |
| Multimedia: Hyperinsulinemia |
| References |
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References
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Further Reading
Keywords
hyperinsulinemia, beta-cell hyperplasia, hyperinsulinemic hypoglycemia, nesidioblastosis, neonatal hyperglycemia, primary hyperinsulinemia, hypoglycemia in children, hypoglycemia in infants, hyperinsulinism, growth hormone deficiency, hypocortisolemia, maternal diabetes, birth asphyxia, macrosomia, Beckwith-Wiedemann syndrome, omphalocele, macroglossia, visceromegaly, drug-induced hyperinsulinism, maternal toxemia, erythroblastosis fetalis, Munchausen syndrome by proxy, nesidioblastosis, islet adenomatosis, beta-cell adenoma, persistent hyperinsulinemic hypoglycemia of infancy, PHHI, leucine-sensitive hypoglycemia, islet cell dysmaturation syndrome
