Human islets expressing HNF1A variant have defective ß cell transcriptional regulatory networks.
J Clin Invest
; 129(1): 246-251, 2019 01 02.
Article
em En
| MEDLINE
| ID: mdl-30507613
ABSTRACT
Using an integrated approach to characterize the pancreatic tissue and isolated islets from a 33-year-old with 17 years of type 1 diabetes (T1D), we found that donor islets contained ß cells without insulitis and lacked glucose-stimulated insulin secretion despite a normal insulin response to cAMP-evoked stimulation. With these unexpected findings for T1D, we sequenced the donor DNA and found a pathogenic heterozygous variant in the gene encoding hepatocyte nuclear factor-1α (HNF1A). In one of the first studies of human pancreatic islets with a disease-causing HNF1A variant associated with the most common form of monogenic diabetes, we found that HNF1A dysfunction leads to insulin-insufficient diabetes reminiscent of T1D by impacting the regulatory processes critical for glucose-stimulated insulin secretion and suggest a rationale for a therapeutic alternative to current treatment.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Transcrição Gênica
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Variação Genética
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Diabetes Mellitus Tipo 1
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Células Secretoras de Insulina
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Fator 1-alfa Nuclear de Hepatócito
Limite:
Adolescent
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Adult
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Humans
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Male
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article