Diabetes mellitus is becoming an increasing concern all over the world. Many people especially in poor communities have been using medicinal plants to treat diabetes and its complications. Much work has been done to find scientific evidence to support the use of medicinal plants in many cases with good evidence to support the traditional use. There has been an increase in research on the use of botanicals for either the treatment and/or management of diabetes in many parts of the world. To start this study an informal survey on plant species used to treat diabetes was carried out with local inhabitants and herbal traders in the Newcastle region (KwaZulu Natal). The plant species were chosen based on their wide use by traditional healers and local inhabitants. The efficacy of the selected plant (Senna alexandrina, Cymbopogon citrates, Cucurbita pepo, Nuxia floribunda, Hypoxis hemerocallidea and Cinnamomum cassia) used to treat diabetes mellitus by traditional healers in KwaZulu Natal province of South Africa was evaluated under controlled laboratory conditions. With the exception of Senna alexandrina and Nuxia floribunda, there has been some independent evidence of the efficacy of these plant species In this study three relevant in vitro and semi in-vivo assays were selected to test the efficacy of different extracts on alpha amylase (carbohydrate digestive enzyme) activity, alpha glucosidase (glucose absorption) activity and islets of Langerhans insulin secretory activity. Hexane, ethyl acetate, acetone and methanol extracts were examined and screened for their phytochemical properties and activity in the selected assays Alpha amylase inhibitory assay Not all extracts of the plant species had α-amylase enzyme inhibitory activity. The acetone extracts of C. pepo and H. hemerocallidea had enzyme inhibition less than that of acarbose positive control (EC50 = 1.82, 0.92 and 0.56 mg/ml respectively). The other plant species that had substantial α-amylase inhibitory activity was the methanol extracts of C. citratus and C. cassia (EC50 = 0.313 and 0.12 mg/ml respectively), ethyl acetate extracts of C. citratus and N. floribunda (EC50 = 1.20 and 1.60 mg/ml respectively). The hexane extracts of C. cassia (0.72 mg/ml), N. floribunda (0.88 mg/ml), C. pepo (0.70 mg/ml) and S. alexandrina (0.083 mg/ml) all had α-amylase inhibitory activity.The best activity was present in the intermediate polarity extracts. If these more apolar plant extracts are not toxic or do not have negative side effects they may be much more efficient than acarbose in managing α-amylase activity. Alpha glucosidase inhibitory assay In contrast to the alpha amylase activity, the inhibitory activity of the non-polar (hexane and ethyl acetate) plant extracts was in general higher than that of polar extracts. With the methanol and acetone extracts the inhibitory activity varied from no activity in the methanol extract of C. cassia to highly active methanol extract of C. pepo (70.3%) and acetone extract of H. hemerocallidea (84.35%). Among the plants studied C. cassia and N. floribunda (bark) had the highest inhibitory activity in the hexane and ethyl acetate extracts, the acetone extract of H. hemerocallidea had the highest inhibitory activity. The hexane crude extracts ofN. floribunda and C. citratus had very high inhibitory activity at the highest concentration tested (1 mg/ml). The ethyl acetate crude extracts of all the plant species used in this study had an inhibitory activity above 90% against α-glucosidase at 1 mg/ml. When compared to acarbose all the plant species used in this screening study had good activity against the α-glucosidase enzyme with the exception of the methanol extract of C. cassia. The inhibitory activity of hexane and ethyl acetate extracts was close to that of the positive control. If the more non-polar plant extracts are not toxic or do not have negative side effects (not tested) it appears that they may be more or less efficient than acarbose in managing α-glucosidase activity. Islets of Langerhans as a target site Only with the H. hemerocallidea acetone extract was there an increase in insulin secretion of 2.5 mIU/L (Table 8) at 8 ug/ml. With all the other extracts the insulin levels were less than 0.2 mIU/L. The positive controls of acarbose and glibenclamide at a concentration of 1 mg/ml stimulated insulin secretion to 11.5 and 19.8 mIU/L respectively. In comparison, the positive controls acarbose and glibenclamide control produce a 5-8 fold greater increase in insulin secretion although the exposure was at a 100-fold higher concentration. This would indicate that the H. hemerocallidea acetone crude extract contains a very potent secretogogue compound. It is possible that higher concentrations of the other plant extracts may also have led to stimulation of insulin production. If the more non-polar plant extracts are not toxic or do not have negative side effects and are biologically available, it appears that they may be much more efficient than acarbose and glibenclamide in managing insulin secretion. Conclusion The best overall activity was observed in the non-polar and intermediate solvents (hexane and ethyl acetate). Although the organic extracts had good activity, it does not explain the use of aqueous extracts by traditional healers because water extracts were not active in the assays. The activity of the C. pepo acetone leaf extract and N. floribunda ethyl acetate bark extract is the first reported evidence of activity with regard to diabetes mellitus. From the in vitro results, it can be concluded some extracts of all the traditionally used species have some merit in the management of diabetes mellitus type II, as suggested by the ethnomedicinal leads. In may be worthwhile following up on this work by isolating the compounds responsible for the biological activities.