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Colorectal cancer and surgery: Insights into insulin resistance and inflammatory markers
Örebro University, School of Medical Sciences.
2024 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The art of surgery has progressively extended from the realm of anatomy to encompass physiology and beyond, in search of further refinement and optimal recovery. Integral to this is a deeper understanding of the body’s essential metabolic and inflammatory responses to surgical trauma.

This thesis aims to provide insights into the intricate interplay between insulin resistance, inflammation and surgical interventions in colorectal cancer patients, as each has an influence on postoperative recovery. Particular emphasis is placed on the role of inflammasomes – central mediators of the innate immune response, adept at detecting and responding to a diverse range of triggers, yet insufficiently explored in these specific contexts.

Study I is a comparative analysis of the hyperinsulinemic–euglycaemic clamp and homeostatic model assessment (HOMA) in determining postoperative insulin resistance in 113 patients undergoing various elective surgeries. The findings establish the clamp as the accurate method, detecting key physiological distinctions missed by HOMA.

Study II, an exploratory case–control study, assesses insulin sensitivity and inflammatory markers in 20 colorectal cancer patients compared to 10 matched healthy controls. Results indicate insulin resistance, reduced inflammasome activity in circulating immune cells and elevated systemic IL-1β and IL-6 levels in patients.

Study III, a pilot exploratory study of 17 patients from Study II, assesses the impact of surgical technique, open versus minimally invasive surgery, on postoperative insulin resistance and inflammation in colorectal cancer resections. It indicates a differential inflammatory response with higher levels in open surgeries, yet a consistent degree of insulin resistance across both surgical techniques.

Study IV explores the perioperative temporal sequencing of inflammation and inflammasome action in 18 patients from Study II undergoing elective colorectal cancer resections. It points to a more immediate and pronounced inflammatory response in open surgery compared to minimally invasive surgery, though both techniques show reduced intraoperative caspase-1 activity.

In conclusion, the hyperinsulinemic euglycaemic clamp is the accurate method in determinations of postoperative insulin resistance. Patients with colorectal cancer, in comparison to matched healthy controls, exhibit insulin resistance and higher levels of inflammation, but decreased inflammasome (caspase-1) activity in circulating immune cells. Finally, colorectal cancer resections induce both insulin resistance and inflammation; however, the surgical technique utilized only significantly affects the latter, with generally higher inflammatory / inflammasome responses in open surgery.

Place, publisher, year, edition, pages
Örebro: Örebro University , 2024. , p. 68
Series
Örebro Studies in Medicine, ISSN 1652-4063 ; 287
National Category
Surgery
Identifiers
URN: urn:nbn:se:oru:diva-110586ISBN: 9789175295398 (print)ISBN: 9789175295404 (electronic)OAI: oai:DiVA.org:oru-110586DiVA, id: diva2:1824812
Public defence
2024-03-15, Örebro universitet, Campus USÖ, X4425, Södra Grev Rosengatan 32, Örebro, 13:00 (English)
Opponent
Supervisors
Available from: 2024-01-08 Created: 2024-01-08 Last updated: 2024-03-04Bibliographically approved
List of papers
1. Determination of insulin resistance in surgery: the choice of method is crucial
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2015 (English)In: Clinical Nutrition, ISSN 0261-5614, E-ISSN 1532-1983, Vol. 34, no 1, p. 123-128Article in journal (Refereed) Published
Abstract [en]

BACKGROUND & AIMS: In elective surgery, postoperative hyperglycaemia and insulin resistance are independent risk factors for complications. Since the simpler HOMA method has been used as an alternative to the hyperinsulinemic normoglycemic clamp in studies of surgery induced insulin resistance, we compared the two methods in patients undergoing elective surgery.

METHODS: Data from 113 non-diabetic patients undergoing elective surgery were used. Insulin sensitivity, both before and after surgery, was quantified by the clamp and HOMA. Pre- and postoperatively, the results of the clamp were compared to HOMA using regression- and correlation analysis. Degree of agreement between the methods was studied using weighted linear kappa and the Bland-Altman test.

RESULTS: Both the clamp and HOMA recorded a mean relative reduction in insulin sensitivity of 39 ± 24% and 39 ± 61% respectively after surgery; with significant correlations (p < 0.01) for pre- and post-operative measures as well as for relative changes. However r(2) values were low: 0.04, 0.07 and 0.03 respectively. The degree of agreement for the relative change in insulin sensitivity using the Bland-Altman test gave a mean of difference 0% but "limits of agreement" (±2SD) was ±125%. This poor inter-method agreement was consolidated by a weighted linear kappa value of 0.18.

CONCLUSION: While the hyperinsulinemic euglycemic clamp measures the postoperative changes in insulin sensitivity, HOMA measures something different. Data using the HOMA method must therefore be interpreted cautiously and is not interchangeable with data obtained from the clamp.

Place, publisher, year, edition, pages
Churchill Livingstone, 2015
Keywords
Glucose, Glucose clamp, HOMA, Insulin, Insulin resistance, Surgery
National Category
Nutrition and Dietetics
Research subject
Nutrition
Identifiers
urn:nbn:se:oru:diva-40276 (URN)10.1016/j.clnu.2014.02.002 (DOI)000349574500020 ()24581942 (PubMedID)2-s2.0-84921433767 (Scopus ID)
Available from: 2015-01-08 Created: 2015-01-08 Last updated: 2024-03-04Bibliographically approved
2. Altered insulin sensitivity and immune function in patients with colorectal cancer
Open this publication in new window or tab >>Altered insulin sensitivity and immune function in patients with colorectal cancer
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2023 (English)In: Clinical Nutrition ESPEN, E-ISSN 2405-4577, Vol. 58, p. 193-200Article in journal (Refereed) Published
Abstract [en]

Background & aims: Insulin resistance and chronic inflammation have been reported in patients with cancer. However, many of the underlying mechanisms and associations are yet to be unveiled. We examined both the level of insulin sensitivity and markers of inflammation in patients with colorectal cancer for comparison to controls.

Methods: Clinical exploratory study of patients with colorectal cancer (n = 20) and matched controls (n = 10). Insulin sensitivity was quantified using the hyperinsulinemic normoglycemic clamp and blood samples were taken for quantification of several key, both intra- and extracellular, inflammatory markers. We analysed the differences in these parameters between the two groups.

Results: Patients exhibited both insulin resistance (M-value, patients median (Mdn) 4.57 interquartile range (IQR) 3.49-5.75; controls Mdn 5.79 (IQR 5.20-6.81), p = 0.049), as well as increased plasma levels of the pro-inflammatory cytokines IL-1b(patients Mdn 0.48 (IQR 0.33-0.58); controls Mdn 0.36 (IQR 0.29-0.42), p = 0.02) and IL-6 (patients Mdn 3.21 (IQR 2.31-4.93); controls Mdn 2.16 (IQR 1.50-2.65), p = 0.02). The latter is present despite an almost two to three fold decrease (p < 0.01) in caspase-1 activity, a facilitating enzyme of IL-1b production, within circulating immune cells.

Conclusion: Patients with colorectal cancer displayed insulin resistance and higher levels of plasma IL-1b and IL-6, in comparison to matched healthy controls. The finding of a seemingly disconnect between inflammasome (caspase-1) activity and plasma levels of key pro-inflammatory cytokines in cancer patients may suggest that, in parallel to dysregulated immune cells, tumour-driven inflammatory pathways also are in effect.

Place, publisher, year, edition, pages
Elsevier, 2023
Keywords
Insulin resistance, Inflammation, Inflammasome, Cytokines, Cancer, Gastrointestinal adenocarcinoma
National Category
Cancer and Oncology Nutrition and Dietetics
Identifiers
urn:nbn:se:oru:diva-109845 (URN)10.1016/j.clnesp.2023.09.917 (DOI)001096215500001 ()38057005 (PubMedID)2-s2.0-85173178914 (Scopus ID)
Funder
Knowledge Foundation, 202100-2924Nyckelfonden
Available from: 2023-11-23 Created: 2023-11-23 Last updated: 2024-03-04Bibliographically approved
3. Insulin resistance and inflammation in open versus minimally invasive colorectal cancer surgery in ERAS
Open this publication in new window or tab >>Insulin resistance and inflammation in open versus minimally invasive colorectal cancer surgery in ERAS
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(English)Manuscript (preprint) (Other academic)
National Category
Surgery
Identifiers
urn:nbn:se:oru:diva-111666 (URN)
Available from: 2024-02-19 Created: 2024-02-19 Last updated: 2024-03-04Bibliographically approved
4. Dynamics of inflammation and inflammasome activation in open versus minimally invasive colorectal surgery for cancer
Open this publication in new window or tab >>Dynamics of inflammation and inflammasome activation in open versus minimally invasive colorectal surgery for cancer
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(English)Manuscript (preprint) (Other academic)
National Category
Surgery
Identifiers
urn:nbn:se:oru:diva-111667 (URN)
Available from: 2024-02-19 Created: 2024-02-19 Last updated: 2024-03-04Bibliographically approved

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