Phases of Metabolic and Soft Tissue Changes in Months Preceding a Diagnosis of Pancreatic Ductal Adenocarcinoma.
Adipocytes
/ metabolism
Animals
Blood Glucose
/ metabolism
Body Temperature
Body Weight
Cachexia
/ etiology
Carcinoma, Pancreatic Ductal
/ blood
Case-Control Studies
Cells, Cultured
Cholesterol, HDL
/ blood
Cholesterol, LDL
/ blood
Exosomes
Humans
Hyperglycemia
/ blood
Intra-Abdominal Fat
/ diagnostic imaging
Mice
Middle Aged
Muscle, Skeletal
/ diagnostic imaging
Pancreatic Neoplasms
/ blood
RNA, Messenger
/ metabolism
Retrospective Studies
Subcutaneous Fat, Abdominal
/ diagnostic imaging
Time Factors
Tomography, X-Ray Computed
Triglycerides
/ blood
Uncoupling Protein 1
/ genetics
Up-Regulation
Asymptomatic
Carcinogenesis
Diabetes
Disease Progression
Journal
Gastroenterology
ISSN: 1528-0012
Titre abrégé: Gastroenterology
Pays: United States
ID NLM: 0374630
Informations de publication
Date de publication:
05 2019
05 2019
Historique:
received:
07
06
2018
revised:
13
12
2018
accepted:
11
01
2019
pubmed:
25
1
2019
medline:
14
5
2019
entrez:
25
1
2019
Statut:
ppublish
Résumé
Identifying metabolic abnormalities that occur before pancreatic ductal adenocarcinoma (PDAC) diagnosis could increase chances for early detection. We collected data on changes in metabolic parameters (glucose, serum lipids, triglycerides; total, low-density, and high-density cholesterol; and total body weight) and soft tissues (abdominal subcutaneous fat [SAT], adipose tissue, visceral adipose tissue [VAT], and muscle) from patients 5 years before the received a diagnosis of PDAC. We collected data from 219 patients with a diagnosis of PDAC (patients) and 657 healthy individuals (controls) from the Rochester Epidemiology Project, from 2000 through 2015. We compared metabolic profiles of patients with those of age- and sex-matched controls, constructing temporal profiles of fasting blood glucose, serum lipids including triglycerides, cholesterol profiles, and body weight and temperature for 60 months before the diagnosis of PDAC (index date). To construct the temporal profile of soft tissue changes, we collected computed tomography scans from 68 patients, comparing baseline (>18 months before diagnosis) areas of SAT, VAT, and muscle at L2/L3 vertebra with those of later scans until time of diagnosis. SAT and VAT, isolated from healthy individuals, were exposed to exosomes isolated from PDAC cell lines and analyzed by RNA sequencing. SAT was collected from KRAS There were no significant differences in metabolic or soft tissue features of patients vs controls until 30 months before PDAC diagnosis. In the 30 to 18 months before PDAC diagnosis (phase 1, hyperglycemia), a significant proportion of patients developed hyperglycemia, compared with controls, without soft tissue changes. In the 18 to 6 months before PDAC diagnosis (phase 2, pre-cachexia), patients had significant increases in hyperglycemia and decreases in serum lipids, body weight, and SAT, with preserved VAT and muscle. In the 6 to 0 months before PDAC diagnosis (phase 3, cachexia), a significant proportion of patients had hyperglycemia compared with controls, and patients had significant reductions in all serum lipids, SAT, VAT, and muscle. We believe the patients had browning of SAT, based on increases in body temperature, starting 18 months before PDAC diagnosis. We observed expression of uncoupling protein 1 (UCP1) in SAT exposed to PDAC exosomes, SAT from mice with PDACs, and SAT from all 5 patients but only 1 of 4 controls. We identified 3 phases of metabolic and soft tissue changes that precede a diagnosis of PDAC. Loss of SAT starts 18 months before PDAC identification, and is likely due to browning. Overexpression of UCP1 in SAT might be a biomarker of early-stage PDAC, but further studies are needed.
Sections du résumé
BACKGROUND & AIMS
Identifying metabolic abnormalities that occur before pancreatic ductal adenocarcinoma (PDAC) diagnosis could increase chances for early detection. We collected data on changes in metabolic parameters (glucose, serum lipids, triglycerides; total, low-density, and high-density cholesterol; and total body weight) and soft tissues (abdominal subcutaneous fat [SAT], adipose tissue, visceral adipose tissue [VAT], and muscle) from patients 5 years before the received a diagnosis of PDAC.
METHODS
We collected data from 219 patients with a diagnosis of PDAC (patients) and 657 healthy individuals (controls) from the Rochester Epidemiology Project, from 2000 through 2015. We compared metabolic profiles of patients with those of age- and sex-matched controls, constructing temporal profiles of fasting blood glucose, serum lipids including triglycerides, cholesterol profiles, and body weight and temperature for 60 months before the diagnosis of PDAC (index date). To construct the temporal profile of soft tissue changes, we collected computed tomography scans from 68 patients, comparing baseline (>18 months before diagnosis) areas of SAT, VAT, and muscle at L2/L3 vertebra with those of later scans until time of diagnosis. SAT and VAT, isolated from healthy individuals, were exposed to exosomes isolated from PDAC cell lines and analyzed by RNA sequencing. SAT was collected from KRAS
RESULTS
There were no significant differences in metabolic or soft tissue features of patients vs controls until 30 months before PDAC diagnosis. In the 30 to 18 months before PDAC diagnosis (phase 1, hyperglycemia), a significant proportion of patients developed hyperglycemia, compared with controls, without soft tissue changes. In the 18 to 6 months before PDAC diagnosis (phase 2, pre-cachexia), patients had significant increases in hyperglycemia and decreases in serum lipids, body weight, and SAT, with preserved VAT and muscle. In the 6 to 0 months before PDAC diagnosis (phase 3, cachexia), a significant proportion of patients had hyperglycemia compared with controls, and patients had significant reductions in all serum lipids, SAT, VAT, and muscle. We believe the patients had browning of SAT, based on increases in body temperature, starting 18 months before PDAC diagnosis. We observed expression of uncoupling protein 1 (UCP1) in SAT exposed to PDAC exosomes, SAT from mice with PDACs, and SAT from all 5 patients but only 1 of 4 controls.
CONCLUSIONS
We identified 3 phases of metabolic and soft tissue changes that precede a diagnosis of PDAC. Loss of SAT starts 18 months before PDAC identification, and is likely due to browning. Overexpression of UCP1 in SAT might be a biomarker of early-stage PDAC, but further studies are needed.
Identifiants
pubmed: 30677401
pii: S0016-5085(19)30101-5
doi: 10.1053/j.gastro.2019.01.039
pmc: PMC6475474
mid: NIHMS1519250
pii:
doi:
Substances chimiques
Blood Glucose
0
Cholesterol, HDL
0
Cholesterol, LDL
0
RNA, Messenger
0
Triglycerides
0
Uncoupling Protein 1
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1742-1752Subventions
Organisme : NIDDK NIH HHS
ID : U01 DK108288
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG034676
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA150190
Pays : United States
Organisme : NCI NIH HHS
ID : R29 CA078383
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA078383
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.
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