University of Cambridge
Amylin, tissue hypoxia and metabolic dysregulation in diabetic heart and liver
Abstract
dc:description.abstractType II diabetes mellitus (T2DM) is a growing burden, with the global prevalence rising from 4.7% of the adult population in 1980 to 8.5% in 2014. Owing to systemic metabolic changes in T2DM and myocardial and hepatic insulin resistance, the diabetic heart and liver are exposed to different levels of metabolites. Amylin, or islet amyloid polypeptide (IAPP), is a 37 amino-acid peptide hormone, that is co-secreted with insulin from pancreatic β-cells in response to nutrient stimuli. Amylin dyshomeostasis occurs in T2DM. Initially, as peripheral insulin resistance develops, β-cells compensate by increasing insulin production. As proinsulin and proIAPP are co-secreted, this also results in an increase in proIAPP production. Consequently, during the hyperinsulinaemic stages of T2DM, hyperamylinaemia also occurs. Human amylin then has the propensity to form oligomers, fibrils, and aggregates in T2DM patients, forming deposits in pancreatic islets and in extra-pancreatic peripheral organs, e.g. the blood vessels and parenchyma of kidneys, the heart, and the brain. Rodent amylin does not have this propensity to form aggregates. Therefore, amylin is an aspect of T2DM that is unexplored in many rodent models. The work presented in this thesis aimed to further our understanding of the impact of amylin dyshomeostasis on metabolic dysfunction in the diabetic heart and liver. In a diabetic rat model expressing human amylin (HIP rats), amylin aggregates were deposited in pancreatic islets, kidney, and cardiomyocytes, in a similar fashion to patients with T2DM. These amylin deposits stimulated hypoxic signalling, with elevated HIF2α levels being observed. Oxidative and energetic stress was also provoked. This resulted in downstream mitochondrial dysfunction and metabolic changes, including a lower Electron Transport Chain (ETC) capacity, and decreased fatty acid oxidation (FAO). In the livers of the HIP rats, the presence of human amylin resulted in an elevated capacity of complexes within the mitochondrial ETC. This enhanced ETC activity was associated with increased supercomplex formation. This was accompanied by an elevation in FAO. These responses are typical of an acute stress response to hypoxia in the liver. To understand the impact of hypoxia on metabolism against a background of T2DM, a milder rat model of T2DM, generated through high-fat feeding and streptozotocin injections, expressing only non-amyloid forming rodent amylin, was exposed to hypoxia. In these rats, there was a trend towards hypoxia lower respiratory capacity in the LEAK state and OXPHOS state supported by the fatty acid-derived substrate, octanoyl carnitine, as well as substrates for complex I&II respiration, and complex II alone. In conclusion, amylin aggregates are deposited around and internalised within cardiomyocytes in HIP rats. HIP rats then exhibit a reduced cardiac respiratory capacity and a reduction in the capacity for fatty acid oxidation. The metabolic perturbations that are unique to the hearts of HIP rats, may be due to amylin aggregate deposition causing tissue hypoxia, supported by our observations of elevated HIF2α expression and hypoxia signalling. In the liver, the presence of human amylin in HIP rats resulted in an elevated cardiac respiratory capacity and rate of fatty acid oxidation, which was associated with elevated mitochondrial supercomplex formation.
Degree
thesis:*- Name dc:type.qualificationname
- Doctor of Philosophy (PhD)
- Level dc:type.qualificationlevel
- Doctoral
- Grantor dc:publisher.institution
- University of Cambridge
- Year dc:date.issued
- 2024
Author and committee
dc:creator, dc:contributor.*- Author dc:creator
-
- Knapton, Alice
- Advisor dc:contributor.advisor
-
- Murray, Andrew
Subjects
dc:subject × 3Rights
dc:rightsIdentifiers
dc:identifier.*- DOI dc:identifier.doi
- https://doi.org/10.17863/CAM.108414
- OAI identifier oai:identifier
- oai:www.repository.cam.ac.uk:1810/368075