Browsing by Author "Faadiel Essop, M."
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- ItemChronic and acute exposure of mouse hearts to fatty acids increases oxygen cost of excitation-contraction coupling(2011) Boardman, N. T.; Larsen, T. S.; Severson, D. L.; Faadiel Essop, M.; Aasum, E.The aim of the present study was to evaluate the underlying processes involved in the oxygen wasting induced by inotropic drugs and acute and chronic elevation of fatty acid (FA) supply, using unloaded perfused mouse hearts from normal and type 2 diabetic (db/db) mice. We found that an acute elevation of the FA supply in normal hearts, as well as a chronic (in vivo) exposure to elevated FA as in db/db hearts, increased myocardial oxygen consumption (MV̇O2unloaded) due to increased oxygen cost for basal metabolism and for excitation-contraction (EC) coupling. Isoproterenol stimulation, on top of a high FA supply, led to an additive increase in MV̇O2unloaded, because of a further increase in oxygen cost for EC coupling. In db/db hearts, the acute elevation of FA did not further increase MV̇O2. Since the elevation in the FA supply is accompanied by increased rates of myocardial FA oxidation, the present study compared MV̇O2 following increased FA load versus FA oxidation rate by exposing normal hearts to normal and high FA concentration (NF and HF, respectively) and to compounds that either stimulate (GW-610742) or inhibit [dichloroacetate (DCA)] FA oxidation. While HF and NF + GW-610742 increased FA oxidation to the same extent, only HF increased MV̇O2unloaded. Although DCA counteracted the HF-induced increase in FA oxidation, DCA did not reduce MV̇O2unloaded. Thus, in normal hearts, acute FA-induced oxygen waste is 1) due to an increase in the oxygen cost for both basal metabolism and EC coupling and 2) not dependent on the myocardial FA oxidation rate per se, but on processes initiated by the presence of FAs. In diabetic hearts, chronic exposure to elevated circulating Fas leads to adaptations that afford protection against the detrimental effect of an acute FA load, suggesting different underlying mechanisms behind the increased MV̇O2 following acute and chronic FA load. © 2011 the American Physiological Society.
- ItemGenetic polymorphisms of organic cation transporters 1 (OCT1) and responses to metformin therapy in individuals with type 2 diabetes mellitus : a systematic review protocol(BioMed Central, 2018-07-25) Mato, Edith P. M.; Guewo-Fokeng, Magellan; Faadiel Essop, M.; Owira, Peter M. O.Background: Metformin is one of the most commonly used drugs for type 2 diabetes mellitus (T2DM). Despite its efficacy and safety, metformin is frequently associated with highly variable glycemic responses, which is hypothesized to be the result of genetic variations in its transport by organic cation transporters (OCTs). This systematic review aims to highlight and summarize the overall effects of OCT1 polymorphisms on therapeutic responses to metformin and to evaluate their potential role in terms of interethnic differences with metformin responses. Methods/design: We will systematically review observational studies reporting on the genetic association between OCT1 polymorphisms and metformin responses in T2DM patients. A comprehensive search strategy formulated with the help of a librarian will be used to search MEDLINE via PubMed, Embase, and CINAHL for relevant studies published between January 1990 and July 2017. Two review authors will independently screen titles and abstracts in duplicate, extract data, and assess the risk of bias with discrepancies resolved by discussion or arbitration of a third review author. Mined data will be grouped according to OCT1 polymorphisms, and their effects on therapeutic responses to metformin will be narratively synthesized. If sufficient numbers of homogeneous studies are scored, meta-analyses will be performed to obtain pooled effect estimates. Funnel plots analysis and Egger’s test will be used to assess publication bias. This study will be reported according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines. Discussion: This review will summarize the genetic effects of OCT1 polymorphisms associated with variabilities in glycemic responses to metformin. The findings of this study could help to develop genetic tests that could predict a person’s response to metformin treatment and create personalized drugs with greater efficacy and safety. Systematic review registration: Registration number: PROSPERO, CRD42017079978
- ItemThe human transketolase-like proteins TKTL1 and TKTL2 are bona fide transketolases(BMC (part of Springer Nature), 2019-01-15) Deshpande, Gaurang P.; Patterton, Hugh-George; Faadiel Essop, M.Background: Three transketolase genes have been identified in the human genome to date: transketolase (TKT), transketolase-like 1 (TKTL1) and transketolase-like 2 (TKTL2). Altered TKT functionality is strongly implicated in the development of diabetes and various cancers, thus offering possible therapeutic utility. It will be of great value to know whether TKTL1 and TKTL2 are, similarly, potential therapeutic targets. However, it remains unclear whether TKTL1 and TKTL2 are functional transketolases. Results: Homology modelling of TKTL1 and TKTL2 using TKT as template, revealed that both TKTL1 and TKTL2 could assume a folded structure like TKT. TKTL1/2 presented a cleft of suitable dimensions between the homodimer surfaces that could accommodate the co-factor-substrate. An appropriate cavity and a hydrophobic nodule were also present in TKTL1/2, into which the diphosphate group fitted, and that was implicated in aminopyrimidine and thiazole ring binding in TKT, respectively. The presence of several identical residues at structurally equivalent positions in TKTL1/2 and TKT identified a network of interactions between the protein and co-factor-substrate, suggesting the functional fidelity of TKTL1/2 as transketolases. Conclusions: Our data support the hypothesis that TKTL1 and TKTL2 are functional transketolases and represent novel therapeutic targets for diabetes and cancer.