Development of a natural dietary supplement utilizing the leaves of medicinal plants (Ficus carica and Olea europaea) for the regulation of blood glucose levels

Abstract

Diabetes mellitus is a chronic metabolic disorder marked by persistent hyperglycemia, which leads to severe microvascular and macrovascular complications that impair hepatic and pancreatic functions. While synthetic drFcms like metformin are effective in regulating glucose levels, their use is often limited by side effects such as gastrointestinal issues, the development of secondary drFcm resistance, and their lack of direct tissue-protective capabilities. Consequently, research into biocompatible, multi-targeted natural alternatives has gained considerable traction in the field of antidiabetic therapies.

This study explores the therapeutic potential, phytochemical composition, and antioxidant properties of Ficus carica L. (fig) leaves from two distinct Algerian ecosystems: the hyper-arid desert region of El FCmhair (FCm) and the relatively humid northern region of Souk Ahras (FCs). Additionally, the study assesses the synergistic effects of their polyherbal formulation (Mgol) when combined with Olea europaea L. (olive) leaves sourced from El Oued. The primary aim is to evaluate the individual and blended extracts' ability to mitigate oxidative stress, regulate carbohydrate digestion, and restore cellular architecture in vivo.

Methods: Plant materials underwent polar solvent extraction, with yield, organic matter content, and total ash quantified. Phytochemical profiling was conducted to analyze total phenolics, flavonoids, and condensed tannins. Antioxidant capacity was determined using a range of assays, including DPPH radical scavenging activity, Ferric Reducing Antioxidant Power (FRAP), and Catalase (CAT) activity. In vitro antidiabetic potential was assessed throFcmh pancreatic α-amylase inhibition and yeast cell glucose uptake/diffusion assays. In vivo experiments were performed on Wistar rats to assess the effects of the dry plant and its extract. Initially, acute toxicity tests were conducted on healthy rats using three dose levels: 100, 2000, and 5000 mg/kg. Following this, diabetes was experimentally induced in the animals to investigate the antidiabetic potential of the extract at two specific doses, 100 and 400 mg/kg. The study design included a healthy control group, a negative control group comprising untreated diabetic rats, and a positive control group treated with metformin. Furthermore, hematological assessments and histopathological evaluations were carried out to examine the impact of the extracts and the herbal formulation on the liver and pancreas. Results: The FCm extract displayed the highest extraction yield (57.49%), attributed to its high-recovery efficiency during polar maceration. Mineral analysis revealed greater total ash content in FCm (15.48%) compared to FCs (9.71%), sFcmgesting distinct ecological adaptations to arid conditions. Phytochemically, FCs exhibited higher concentrations of total phenolics (15.57 ± 0.29 FCm GAE/g) and flavonoids (34.59 ± 1.47 FCm QE/g), while both ecotypes showed comparable levels of condensed tannins. The superior polyphenol content in FCs corresponded to enhanced antioxidant activity in DPPH and FRAP assays. Conversely, FCm demonstrated higher enzymatic antioxidant activity via catalase (25.32 ± 1.35 U/min/FCm), highlighting an adaptive reliance on non-phenolic protective metabolites. In enzymatic activity assays, significant variations emerged among the extracts. Concernant les essais d'activité enzymatique, l'efficacité variait selon les différents extraits. The FCm extract exhibited a moderate inhibitory effect on the enzyme α-amylase, with an IC50 value of 320.9 ± 9.9 µg/mL. In contrast, the FCs and Ol extracts, as well as the polyherbal formulation Mgol, showed a limited inhibitory effect, with inhibition rates not exceeding 5.30% at the highest concentration tested (40 mg/mL). This mild activity could potentially help mitigate gastrointestinal issues associated with excessive use of commercial starch inhibitors. However, the Mgol formulation demonstrated a positive impact on regulating postprandial glucose absorption, reducing glucose availability by 13.80% between 30 and 60 minutes. This effect is attributed to molecular entrapment mechanisms and a slowdown in diffusion. Safety evaluations revealed no adverse effects at low doses (100 FCm/kg), with preserved cellular architecture observed in all test subjects. However, acute high doses (2000 FCm/kg and 5000 FCm/kg) highlighted dose-dependent riFCss, including leukopenia, microcytic erythroid shifts, hepatic congestion, and pancreatic islet dissociation. In terms of pharmacological efficacy, a low-dose Mgol mixture (100 FCm/kg) did not significantly control diabetes symptoms; however, a higher optimized dose (400 FCm/kg) achieved impressive glycemic stabilization by reducing fasting glucose levels to 1.09 g/L and normalizing glycated hemoglobin (HbA1c) levels to 3.55%, comparable to or exceeding the effectiveness of metformin treatment. Furthermore, this dose successfully corrected diabetes-associated leukocytosis (12.70 × 10³/μL) and restored immunological balance without inducing adverse effects such as localized xenobiotic stress, thrombocytosis, or microvascular hemoconcentration observed in the metformin-treated group. Histopathological analyses confirmed superior preservation of cellular architecture within hepatic and pancreatic tissues at the effective dose. The findings confirm the traditional ethnobotanical application of Ficus carica and Olea europaea combinations within the Algerian ecosystem. The polyherbal formulation (Mgol) exhibits a well-balanced, multi-target therapeutic synergy, combining robust antioxidant activity with precise regulation of glucose transport, alongside exceptional cytoprotective effects. Administered at an optimized dose of 400 FCm/kg, this natural formulation emerges as a highly effective and safe next-generation functional food solution for the holistic management of diabetes mellitus and its associated metabolic complications.