The mechanistic basis of metabolic response to surgery and postoperative insulin resistance in patients having abdominal surgery

Varadhan, Krishna Kumar (2015) The mechanistic basis of metabolic response to surgery and postoperative insulin resistance in patients having abdominal surgery. PhD thesis, University of Nottingham.

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Abstract

Postoperative insulin resistance (POIR) is a hallmark feature in patients having major abdominal surgery. Surgical stress may induce changes in metabolic pathways that perturb glucose homeostasis, resulting in stress hyperglycaemia. The studies described in the present thesis set out to examine the evidence behind (1) the ‘Enhanced Recovery After Surgery’ pathway (2) preoperative carbohydrate drinks (CHO), in attenuating the surgical stress response and (3) to investigate the mechanistic basis of metabolic response to surgery and the development of postoperative insulin resistance in patients having major abdominal surgery.

Meta-analysis of randomised studies in patients having major abdominal surgery showed that ERAS pathway was associated with a significant reduction in length of hospital stay and postoperative complications. Meta-analysis of randomised studies using CHO was also associated with reduced length of stay and decreased POIR in support of reduced fasting times and CHO, before surgery.

The study in patients having major abdominal surgery showed that surgical trauma was associated with increased skeletal muscle interleukin-6 and pyruvate dehydrogenase kinase isoform-4 (PDK4) mRNA and protein expression. Increased PDK4 was associated with a concomitant reduction in pyruvate dehydrogenase complex (PDC) activity that controls the rate of muscle carbohydrate oxidation in mitochondria, and contributed to impaired glucose tolerance and decreased mitochondrial ATP production postoperatively.

One hypothesis is that by maximising the contribution of carbohydrate derived oxidative ATP regeneration by activating the PDC with the synthetic PDK4 inhibitor dichloroacetate (DCA) and/or by increasing muscle glucose uptake using CHO may reverse the changes in carbohydrate oxidation seen postoperatively. The results from the study showed that administration of either CHO or CHO with DCA attenuates the impairment of CHO oxidation and the development of POIR, induced by surgical stress. Furthermore, DCA increased mitochondrial CHO oxidation above that achieved by CHO alone, which waned by 48 hours after surgery.

Item Type: Thesis (University of Nottingham only) (PhD)
Supervisors: Lobo, D.N.
Greenhaff, P.L.
Keywords: Abdominal surgery; Insulin resistance
Subjects: W Medicine and related subjects (NLM Classification) > WI Digestive system
Faculties/Schools: UK Campuses > Faculty of Medicine and Health Sciences > School of Medicine
Item ID: 29095
Depositing User: Varadhan, Krishna
Date Deposited: 06 Oct 2015 08:56
Last Modified: 13 Sep 2016 17:44
URI: http://eprints.nottingham.ac.uk/id/eprint/29095

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