Malaria and glucose

Sugar feeding is a fundamental characteristic of mosquito life. It is the basic food of adult mosquitoes, as floral nectar or honeydew. It is the only nutrient consumed by males and probably the more common one for females, even if they need vertebrate blood to produce eggs.

Malaria parasites also are dependent on glucose as a nutrient source. As Plasmodium has no capacity to store energy in the form of glycogen they rely entirely on an exogenous supply of glucose. The infected erythrocyte exhibits a substantial increase in its permeability to low molecular weight sugar. The metabolism of the parasite utilizes up to 75 times more glucose than uninfected erythrocytes. Glucose is vital for Plasmodium. An in vitro study ( H Humeida et al., J of Diabetology, October 2011, 3:6) has shown that growth and proliferation is impaired below 5.5 mM.

Hypoglycemia is a common clinical problem in neonates, is less common in infants and toddlers, and is rare in older children. In children < 6 years the blood glucose is on the average 8.3 mM ( 150 mg/ dL), reaches in fact a maximum at 5-6 years, and above that age stabilizes around 6.1 mM. Concentrations above 11.0 mM are considered as overt hyperglycaemia. The normoglycemic range of healthy individuals the range is 3.0 – 7.0 mM. The threshold below which parasite proliferation is impaired falls well in the range of normal blood glucose levels in vivo. It is very common that after a night of fasting levels of 3mM are reached. This low level can be rapidly reverted by the ingestion of glucose: 75 gr for example increase the plasma concentrations after one hour from 5.2 mM to 7.1 mM to fall back at 5.2 mM after 3 hours.

Estimating individual exposure to malaria in the field on a cohort of 2425 children and young adults ( A Olotu et al., PLoS One 7:3, 2012 e32929) it was found that probability of infection is highest at 5 years at 0.7, drops to 0.4 at 10 years and to 0.3 at 20 years There is a striking parallelism with blood glucose levels in the previous paragraph. A case-control study of 1 466 urban adults in Ghana found that patients with type 2 diabetes had a 46% increased risk of infection with Plasmodium falciparum ( I Danquah et al., Emerg Infect Dis 16:10, 2010, 1601-04).

In malaria the pro-inflammatory cytokines (TNF-α, IL-1 β, IL-6) increase glucose in the blood (A Kiely et al., J Endrocinol, 195, 2007, 113-123). Gastric and small intestine permeability for sucrose is increased in malaria patients (P Wilairatana et al., Clinical Infect Dis., 24, 1997, 430-405).In Kenya hyperglycemia was present in 49.4 % of children with malaria (G Fadhil, Master dissertation, Makerere University, 2011), but if the disease evolves into severe or cerebral malaria hypoglycemia will be commun. In this case, sugar can probably be considered as a “first aid” treatment.

Falciparum malaria increases glucose production by approximately 25% in adult patients ( E Dekker et al., Am J Physiol 272, 1997, 1059-64). This is particularly the case in pregnant women with malaria where higher glucose levels are common ( H Van Thien et al., Clin Nutr 23:1, 2004, 59-67). It is not uncommon for sugar levels to rise during pregnancy. In about 10 to 20 percent of cases, a woman will develop a condition known as gestational diabetes, in which blood sugar levels are too high.
There is evidence that this higher glucose level increases the attractiveness to for Anopheles feeding. This has been demonstrated for pregnant women where the number of mosquitoes approaching the patient each night is 1.7-4.5 times higher ( J Ansell et al., Trans R Soc Trop Med Hyg 96:2, 2002, 113-116). The biting rates were found to 0.94 bites/woman-night for pregnant women versus 0.49 for non pregnant ( YE Himeidan et al., Ann Trop Med Parasitol, 98, 2004, 631-633). The consumption of soft drinks and beer in the evening also sharply increases human attractiveness to malaria mosquitoes. The ingested carbohydrates provide a highly nutritious blood-meal ( T Levèvre et al., PLoS One. 2010 Mar 4;5(3):e9546.)

On the other hand there is also a growing body of evidence that glucose ingestion causes a number of pro-inflammatory changes in normal as well as diabetic humans,but that insulin has been found to have anti-inflammatory effects (Aljada et al., Metab Clin Exp 55, 2006, 1177-85). Glucose stimulates the endothelial production of the pro-inflammatory Interleukin-8 ( S Srinivasan et al., Circulation Research, 92, 2003, 371-377) and probably the adhesion of Plasmodium falciparum parasites.

All artemisia species seem to have an hypoglycemic effect. Treatment of rats with Artemisia annua aqueous extract reduced the serum glucose after 4 weeks from 110 to 70 mg/mL (TB Mojarad et al., Iranian Biomedical Journal, 9:2, 2005, 57-62). In South Africa Artemisia afra is extensively used for several diseases including diabetes . Methanol extracts of A. absinthium have a strong hypoglycemic and hepatoprotective activity ( BJ Goud, Int J Adv Pharmac Res., 2:7, 2011). For A. herba alba the ethanol-water extract produced stronger hypoglycemic effect than the hexane extract ( NE Awad et al., J Appl Pharmac Sc. 02:03, 2012, 30-39). A. sieberi has been studied for a similar effect in Iran.

Remains the question which constituents of artemisia herbs cause this hypoglycemic effect. Polyphenols and essential oils only have a minor impact (NE Awad et al., J Appl Pharmaceutical Sc., 02, 2012, 30-39) and their role is controversial. Quercetin and quercetrin for example caused hypoglycaemia in rats, while rutin and morin showed almost no difference ( NA Ammar, Archives of Pharmaceutical Research, 11:2. 1988, 16-168). Ellagic acid, a very effective antimalarial used in India, also has strong antidiabetic efficacy (P. Maliny et al., Asian J Pharmac Clin Res. 4:3, 2011). Nerolidol which is also present in Artemisia herba alba has hypoglycemic effects ( J Chen et al., J of Phytherapy and Phytopharmacol, Jan 1, 2008).

But saponins and polysaccharides seem to have the major effect. They inhibit the intestinal absorption of glucose. They stimulate the insulin production, are anti-inflammatory and modulate autoimmunity ( Fei Wang et al., Coll of Chem & Life Sci. Maoming China). Ginseng saponins are well known for these properties. The effect of soluble tea polysaccharides ( X Zhou et al., J Agricol Food Chem 55:14, 2007, 5523-5528) and the effect aqueous Artemisia annua extract on hyperglycemia in rats has been well described ( T Mojarad et al., Iranian Biomed J. 9, 2005, 57-62).

In none of these prophylactive and protective effects artemisinin seems to play a role. Artemisias are marvelous medicinal plants but we are far from having elucidated all their secrets. But is probably wise not to take this bitter tea with too much sugar or honey. Anyway stevia is an interesting and cheaper alternative.

Pierre Lutgen IFBV-BELHERB-, Luxembourg. lutgenp@gms.lu
Patrick E Ogwang, Makerere University, Kampala

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