Fatty acids and saccharides from Costus spicatus (Jacq.) flower exhibits binding tendency towards phosphoenolpyruvate carboxykinase and α-amylase associated with insulin resistance in polycystic ovarian syndrome.

Polycystic Ovarian Syndrome (PCOS) is an endocrine disorder characterized by anovulation, oligomenorrhea, amenorrhea, hyperandrogenism and polycystic ovaries. PCOS affects 4-10% of women of reproductive age (15-49 years). PCOS often exhibit non-reproductive metabolic abnormalities such as obesity, elevated insulin, insulin resistance, dyslipidemia with a high propensity of cardiovascular disease and type II diabetes mellitus (DM).  Insulin resistance along with its compensatory hyperinsulinemia, are hallmarks of PCOS and predisposes women with this condition to a higher risk of impaired glucose tolerance and type 2 diabetes mellitus (T2DM). Studies have reported that 30-40% of women with PCOS have impaired glucose tolerance, and as many as 10% develop T2DM by the age of 40. In diabetic patients, an altered rate of gluconeogenesis is responsible for increased hepatic glucose output (HGO) and therefore, sustained hyperglycemia observed in both insulin-dependent DM and non-insulin dependent DM. Expression of the gene for cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C) is induced during diabetes, both in animals and in human patients. α-Amylase is responsible for postprandial glucose levels. One of the therapeutic targets currently introduced in the management of type 2 DM is the inhibition of α-amylase to decrease the reabsorption of glucose in the intestine and postprandial blood glucose levels. Medicinal plants encompass a rich source of active compounds that have anti-diabetic properties. Costus spicatus, commonly known as Insulin plant, whose flower has been used in folkloric medicine to treat diabetes mellitus and other associated pathological manifestations. The current therapeutic approach to treating PCOS involves the use of insulin sensitizers such as metformin, since the central core of PCOS etiology is through insulin resistance. Therefore, phytosterols and saccharides from aqueous extract of Costus spicatus flower were investigated for their inhibitory activities against PEPCK and α-amylase in silico as potential novel therapeutic targets for diabetes mellitus treatment associated with PCOS. Phytochemical constituents of the plant were determined using Gas Chromatography-Mass Spectrophotometry (GC-MS), while molecular docking of the compounds with PEPCK and α-amylase was carried out using Vina. Thereafter, the binding modes were determined using Discovery Studio Visualizer, 2020. GCMS analysis of aqueous extract of Costus spicatus flower revealed the presence of several compounds including; Methyl 6-O-[1-methylpropyl]-beta-d-galactopyranoside, O-Decylhydroxylamine, Acetic acid phenyl ester, Formic acid phenyl ester, d-Lyxo-d-manno-nononic-1,4-lactone, galacto-heptulose palmitoleic acid, and oleic acid.  Molecular docking revealed that Methyl 6-O-[1-methylpropyl]-beta-d-galactopyranoside, O-Decylhydroxylamine, Acetic acid phenyl ester, Formic acid phenyl ester, d-Lyxo-d-manno-nononic-1,4-lactone, galacto-heptulose, palmitoleic acid, and oleic acid had higher binding affinity values between (-5.9 to -9.1 kcal/mol) for PEPCK and (-5.4 to -7.9 kcal/mol) for α-amylase compared to the standard drug metformin’s -5.5 kcal/mol PEPCK and -5.0 kcal/mol for α-amylase. The compounds also interacted with key amino acid residues crucial to the enzyme’s activities.

This study identified three phytosaccharides; Methyl-6-O-[1-methylpropyl]-beta-galactopyranoside, galacto-heptulose, d-Lyxo-d-manno-nononic-1,4-lactone and two fatty acids; oleic acid and palmitoleic acid as potential multi-target inhibitors of PEPCK and α-amylase. Therefore, these compounds can be explored as potential therapeutic agents for the management of insulin resistance in PCOSsubject to further experimental validation.