Investigating the functional and metabolic role of carnitine in the diabetic heart using hyperpolarized MRI
<p>Diabetes increases the incidence of myocardial infarction and heart failure, which are leading causes of mortality in diabetic patients. L-carnitine levels are decreased in the plasma of diabetic patients and L-carnitine supplementation has been shown to have protective effects. L-carnitine...
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| Other Authors: | |
| Format: | Thesis |
| Language: | English |
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2018
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| _version_ | 1824459004594618368 |
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| author | Savic, D |
| author2 | Tyler, D |
| author_facet | Tyler, D Savic, D |
| author_sort | Savic, D |
| collection | OXFORD |
| description | <p>Diabetes increases the incidence of myocardial infarction and heart failure, which are leading causes of mortality in diabetic patients. L-carnitine levels are decreased in the plasma of diabetic patients and L-carnitine supplementation has been shown to have protective effects. L-carnitine transports fatty acids into the mitochondria allowing for subsequent —-oxidation, but it can also export acetyl-CoA from the mitochondria through acetylcarnitine and thereby relieve PDH-flux.</p> <p>The aim of this thesis was to explore the effects of modulating L-carnitine levels on in vivo metabolism and function in the diabetic heart. Hyperpolarized MRI was used to assess metabolism, while CINE MRI was used for the assessment of cardiac function. A Langendorff method was used to determine the ex vivo effect of L-carnitine on functional recovery post-ischemia.</p> <p>Different diabetic models were initially investigated to find the most appropriate model in which to modulate L-carnitine levels. A neonatal model of diabetes showed decreased aerobic to anaerobic metabolism (50 %) in conjunction with functional impairment, which could be reversed with Glibenclamide treatment. A fasted streptozotocin induced rat model showed superior SNR on MRI and was pursued further. PDH-flux and alanine metabolism were decreased (>60%) with diabetes which coincided with functional impairments. Sustained hyperglycaemia for four weeks led to an elevation in lactate and alanine (>140 %), while also elevating stroke volume.</p> <p>L-carnitine treatment (3 g/kg/day, i.p.) elevated acetylcarnitine (AC) levels (219 %) and slowed down the progression of hyperglycaemia in diabetes, while elevating PDH-flux (51 %), allowing for improved diastolic function (16 %) in vivo, and improved functional recovery post-ischemia ex vivo (270 %). However detrimental effects were observed in control animals treated with L-carnitine.</p> <p>Daily Mildronate treatment, which inhibits L-carnitine uptake, reduced AC levels (52 %) and elevated PDH-flux (214 %) in the diabetics. These metabolic changes were not accompanied by functional changes. However, improved ex vivo functional recovery post-ischemia (34 %) was observed, but did not reach the level of recovery that L-carnitine had on the ex vivo heart.</p> <p>This work has clarified that the use of L-carnitine treatment in diabetes can enhance carbohydrate metabolism and is more beneficial than decreasing L-carnitine levels with Mildronate. This work has shown the potential for using hyperpolarized and CINE MRI in better understanding the mechanism of L-carnitine’s effect on the diabetic heart, and it may provide new insights into novel therapeutics.</p> |
| first_indexed | 2025-02-19T04:34:54Z |
| format | Thesis |
| id | oxford-uuid:7e29c207-3061-478c-92bc-0e23aba71d0c |
| institution | University of Oxford |
| language | English |
| last_indexed | 2025-02-19T04:34:54Z |
| publishDate | 2018 |
| record_format | dspace |
| spelling | oxford-uuid:7e29c207-3061-478c-92bc-0e23aba71d0c2025-01-27T08:38:54ZInvestigating the functional and metabolic role of carnitine in the diabetic heart using hyperpolarized MRIThesishttp://purl.org/coar/resource_type/c_db06uuid:7e29c207-3061-478c-92bc-0e23aba71d0cDiabetesMetabolismMildronatePhysiologyCarnitineCardiovascular system--DiseasesDiabetic heart diseaseDiabetic treatmentsHyperpolarized MRIMagnetic resonance imagingEnglishORA Deposit2018Savic, DTyler, DHeather, LEvans, RStuckey, D<p>Diabetes increases the incidence of myocardial infarction and heart failure, which are leading causes of mortality in diabetic patients. L-carnitine levels are decreased in the plasma of diabetic patients and L-carnitine supplementation has been shown to have protective effects. L-carnitine transports fatty acids into the mitochondria allowing for subsequent —-oxidation, but it can also export acetyl-CoA from the mitochondria through acetylcarnitine and thereby relieve PDH-flux.</p> <p>The aim of this thesis was to explore the effects of modulating L-carnitine levels on in vivo metabolism and function in the diabetic heart. Hyperpolarized MRI was used to assess metabolism, while CINE MRI was used for the assessment of cardiac function. A Langendorff method was used to determine the ex vivo effect of L-carnitine on functional recovery post-ischemia.</p> <p>Different diabetic models were initially investigated to find the most appropriate model in which to modulate L-carnitine levels. A neonatal model of diabetes showed decreased aerobic to anaerobic metabolism (50 %) in conjunction with functional impairment, which could be reversed with Glibenclamide treatment. A fasted streptozotocin induced rat model showed superior SNR on MRI and was pursued further. PDH-flux and alanine metabolism were decreased (>60%) with diabetes which coincided with functional impairments. Sustained hyperglycaemia for four weeks led to an elevation in lactate and alanine (>140 %), while also elevating stroke volume.</p> <p>L-carnitine treatment (3 g/kg/day, i.p.) elevated acetylcarnitine (AC) levels (219 %) and slowed down the progression of hyperglycaemia in diabetes, while elevating PDH-flux (51 %), allowing for improved diastolic function (16 %) in vivo, and improved functional recovery post-ischemia ex vivo (270 %). However detrimental effects were observed in control animals treated with L-carnitine.</p> <p>Daily Mildronate treatment, which inhibits L-carnitine uptake, reduced AC levels (52 %) and elevated PDH-flux (214 %) in the diabetics. These metabolic changes were not accompanied by functional changes. However, improved ex vivo functional recovery post-ischemia (34 %) was observed, but did not reach the level of recovery that L-carnitine had on the ex vivo heart.</p> <p>This work has clarified that the use of L-carnitine treatment in diabetes can enhance carbohydrate metabolism and is more beneficial than decreasing L-carnitine levels with Mildronate. This work has shown the potential for using hyperpolarized and CINE MRI in better understanding the mechanism of L-carnitine’s effect on the diabetic heart, and it may provide new insights into novel therapeutics.</p> |
| spellingShingle | Diabetes Metabolism Mildronate Physiology Carnitine Cardiovascular system--Diseases Diabetic heart disease Diabetic treatments Hyperpolarized MRI Magnetic resonance imaging Savic, D Investigating the functional and metabolic role of carnitine in the diabetic heart using hyperpolarized MRI |
| title | Investigating the functional and metabolic role of carnitine in the diabetic heart using hyperpolarized MRI |
| title_full | Investigating the functional and metabolic role of carnitine in the diabetic heart using hyperpolarized MRI |
| title_fullStr | Investigating the functional and metabolic role of carnitine in the diabetic heart using hyperpolarized MRI |
| title_full_unstemmed | Investigating the functional and metabolic role of carnitine in the diabetic heart using hyperpolarized MRI |
| title_short | Investigating the functional and metabolic role of carnitine in the diabetic heart using hyperpolarized MRI |
| title_sort | investigating the functional and metabolic role of carnitine in the diabetic heart using hyperpolarized mri |
| topic | Diabetes Metabolism Mildronate Physiology Carnitine Cardiovascular system--Diseases Diabetic heart disease Diabetic treatments Hyperpolarized MRI Magnetic resonance imaging |
| work_keys_str_mv | AT savicd investigatingthefunctionalandmetabolicroleofcarnitineinthediabeticheartusinghyperpolarizedmri |