Browsing by Author "Reuter, Sulandy"

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    TKTL1 plays a critical role in ameliorating intracellular oxidative stress under hyperglycemic conditions
    (Stellenbosch : Stellenbosch University, 2018-03) Reuter, Sulandy; Essop, M. Faadiel; Joseph, Danzil; Stellenbosch University. Faculty of Science. Dept. of Physiological Sciences.
    ENGLISH ABSTRACT: Diabetes is a growing, global concern, reaching a prevalence far beyond the projected statistics. Hyperglycemia is a common denominator of type 1 and type 2 diabetes mellitus that if left untreated, results in detrimental outcomes, e.g. oxidative damage. The pentose phosphate pathway (glucose-6-phosphate dehydrogenase [G6PD] and transketolase [TKT] as rate-limiting enzymes) offers an alternate ‟safer” route for excess metabolic fuels, while also replenishing anti-oxidant defenses and thus potentially offers value as a novel therapeutic target. As TKT-like 1 (TKTL1), a relatively novel member of the transketolase family, has been overlooked in this regard, we employed a TKTL1-knock-out (KO) mouse model as a targeted approach to evaluating TKTL1 function. Multiple low doses of streptozotocin (STZ) (40 mg/kg, intraperitoneal injections on five consecutive days) were used to induce hyperglycemia, a pathophysiologic state known to culminate in oxidative stress and damaging outcomes. Hyperglycemia incidence was 40% and 90% in wild-type (WT) and TKTL1-KO STZ-injected male groups, respectively, while only the TKTL1-KO STZ group displayed significantly higher blood glucose levels compared to the WT control (p<0.001) and the TKTL1-KO control group (p<0.001). The male TKTL1-KO STZ-treated group displayed larger relative liver weights (p<0.001) and kidney weights (p<0.05), respectively, compared to both WT and TKTL1-KO controls. Gastrocnemii weight of the TKTL1-KO STZ-treated group was lower than that of the WT control group (p<0.01). There was a significant, negative correlation between liver G6PD activity and blood glucose levels (Spearman’s correlation coefficient [r]=-0.37, p=0.03) while this correlation was not observed in cardiac tissue. In the latter, both TKTL1-KO groups displayed ~50% diminished transketolase activity compared to the WT control (p<0.001). No significant differences were noted in any of the oxidative stress and damage assessments of blood, heart, or liver samples. However, several adaptations were revealed in hepatic anti oxidant defenses: STZ-treated TKTL1-KO mice displayed increased catalase activity (p<0.05), with catalase activity showing a significant, positive correlation with blood glucose (r=0.39, p=0.02); ferric reducing anti-oxidant power (FRAP) concentrations as well as the reduced glutathione (GSH):to oxidized glutathione (GSSG) ratio were, significantly decreased in STZ-treated TKTL1-KO group (p<0.05) while both of these measurements were negatively correlation with blood glucose levels (r=0.45, p<0.01 for FRAP, r=-0.36, p=0.03 for GSH:GSSG ratio). Our data reveal that TKTL1 may play an anti-oxidant role in the liver to protect against hyperglycemia and to maintain overall glucose homeostasis. Thus our study demonstrates novel insights into TKTL1 function and shows that it remains a feasible therapeutic target for the treatment of diabetes.