Salvia triloba attenuated insulin resistance in rats with type-2 diabetes induced by streptozotocin-nicotinamide.
Background
The genus Salvia, also known as sage, belongs to Lamiacae and comprises about 900 species worldwide. Many Salvia species are located in Mediterranean and possess therapotic uses against wideranging healthy problems. Owing to their hypoglycemic effects, some Salvia species have been found beneficial for diabetes(1). Salvia triloba is the most significant medical Salvia species used in Turkey (2). Though there being supportive evidences on determination antidiabetic properties of Salvia species, no study has been conducted to investigate Salvia triloba potency against diabetes until this time.

Aim
We aimed to evaluate the potential effects of Salvia triloba on diabetes type-2 (T2DM) and the mechanisms of action underlying of it. In case of it’s being found potent, we are hoping to offer an alternative approach to patients, via a preparation made of major components isolated from the plant.

Method
OGTT was applied on normal rats for dose selection, 200 mg/kg was found appropriate comparing with 100 and 400 mg/kg. To induce T2DM, after 15 minutes from the administration of nicotinamide (100 mg/kg), all rats were given a intraperitoneal injection of streptozotocin (55mg/kg). The Sprague-Dawley rats were divided into four groups as to be 6 rats for each: diabetic rats, diabetic rats treated orally with 400 mg/kg/day metformin, diabetic rats treated orally with 200 mg/kg/day Salvia triloba methanolic extract, normal rats treated orally with 10ml/kg/day saline. Blood samples were collected weekly to detect postprandial blood glucose levels (BGL). ITT, OGTT was performed on 15th and 18th days, respectively.  On 21th day, rats were decapitated for further investigations. Two-way ANOVA with Bonferroni post test were used for statistical analysis. 

Results
In diabetic rats, BGL was considerable higher (p<0.0001) than existing in the others. After 3 weeks, Salvia triloba extract, caused a remarkable drop in BGL by 45%. Specifically, the most critical reduction was performed at the end of first week by 30%, followed by a gradual fall in later weeks. Conversely, metformin lowered 57% of BGL at the end of experiment, consequently the proportions of decrease in BGL with the administration of Salvia triloba extract and metformin had parallelism. In OGTT, BGL rose significantly (p<0.0001) in diabetic and Salvia triloba  rats compared to normal and metformin groups, 30 min after of glucose challenge while the fluctations in that of metformin was found insignificant. However,  differences between the last value of BGL in Salvia triloba extract and metformin groups were not distinct (95,67±3,98 and 86.17±4.17, respectively). During ITT, diabetic rats were in a continuous declining (p<0.0001) trend. In Salvia triloba  and metformin groups, there was a slight decrease (nonsense) at 30th min of experiment. Moreover, BGL restoration rates in Salvia triloba  and metformin groups were 89% and 97%, respectively.

Discussion
T2DM rats showed severe hyperglycemia upon administration of glucose and impaired glucose tolerance following OGTT compared to sham and metformin, which this confirms the accurate establishment of model. OGTT and ITT are the indicators of insulin resistance and OGTT reflects the functions of beta-cells (3). During first 30 min of OGTT, Salvia triloba was effectless while metformin achieved to stabilize BGL. Nonetheless, from 30th min, Salvia triloba  reduced BGL in a sharp manner so that the last BGL of Salvia triloba and metformin groups were very similar. Hence, Salvia triloba extract could reverse BGL effectively. ITT showed that Salvia triloba rats preserved their BGL through tolerating challenge of insulin while diabetic rats were not able to do that.The results of both OGTT and ITT suggest that Salvia triloba extract attenuated insulin resistance. These curative effects can be mediated by the recovery of the damaged insulin releasing due to beta cell dysfunction and stimulated glucose uptake, consequently improving insulin sensitization and glucose utilization. In conclusion, this study point to the potential, therapotic influences of Salvia triloba on diabetic conditions through different mechanisms. 

1. Lopresti AL, Salvia (Sage): A Review of its Potential Cognitive-Enhancing and Protective Effects Drugs R D. 2017;17(1):53-64. 
2. Kosar M et al., A Simple Method to Obtain Essential Oils from Salvia triloba L. and Laurus nobilis L. by Using Microwave-assisted Hydrodistillation, Z Naturforsch C. 2005;60(5-6):501-4.
3. Stephen IS et al., Protective effects of Ficus carica leaves on glucose and lipids levels, carbohydrate metabolism enzymes and β-cells in type 2 diabetic rats, Pharm Biol. 2017;55(1):1074-1081.