Evaluation Of The Antidiabetogenic Effects Of The Freeze-Dried Extracts Of Rotheca Myricoides On Type 2 Diabetes In An Animal Model

Abstract

Type 2 diabetes is a complex metabolic disorder essentially characterized by alterations in lipid metabolism, insulin resistance and pancreatic β-cell dysfunction. Rotheca myricoides (Hochst.) Steane & Mabb is a plant frequently used in traditional African medicine in the management of diabetes. Type 2 diabetes accounts for 90% of diabetes with obesity being the most common risk factor for the development of T2D. Current treatment modalities do not cure or reverse the progression of the disease as end organ damage still develops despite adequate glycaemic control, underscoring the need for newer more efficacious drugs for the management of T2D. This study evaluated the antidiabetogenesis effects of freeze-dried extracts of Rotheca myricoides (Hochst.) Steane & Mabb in a diet and low dose streptozocin type 2 diabetes animal models. Type 2 diabetes was induced by dietary manipulation for 56 days and intraperitoneal administration of streptozocin (30 mg/kg). The extracts and pioglitazone were administered throughout the study period by daily oral gavage. The study was conducted in two phases. In the first phase (efficacy experiment), forty (40) freshly-weaned Sprague Dawley rats were randomly assigned into the negative control (high fat/ high fructose diet), low dose test (50mg/kg RMFE), high dose test (100mg/kg RMFE) and positive control (Pioglitazone, 20mg/kg) groups. In the second phase (mechanism of action experiment), twenty-four rats (24) were randomly assigned to the negative control (normal saline), positive control (50mg/kg extract), test group I (50 mg/kg extract plus 23mg/kg indinavir sulphate) and test group II (Indinavir sulphate 23mg/kg). Physiological and biochemical tests assayed include body weight, fasting blood sugars, oral glucose tolerance test, fasting serum insulin levels, lipid profile, hepatic triglycerides, hepatic index, adipose tissue weights, serum uric acid and branched-chains amino acids, and fasting insulin levels. The extract lowered the body weight of the rats by inhibiting the enzyme fatty acid synthase which is important in fatty acid synthesis (P < 0.0001). The extract also decreased fasting blood glucose and improved insulin sensitivity which was attributed to the enhanced glucose uptake by adipose tissue and muscle secondary to the xiii upregulation of GLUT-4 transporters expression (P < 0.0001). The liver indices were also reduced [hepatic triglycerides, liver weight, hepatic weight to body weight ratio (P < 0.0001)]. This was attributed to the improvement in insulin signalling. The extract lowered the serum lipids which was directly attributed to the improvement in insulin signalling, activation of PPAR α receptor which activates the gene for liver acyl-CoA oxidase increasing fatty acid oxidation in the liver, this action lowers hepatic lipids and in effect, serum lipid levels, controlling and preventing the hyperlipidaemia seen in diabetes. The extract caused a reduction of adipose tissue weights by activating AMPK pathway and preventing the accumulation of ectopic fat (P < 0.0001). A reduction of branched-chain amino acid was attributed to increased expression of the branched-chain ketoacid dehydrogenase complex, hence upregulation of adipose tissue branched-chain amino metabolizing enzyme. The reduction in serum uric acid exhibited by Rotheca myricoides (Hochst.) Steane & Mabb was due to reduced cellular oxidative stress. The freeze-dried extracts of Rotheca myricoides (Hochst.) Steane & Mabb possessed significant antihyperglycemic and anti-dyslipidemic effects. In addition, it lowered body weight, adipose tissue weight, branched-chain amino acids, serum uric acid, as well as hepatic triglycerides and hepatic weight. These findings therefore demonstrate that Rotheca myricoides (Hochst.) Steane & Mabb possesses antidiabetogenesis effects in an animal model of type 2 diabetes.