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We have previously shown that infection with Plasmodium yoeliimalaria or injection of extracts from malaria-parasitized red cells induces hypoglycemia in normal mice and normalizes the hyperglycemia in mice made moderately diabetic with streptozotocin. Inositol phosphoglycans (IPGs) are released outside cells by hydrolysis of membrane-bound glycosylphosphatidylinositols (GPIs), and act as second messengers mediating insulin action. The C57BL/Ks-db/dband C57BL/6J-ob/obmice offer good models for studies on human obesity and Type 2 diabetes. In the present study, we show that a single iv injection of IPG-A or IPG-P extracted from P. yoeliisignificantly (P< 0.02) lowers the blood glucose in STZ-diabetic, db/db,and in ob/obmice for at least 4–6 h. Using rat white adipocytes, IPG-P increased lipogenesis by 20–30% in the presence and absence of maximal concentrations of insulin (10−8M) (P< 0.01) and stimulated pyruvate dehydrogenase (PDH) phosphatase in a dose-related manner. Both IPG-A and IPG-P inhibited c-AMP-dependent protein kinase (PKA) in a dose-related manner. Compositional analysis of IPGs after 24 h hydrolysis revealed the presence of myo-inositol, phosphorus, galactosamine, glucosamine, and glucose in both IPG-A and IPG-P. However, hydrolysis of IPGs for 4 h highlighted differences between IPG-A and IPG-P. There are some functional similarities between P. yoeliiIPGs and those previously described for mammalian liver. However, this is the first report of the hypoglycemic effect of IPGs in murine models of Type 2 diabetes. We suggest that IPGs isolated from P. yoelii,when fully characterized, may provide structural information for the synthesis of new drugs for the management of diabetes mellitus.

C57BL/KsJ-db/dband C57BL/KsJ-ob/obmice are good models for studies on human obesity and type 2 diabetes. We have previously shown that infection with blood-stage malaria or injection of extracts from malaria-parasitized red blood cells induces hypoglycemia in normal mice and normalizes hyperglycemia in mice made moderately diabetic by streptozotocin. In the present study, we show that a single intravenous (IV) injection of Formalin-fixed Plasmodium yoeliiYM (FFYM) preparation decreases blood glucose in db/dbmice from an initial value of 19 mmol/L to a normal value of 7 mmol/L (P< .0001) for at least 24 hours and reduces food intake. Plasma insulin concentrations in db/dbmice were not altered. FFYM was also active in normal and ob/obmice, an effect associated with an increase in plasma insulin. Although the rate of weight gain in lean ob/+ and lean db/+ was not altered by this treatment, there was a significant reduction in weight gain in db/dband ob/obmice (P< .001). We suggest that malaria-derived molecules, when fully characterized, may provide structural information for the development of new agents for the management of type 2 diabetes.