Novel de novo mutation in sulfonylurea receptor 1 presenting as hyperinsulinism in infancy followed by overt diabetes in early adolescence

Maha Abdulhadi-Atwan, Jeremy D. Bushman, Sharona Tornovsky-Babaey, Avital Perry, Abdulsalam Abu-Libdeh, Benjamin Glaser, Show-Ling Shyng, David H. Zangen

Research output: Contribution to journalArticle

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Abstract

OBJECTIVE-Congenital hyperinsulinism, usually associated with severe neonatal hypoglycemia, may progress to diabetes, typically during the 4th decade of life in nonpancreatectomized patients. We aimed to genotype the ATP-sensitive K + channel in a 10.5-year-old girl presenting with overt diabetes following hyperinsulinism in infancy. RESEARCH DESIGN AND METHODS-A female aged 10.5 years presented with new-onset, antibody-negative diabetes (A1C 10.6%). She was born large for gestational age (5 kg) to a nondiabetic mother and developed frequent hypoglycemic episodes, which persisted until age 3 years and responded initially to intravenous glucose and later to oral sweets. Currently, she is fully pubertal and obese (BMI 30.2 kg/m 2), with a partially controlled convulsive disorder (since age 1 year) and poor school performance. Glucose levels were > 11.1 mmol/l throughout 72 h of continuous glucose monitoring, with low insulin secretion during intravenous glucose tolerance testing. KCNJ11 and ABCC8 mutation analysis was performed, and the mutation identified was characterized in COSm6 cells. RESULTS-A novel, de novo heterozygous ABCC8 sulfonylurea receptor (SUR)1 mutation (R370S) was identified in the patient's DNA but not in that of either parent. Cotransfection of Kir6.2 and mutant SUR1 demonstrate that the mutated protein is expressed efficiently at the cell surface but fails to respond to MgADP, resulting in minimal channel activity. Interestingly, the heterozygous channel (WT:R370S) responded well to glibenclamide, a finding that lead to the successful initiation of sulfonylurea therapy. CONCLUSIONS-This new ABCC8 mutation is associated with neonatal hyperinsulinism progressing within 10 years to insulinopenic diabetes. Consistent with in vitro findings, the patient responded to sulfonylurea treatment. The mechanism causing the relatively rapid loss in β-cell function is not clear, but it may involve mutation-induced increased β-cell apoptosis related to increased metabolic demand.

Original languageEnglish (US)
Pages (from-to)1935-1940
Number of pages6
JournalDiabetes
Volume57
Issue number7
DOIs
StatePublished - Jul 2008

Fingerprint

Sulfonylurea Receptors
Hyperinsulinism
Mutation
Congenital Hyperinsulinism
Glucose
Glyburide
Glucose Tolerance Test
Hypoglycemia
Hypoglycemic Agents
Adenosine Diphosphate
Gestational Age
Research Design
Adenosine Triphosphate
Genotype
Mothers
Insulin
Apoptosis
Antibodies
DNA
Therapeutics

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Abdulhadi-Atwan, M., Bushman, J. D., Tornovsky-Babaey, S., Perry, A., Abu-Libdeh, A., Glaser, B., ... Zangen, D. H. (2008). Novel de novo mutation in sulfonylurea receptor 1 presenting as hyperinsulinism in infancy followed by overt diabetes in early adolescence. Diabetes, 57(7), 1935-1940. https://doi.org/10.2337/db08-0159

Novel de novo mutation in sulfonylurea receptor 1 presenting as hyperinsulinism in infancy followed by overt diabetes in early adolescence. / Abdulhadi-Atwan, Maha; Bushman, Jeremy D.; Tornovsky-Babaey, Sharona; Perry, Avital; Abu-Libdeh, Abdulsalam; Glaser, Benjamin; Shyng, Show-Ling; Zangen, David H.

In: Diabetes, Vol. 57, No. 7, 07.2008, p. 1935-1940.

Research output: Contribution to journalArticle

Abdulhadi-Atwan, M, Bushman, JD, Tornovsky-Babaey, S, Perry, A, Abu-Libdeh, A, Glaser, B, Shyng, S-L & Zangen, DH 2008, 'Novel de novo mutation in sulfonylurea receptor 1 presenting as hyperinsulinism in infancy followed by overt diabetes in early adolescence', Diabetes, vol. 57, no. 7, pp. 1935-1940. https://doi.org/10.2337/db08-0159
Abdulhadi-Atwan M, Bushman JD, Tornovsky-Babaey S, Perry A, Abu-Libdeh A, Glaser B et al. Novel de novo mutation in sulfonylurea receptor 1 presenting as hyperinsulinism in infancy followed by overt diabetes in early adolescence. Diabetes. 2008 Jul;57(7):1935-1940. https://doi.org/10.2337/db08-0159
Abdulhadi-Atwan, Maha ; Bushman, Jeremy D. ; Tornovsky-Babaey, Sharona ; Perry, Avital ; Abu-Libdeh, Abdulsalam ; Glaser, Benjamin ; Shyng, Show-Ling ; Zangen, David H. / Novel de novo mutation in sulfonylurea receptor 1 presenting as hyperinsulinism in infancy followed by overt diabetes in early adolescence. In: Diabetes. 2008 ; Vol. 57, No. 7. pp. 1935-1940.
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abstract = "OBJECTIVE-Congenital hyperinsulinism, usually associated with severe neonatal hypoglycemia, may progress to diabetes, typically during the 4th decade of life in nonpancreatectomized patients. We aimed to genotype the ATP-sensitive K + channel in a 10.5-year-old girl presenting with overt diabetes following hyperinsulinism in infancy. RESEARCH DESIGN AND METHODS-A female aged 10.5 years presented with new-onset, antibody-negative diabetes (A1C 10.6{\%}). She was born large for gestational age (5 kg) to a nondiabetic mother and developed frequent hypoglycemic episodes, which persisted until age 3 years and responded initially to intravenous glucose and later to oral sweets. Currently, she is fully pubertal and obese (BMI 30.2 kg/m 2), with a partially controlled convulsive disorder (since age 1 year) and poor school performance. Glucose levels were > 11.1 mmol/l throughout 72 h of continuous glucose monitoring, with low insulin secretion during intravenous glucose tolerance testing. KCNJ11 and ABCC8 mutation analysis was performed, and the mutation identified was characterized in COSm6 cells. RESULTS-A novel, de novo heterozygous ABCC8 sulfonylurea receptor (SUR)1 mutation (R370S) was identified in the patient's DNA but not in that of either parent. Cotransfection of Kir6.2 and mutant SUR1 demonstrate that the mutated protein is expressed efficiently at the cell surface but fails to respond to MgADP, resulting in minimal channel activity. Interestingly, the heterozygous channel (WT:R370S) responded well to glibenclamide, a finding that lead to the successful initiation of sulfonylurea therapy. CONCLUSIONS-This new ABCC8 mutation is associated with neonatal hyperinsulinism progressing within 10 years to insulinopenic diabetes. Consistent with in vitro findings, the patient responded to sulfonylurea treatment. The mechanism causing the relatively rapid loss in β-cell function is not clear, but it may involve mutation-induced increased β-cell apoptosis related to increased metabolic demand.",
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AU - Perry, Avital

AU - Abu-Libdeh, Abdulsalam

AU - Glaser, Benjamin

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AU - Zangen, David H.

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N2 - OBJECTIVE-Congenital hyperinsulinism, usually associated with severe neonatal hypoglycemia, may progress to diabetes, typically during the 4th decade of life in nonpancreatectomized patients. We aimed to genotype the ATP-sensitive K + channel in a 10.5-year-old girl presenting with overt diabetes following hyperinsulinism in infancy. RESEARCH DESIGN AND METHODS-A female aged 10.5 years presented with new-onset, antibody-negative diabetes (A1C 10.6%). She was born large for gestational age (5 kg) to a nondiabetic mother and developed frequent hypoglycemic episodes, which persisted until age 3 years and responded initially to intravenous glucose and later to oral sweets. Currently, she is fully pubertal and obese (BMI 30.2 kg/m 2), with a partially controlled convulsive disorder (since age 1 year) and poor school performance. Glucose levels were > 11.1 mmol/l throughout 72 h of continuous glucose monitoring, with low insulin secretion during intravenous glucose tolerance testing. KCNJ11 and ABCC8 mutation analysis was performed, and the mutation identified was characterized in COSm6 cells. RESULTS-A novel, de novo heterozygous ABCC8 sulfonylurea receptor (SUR)1 mutation (R370S) was identified in the patient's DNA but not in that of either parent. Cotransfection of Kir6.2 and mutant SUR1 demonstrate that the mutated protein is expressed efficiently at the cell surface but fails to respond to MgADP, resulting in minimal channel activity. Interestingly, the heterozygous channel (WT:R370S) responded well to glibenclamide, a finding that lead to the successful initiation of sulfonylurea therapy. CONCLUSIONS-This new ABCC8 mutation is associated with neonatal hyperinsulinism progressing within 10 years to insulinopenic diabetes. Consistent with in vitro findings, the patient responded to sulfonylurea treatment. The mechanism causing the relatively rapid loss in β-cell function is not clear, but it may involve mutation-induced increased β-cell apoptosis related to increased metabolic demand.

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