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Congenital Hyperinsulinism Medication

  • Author: Robert S Gillespie, MD, MPH; Chief Editor: Stephen Kemp, MD, PhD  more...
 
Updated: Dec 16, 2015
 

Medication Summary

Diazoxide, octreotide, and nifedipine are the primary medications used in long-term treatment of congenital hyperinsulinism (CHI), or persistent hyperinsulinemic hypoglycemia of infancy (PHHI).[22] Some authors also recommend using chlorothiazide in conjunction with diazoxide for a synergistic effect. Most of these agents have significant adverse effects, especially with long-term use. Nifedipine appears to have considerably fewer adverse effects than the others.

Patients may require continuous intravenous (IV) glucose infusion. Glucagon may also be administered emergently to maintain adequate blood glucose levels.

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Glucose-Elevating Agents

Class Summary

Insulin secretion may be altered by various mechanisms. 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.

In CHI, functional abnormalities are believed to exist in the adenosine triphosphate (ATP)-sensitive potassium channels (composed of the sulfonylurea receptor [SUR gene abnormality] and the potassium channel pore protein [Kir6.2 gene abnormality]). 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 action of these calcium channels, decreasing insulin secretion.

Nifedipine is the only calcium channel blocker for which clinical trials have been performed in patients with CHI. The use of other calcium channel blockers given in liquid formulations or by alternative drug-delivery systems remains a promising area for future research. Thiazide diuretics also inhibit insulin secretion.

In CHI, chlorothiazide should be used in conjunction with diazoxide. It exerts a synergistic effect on inhibiting insulin secretion by activating a different potassium channel.

In addition to the agents described above, prompt-acting glycogenolysis is achieved with glucagon. Emergent blood glucose level elevation requires IV dextrose. Corticosteroids are rarely used for gluconeogenesis in the long term, because of their risk of toxicity.

Octreotide (Sandostatin)

 

Octreotide is a peptide with a pharmacologic action similar to that of somatostatin. It is a more potent inhibitor of insulin, glucagon, and growth hormone secretion than somatostatin. It elicits diverse endocrine effects, including suppression of luteinizing hormone (LH) response to gonadotropin-releasing hormone (GnRH), decreased splanchnic blood flow, and inhibition of release of serotonin, gastrin, vasoactive intestinal peptide (VIP), secretin, motilin, pancreatic polypeptide, and thyroid-stimulating hormone (TSH).

Octreotide decreases gallbladder contractility and bile secretion. It is used in CHI primarily for its ability to inhibit insulin secretion.

Diazoxide (Proglycem)

 

Diazoxide is an antihypertensive agent that relaxes smooth muscle in the peripheral arterioles. It is related to the thiazide class of drugs but has no diuretic action. It inhibits pancreatic secretion of insulin, stimulates glucose release from the liver, and stimulates catecholamine release.

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Diuretics, Thiazide

Class Summary

Some authors recommend using chlorothiazide in conjunction with diazoxide for a synergistic effect.

Chlorothiazide (Diuril)

 

When combined with diazoxide, chlorothiazide elicits a synergistic effect on inhibiting insulin secretion by activating a different potassium channel. It also counteracts the salt and water retention induced by diazoxide.

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Cardiovascular, Other

Class Summary

Use of nifedipine in CHI is relatively new, but initial reports suggest that it is effective and extremely well tolerated.

Nifedipine (Adalat, Procardia, Nifediac, Nifedical XL)

 

Nifedipine, a later addition to the therapeutic armamentarium, is a calcium channel blocker that helps reduce the influx of calcium into beta cells, which is a necessary step for insulin secretion. This effect occurs with doses much lower than those traditionally used for other indications (eg, angina pectoris). Nifedipine appears to have considerably fewer adverse effects compared with other agents.[13]

Most information on adverse effects of, and interactions with, nifedipine has been obtained from studies of adults using the drug for angina pectoris at proportionately higher doses than those used in children for CHI.

A liquid formulation is not available commercially. The drug is supplied as a 10-mg liquid-in-gelcap. To measure smaller doses, the contents may be aspirated with a syringe and needle, but it is very difficult to do this accurately because of the extremely small volume of fluid in the gelcap. Extended-release (ER) formulations have also been employed in CHI.

Dextrose (Glutol, Enfamil Glucose, Similac Glucose, Glutose 15)

 

Dextrose is used for prompt elevation of serum glucose. It is a monosaccharide that is absorbed from the intestine and then distributed, stored, and used by the tissues. Parenterally injected dextrose is used in patients unable to sustain adequate oral intake. Direct oral absorption results in a rapid increase in blood glucose concentrations. Dextrose is effective in small doses, and no evidence indicates that it may cause toxicity. Concentrated dextrose infusions provide higher amounts of glucose and increased caloric intake in a small volume of fluid.

Glucagon (GlucaGen)

 

Glucagon, a polypeptide hormone, is produced by pancreatic alpha cells of the islets of Langerhans. Its effects on blood glucose are the opposite of those exerted by insulin. Glucagon elevates blood glucose levels by inhibiting glycogen synthesis and enhancing formation of glucose from noncarbohydrate sources such as proteins and fats (gluconeogenesis).

Glucagon increases hydrolysis of glycogen to glucose (glycogenolysis) in the liver, in addition to accelerating hepatic glycogenolysis and lipolysis in adipose tissue. Glucagon also increases the force of contraction in the heart and has a relaxant effect on the gastrointestinal tract.

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Contributor Information and Disclosures
Author

Robert S Gillespie, MD, MPH Physician, Department of Pediatrics, Cook Children's Medical Center

Disclosure: Received consulting fee from Alexion Pharmaceuticals for consulting.

Coauthor(s)

Stephen Ponder, MD, CDE Director, Division of Pediatric Endocrinology, Department of Pediatrics, Driscoll Children's Hospital; Professor of Pediatrics, Texas A&M Health Science Center College of Medicine

Stephen Ponder, MD, CDE is a member of the following medical societies: American Academy of Pediatrics, American Diabetes Association, Endocrine Society, Pediatric Endocrine Society, Southern Society for Pediatric Research

Disclosure: Nothing to disclose.

Chief Editor

Stephen Kemp, MD, PhD Former Professor, Department of Pediatrics, Section of Pediatric Endocrinology, University of Arkansas for Medical Sciences College of Medicine, Arkansas Children's Hospital

Stephen Kemp, MD, PhD is a member of the following medical societies: American Academy of Pediatrics, American Association of Clinical Endocrinologists, American Pediatric Society, Endocrine Society, Phi Beta Kappa, Southern Medical Association, Southern Society for Pediatric Research

Disclosure: Nothing to disclose.

Acknowledgements

George P Chrousos, MD, FAAP, MACP, MACE, FRCP(London) Professor and Chair, First Department of Pediatrics, Athens University Medical School, Aghia Sophia Children's Hospital, Greece; UNESCO Chair on Adolescent Health Care, University of Athens, Greece

George P Chrousos, MD, FAAP, MACP, MACE, FRCP(London) is a member of the following medical societies: American Academy of Pediatrics, American College of Endocrinology, American College of Physicians, American Pediatric Society, American Society for Clinical Investigation, Association of American Physicians, Endocrine Society, Pediatric Endocrine Society, and Society for Pediatric Research

Disclosure: Nothing to disclose.

Thomas A Wilson, MD Professor of Clinical Pediatrics, Chief and Program Director, Division of Pediatric Endocrinology, Department of Pediatrics, The School of Medicine at Stony Brook University Medical Center

Thomas A Wilson, MD is a member of the following medical societies: Endocrine Society, Pediatric Endocrine Society, and Phi Beta Kappa

Disclosure: Nothing to disclose.

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

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Pancreatic specimen showing congenital hyperinsulinism (CHI) viewed at low power. Paler-staining cells are neuroendocrine (islet) cells, which should be arranged in discrete islands within acinar lobules. Acinar cells are exocrine cells that have denser-staining, dark eosinophilic cytoplasm. These acinar cells are arranged in acini. In CHI, more neuroendocrine cells are present, and they are arranged more diffusely throughout the lobules. Image courtesy of Phil Collins, MD.
Pancreatic specimen showing diffuse congenital hyperinsulinism (CHI) viewed at medium power. Paler-staining cells are neuroendocrine (islet) cells, which should be arranged in discrete islands within acinar lobules. Acinar cells are exocrine cells that have denser-staining, dark eosinophilic cytoplasm. These acinar cells are arranged in acini. In CHI, more neuroendocrine cells are present, and they are arranged more diffusely throughout lobules. Image courtesy of Phil Collins, MD.
Pancreatic specimen showing diffuse congenital hyperinsulinism (CHI) viewed at high power. Paler-staining cells are neuroendocrine (islet) cells, which should be arranged in discrete islands within acinar lobules. Acinar cells are exocrine cells that have denser-staining, dark eosinophilic cytoplasm. These acinar cells are arranged in acini. In CHI, more neuroendocrine cells are present, and they are arranged more diffusely throughout lobules. Image courtesy of Phil Collins, MD.
Normal pancreas. There are fewer paler-staining neuroendocrine (islet) cells, and they are arranged in more discrete islands. Image courtesy of Tom Milligan, MD, Driscoll Children's Hospital, Corpus Christi, Tex.
Combined positron emission tomography (PET)/computed tomography (CT) scan of focal lesion in head of pancreas of infant with congenital hyperinsulinism. Uptake of 18F-L-DOPA glows brightly in head of pancreas (center), pinpointing abnormal cells in focal hyperinsulinism. Large glowing areas lower in image are kidneys, where 18F-L-DOPA is excreted. Image courtesy of Charles Stanley, MD, Children's Hospital of Philadelphia.
 
 
 
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