Reversal of type 2 diabetes in mice by products of malaria parasites II. Role of inositol phosphoglycans (IPGs)

We have previously shown that infection with Plasmodium yoelii malaria or i njection of extracts from malaria-parasitized red cells induces hypoglycemi a in normal mice and normalizes the hyperglycemia in mice made moderately d iabetic with streptozotocin. Inositol phosphoglycans (IPGs) are released ou tside cells by hydrolysis of membrane-bound glycosylphosphatidylinositols ( GPIs), and act as second messengers mediating insulin action. The C57BL/Ks- db/db and C57BL/6J-ob/ob mice offer good models for studies on human obesit y and Type 2 diabetes. In the present study, we show that a single iv injec tion of IPG-A or IPG-P extracted from P. yoelii significantly (P < 0.02) lo wers the blood glucose in STZ-diabetic, db/db, and in ob/ob mice for at lea st 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(-8) M) (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 afte r 24 h hydrolysis revealed the presence of myo-inositol, phosphorus, galact osamine, glucosamine, and glucose in both IPG-A and IPG-P. However, hydroly sis of IPGs for 4 h highlighted differences between IPG-A and IPG-P. There are some functional similarities between P. yoelii IPGs and those previousl y described for mammalian liver. However, this is the first report of the h ypoglycemic effect of IPGs in murine models of Type 2 diabetes. We suggest that IPGs isolated from P. yoelii, when fully characterized, may provide st ructural information for the synthesis of new drugs for the management of d iabetes mellitus. (C) 2001 Academic Press.