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Phases of Metabolic and Soft Tissue Changes in Months Preceding a Diagnosis of Pancreatic Ductal Adenocarcinoma.
Gastroenterology 2019; 156(6):1742-1752G

Abstract

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+/LSLG12D P53flox/flox mice with PDACs, C57/BL6 (control) mice, and 5 patients and analyzed by histology and immunohistochemistry.

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.

Authors+Show Affiliations

Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.Department of Biochemistry and Molecular Biology, Mayo Clinic, Jacksonville, Florida.Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.Department of Biochemistry and Molecular Biology, Mayo Clinic, Jacksonville, Florida.Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.Department of Biochemistry and Molecular Biology, Mayo Clinic, Jacksonville, Florida.Department of Radiology Informatics, Mayo Clinic, Rochester, Minnesota.Department of Radiology Informatics, Mayo Clinic, Rochester, Minnesota.Division of Radiology, Mayo Clinic, Rochester, Minnesota.Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, Minnesota.Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota.Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota.Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.Department of Biochemistry and Molecular Biology, Mayo Clinic, Jacksonville, Florida. Electronic address: Mukhopadhyay.debabrata@mayo.edu.Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota. Electronic address: Chari.suresh@mayo.edu.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30677401

Citation

Sah, Raghuwansh P., et al. "Phases of Metabolic and Soft Tissue Changes in Months Preceding a Diagnosis of Pancreatic Ductal Adenocarcinoma." Gastroenterology, vol. 156, no. 6, 2019, pp. 1742-1752.
Sah RP, Sharma A, Nagpal S, et al. Phases of Metabolic and Soft Tissue Changes in Months Preceding a Diagnosis of Pancreatic Ductal Adenocarcinoma. Gastroenterology. 2019;156(6):1742-1752.
Sah, R. P., Sharma, A., Nagpal, S., Patlolla, S. H., Sharma, A., Kandlakunta, H., ... Chari, S. T. (2019). Phases of Metabolic and Soft Tissue Changes in Months Preceding a Diagnosis of Pancreatic Ductal Adenocarcinoma. Gastroenterology, 156(6), pp. 1742-1752. doi:10.1053/j.gastro.2019.01.039.
Sah RP, et al. Phases of Metabolic and Soft Tissue Changes in Months Preceding a Diagnosis of Pancreatic Ductal Adenocarcinoma. Gastroenterology. 2019;156(6):1742-1752. PubMed PMID: 30677401.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Phases of Metabolic and Soft Tissue Changes in Months Preceding a Diagnosis of Pancreatic Ductal Adenocarcinoma. AU - Sah,Raghuwansh P, AU - Sharma,Ayush, AU - Nagpal,Sajan, AU - Patlolla,Sri Harsha, AU - Sharma,Anil, AU - Kandlakunta,Harika, AU - Anani,Vincent, AU - Angom,Ramcharan Singh, AU - Kamboj,Amrit K, AU - Ahmed,Nazir, AU - Mohapatra,Sonmoon, AU - Vivekanandhan,Sneha, AU - Philbrick,Kenneth A, AU - Weston,Alexander, AU - Takahashi,Naoki, AU - Kirkland,James, AU - Javeed,Naureen, AU - Matveyenko,Aleksey, AU - Levy,Michael J, AU - Mukhopadhyay,Debabrata, AU - Chari,Suresh T, Y1 - 2019/01/22/ PY - 2018/06/07/received PY - 2018/12/13/revised PY - 2019/01/11/accepted PY - 2020/05/01/pmc-release PY - 2019/1/25/pubmed PY - 2019/5/14/medline PY - 2019/1/25/entrez KW - Asymptomatic KW - Carcinogenesis KW - Diabetes KW - Disease Progression SP - 1742 EP - 1752 JF - Gastroenterology JO - Gastroenterology VL - 156 IS - 6 N2 - 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+/LSLG12D P53flox/flox mice with PDACs, C57/BL6 (control) mice, and 5 patients and analyzed by histology and immunohistochemistry. 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. SN - 1528-0012 UR - https://www.unboundmedicine.com/medline/citation/30677401/Phases_of_Metabolic_and_Soft_Tissue_Changes_in_Months_Preceding_a_Diagnosis_of_Pancreatic_Ductal_Adenocarcinoma_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0016-5085(19)30101-5 DB - PRIME DP - Unbound Medicine ER -