More on diabetes and malaria from Palestine

n diabetes and malaria from PalestineAs stated in previous blogs diabetes is on the rise everywhere. It is a debilitating and often fatal disease per se but it also increases the incidence of malaria because higher glucose contents in the blood are a fertile terrain for Plasmodium falciparum.
It is the general belief that malaria patients are poor in antioxidant defenses and that supplementation with antioxidants (vitamins, polyphenols) will alleviate the severity of malaria infections. It is thus surprising that the University of Al Quds finds that the total antioxidant status in type 2 diabetic patients in Palestine in significantly higher compared to control subjects. The study involved 212 diabetic subjects and 208 normal subjects (AT Kharroubi et al., J Diabetes Research, 2015 ID461271).
A similar finding had already been made in Romania on a reduced number of 15 patients: the total antioxidant capacity of plasma increased in type 2 diabetes (O Saviu et al, J Internat Med Res. 2012, 40, 709-716).
Already in 1999 it had been found that in diabetic condition antioxidant enzyme levels are elevated (M Ramanathan et al., Indian J Exp Biol 1999, 37, 182-3). It is generally accepted that reactive oxygen species and oxidative stress impair beta-cell function in the pancreas and reduce insulin secretion. Pancreatic islets are known for their extremely low antioxidative defense status and their unusual susceptibility to ROS (E Gurgul et al., Diabetes 2004, 53, 2271-78). And any increase in ROS can markedly impair insulin secretion.
Confronted with low levels of insulin, which has anti-inflammatory properties (Aljada et al., Metab Clin Exp 55, 2006, 1177-85), diabetic beta-cells try self-protection against oxidative stress through an adaptive up-regulation of their antioxidant defenses (Gregory Lacraz et al, PLoS ONE 2009, 4-8, e6500). But often this protection is not sufficient and it is often proposed to supplement antioxidants in the treatment of diabetes. A review published in 2011 reviews all human clinical trials where antioxidants were studied as an adjuvant to standard diabetes treatment. The authors came to the surprising conclusion that there is not any established benefit for antioxidants use in the management of diabetic complications. They interfer with the physiologic redox balance. Therefore, routine vitamin of mineral supplementation should not be generally recommended (S Golbidi et al, Curr Diabetes Rev 20117, 106-25).

One of the neglected side effects of diabetes is the generation of large quantities of hydrogen peroxide.
Healthy pancreatic beta-cells exhibit a dramatic response to nutrients and glucose through hypersecretion of insulin in order to maintain energy homeostasis. Many studies have suggested that chronic exposure of pancreatic beta-cells to high levels of glucose may contribute to impaired beta-cell function, leading to the production of ROS. Intriguingly, compared to other tissues, beta-cells have a lower abundance of antioxidant defense such as superoxide dismutase (SOD), catalase, and glutathione peroxidase (GPx). The ROS produced include superoxide and hydroxyl radicals. These may subsequently be converted to hydrogen peroxide (Y Ihara et al., Diabetes. 1999 , 48 927-32). A study from Tunesia shows that the hydrogen peroxide concentration in plasma is increased fourfold in type 2 diabetes compared to controls (A Msolly et al., J Cardiovascul Disease, 2013, 1, 48-51). It was based on 200 confirmed type 2 diabetes patients and 200 controls recruited in the regional blood transfusion center of Sousse. There was a strong positive linear correlation between glycated hemoglobin and hydrogen peroxide, between free fatty acids and hydrogen peroxide concentration and a negative correlation between quantitative insulin index and hydrogen peroxide. Another paper documents that insulin treatment reduces the hydrogen peroxide concentration in blood (A Bravard et al., Am J Physiol Endocrinol Metab, 2011, 300, E581-E591).
At sites of inflammation hydrogen peroxide appears to modulate the inflammatory process and inactivates NFκB. Due to its permeability in many tissues, it operates as an intracellular and intercellular messenger, but at high concentrations it becomes toxic, especially in insulin producing cells known for their extremely low antioxidant equipment against hydrogen peroxide (B Halliwell et al., FEBS Letters 2000, 486, 10-13). Hydrogen peroxide could also plays a role in the regulation of renal function. Renal medullary hydrogen peroxide production is increased in diabetics (D Patinha et al., Life Sci, 2014, 108, 71-9).
Hydrogen peroxide has another side effect. It decreases endothelial nitric oxide synthase NOS promoter activity (Kumar S et al., DNA Cell Biol. 2009, 2:119-29). It is well documented that NOS and NO generated by this enzyme have important endothelial functions and its inhibition may explain most of the cardiovascular problems generated by diabetes.

Several biomarkers of metabolic acidosis, including lower plasma bicarbonate have been associated with insulin in cross-sectional studies. A team from Canada conducted a study called the “Nurses Health Study”. Plasma bicarbonate was measured in 630 women who did not have type 2 diabetes mellitus at the time of the blood draw in 1989 but developed the disease during 10 years of follow-up. The outcome was that higher plasma bicarbonate levels were associated with lower odds of incident type 2 diabetes mellitus (EI Mandel et al., CMAJ, 2012, 184, E179)
The pancreas generates a lot of sodium bicarbonate. The rate of decomposition of hydrogen peroxide has been measured in aqueous sodium carbonate solutions (0.1-1.0 M). It is decomposed in a few minutes and 10 times faster than in a sodium hydroxide solution (HH Lee et al., 2000, Tappi Journal)(U von Gunten et al, Ozone Science and Engineering Journal, 2000, 22, 305-328).
The role of bicarbonate and hydrogen peroxide in diabetes deserve much more research. Because it has an impact on malaria too. As the University of Quds has shown bicarbonate strongly contributes to the inhibition of beta-hematin crystallization (Suhair Jaber et al., J Pharmacy Pharmacol 2015, 3, 63-72).

It is astonishing and frustrating that the impact of diabetes on Plasmodium proliferation is known since more than 100 years. In 1912 Bass and Johnson reported that the addition of glucose was necessary for successful in vitro cultivation of the human malaria parasites Plasmodium falciparum and vivax. However, blood from a diabetic person was successfully used in the culture medium without addition of glucose. They also reported that the amount of quinine sufficient to control malaria infections was ineffective in this case. As a result of these observations they came to the conclusion that the elevated blood sugar from a diabetic patient provided a medium which could better support the growth and reproduction of parasites than could the blood of a non-diabetic person.

Pierre Lutgen
Mutaz Akkawi
17 december 2015.

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