Whole body modelling of glucose metabolism in malaria patients

Green, Kathleen (2017-03)

ENGLISH ABSTRACT : Diagnosing a patient with a disease is typically done by considering a list of clinical symptoms. For severe malaria two of the key pathophysiological indicators for poor chances of survival are hypoglycemia (blood glucose < 2.2 mmol/L) and lactic acidosis (blood lactate > 5 mmol/L). These could be due to accelerated glycolytic flux (conversion of glucose to lactate) in parasite infected red blood cells, anaemia brought about by the parasites destroying the red blood cells, or reduced perfusion resulting from coagulation of red blood cells (parasites change the red blood cell shape) in the bloodstream. To date, no mathematical models exist that can quantify the relative contribution of increased glycolytic flux to hypoglycemia and lactic acidosis. In this study we constructed a physiologically relevant model of human glucose metabolism that contains the molecular mechanisms of erythrocyte and Plasmodium glycolysis. This allows for the investigation of the extent to which hypoglycaemia and lactic acidosis can be explained by the increased metabolic burden of the parasite. This was accomplished by combining three independent models of glucose metabolism in the parasite, red blood cell and the whole body to form a model of glucose metabolism at the level of the whole body that now contained mechanistic detail of reactions at the level of the red blood cell and malaria parasite (the green1 model). Predictions from the green1 model were compared to clinical data which showed that the increased glycolytic flux caused by the presence of the parasites could be sufficient to explain clinical symptoms of hypoglycemia and lactic acidosis seen in malaria patients. It was seen that for the strength of this modelling technique to be tested, better quality data are needed to validate the model predictions. Furthermore with local and global sensitivity analysis it was observed that there are reactions and parameters in the Plasmodium glycolysis pathway that could guide the development of possible drug targets that could lead to a reversal of hypoglycemia and lactic acidosis.

AFRIKAANSE OPSOMMING : Diagnose van ’n pasiënt met ’n siekte word tipies gedoen deur die oorweging van ’n lys kliniese simptome. Vir ernstige malaria is twee van die belangrikste patofisiologiese aanwysers vir swak kanse op oorlewing hipoglukemie (bloedglukose <2.2 mmol/L) en laktaatversuring (bloed laktaat> 5 mmol/L). Dit kan wees as gevolg van versnelde glikolitiese fluksie (omskakeling van glukose na laktaat) in parasietgeinfekteerde rooibloedselle, bloedarmoede teweeg gebring word deur die vernieteging van rooibloedselle deur parasiete, verminderde perfusie as gevolg van koagulasie van rooibloedselle (parasiete verander die rooibloedselle se vorm) in die bloedstroom. Tot op datum, bestaan geen wiskundige modelle wat die relatiewe bydrae van verhoogde glikolitiese vloed te hipoglukemie en laktaatversuring kan kwantifiseer. In hierdie studie het ons ’n fisiologies relevante model van menslike glukose metabolisme gebou wat die molekulêre meganismes van direritrosiet en Plasmodium glikolise bevat. Dit maak voorsiening vir die ondersoek na die mate waarin hipoglukemie en laktaatversuring verduidelik kan word deur die verhoogde glikolitiese las van die parasiet. Dit is bewerkstellig deur die kombinering van drie onafhanklike modelle van glukose metabolisme in die parasiet, rooibloedselle en die hele liggaam om ’n model van glukose metabolisme te vorm op die vlak van die hele liggaam wat nou meganistiese besonderhede van reaksies vervat op die vlak van die rooibloedsel en malariaparasiet (die green1 model). Voorspellings van die green1 model is vergelyk met kliniese data wat toon dat die verhoogde glikolitiese fluksie wat veroorsaak word deur die teenwoordigheid van die parasiete voldoende is om kliniese simptome van hipoglukemie en laktaatversuring gesien in malaria pasiënte te verduidelik. Dit is gesien dat vir die krag van hierdie modelle tegniek om getoets te word, ’n beter gehalte data benodig word om die model voorspellings te versterk. Verder met plaaslike en globale sensitiwiteitsanalise is dit opgemerk dat daar reaksies en parameters in die Plasmodium glikolitiese pad is wat lig kan werp op die ontwikkeling van moontlike dwelm-teikens en sodoende kan lei tot ’n ommekeer van hipoglukemie en laktaatversuring.

Thesis (MSc)--Stellenbosch University, 2017

Thesis

Please refer to this item in SUNScholar by using the following persistent URL: http://hdl.handle.net/10019.1/101094
This item appears in the following collections: