Anti-diabetic and anti-inflammatory effects of medicinal plants in a type 2 diabetic animal model

Medicinal plants have been suggested since ancient times to be a good source of drugs for treating diabetes. The aims of this thesis were to identify the anti-diabetic effects and to understand further the mechanisms involved for two traditional plants, borapetol B (C1) isolated from Tinospora crispa, and Gynostemma pentaphyllum (GP), in diabetic rats. The effects of GP extract on innate immune mechanisms in the urinary tract were also investigated.

In Paper I, an oral administration of C1 significantly decreased blood glucose levels and increased plasma insulin levels in treated rats, compared to placebo groups, in both Wistar (W) and diabetic Goto Kakizaki (GK) rats. C1 dose-dependently increased insulin secretion from W and GK rat islets. In perifusions of W and GK rat islets, insulin secretion was increased by C1 in low and high glucose, and returned to basal levels when C1 was omitted, indicating that the compound did not cause leakage of insulin by damaging islet beta cells. This study provides evidence that C1 possesses anti-diabetic properties mainly due to its stimulation of insulin release.

In Paper II, when exploring the mechanisms of insulin release in W and GK pancreatic islets we showed that the C1 effect was partly via K-ATP channels, since the potassium channel blocker diazoxide partly but not totally suppressed C1 stimulation at 16.7 mM glucose. The C1 effect was also dependent on L-type Ca2+ channels, since the calcium blocker nifedipine suppressed the insulin response to C1 at 16.7 mM glucose. There was no modulation by PKA and PKC inhibitors. Furthermore, the C1 effect was partly dependent on pertussis toxin sensitive Ge-protein. Therefore, the major stimulatory effect of C1 might be on the process of exocytosis.

In Paper III, two weeks’ treatment with GP extract in GK rats significantly improved blood glucose, plasma insulin levels and insulin secretion from islets isolated from the treated rats. Furthermore, when tested in vitro, GP extract dose-dependently stimulated insulin release from the isolated rat islets at high glucose concentrations. GP-induced insulin release is partly mediated via K-ATP and L-type Ca2+ channels. The effects of GP were also mediated via the PKA system, and partly dependent on pertussis toxin sensitive Ge-protein at high glucose concentrations.

In Paper IV, ex vivo infection experiments demonstrated that the pro-inflammatory response to E. coli was attenuated in bladder tissue from diabetic GK rats receiving GP extract, compared to untreated rats. In vitro assays using uroepithelial cells challenged with E. coli corroborated these results. Moreover, GP treatment modulated the expression of antimicrobial peptides. With these properties, GP might be a beneficial supplement for diabetic patients with a history of urinary tract infection.

List of scientific papers

I. Ezarul Faradianna Lokman, Harvest F. Gu, Wan Nazaimoon Wan Mohamud, Mashitah M. Yusoff, Keh Leong Chia, Claes-Göran Östenson (2013). Anti-diabetic effect of oral borapetol B compound, isolated from the plant Tinospora crispa, by stimulating insulin release. Evidence Based Complementary and Alternative Medicine.
https://doi.org/10.1155/2013/727602

II. Ezarul Faradianna Lokman, Harvest F. Gu, Wan Nazaimoon Wan Mohamud, Mashitah M. Yusoff, Keh Leong Chia, Claes-Göran Östenson (2014). The possible mechanisms on stimulation of insulin release in pancreatic islets by borapetol B isolated from Tinospora Crispa. International Journal of Medicine and Medical Sciences 47(1): 1461-1468.

III. Ezarul Faradianna Lokman, Harvest F. Gu, Wan Nazaimoon Wan Mohamud, Claes-Göran Östenson. Evaluation of anti-diabetic effects of Gynostemma Pentaphyllum on insulin release. [Submitted].

IV. Petra Lüthje, Ezarul Faradianna Lokman, Claes-Göran Östenson, Annelie Brauner. Gynostemma pentaphyllum exhibits anti-inflammatory properties and modulates antimicrobial peptide expression in the urinary bladder. [Submitted].