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The Effects of Hypoglycaemia on Inflammation and Atherosclerosis.

Iqbal, Ahmed (2019) The Effects of Hypoglycaemia on Inflammation and Atherosclerosis. PhD thesis, University of Sheffield.

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Hypoglycaemia is associated with cardiovascular (CV) events in diabetes. The mechanisms through which hypoglycaemia may increase CV risk, however, remain to be elucidated. I hypothesised that hypoglycaemia induces activation of the innate immune system, through: monocyte mobilisation and activation, increased platelet reactivity and platelet-leukocyte interactions and therefore accelerates pre-established atherosclerosis through inflammatory pathways. I conducted studies in both man and mouse. In a novel human experimental model of combined hypoglycaemia and low-dose endotoxin challenge, I studied 24 healthy participants that underwent either a hyperinsulinaemic-hypoglycaemic (2.5 mmol/l) (n=8), euglycaemic (6.0 mmol/l) (n=8) or sham-saline clamp (n=8) (normoglycaemic conditions). To determine if antecedent hypoglycaemia modified innate immune responses, all participants then received a low dose (0.3 ng/kg) intravenous endotoxin challenge 48 hours later. I studied in vivo monocyte mobilisation and monocyte-platelet interactions. In comparison to controls, hypoglycaemia increased total leukocytes and significantly mobilised pro-inflammatory CD16+ monocytes. Platelet aggregation to agonist, and formation of monocyte-platelet aggregates, increased following hypoglycaemia with significant aggregation of CD16+ monocytes and platelets. Compared to euglycaemia, hypoglycaemia caused greater leukocyte mobilisation in response to endotoxin stimulation 48 hours later. In mice, I developed a unique model of recurrent insulin induced hypoglycaemia (n=10) or sham-saline injection (n=10) in high fat diet fed Apolipoprotein E deficient mice (ApoE -/-) that had pre-established atherosclerotic plaques. I show that 8 episodes of a modest recurrent hypoglycaemic stimulus over 4 weeks compared to sham-saline injection resulted in a trend towards increased total atherosclerotic burden in whole aortae. I conclude that hypoglycaemia mobilises monocytes, increases platelet reactivity, promotes interaction between platelets and pro-inflammatory monocyte subsets, and changes the subsequent immune response to endotoxin in humans. In mice, data suggest pro-atherosclerotic effects of recurrent hypoglycaemia that abolish anti-atherogenic effects of insulin. Collectively, these data highlight mechanisms whereby hypoglycaemia may increase CV risk.

Item Type: Thesis (PhD)
Academic Units: The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Medicine (Sheffield)
Depositing User: Dr Ahmed Iqbal
Date Deposited: 18 Dec 2019 13:21
Last Modified: 18 Dec 2019 13:21
URI: http://etheses.whiterose.ac.uk/id/eprint/25559

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