The World Health Organization (WHO) defines Diabetes mellitus (DM) as a chronic metabolic disease characterized by elevated blood glucose levels. DM causes complications such as vascular diseases, heart conditions, blindness, renal failure, and neurological disorders. Type 1 diabetes (T1D), also known as insulin-dependent diabetes, is a chronic condition where the pancreas produces little or no insulin, which cannot be prevented. In contrast, Type 2 diabetes (T2D) typically occurs in adults, is the most common form, and is frequently associated with obesity. T2D can be prevented by avoiding complications and premature death. ¹

In 2022, an estimated 828 million adults worldwide had DM, with prevalence increasing in 155 countries for men and 132 for women. Between 1990 and 2022, age-standardized prevalence rose from 7% to 14%, justifying the need to explore alternative treatments. ²

In the Americas, 112 million adults over the age of 18 are living with DM. According to data released in a report by the Pan American Health Organization (PAHO), under the heading ‘country profiles - diabetes disease burden, 2023’, revealed that DM (excluding diabetic kidney disease) increased and that the total number of deaths in 2019 was 141 812 distributed in middle-to-high income groups. ³

A projection for 2045 in Latin America and the Caribbean (LAC) estimated that the number of people with DM would reach 49 million, with a prevalence of 11.9%. Globally, it is projected that by 2035, DM2 cases would rise to 643 million, a 50% increase from current figures. ⁴ A review study concluded that individuals with T2DM in Latin American developing countries face a higher risk of cardiovascular or all-cause mortality compared to those in developed countries. ⁵

Conventional therapies for DM1 include insulin administration, while DM2 relies on oral hypoglycemic agents such as metformin. The American Diabetes Association (ADA) 2024 guidelines recommend GLP-1 analogs and SGLT2 inhibitors as first-line treatments for MN2 patients with cardiovascular disease (CV), heart failure, or chronic kidney disease. ⁶

Hypoglycemia has been exposed as one of the most serious adverse side effects of anti-diabetic treatments. Numerous epidemiological studies have highlighted the importance of a diet rich in plant foods including vegetables, fruits, spices and condiments in the prevention and treatment of DM. Various plants are used for their anti-diabetic and hypoglycemiant c effects, such as Morus alba L. (‘mulberry’), Juglans regia L. (‘walnut’), which are widely used throughout the world. In Peru, there is a wide diversity of plant species with hypoglycemiant effects, some of which belong to traditional medicine and are being studied for their use and toxicity. ⁷

Various parts of the plant have been used to obtain extracts and identify their metabolites. Among the widely studied antidiabetic plants, M. alba “mulberry” stands out, whose metabolites present in the leaves include flavonoids such as rutin and quercetin-3-triglyceride, which were shown to have hypoglycemic and pharmacological effects on DM2 in animal models and humans, as synthesized in our ongoing phytochemical and pharmacological reviews. ^{8– 11}

Another plant to consider is A. wilkesiana Müll. Arg. whose aqueous extract prepared from its leaves revealed the presence of bioactive principles such as: coumarins, polyphenols, flavins, terpenes, tannins and saponosides, which have a potentiating effect on diabetic nephropathy. ¹²

In Iran, the hydrosol of J. regia is traditionally used to regulate blood sugar in patients with DM. Various bioactive metabolites have been identified in it, including flavonoids, phenolic compounds, limonene, myrcenes, linalool, beta-pharmesene, borneol monoterpenes, caffeic acid and coumaric acids, sinapic acid, ferulic acid, juglone, 1,4-naphthoquinone, 3-3′-bisjuglone, cyclo-tri-juglone, regiolone, tripertenes, betulin and botulinic acid. ^{13– 16}

In Peru, several medicinal plants, such as Geranium ayavacense Linnaeus. and Geranium ruizii Hieron (‘pasuchaca’), are recognized in traditional medicine for their medicinal properties. These plants have demonstrated hypoglycemic effects in experimental models using hyperglycemic rats ( Rattus rattus var. albinus), with leaves are used in infusions and flowers in hydroethanolic extracts. Other species with similar therapeutic properties include Psoralea glandulosa Linnaeus. (‘cullen’), Physalis angulata Linnaeus (‘mullaca’), and Smallanthus sonchifolius (Poepp.) H. Rob (‘yacón’). ^{17– 20}

Numerous studies on the genus Acalypha have demonstrated its pharmacological properties, including antimicrobial effects ( A. integrifolia and A. wilkesiana), anti-inflammatory effects ( A. fruticosa Forsskal.), and anticancer effects ( A. monostachya). ^{21– 24}

Acalypha argomuelleri Briq., commonly known as ‘Sweet stick’, is a species distributed from Ecuador to Peru. It is a shrub that primarily grows in tropical rainforest, found in the Andean region between 2,000 and 2,800 m.s.n.m. Taxonomically, it belongs to the class Equisetopsida, subclass Magnoliidae, order Malpighiales, family Euphorbiaceae, and the genus Acalypha. Euphorbiaceae is one of the largest plant families, comprising numerous genera and approximately 6,300 species; Acalypha is the third largest genus within this family, including around 500 species. ^{25, 26}

This study aimed to assess the hypoglycemic effect of the aqueous extract of Acalypha argomuelleri Briq. (EAAA) using an experimental model, as no scientific evidence is currently available regarding its medicinal properties. Despite its traditional use in folk medicine, the therapeutic potential of this species remains unexplored in the scientific literature. Therefore, this research seeks not only to address this gap but also to investigate the potential of Acalypha. argomuelleri as a natural alternative for glycemic control—an approach that could prove beneficial for communities that rely heavily on traditional medicine.

The study was carried out between January and December 2024. During this period, the following stages were completed: collection and botanical identification of the plant material, conditioning and acclimatisation of the experimental animals, as well as the preparation and administration of the alcoholic extract, followed by that of the aqueous extract of Acalypha argomuelleri Briq. The experimental phase was then carried out in the experimental physiology laboratory of the Universidad Nacional Pedro Ruiz Gallo between June and December. Blood glucose measurements were taken at specific times according to the experimental design, and the data obtained were statistically analysed to evaluate the hypoglycaemic effect of the extract. Although extended measurements de 120 y 180 minutes) may provide additional information, our study focused on the early hypoglycaemic response, adequately captured within 90 minutes. Future studies will consider longer follow-up times, especially in diabetic and chronic models.

The research followed a quantitative, true experimental approach, appropriate for the study as it allows the establishment of causal relationships between the administration of the extract and changes in glucose levels. The study was prospective with a longitudinal design. A completely randomized design with control and treatment groups was used to evaluate the hypoglycemic effect of the aqueous extract of A. argomuelleri (AEAA) in hyperglycemic Rattus rattus var. albinus. a.

The male rats were housed in metal cages containing sterile wood shavings. The temperature was controlled at 20–24 °C, the humidity at 50–60%, and the lighting was on a 12-hour cycle. They were fed a standard diet and had access to water at all times. No environmental enrichment was applied. a.

The protocol avoided painful procedures. Nontoxic doses were used, and animals were monitored regularly.

The corresponding permits were obtained from the National Forest and Wildlife Service (SERFOR) (Resolutions No. D000120-2023-MIDAGRI-SERFOR-ATFFS-CAJAMARCA and No. D000167-2024) for the collection of Acalypha argomuelleri Briq., as well as authorization from the Research Department of the Lambayeque Regional Hospital (HRL), including approval from the Institutional Research Ethics Committee for the use of animals (No. 026-2025).

The collection of A. argomuelleri Briq. leaves at the flowering stage were carried out in the district of Querocoto, Chota province, Peru. The leaves of the plant were used, taking into account the traditional medicinal use by the population. The coordinates of the collection area were 6°24′53″S 79°04′03″W. In situ plant samples were taken and transported to the Universidad Nacional de Trujillo, where they were deposited in the Herbarium Truxillensis (HUT) (Trujillo–La Libertad) for proper identification and registration under number 65645 on 20/09/2024.

No previous protocol was registered en a public database. The experimental design was reviewed and approved by the Hospital ethics Committee.

Phytochemical analysis of A. argomuelleri leaves revealed the presence of flavonoids in moderate proportions, high levels of phenolic compounds, and the absence of sugars. This bioactives compounds, commonly found in other Acalypha species, may have been responsible for the observed effects on glucose regulation due to their highly significant hypoglycemic medicinal properties. Previous studies have documented that the hypoglycemic effects of plants associated with the presence of flavonoids and phenols, for example M. alba y A. wilkesiana, are often attributed to their ability to enhance the function of pancreatic tissue, specifically the β-cells. This effect may be achieved either by stimulating insulins secretion or by reducing intestinal glucose absorption. ^{12, 31}

These results ( Table 1) suggest that, in the absence of AEAA, the glycemic homeostasis of the rats remained relatively stable over time, although individual fluctuations were observed. Such variations could be influenced by physiological factors such as basal metabolism, prior diet, or compensatory responses to fasting before treatment administration. ³²

The results obtained with AEAA at a dose of 100 mg/kg showed a variable response in blood glucose levels in rats, indicating a partially regulatory effect with individual differences in response and, consequently, a lack of uniformity in outcomes. This variability could be related to the action of the extract´s bioactive compounds—mainly flavonoids and phenols—which are known to modulate glucose metabolism. Additionally, these variations might be attributed to genetic factors, differences in extract absorption, or the complexity of interactions involving flavonoids and phenols. ³³

At a dose of 150 mg/kg, a progressive decrease in blood glucose levels was observed in most rats, reaching near-normal values at 60 and 90 minutes. The lower individual variability and grater stability in glucose levels at 90 minutes suggest that this dose of AEAA may be more effectively modulating glucose absorption and metabolism than the 100 mg/kg dose. This effect could be attributed to the action of bioactive compounds, primarily flavonoids and phenols, which according to various studies, can influence glycemic homeostasis through mechanisms such as the inhibition of digestive enzymes (α-glucosidase y la α-amylase) and stimulation of insulin secretion. ³⁴ Furthermore, the observed response in this treatment indicates that, although the effect is significant, individual differences persist, which may be linked to genetic factors or variations in the absorption and bioavailability of the extract. ³⁵

In contrast, the results obtained with AEAA at a dose of 300 mg/kg showed a faster, sustained, and more uniform reduction in blood glucose levels. The average basal glucose recorded before hyperglycemia induction was 78 mg/dL reaching a peak of 391 mg/dL, which is characteristic of the experimental model. However, by 90 minutes glucose values were significantly lower compared to other treatments, suggesting that this dose has a more pronounced and long-lasting hypoglycemic effect.

This more consistent response could be linked to a higher concentration of bioactive compounds that optimize glucose utilization in peripheral tissues, promoting more effective regulation of glycemic homeostasis. ³⁶ Additionally, it has been proposed that flavonoids and phenols present in Acalypha species not only stimulate insulin secretion but also protect pancreatic β-cells by reducing oxidative stress and modulating the expression of pro- and anti-apoptotic genes. ^{37, 38}

The 300 mg/kg dose demonstrated the highest hypoglycemic efficacy, with a sustained reduction in blood glucose levels to near-normoglycemia values at 90 minutes. This finding combined with the absence of reducing sugars in the extract, suggests that the optimal concentration of flavonoids and phenols may act effectively through a multifactorial mechanism targeting multiple metabolic pathways: (1) inhibition of α-glucosidase, (2) modulation of intestinal glucose absorption, and (3) protection of pancreatic β-cells against oxidative stress — key mechanisms associated with antidiabetic effects in plants such as M. alba and other Acalypha species. ⁸

However, the variability observed (CV > 50% at 30 minutes) highlights the influence of individual factors such as basal metabolism, bioavailability of active compounds, and hormonal fluctuations, ³⁹ which could affect treatment response and therapeutical efficacy. Future studies—including a comprehensive phytochemical analysis and chronic diabetes models—will clarify whether A. argomuelleri Briq. Possesses additional antidiabetic effects (e.g., improvement insulin resistance or reduction of systemic oxidative stress). Current evidence indicates that the hypoglycemic effect of AEAA is dose-dependent, suggesting that the highest dose is the most effective long-term. This finding aligns with other studies in experimental models, where doses ranging from 200 to 500 mg/kg showed significant glucose reduction by 120 minutes. ^{40– 42}

Eight rats per group were used, which is an adequate and commonly accepted number in preclinical pharmacological evaluation studies. This sample size allowed statistically significant differences to be observed between groups, although it is recognized that further studies with larger samples could strengthen the evidence and facilitate the exploration of additional mechanisms.

While the results obtained provide evidence of the hypoglycemic effect of A. argomuelleri Briq., it is important to note that this study was conducted in an experimental model using healthy albino rats. Future studies could evaluate the extract’s impact on induced diabetes models to determine its effectiveness under pathological conditions. Additionally, more detailed phytochemical analyses would be relevant to identify the compounds responsible for the hypoglycemic effect and elucidate their mechanism of action.

Taken together, these findings suggest that AEAA could represent a natural alternative in complementary medicine for blood glucose control, with potential therapeutic applications in the management of type 2 diabetes mellitus (T2DM). Even though EAAA showed a significant hypoglycaemic effect in the animal model, it is not possible to assign a percentage of efficacy in humans without conducting controlled clinical studies. It would be prudent, and by analogy with other phytochemicals used as adjuvants, to consider that it would have a modest effect as a complementary therapy, provided that standardised extracts are available. The next phase of this study will involve evaluating the antidiabetic effect in a specific animal model for DM2 and, in addition, characterising the specific bioactive metabolites by conducting toxicological studies to ensure their safety and identify the compounds responsible for the observed activity. Likewise, in order to move towards a marketable pharmaceutical product, sequential steps are required, including standardisation under GMP (Good Manufacturing Practices) standards, pharmacokinetics and clinical trials in all phases.

It is suggested that the findings could be a basis for studies in other animal models or in humans, although a direct clinical application is not yet proposed.

This study represents a pioneering contribution to the evaluation of the hypoglycemic effect of the aqueous extract of Acalypha argomuelleri Briq. (AEAA) in albino rats, as o prior documented research exists on the species in relation to blood glucose regulation. The key findings are as follows: •

The aqueous extract of Acalypha argomuelleri Briq. At a dose of 300 mg/kg, significantly reduced blood glucose levels in Rattus rattus var. albinus compared to the control group, demonstrating a dose-dependent hypoglycemic effect.

The corresponding permits were obtained from the National Forest and Wildlife Service (SERFOR) (Resolutions No. D000120-2023-MIDAGRI-SERFOR-ATFFS-CAJAMARCA and No. D000167-2024) for the collection of Acalypha argomuelleri Briq., as well as authorization from the Research Department of the Lambayeque Regional Hospital (HRL), including approval from the Institutional Research Ethics Committee for the use of animals (No. 026-2025).