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Does diabetes have antimalarial properties

March 23, 2017 - 20:28 -- Pierre Lutgen

A thesis from Sudan presents troubling facts

             Hassan Humeida. Der Verlauf von Malaria bei Patienten mit Diabetes mellitus in Afrika - Feldforschungen im Zentral-Sudan - Dissertation. Giessen, Februar 2011 Justus-Liebig-Universität

Comparing a cohort B of 126 people with malaria alone vs. a cohort A of 64 people with diabetes and malaria they find a lower parasitemia, much less secondary effects and less malaria symptoms in group A. The duration of malaria is much longer in the low glucose group B. Insulin has no influence. Malaria-specific symptoms, such as fever, nausea and vomiting were significantly less reported from diabetes patients than from healthy individuals.

A recent paper from Nigeria confirms the thesis of the University of Giessen describing large scale assessments in Sudan: malaria takes a more difficult course in diabetes patients than in healthy individuals. In Nigeria the malaria parasite load (number/µl of blood) was 2943 for non-diabetics, but only 2376 for diabetics. The fasting blood glucose (mmol/L) was 3.89 in non-diabetics and 6.96 in diabetics. Analysis of liver health parameters showed that there was no significant difference for albumin, ALAT, ASAT, bilirubin, except maybe for alkaline phosphatase.

            Ndiok E O, Ohimain E I, Izah S C. Incidence of Malaria in Type 2 Diabetic Patients and the Effect on the Liver. Journal of Mosquito Research 2016. Vol 6 No 15, 1-8

In fact there are other papers from Nigeria describing the same beneficial effect of diabetes on malaria. 100 subjects were involved in the trials at an age between 40 and 70, years. The mean parasitic count of the diabetics with malaria was significantly lower than for non-diabetics (103.9 vs 164.4 count/mL). The liver function profile was not significantly different.

            EJ Ikekhazu, EE Neboh, MW Nwobodo. Type-2 Diabetes Mellitus and Malaria Parasitemia: Effect on Liver Function Tests. Asian J Med Sc, 2010 214-217

A more ancient study from India finds that in 76 malaria infected diabetics fever is absent in 16 cases and only in 2 cases for the 72 non-diabetics. The parasite count was 4560 in the non-diabetics and 2058 in the diabetics

           M K Mohapatra, Profile of Severe Falciparum Malaria in Diabetics. Int J Diab Dev Countries, 2001, vol 21, 156.161

This confirms a study from 1995 on streptozotocin induced diabetic mice. They were less anaemic, exerted a significant control of parasitemia and showed enhanced phagocytic activity compared with normal mice. The mice were infected with 3 different types of parasites: Plasmodium berghei, yoelii and chabaudi. In some cases, parasitemia was up to 90% lower in the first 7-10 days of the infection for the diabetic mice.

           K.Elased, JB de Souza, JH Playfair. Blood-stage malaria infection in diabetic mice. Clin Exp Immunol 1995 99, 440-444.

Hypoglycemia is one of all causes of death in malaria disease. Diabetes might protect against hypoglycemia.

           Muthiata Sihabud, Voravuth Somsak, Effect of Black tea extract on hypoglycemia induced by Plasmodium berghei Infection in mice. Malaria Control & Elimination, 2015 ISSN 2470-6965

Glucose produces peroxides and hydrogen peroxide which kill the Plasmodium parasite. The production of reactive oxygen species is increased in hyperglycaemia. It was found in Tunesia that the H₂O₂ concentration was increased fourfold in type 2 diabetes compared with controls. The same authors found a strong positive correlation between glycated hemoglobin and hydrogen peroxide concentration, and between free fatty acid concentration and hydrogen peroxide

           A Msolly, A Miled, A Kassab. Hydrogen peroxide: an oxidant stress indicator in type 2 diabetes mellitus. J of Cardiovacular Disease, 2013, 1,2, 48-52.

           Zhimin Tao, Ryan A. Raffel, Abdul-Kader Souid and Jerry Goodisma, Kinetic Studies on Enzyme-Catalyzed Reactions: Oxidation of Glucose, Decomposition of Hydrogen Peroxide and their Combination. Biophys J. 2009 Apr 8; 96(7): 2977–2988. doi: 10.1016/j.bpj.2008.11.071

          T Tzanov, Costa, G Gübitz, Hydrogen peroxide generation with immobilized glucose oxidase for textile bleaching J Biotechn 2002, 93, 87-4

          Bonnefont-Rousselot D, Glucose and reactive oxygen species. Curr Opinion Clin Nutr Metab Care, 2002 5(5). 561-8

          Ksiazek K, Wisniewska J, The role of glucose and reactive oxygen species in diabetes mellitus. Przegl Lek, 2001, 58(10), 915-8.

          Patinha D, Afonso J, Sousa T, Morato M. Diabetes-induces increase of renal medullary hydrogen peroxide. Life Sci2014 108, 71-79

Diabetes mellitus is characterized by hyperglycemia, an abnormal elevation of the blood glucose level. Hyperglycemia generates oxygen free radicals, advanced glycated end products, ROS and inhibits glutathione GSH. This is exactly what the Plasmodium parasite tries to avoid and even to counteract. Hyperglycemia would does have an action similar to that of many antimalarial drugs which attack the parasite by the same oxidative mechanism.

           Aljada et al. Glucose ingestion induces an increase in intranuclear nuclear factor kappaB, a fall in cellular inhibitor kappaB, and an increase in tumor necrosis factor alpha messenger RNA by mononuclear cells in healthy human subjects. Metab Clin Exp 55:1177-85 (2006)

Glucose itself is subject to autoxidation. This reaction is facilitated by the close proximity between a hydroxyl and aldehyde function. Diabetes leads to a depletion of the antioxidant defense of the parasite which eventually will be eliminated. A growing body of evidence suggests that hyperglycemia induced oxidative stress plays an important role. Some authors call this “the antioxidant paradox of diabetes mellitus”.

           Jingbo Pi Yushi Bai Sheila Collins. Reactive oxygen species as a signal in glucose-stimulated insulin secretion. Diabetes, vol 56, 2007 1783-1791

           Sheikh-Ali M, Chehade JM, Mooradjan. The antioxidant paradox in diabetes mellitus. Am. J. Ther 20011, 18(3), 266-78.

           U Karunakaran, Keun-Gyu Park. A systematic review of oxidative stress and ssafety of antioxidants in diabetes. Pathophysiology. 2013, 37, 106-112

           M Chattopadhyay, VK Khemka, G Chatterjee. Enhanced ROS production and oxidative damage in subcutaneous white adipose tissue mitochondria in obese and type 2 diabetes subjects. Mol Cell Biochem 2015, 399, 95-103

High glucose can enhance myeloperoxidase (MPO) and MPO-catalyzed hypochlorous acid which play important roles as mild oxidants and can harm microbes and parasites.

          Tian R, Ding Y, Peng YY, Lu N. Myeloperoxidase amplified high glucose-induced endothelial dysfunction in vasculature: Role of NADPH oxidase and hypochlorous acid. Biochem Biophys Res Commun. 2017 Mar 11;484(3):572-578. doi: 10.1016/j.bbrc.2017.01.132

          Thomas E I, Myeloperoxidase, hydrogen peroxide, chloride microbial system: Infect Immun 1979, 23, 522-531Clin Chim Acta.

          Ghoshal K, Das S, Aich K, Goswami 2, Chowdhury S, Bhattacharyya M. A novel sensor to estimate the prevalence of hypochlorous (HOCl) toxicity in individuals with type 2 diabetes and dyslipidemia. 2016 Jul 1;458:144-53. doi: 10.1016/j.cca.2016.05.006.

Toxoplasma gondii are susceptible to the hydrogen peroxide produced by glucose and glucose oxidase

          H Murray, Z Cohn. Macrophage oxygen-dependent antimicrobial activity. Susceptibility of Toxoplaasma gondii. J Exp Med , 1979, 150, 938-949

Glucose produces peroxides not only in animals but also in plants, by glucose auto-oxidation. In Artemisia annua sugars function in artemisinin biosynthesis.

          PR Arsenault, DR Vail, KK Wobbe, PJ Weathers, Effect of sugars on artemisin production in Artemisia annua. Molecules, 2010, 15(4), 2302-2318.

          I Couée, C Sulmon, A El Amrani: Involvement of soluble sugars in reactive oxygen species balance and responses to oxidative stress in plants. J Exper Botany, 2006, 57, 449-459  

Diabetes 2 patients are deficient in catalase. Erythrocyte catalase is the main regulator of hydrogen peroxide metabolism, and any inherited or acquired catalase deficiency may cause increased hydrogen peroxide concentrations toxic for the pancreas but also for parasites.

         L Goth. Catalase deficiency and type 2 diabetes. Diabetes Care, vol 31 no 12.

         Fernandes RC, Hasan M, Gupta H, Geetha K, Host genetic variations in glutathione-S-transferases, superoxide dismutases and catalase genes influence susceptibility to malaria infection in an Indian population. Mol Genet Genomics. 2015 Jun;290(3):1155-68. doi: 10.1007/s00438-014-0984-4.

                                                                                                                       G6PD

It is well known that G6PD deficiency protects against malaria. High glucose impairs G6PD activity and leads to increased oxidative stress.

             Zhang Z , Liew CW, Handy DE, Zhang Y, Leopold JA, Hu J, Guo L, Kulkarni RN, Loscalzo J, Stanton RC.High glucose inhibits glucose-6-phosphate dehydrogenase, leading to increased oxidative stress and beta-cell apoptosis. FASEB J. 2010 May;24(5):1497-505. doi: 10.1096/fj.09-136572.

Hyperglycaemia can reduce expression of the G6PD gene and activity of the enzyme. In a large cohort study among 940,085 individuals, 52,371 had G6PD deficiency. A significantly higher proportion of patients with G6PD deficiency was found among the diabetic population aged 45–64 years.

             Anthony D. Heymann, Yossi Cohen, and Gabriel Chodick, , Glucose-6-Phosphate Dehydrogenase Deficiency and Type 2 Diabetes. Diabetes Care 2012 Aug; 35(8): e58-e58.

             Carette C, Dubois-Laforgue D, Gautier JF, Timsit J. Diabetes mellitus and glucose-6-phosphate dehydrogenase deficiency: from one crisis to another. Diabetes Metab. 2011 Feb;37(1):79-82. doi: 10.1016/j.diabet.2010.09.004. Epub 2010 Dec 13.

                                                                                                             Erythropoiesis

In a British trial, in mice infected with P. yoelii, P berghei and P. chahaudi diabetic mice were less anaemic, exerted a significant control of parasitaemia. During the course of all three infections the levels of parasitemia in diabetic mice were significantly lower, in some cases up to 90%. Phagocytic activity was enhanced in diabetics suggesting that different forms of macrophage activation may lead to different results in malaria. Injection of insulin had little or no effect There is some evidence of enhanced erythropoiesis in diabetic patients, and if this also occurs in mice, it might explain why the diabetic mice, despite clearing autologous erythrocytes faster than normal mice, were not more anaemic, either before or during the malaria infection

            K.Elased, JB de Souza, JH Playfair. Blood-stage malaria infection in diabetic mice. Clin Exp Immunol 1995 99, 440-444

                                                                                              Cerebral malaria and ammonia

Hypoglycaemia is one of the major causes of cerebral malaria. Ammonia is known to accumulate in brain tissue deprived of an adequate supply of glucose.

            CF Kiire. Hypoglycemia and cerebral malaria. Postgraduate Medical Journal. 1986, 62, 401-402 RM Gardiner, The Effects of Hypoglycaemia on cerebral Blood flow and Metabolism. J Physiol 1980, 298, 37.51

This effect is known for more than 50 years. It has been demonstrated both in vitro and in vivo by the measurement of brain tissue ammonia concentrations. A net loss of ammonia by the brain to the circulation has been observed during hypoglycaemia. Their results provide confirmatory evidence that a rise in cerebral ammonia concentration accompanies hypoglycaemia.

            Lewis, L. D., Ljundgren, B., Norberg, K. Changes in carbohydrate substrates, amino acids and ammonia in the brain during insulin-induced hypoglycaemia.J. Neurochem. 23, 659-671.

            King, L. J., Carl, J. L. & Lao, L. Brain amino acids during convulsions. (1974). J. Neurochem.22, 307

Cerebral malaria is the most severe complication associated with Plasmodium falciparum infection. Several potential mechanisms including mechanical obstruction of brain microvasculature, inflammation, oxidative stress, have been suggested to play a role. However, these proposed mechanisms, even when considered together, do not fully explain the pathogenesis and clinicopathological features of human cerebral malaria. This necessitates consideration of alternative pathogenic mechanisms. P. falciparum generates substantial amounts of ammonia as a catabolic by-product, but lacks detoxification mechanisms.

            Zeuthen, T., B. Wu, S. Pavlovic-Djuranovic, L. M. Holm, N. L. Ammonia permeability of the aquaglyceroporins from Plasmodium falciparum, Toxoplasma gondii and Trypanosoma brucei. Mol Microbiol. 2006. 61:1598-608.

In severe malaria, a large number of malaria parasites in the brain can directly generate substantial amounts of ammonia, which may in turn overwhelm brain ammonia metabolism. Elevated levels of ammonia alter brain functions, initiating a cascade of toxic effects that ultimately lead to various clinical manifestations including brain edema, seizures, coma. Elevated brain ammonia can cause long term neurocognitive sequelae, observed among cerbral malaria survivors. There is no promising therapeutic agent against ammonia-induced complications. Arginine, proanthocyanidins and taurine, derived from the amino-acid methionine, present in Artemisia plants, may present some interesting options with clinical value.

Arginine mitigates the detrimental effect of ammonia.

             Sammy Kimoloi, Khalid Rashid. Potential role of Plasmodium falciparum-derived ammonia in the pathogenesis of cerebral malaria: Frontiers in Neuroscience. DOI: 10.3389/fnins.2015.00234

             MW Goodman, L Zieve, FB Cerra. Mechanism of arginine protection against ammonia intoxication in the rat. Am J Physiol. 1984, 247, G290-5

             Naomi K, L-arginine and ammonia toxicity. Nutrition Reviews 1959, 187-188

             Leslie Zieve Carolyn Lyftogt, Donna Raphael. Ammonia toxicity: Comparative protective effect of various arginine and ornithine derivatives Metabolic Brain Disease March 1986, Volume 1, Issue 1, pp 25–35.

             Weil-Malherbe H, Gordon J. Amino acid metabolism and ammonia formation in brain slices. J Neurochem. 1971 Sep;18(9):1659-72.

             JL Fahey. Toxicity and blood ammonia rise resulting from intravenous amino acid administration. Am J Med. 1957, 23, 860-69

In these trials of Fahey, a nontoxic intravenous l-amino acid mixture became markedly toxic when l-arginine and l-histidine were deleted from the mixture and was capable of producing convulsions and death in dogs. Associated with these infusions was a marked increase in blood ammonia levels that coincided with the signs of toxicity. Similar toxicity was produced by infusion of ammonium salts. L-arginine administration prevented the blood ammonia rise and toxicity.

Another promising molecule to alleviate the detrimental effects of ammonia is taurine.

             Reza Heidaria, Akram Jamshidzadeha, Hossein Niknahada, Effect of taurine on chronic and acute liver injury: Focus on blood and brain ammonia. Toxicology Reports, Volume 3, 2016, 870–879

Hyperammonemia is associated with chronic and acute liver injury. Taurine is spontaneously released by nervous cells (astrocytes) by abnormal raises in ammonia, probably as a protection. J Albrecht. Ammonia stimulates the release of taurine from cultured astrocytes. Brain Res 1994 PMID 7820697 Taurine administration (500 and 1000 mg/kg, i.p), effectively reduced brain ammonia and brain edema. Taurine is not only a useful and safe agent to preserve liver function, but also prevents hyperammonemia. Taurine is present in meat, eggs and mothermilk. Glycine, another amino-acid, present in vegetables and competitor of taurine for bile acids, however leads to a marked rise in blood ammonia.

Proanthocyanidins are known to be beneficial in moderate concentrations in pastures and animal feed because of their ability to bind with dietary protein in the rumen, prevents pasture bloat due to ammonium.

             S Gonzales, ML Pabon, , J Carulla, Effects of tannin on ammonia release and dry matter degradation of soy bean meal.Arch Latinoam Prod Anim 2002, 10, 97-101                CR Stockdale, Incidence of bloat in lactating dairy cows fed clover-dominant herbage and maize silage. Proc Aust Soc Anim Prod 1994. 20, 214-220

Already in 1926 it was found that ammonia influenced the glucose level of the blood. Hyperglycaemia may be considered as a means of protection against increases in ammonia. This forms a basis for the use of of glucose in cases of ammonia intoxication.

             AA Horvath. Ammonia and blood sugar, J Biol Chem 1926, 70 289-296

             Satoshi Fujii, Hironobu Tsuchida, and Masahiko Kōmoto. Chemical Studies on the Reaction Products of Glucose and Ammonia. Agricultural And Biological Chemistry Vol. 30 , Iss. 1,1966

             Henry Brown, MD; Edward O'Hara, MD; Mayo E. Brown, PhD; et al Victor H. Covelli, MD; Dimitri Konda; William V. McDermott Jr., MD. Relation of Blood Glucose to Blood Ammonia and Urea Cycle. JAMA. 1967;199(9):641-646. doi:10.1001/jama.1967.03120090083015

In a trial in Sweden severe hypoglycemia was induced by insulin in lightly anaesthetized rats. All animals showed extensive deterioration of the cerebral energy state. There was an associated rise in ammonia concentration to about 3μmol-g-1. Administration of glucose brought about extensive recovery of cerebral energy metabolism

            Agardh CD, Folbergrová J, Siesjö BK. Cerebral metabolic changes in profound, insulin-induced hypoglycemia, and in the recovery period following glucose administration. J Neurochem. 1978 Nov;31(5):1135-42.

Aminoglucose or Glucose ammonia was investigated more than hundred years ago. Glucose exhibited an unusual degree in alcohol containing ammonia gas. Small aggregates of crystals precipitated out of the solution.

            Lobry de Bruyn and Franchimont, Rec. trav., (1895). 12, 286

Protein intake restrictions during cerebral malaria and promotion of anabolism by rapid administration of intravenous dextrose solution could reduce ammonia formation and toxicity.

            Sammy Kimoloi, Khalid Rashid. Potential role of Plasmodium falciparum-derived ammonia in the pathogenesis of cerebral malaria: Frontiers in Neuroscience. DOI: 10.3389/fnins.2015.00234

All this confirms that diabetes and hyperglycaemia might alleviate cerebral malaria as found by the Sudanese research team (H Humeida op.cit.)

                                                                                           Antidiabetic drugs and malaria?

If the administration of antidiabetic drugs in malaria patients does indeed have deleterious effects on the outcome of the malaria infection, this really deserves more studies. It is disturbing that this information is available in the scientific literature since decades, but ignored by WHO, by pharmaceutical and medical authorities. But antidiabetic drugs are a huge market. According to a study of Global Market Insights Inc. Delaware, the Antidiabetics Market size will be worth USD 116 Billion by 2023.