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Pancreatic Histopathology of Human Monogenic Diabetes Due to Causal Variants in KCNJ11, HNF1A, GATA6, and LMNA

Monogenic diabetes is thought to account for 2% of all diabetes cases, but most patients receive misdiagnoses of type 1 or type 2 diabetes. To date, little is known about the histopathological features of pancreata from patients with monogenic diabetes. Retrospective study of the JDRF Network for Pa... Full description

Journal Title: The journal of clinical endocrinology and metabolism 2018, Vol.103 (1), p.35-45
Main Author: Sanyoura, May
Other Authors: Jacobsen, Laura , Carmody, David , del Gaudio, Daniela , Alkorta-Aranburu, Gorka , Arndt, Kelly , Hu, Ying , Kobiernicki, Frances , Kusmartseva, Irina , Atkinson, Mark A , Philipson, Louis H , Schatz, Desmond , Campbell-Thompson, Martha , Greeley, Siri Atma W
Format: Electronic Article Electronic Article
Language: English
Subjects:
Publisher: United States: Copyright Oxford University Press
ID: ISSN: 0021-972X
Link: https://www.ncbi.nlm.nih.gov/pubmed/28938416
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recordid: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_5761488
title: Pancreatic Histopathology of Human Monogenic Diabetes Due to Causal Variants in KCNJ11, HNF1A, GATA6, and LMNA
format: Article
creator:
  • Sanyoura, May
  • Jacobsen, Laura
  • Carmody, David
  • del Gaudio, Daniela
  • Alkorta-Aranburu, Gorka
  • Arndt, Kelly
  • Hu, Ying
  • Kobiernicki, Frances
  • Kusmartseva, Irina
  • Atkinson, Mark A
  • Philipson, Louis H
  • Schatz, Desmond
  • Campbell-Thompson, Martha
  • Greeley, Siri Atma W
subjects:
  • Abridged Index Medicus
  • Adolescent
  • Adult
  • Amyloidosis
  • Atrophy
  • Autoantibodies
  • Beta cells
  • Body mass index
  • Child
  • Clinical Research Articles
  • Clinical s
  • Diabetes
  • Diabetes mellitus (insulin dependent)
  • Diabetes mellitus (non-insulin dependent)
  • Diabetes Mellitus - genetics
  • Diabetes Mellitus - pathology
  • Editor's Choice
  • endocrine system
  • Female
  • GATA6 Transcription Factor - genetics
  • Genetic screening
  • Genetic Testing
  • Genetic variance
  • Genetic Variation
  • Hepatocyte Nuclear Factor 1-alpha - genetics
  • Histology
  • Histopathology
  • Humans
  • Insulin
  • Insulitis
  • Lamin Type A - genetics
  • Male
  • metabolic diseases
  • nutritional
  • Pancreas
  • Pancreas - metabolism
  • Pancreas - pathology
  • Potassium Channels, Inwardly Rectifying - genetics
  • Prognosis
  • Retrospective Studies
ispartof: The journal of clinical endocrinology and metabolism, 2018, Vol.103 (1), p.35-45
description: Monogenic diabetes is thought to account for 2% of all diabetes cases, but most patients receive misdiagnoses of type 1 or type 2 diabetes. To date, little is known about the histopathological features of pancreata from patients with monogenic diabetes. Retrospective study of the JDRF Network for Pancreatic Organ Donors with Diabetes biorepository to identify possible cases of monogenic diabetes and to compare effects of genetic variants on pancreas histology. We selected cases of diabetes for genetic testing on the basis of criteria that included young age at diagnosis, low body mass index, negative autoantibody status, and/or detectable C-peptide level. Samples underwent next-generation-targeted sequencing of 140 diabetes/diabetes-related genes. Pancreas weight and histopathology were reviewed. Forty-one of 140 cases of diabetes met the clinical inclusion criteria, with 38 DNA samples available. Genetic variants of probable clinical significance were found in four cases: one each in KCNJ11, HNF1A, GATA6, and LMNA. The KCNJ11 and HNF1A samples had significantly decreased pancreas weight and insulin mass similar to that of type 1 diabetes but had no insulitis. The GATA6 sample had severe pancreatic atrophy but with abundant β cells and severe amyloidosis similar to type 2 diabetes. The LMNA sample had preserved pancreas weight and insulin mass but abnormal islet architecture and exocrine fatty infiltrates. Four cases of diabetes had putative causal variants in monogenic diabetes genes. This study provides further insight into the heterogeneous nature of monogenic diabetes cases that exhibited clinical and pathophysiological features that overlap with type 1/type 2 diabetes.
language: eng
source:
identifier: ISSN: 0021-972X
fulltext: no_fulltext
issn:
  • 0021-972X
  • 1945-7197
url: Link


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titlePancreatic Histopathology of Human Monogenic Diabetes Due to Causal Variants in KCNJ11, HNF1A, GATA6, and LMNA
creatorSanyoura, May ; Jacobsen, Laura ; Carmody, David ; del Gaudio, Daniela ; Alkorta-Aranburu, Gorka ; Arndt, Kelly ; Hu, Ying ; Kobiernicki, Frances ; Kusmartseva, Irina ; Atkinson, Mark A ; Philipson, Louis H ; Schatz, Desmond ; Campbell-Thompson, Martha ; Greeley, Siri Atma W
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descriptionMonogenic diabetes is thought to account for 2% of all diabetes cases, but most patients receive misdiagnoses of type 1 or type 2 diabetes. To date, little is known about the histopathological features of pancreata from patients with monogenic diabetes. Retrospective study of the JDRF Network for Pancreatic Organ Donors with Diabetes biorepository to identify possible cases of monogenic diabetes and to compare effects of genetic variants on pancreas histology. We selected cases of diabetes for genetic testing on the basis of criteria that included young age at diagnosis, low body mass index, negative autoantibody status, and/or detectable C-peptide level. Samples underwent next-generation-targeted sequencing of 140 diabetes/diabetes-related genes. Pancreas weight and histopathology were reviewed. Forty-one of 140 cases of diabetes met the clinical inclusion criteria, with 38 DNA samples available. Genetic variants of probable clinical significance were found in four cases: one each in KCNJ11, HNF1A, GATA6, and LMNA. The KCNJ11 and HNF1A samples had significantly decreased pancreas weight and insulin mass similar to that of type 1 diabetes but had no insulitis. The GATA6 sample had severe pancreatic atrophy but with abundant β cells and severe amyloidosis similar to type 2 diabetes. The LMNA sample had preserved pancreas weight and insulin mass but abnormal islet architecture and exocrine fatty infiltrates. Four cases of diabetes had putative causal variants in monogenic diabetes genes. This study provides further insight into the heterogeneous nature of monogenic diabetes cases that exhibited clinical and pathophysiological features that overlap with type 1/type 2 diabetes.
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subjectAbridged Index Medicus ; Adolescent ; Adult ; Amyloidosis ; Atrophy ; Autoantibodies ; Beta cells ; Body mass index ; Child ; Clinical Research Articles ; Clinical s ; Diabetes ; Diabetes mellitus (insulin dependent) ; Diabetes mellitus (non-insulin dependent) ; Diabetes Mellitus - genetics ; Diabetes Mellitus - pathology ; Editor's Choice ; endocrine system ; Female ; GATA6 Transcription Factor - genetics ; Genetic screening ; Genetic Testing ; Genetic variance ; Genetic Variation ; Hepatocyte Nuclear Factor 1-alpha - genetics ; Histology ; Histopathology ; Humans ; Insulin ; Insulitis ; Lamin Type A - genetics ; Male ; metabolic diseases ; nutritional ; Pancreas ; Pancreas - metabolism ; Pancreas - pathology ; Potassium Channels, Inwardly Rectifying - genetics ; Prognosis ; Retrospective Studies
ispartofThe journal of clinical endocrinology and metabolism, 2018, Vol.103 (1), p.35-45
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0Copyright © Oxford University Press 2015
1Copyright © 2017 Endocrine Society
2Copyright © 2018 Endocrine Society
3Copyright © 2018 Endocrine Society 2018
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2Carmody, David
3del Gaudio, Daniela
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5Arndt, Kelly
6Hu, Ying
7Kobiernicki, Frances
8Kusmartseva, Irina
9Atkinson, Mark A
10Philipson, Louis H
11Schatz, Desmond
12Campbell-Thompson, Martha
13Greeley, Siri Atma W
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1The journal of clinical endocrinology and metabolism
addtitleJ Clin Endocrinol Metab
descriptionMonogenic diabetes is thought to account for 2% of all diabetes cases, but most patients receive misdiagnoses of type 1 or type 2 diabetes. To date, little is known about the histopathological features of pancreata from patients with monogenic diabetes. Retrospective study of the JDRF Network for Pancreatic Organ Donors with Diabetes biorepository to identify possible cases of monogenic diabetes and to compare effects of genetic variants on pancreas histology. We selected cases of diabetes for genetic testing on the basis of criteria that included young age at diagnosis, low body mass index, negative autoantibody status, and/or detectable C-peptide level. Samples underwent next-generation-targeted sequencing of 140 diabetes/diabetes-related genes. Pancreas weight and histopathology were reviewed. Forty-one of 140 cases of diabetes met the clinical inclusion criteria, with 38 DNA samples available. Genetic variants of probable clinical significance were found in four cases: one each in KCNJ11, HNF1A, GATA6, and LMNA. The KCNJ11 and HNF1A samples had significantly decreased pancreas weight and insulin mass similar to that of type 1 diabetes but had no insulitis. The GATA6 sample had severe pancreatic atrophy but with abundant β cells and severe amyloidosis similar to type 2 diabetes. The LMNA sample had preserved pancreas weight and insulin mass but abnormal islet architecture and exocrine fatty infiltrates. Four cases of diabetes had putative causal variants in monogenic diabetes genes. This study provides further insight into the heterogeneous nature of monogenic diabetes cases that exhibited clinical and pathophysiological features that overlap with type 1/type 2 diabetes.
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1Adolescent
2Adult
3Amyloidosis
4Atrophy
5Autoantibodies
6Beta cells
7Body mass index
8Child
9Clinical Research Articles
10Clinical s
11Diabetes
12Diabetes mellitus (insulin dependent)
13Diabetes mellitus (non-insulin dependent)
14Diabetes Mellitus - genetics
15Diabetes Mellitus - pathology
16Editor's Choice
17endocrine system
18Female
19GATA6 Transcription Factor - genetics
20Genetic screening
21Genetic Testing
22Genetic variance
23Genetic Variation
24Hepatocyte Nuclear Factor 1-alpha - genetics
25Histology
26Histopathology
27Humans
28Insulin
29Insulitis
30Lamin Type A - genetics
31Male
32metabolic diseases
33nutritional
34Pancreas
35Pancreas - metabolism
36Pancreas - pathology
37Potassium Channels, Inwardly Rectifying - genetics
38Prognosis
39Retrospective Studies
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6Hu, Ying
7Kobiernicki, Frances
8Kusmartseva, Irina
9Atkinson, Mark A
10Philipson, Louis H
11Schatz, Desmond
12Campbell-Thompson, Martha
13Greeley, Siri Atma W
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titlePancreatic Histopathology of Human Monogenic Diabetes Due to Causal Variants in KCNJ11, HNF1A, GATA6, and LMNA
authorSanyoura, May ; Jacobsen, Laura ; Carmody, David ; del Gaudio, Daniela ; Alkorta-Aranburu, Gorka ; Arndt, Kelly ; Hu, Ying ; Kobiernicki, Frances ; Kusmartseva, Irina ; Atkinson, Mark A ; Philipson, Louis H ; Schatz, Desmond ; Campbell-Thompson, Martha ; Greeley, Siri Atma W
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0Abridged Index Medicus
1Adolescent
2Adult
3Amyloidosis
4Atrophy
5Autoantibodies
6Beta cells
7Body mass index
8Child
9Clinical Research Articles
10Clinical s
11Diabetes
12Diabetes mellitus (insulin dependent)
13Diabetes mellitus (non-insulin dependent)
14Diabetes Mellitus - genetics
15Diabetes Mellitus - pathology
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17endocrine system
18Female
19GATA6 Transcription Factor - genetics
20Genetic screening
21Genetic Testing
22Genetic variance
23Genetic Variation
24Hepatocyte Nuclear Factor 1-alpha - genetics
25Histology
26Histopathology
27Humans
28Insulin
29Insulitis
30Lamin Type A - genetics
31Male
32metabolic diseases
33nutritional
34Pancreas
35Pancreas - metabolism
36Pancreas - pathology
37Potassium Channels, Inwardly Rectifying - genetics
38Prognosis
39Retrospective Studies
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7Kobiernicki, Frances
8Kusmartseva, Irina
9Atkinson, Mark A
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8Kusmartseva, Irina
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10Philipson, Louis H
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1These authors are co-first authors who contributed equally to this work.
abstractMonogenic diabetes is thought to account for 2% of all diabetes cases, but most patients receive misdiagnoses of type 1 or type 2 diabetes. To date, little is known about the histopathological features of pancreata from patients with monogenic diabetes. Retrospective study of the JDRF Network for Pancreatic Organ Donors with Diabetes biorepository to identify possible cases of monogenic diabetes and to compare effects of genetic variants on pancreas histology. We selected cases of diabetes for genetic testing on the basis of criteria that included young age at diagnosis, low body mass index, negative autoantibody status, and/or detectable C-peptide level. Samples underwent next-generation-targeted sequencing of 140 diabetes/diabetes-related genes. Pancreas weight and histopathology were reviewed. Forty-one of 140 cases of diabetes met the clinical inclusion criteria, with 38 DNA samples available. Genetic variants of probable clinical significance were found in four cases: one each in KCNJ11, HNF1A, GATA6, and LMNA. The KCNJ11 and HNF1A samples had significantly decreased pancreas weight and insulin mass similar to that of type 1 diabetes but had no insulitis. The GATA6 sample had severe pancreatic atrophy but with abundant β cells and severe amyloidosis similar to type 2 diabetes. The LMNA sample had preserved pancreas weight and insulin mass but abnormal islet architecture and exocrine fatty infiltrates. Four cases of diabetes had putative causal variants in monogenic diabetes genes. This study provides further insight into the heterogeneous nature of monogenic diabetes cases that exhibited clinical and pathophysiological features that overlap with type 1/type 2 diabetes.
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pmid28938416
doi10.1210/jc.2017-01159
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