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HNF1A Deficiency Impairs β-Cell Fate...

Gonzalez, Bryan Jose.

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HNF1A Deficiency Impairs β-Cell Fate, Granule Maturation and Function.

Record Type:	Electronic resources : Monograph/item
Title/Author:	HNF1A Deficiency Impairs β-Cell Fate, Granule Maturation and Function./
Author:	Gonzalez, Bryan Jose.
Published:	Ann Arbor : ProQuest Dissertations & Theses, : 2019,
Description:	175 p.
Notes:	Source: Dissertations Abstracts International, Volume: 80-12, Section: B.
Contained By:	Dissertations Abstracts International80-12B.
Subject:	Cellular biology. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=13885355
ISBN:	9781392182451

HNF1A Deficiency Impairs β-Cell Fate, Granule Maturation and Function.
Gonzalez, Bryan Jose.

HNF1A Deficiency Impairs β-Cell Fate, Granule Maturation and Function. - Ann Arbor : ProQuest Dissertations & Theses, 2019 - 175 p.

Source: Dissertations Abstracts International, Volume: 80-12, Section: B.

Thesis (Ph.D.)--Columbia University, 2019.

This item is not available from ProQuest Dissertations & Theses.

Mutations in HNF1A cause Maturity Onset Diabetes of the Young type 3, the second most frequent form of diabetes caused by single gene mutation. We generated human stem cell-derived pancreatic endocrine cells with clinically pathogenic mutations in HNF1A and show that HNF1A deficiency impairs endocrine cell fate, insulin granule maturation and the secretion of insulin in response to glucose. Single-cell RNA sequencing reveals that HNF1A orchestrates a network of genes involved in β-cell fate, granule maturation, glucose metabolism, calcium ion binding and hormone exocytosis. In both patients and stem cell-derived β-cells, HNF1A deficiency altered the stoichiometry of secreted insulin to c-peptide. Sulfonylurea, used in the treatment of these patients, restored both insulin secretion and stoichiometry. The uncoupling of insulin and c-peptide secretion as described here questions the common practice of using c-peptide as a proxy to evaluate β-cell function. We also demonstrate that correction of the HNF1A mutations restores function, providing a path to cell-based replacement therapy.

ISBN: 9781392182451Subjects--Topical Terms:

3172791
Cellular biology.
Subjects--Index Terms:

Beta-cells

HNF1A Deficiency Impairs β-Cell Fate, Granule Maturation and Function.
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245 1 0 $a HNF1A Deficiency Impairs β-Cell Fate, Granule Maturation and Function.
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300 $a 175 p.
500 $a Source: Dissertations Abstracts International, Volume: 80-12, Section: B.
500 $a Publisher info.: Dissertation/Thesis.
500 $a Advisor: Egli, Dieter;Leibel, Rudolph.
502 $a Thesis (Ph.D.)--Columbia University, 2019.
506 $a This item is not available from ProQuest Dissertations & Theses.
506 $a This item must not be sold to any third party vendors.
520 $a Mutations in HNF1A cause Maturity Onset Diabetes of the Young type 3, the second most frequent form of diabetes caused by single gene mutation. We generated human stem cell-derived pancreatic endocrine cells with clinically pathogenic mutations in HNF1A and show that HNF1A deficiency impairs endocrine cell fate, insulin granule maturation and the secretion of insulin in response to glucose. Single-cell RNA sequencing reveals that HNF1A orchestrates a network of genes involved in β-cell fate, granule maturation, glucose metabolism, calcium ion binding and hormone exocytosis. In both patients and stem cell-derived β-cells, HNF1A deficiency altered the stoichiometry of secreted insulin to c-peptide. Sulfonylurea, used in the treatment of these patients, restored both insulin secretion and stoichiometry. The uncoupling of insulin and c-peptide secretion as described here questions the common practice of using c-peptide as a proxy to evaluate β-cell function. We also demonstrate that correction of the HNF1A mutations restores function, providing a path to cell-based replacement therapy.
590 $a School code: 0054.
650 4 $a Cellular biology. $3 3172791
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653 $a HNF1A
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