Urinary markers of nucleic acid oxidation and cancer in type 2 diabetes

AbstractGlucagon-like peptide 1 receptor agonists have shown cardioprotective effects which have been suggested to be mediated through inhibition of oxidative stress. We investigated the effect of treatment with a glucagon-like peptide 1 receptor agonist (liraglutide) on oxidative stress measured as urinary nucleic acid oxidation in persons with type 2 diabetes. Post-hoc analysis of two independent, randomised, placebo-controlled and double-blinded clinical trials. In a cross-over study where persons with type 2 diabetes and microalbuminuria (LIRALBU, n = 32) received liraglutide (1.8 mg/day) or placebo for 12 weeks in random order, separated by 4 weeks of wash-out. In a parallel-grouped study where obese persons with type 2 diabetes (SAFEGUARD, n = 56) received liraglutide (1.8 mg/day), sitagliptin (100 mg/day) or placebo for 12 weeks. Endpoints were changes in the urinary markers of DNA oxidation (8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG)) and RNA oxidation [8-oxo-7,8-dihydroguanosine (8-oxoGuo)]. In LIRALBU, we observed no significant differences between treatment periods in urinary excretion of 8-oxodG [0.028 (standard error (SE): 0.17] nmol/mmol creatinine, p = 0.87) or of 8-oxoGuo [0.12 (0.12) nmol/mmol creatinine, p = 0.31]. In SAFEGUARD, excretion of 8-oxodG was not changed in the liraglutide group [2.8 (− 8.51; 15.49) %, p = 0.62] but a significant decline was demonstrated in the placebo group [12.6 (− 21.3; 3.1) %, p = 0.02], resulting in a relative increase in the liraglutide group compared to placebo (0.16 nmol/mmol creatinine, SE 0.07, p = 0.02). Treatment with sitagliptin compared to placebo demonstrated no significant difference (0.07 (0.07) nmol/mmol creatinine, p = 0.34). Nor were any significant differences for urinary excretion of 8-oxoGuo liraglutide vs placebo [0.09 (SE: 0.07) nmol/mmol creatinine, p = 0.19] or sitagliptin vs placebo [0.07 (SE: 0.07) nmol/mmol creatinine, p = 0.35] observed. This post-hoc analysis could not demonstrate a beneficial effect of 12 weeks of treatment with liraglutide or sitagliptin on oxidatively generated modifications of nucleic acid in persons with type 2 diabetes.

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Pathology, Risk Factors, and Oxidative Damage Related to Type 2 Diabetes-Mediated Alzheimer’s Disease and the Rescuing Effects of the Potent Antioxidant Anthocyanin

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/4051207 ◽

2021 ◽

Vol 2021 ◽

pp. 1-14

Author(s):

Muhammad Sohail Khan ◽

Muhammad Ikram ◽

Tae Ju Park ◽

Myeong Ok Kim

Keyword(s):

Alzheimer’S Disease ◽

Insulin Resistance ◽

Type 2 Diabetes ◽

Alzheimer's Disease ◽

Inflammatory Cytokines ◽

Amyloid Beta ◽

Acid Oxidation ◽

Chronic Hyperglycemia ◽

Underlying Mechanisms

The pathology and neurodegeneration in type 2 diabetes- (T2D-) mediated Alzheimer’s disease (AD) have been reported in several studies. Despite the lack of information regarding the basic underlying mechanisms involved in the development of T2D-mediated AD, some common features of the two conditions have been reported, such as brain atrophy, reduced cerebral glucose metabolism, and insulin resistance. T2D phenotypes such as glucose dyshomeostasis, insulin resistance, impaired insulin signaling, and systemic inflammatory cytokines have been shown to be involved in the progression of AD pathology by increasing amyloid-beta accumulation, tau hyperphosphorylation, and overall neuroinflammation. Similarly, oxidative stress, mitochondrial dysfunction, and the generation of advanced glycation end products (AGEs) and their receptor (RAGE) as a result of chronic hyperglycemia may serve as critical links between diabetes and AD. The natural dietary polyflavonoid anthocyanin enhances insulin sensitivity, attenuates insulin resistance at the level of the target tissues, inhibits free fatty acid oxidation, and abrogates the release of peripheral inflammatory cytokines in obese (prediabetic) individuals, which are responsible for insulin resistance, systemic hyperglycemia, systemic inflammation, brain metabolism dyshomeostasis, amyloid-beta accumulation, and neuroinflammatory responses. In this review, we have shown that obesity may induce T2D-mediated AD and assessed the recent therapeutic advances, especially the use of anthocyanin, against T2D-mediated AD pathology. Taken together, the findings of current studies may help elucidate a new approach for the prevention and treatment of T2D-mediated AD by using the polyflavonoid anthocyanin.

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Effects of a highly controlled carbohydrate-reduced high-protein diet on markers of oxidatively generated nucleic acid modifications and inflammation in weight stable participants with type 2 diabetes; a randomized controlled trial

Scandinavian Journal of Clinical and Laboratory Investigation ◽

10.1080/00365513.2020.1759137 ◽

2020 ◽

Vol 80 (5) ◽

pp. 401-407 ◽

Cited By ~ 1

Author(s):

Mads Juul Skytte ◽

Amirsalar Samkani ◽

Arne Astrup ◽

Thomas Meinert Larsen ◽

Jan Frystyk ◽

...

Keyword(s):

Type 2 Diabetes ◽

Randomized Controlled Trial ◽

Nucleic Acid ◽

Controlled Trial ◽

High Protein Diet ◽

High Protein ◽

Protein Diet ◽

Randomized Controlled

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Fatty Acid Incubation of Myotubes From Humans With Type 2 Diabetes Leads to Enhanced Release of -Oxidation Products Because of Impaired Fatty Acid Oxidation: Effects of Tetradecylthioacetic Acid and Eicosapentaenoic Acid

Diabetes ◽

10.2337/db08-1043 ◽

2008 ◽

Vol 58 (3) ◽

pp. 527-535 ◽

Cited By ~ 47

Author(s):

A. J. Wensaas ◽

A. C. Rustan ◽

M. Just ◽

R. K. Berge ◽

C. A. Drevon ◽

...

Keyword(s):

Type 2 Diabetes ◽

Fatty Acid ◽

Eicosapentaenoic Acid ◽

Fatty Acid Oxidation ◽

Oxidation Products ◽

Acid Oxidation ◽

Tetradecylthioacetic Acid ◽

Impaired Fatty Acid

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Assessment of myocardial metabolic flexibility and work efficiency in human type 2 diabetes using 16-[18F]fluoro-4-thiapalmitate, a novel PET fatty acid tracer

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00437.2015 ◽

2016 ◽

Vol 310 (6) ◽

pp. E452-E460 ◽

Cited By ~ 25

Author(s):

K. J. Mather ◽

G. D. Hutchins ◽

K. Perry ◽

W. Territo ◽

R. Chisholm ◽

...

Keyword(s):

Type 2 Diabetes ◽

Oxygen Consumption ◽

Fatty Acid ◽

Fatty Acid Oxidation ◽

Acid Oxidation ◽

Metabolic Flexibility ◽

Work Efficiency ◽

Myocardial Fatty Acid ◽

Fuel Selection

Altered myocardial fuel selection likely underlies cardiac disease risk in diabetes, affecting oxygen demand and myocardial metabolic flexibility. We investigated myocardial fuel selection and metabolic flexibility in human type 2 diabetes mellitus (T2DM), using positron emission tomography to measure rates of myocardial fatty acid oxidation {16-[18F]fluoro-4-thia-palmitate (FTP)} and myocardial perfusion and total oxidation ([11C]acetate). Participants underwent paired studies under fasting conditions, comparing 3-h insulin + glucose euglycemic clamp conditions (120 mU·m−2·min−1) to 3-h saline infusion. Lean controls ( n = 10) were compared with glycemically controlled volunteers with T2DM ( n = 8). Insulin augmented heart rate, blood pressure, and stroke index in both groups (all P < 0.01) and significantly increased myocardial oxygen consumption ( P = 0.04) and perfusion ( P = 0.01) in both groups. Insulin suppressed available nonesterified fatty acids ( P < 0.0001), but fatty acid concentrations were higher in T2DM under both conditions ( P < 0.001). Insulin-induced suppression of fatty acid oxidation was seen in both groups ( P < 0.0001). However, fatty acid oxidation rates were higher under both conditions in T2DM ( P = 0.003). Myocardial work efficiency was lower in T2DM ( P = 0.006) and decreased in both groups with the insulin-induced increase in work and shift in fuel utilization ( P = 0.01). Augmented fatty acid oxidation is present under baseline and insulin-treated conditions in T2DM, with impaired insulin-induced shifts away from fatty acid oxidation. This is accompanied by reduced work efficiency, possibly due to greater oxygen consumption with fatty acid metabolism. These observations suggest that improved fatty acid suppression, or reductions in myocardial fatty acid uptake and retention, could be therapeutic targets to improve myocardial ischemia tolerance in T2DM.

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