Pancreatic Beta Cell Regeneration Research Articles

Negative cell cycle regulation by calcineurin is necessary for proper beta cell regeneration in zebrafish.

Stimulation of pancreatic beta cell regeneration could be a therapeutic lead to treat diabetes. Unlike humans, the zebrafish can efficiently regenerate beta cells, notably from ductal pancreatic progenitors. To gain insight into the molecular pathways involved in this process, we established the transcriptomic profile of the ductal cells after beta cell ablation in the adult zebrafish. These data highlighted the protein phosphatase calcineurin (CaN) as a new potential modulator of beta cell regeneration. We showed that CaN overexpression abolished the regenerative response, leading to glycemia dysregulation. On the opposite, CaN inhibition increased ductal cell proliferation and subsequent beta cell regeneration. Interestingly, the enhanced proliferation of the progenitors was paradoxically coupled with their exhaustion. This suggests that the proliferating progenitors are next entering in differentiation. CaN appears as a guardian which prevents an excessive progenitor proliferation to preserve the pool of progenitors. Altogether, our findings reveal CaN as a key player in the balance between proliferation and differentiation to enable a proper beta cell regeneration.

Negative cell cycle regulation by calcineurin is necessary for proper beta cell regeneration in zebrafish

Stimulation of pancreatic beta cell regeneration could be a therapeutic lead to treat diabetes. Unlike humans, the zebrafish can efficiently regenerate beta cells, notably from ductal pancreatic progenitors. To gain insight into the molecular pathways involved in this process, we established the transcriptomic profile of the ductal cells after beta cell ablation in the adult zebrafish. These data highlighted the protein phosphatase calcineurin (CaN) as a new potential modulator of beta cell regeneration. We showed that CaN overexpression abolished the regenerative response, leading to glycemia dysregulation. On the opposite, CaN inhibition increased ductal cell proliferation and subsequent beta cell regeneration. Interestingly, the enhanced proliferation of the progenitors was paradoxically coupled with their exhaustion. This suggests that the proliferating progenitors are next entering in differentiation. CaN appears as a guardian which prevents an excessive progenitor proliferation to preserve the pool of progenitors. Altogether, our findings reveal CaN as a key player in the balance between proliferation and differentiation to enable a proper beta cell regeneration.

Exploring the therapeutic effects of Moringa Oleifera on inflammation and chronic diseases

Background: The inflammatory process is an immune system response to injuries, infections, or harmful stimuli. Chronic Diseases are diseases that are mostly immune-mediated by inflammatory mediators, and according to the World Health Organization, these diseases represent 74% of the causes of death in the world. Moringa oleifera (M. oleifera), is a versatile plant rich in bioactive compounds, has garnered attention for its potential therapeutic properties. Objective: this study aims to investigate the anti-inflammatory properties of M. oleifera and its potential influence on chronic diseases as well. Methods: This review was performed based systematic analysis of literature. Results: Anti-inflammatory activity was observed through the reduction in levels of IL-1, IL-6, IL-10, TNF-alpha, prostaglandin E2, and COX-2. Additionally, anti-hyperglycemic effects, normalization of lipid profiles, regeneration of hepatocytes and pancreatic beta cells, and a reduction in the concentration of reactive oxygen species were also described. Conclusion: These findings support the use of the M. oleifera plant as an effective treatment for diseases/disorders associated with inflammation.

Evaluation of Beta-cell Regeneration Property of Methanolic Extract of Momordica Dioica in Wistar Rat Model

Background: Despite the existence of various medications for diabetes, many individuals still struggle with the condition due to the potential side effects associated with current treatments. Traditional healers have long relied on medicinal plants with potential antidiabetic properties. One such plant is Momordica dioica, although its traditional use lacks experimental studies to support its efficacy in managing diabetes. Among them, Momordica dioica is one however there are no experimental studies on beta-cell regeneration that support the current traditional uses. Objective: The main aim of the current research is to identify Momordica dioica's methanolic extract's capacity for beta cell regeneration. Methods: Air-dried Fruit of Momordica Dioica was extracted using methanol, and acute oral toxicity studies were performed on methanolic extract in accordance with OECD guideline version 18. By using the HPTLC method, the Active Constituent in charge of the activity was verified. The HPTLC method was used to confirm active constituents that were responsible for the activity. The pancreatic beta cell regeneration as well as Fasting blood glucose level was used to evaluate the anti-diabetic effect. Single-dose STZ-induced type 2 diabetes mellitus was used to evaluate anti-antidiabetic activity. Results: Momordica dioica’s methanolic extract with doses of 100mg/kg and rest combination with standard showed a significant (p < 0.0001) anti-diabetic effect. Maximum anti-diabetic effects at doses as HE100mg/kg and all combinations were compared to standard and observed from Day 21 induction of diabetes by Streptozotocin; total tested doses of the extract inhibited the destruction of beta-cell significantly (p < 0.0001, p < 0.001). Conclusion: The existence of berberine, a quaternary ammonium salt of the alkaloid benzyl-iso-quinoline present in the extract, had a potential anti-diabetic effect and beta-cell regeneration property which supports the ancient beliefs.

Role of Human Umbilical Cord Blood-derived Stem Cells versus their Conditioned Medium on the Regeneration of Pancreatic Beta Cells in a Rat Model of Diabetes Mellitus

Role of Human Umbilical Cord Blood-derived Stem Cells versus their Conditioned Medium on the Regeneration of Pancreatic Beta Cells in a Rat Model of Diabetes Mellitus

In vivo study of celery (Apium graveolens L) extract for regenerating pancreatic β-cell

Background: The celery plant (Apium graveolens L.) is a widely distributed herbal plant globally known for being a significant source of natural active products, including phenolic compounds and antioxidants demonstrating antidiabetic activity. Previous research findings have indicated the impact of celery leaf extract on reducing blood glucose levels. However, up to now, there is a dearth of research investigating the potential effect of celery leaf extract on the regeneration of pancreatic beta cells in mice with diabetes models.Objective: This study aims to determine the effect of the ethanol extract of celery leaves on the number of pancreatic cells in Streptozotocin (STZ)-induced mice.Method: This research method uses a randomized controlled group posttest only design. Experimental animals were divided into five groups, including a group of experimental animals in a healthy condition, the group with hyperglycemia, hyperglycemia group with celery extract at 200 mg/kg BW, hyperglycemia group with celery extract at 400 mg/kg, and hyperglycemia group with extract celery is 800 mg/kg BW. Termination was performed on day 60 after therapy and pancreas hematoxylin and eosin staining. They are counting the number of cells with a photo slide with 400x magnification in 5 fields of view—statistical analysis using One-Way ANOVA.Results: The study revealed that celery extract could increase the number of pancreatic cells compared to the control group (P<0.002). Notably, the highest increase in pancreatic cell count was observed in the group administered with 400 mg/BW of celery extract.Conclusion: Celery leaf extract effectively increased the number of beta cells in vivo.

Trends in the Application of Stem Cells for the Treatment of Diabetes

Diabetes mellitus is a global epidemic that showed a dramatic worldwide increase in its incidence and has been associated with life threatening complications if not detected and managed properly. Even though, insulin and oral anti-diabetic drugs were used for its management, lots of efforts are made to improve patient’s care by pancreas and islet transplantation along with stem cell therapies like embryonic stem cells, induced pluripotent stem cells and adult mesenchymal stem cells. Adult stem cells, which are also termed as somatic stem cells or resident stem cells, are a type of undifferentiated cells, resided in a differentiated tissue, organ or organism, in a specialized structural local microenvironment, called stem cell niche. The stem cell niche, is the in vivo microenvironment where stem cells are located and receive extrinsic signals interact and integrate to influence stem cell behavior that generally determine their fate. ESC showed unlimited differentiation into insulin producing β-cells with ethical concerns. MSCs possess the capacity to differentiate into islet-like insulin producing cells, to promote the regeneration of pancreatic islet beta cells and protect endogenous pancreatic islet beta cells from apoptosis through immunomodulatory mechanisms.

Generation of a Transgenic Zebrafish Model for Pancreatic Beta Cell Regeneration

Background: Diabetes is a major worldwide health problem. It is widely accepted that the beta cell mass decreases in type I diabetes (T1D). Accordingly, beta cell regeneration is a promising approach to increase the beta cell mass in T1D patients. However, the underlying mechanisms of beta cell regeneration have yet to be elucidated. One promising avenue is to create a relevant animal model to explore the underlying molecular and cellular mechanisms of beta cell regeneration. The zebrafish can be considered a model in beta cell regeneration studies because the pancreas structure and gene expression pattern are highly conserved between human and zebrafish. Materials and Methods: In this study, the Tol2 transposase was exploited to generate a Tg(Ins:egfp-nfsB) zebrafish model that expressed a fusion protein composed of enhanced green fluorescent protein (EGFP) and nitroreductase (NTR) under control of the Ins promoter. Results: Metronidazole (MTZ) treatment of Tg(ins:egfp-nfsB) zebrafish larvae led to selective ablation of beta cells. Proof-of-concept evidence for beta cell regeneration in the transgenic larvae was observed two days after withdrawal of MTZ. Conclusion: This study suggests that the Tg(ins:egfp-nfsB) zebrafish can be used as a disease model to study beta cell regeneration and elucidate underlying mechanisms during the regeneration process. [GMJ.2019;8:e1056]

The effect of lemon extract (Citrus limon) on the blood sugar levels and pancreatic beta cell regeneration in alloxan-induced hyperglycemic mice

Background: High blood sugar levels that exceed normal limits or commonly refered to as hyperglycemia, is an early symptom of diabetes mellitus. Objectives: This study explored the effect of lemon (Citrus limon) extract on blood sugar levels and pancreatic b cell regeneration in alloxan-induced hyperglycemic mice (Mus musculus). Method: This research is an experimental study using a post-test group. The sampling was carried out using a randomization method. By administering 125 mg/kg BW of alloxan, the sample was conditioned for hyperglycemia. The samples were divided into five groups: normal control, alloxan-induced control, and three treatment groups that received lemon extract with dosages of 100 mg/kg BW, 300 mg/kg BW and 500 mg/kg BW, respectively. Semiquantitative analysis was used to evaluate pancreatic damage. Results: The results showed that lemon extract can decrease blood sugar levels. Histopathological imaging revealed a significant improvement in b cell distribution and decreased vacuolization in the Langerhans islets of mice administered lemon extract. No significant differences were observed among different dosages of lemon extract (p>0.05). Conclusion: Our findings underscore the potential therapeutic benefits of lemon extract in managing blood sugar levels and promoting pancreatic b cell regeneration in alloxan-induced mice.

Investigation of Kelussia Odoratissima and Angelica Sinensis Similarities in Zebrafish-based In-vivo Bioactivity Assays and Their Chemical Composition.

Kelussia odoratissima and Angelica sinensis are two medicinal plants commonly used in Iran and China, respectively. They have been used in their indigenous traditional medicine, for various diseases including, blood refining, inflammation, cold, flu, stress, cardiovascular diseases, and nervous disorders. This study was conducted to evaluate the volatile oil composition of K. odoratissima leaves (KVL) and A. sinensis root (AVR); we also examined the biological activity of essential oils (EOs) and hydroalcoholic extracts of both plants using two different transgenic zebrafish (Danio rerio) models: angiogenesis and pancreatic beta cell (pBC) regeneration models. Both EOs were isolated by hydrodistillation and analysed by GC and GC/MS. For viability tests, larvae were treated with different concentrations of extracts to determine an appropriate starting concentration. Hydroalcoholic extracts and EOs have been tested in a dose-dependent manner for their biological activity using tissue-specific transgenic zebrafish Tg(fli-1: EGFP) and Tg (ins: GFP-NTR) embryos and larvae. One-way ANOVA was used to compare the mean of pBC area and intersegmental vessels (ISVs) outgrowth between the treatment groups. Eleven compounds were in common to both oils, comprising 51.3% of KVL and 61.7% of AVR, of which 39.3% in KVL and 37.6% in AVR were phthalide structures. Results revealed that both EOs blocked ISVs formation in the Tg (fli-1: EGFP) embryos increased to 10% of the control value, while both hydroalcoholic extracts did not show any anti-angiogenesis effects in these embryos. In addition, AVR has been shown to significantly induce PBC regeneration following ablation in the Tg (ins: GFP-NTR), but its regenerative activity was lower than that of 5'-N-ethylcarboxamidoadenosine (NECA) as a positive control. Taken together, the anti-angiogenesis activity of both EOs could be attributed to the phthalide structures while for the PBC regenerative activity, other compounds including β-Thujaplicinol, exclusively existing in AVR, might be effective. Although the genera, organs, and origin of these plants are different, their similar chemical composition and biological activities make them valuable resources for further investigation in basic medical and pharmaceutical science.

Regeneration of Pancreatic Beta Cells by Modulation of Molecular Targets Using Plant-Derived Compounds: Pharmacological Mechanisms and Clinical Potential.

Type 2 diabetes (T2D) is characterized by pancreatic beta-cell dysfunction, increased cell death and loss of beta-cell mass despite chronic treatment. Consequently, there has been growing interest in developing beta cell-centered therapies. Beta-cell regeneration is mediated by augmented beta-cell proliferation, transdifferentiation of other islet cell types to functional beta-like cells or the reprograming of beta-cell progenitors into fully differentiated beta cells. This mediation is orchestrated by beta-cell differentiation transcription factors and the regulation of the cell cycle machinery. This review investigates the beta-cell regenerative potential of antidiabetic plant extracts and phytochemicals. Various preclinical studies, including in vitro, in vivo and ex vivo studies, are highlighted. Further, the potential regenerative mechanisms and the intra and extracellular mediators that are of significance are discussed. Also, the potential of phytochemicals to translate into regenerative therapies for T2D patients is highlighted, and some suggestions regarding future perspectives are made.

Bone morphogenetic protein-7 attenuates pancreatic damage under diabetic conditions and prevents progression to diabetic nephropathy via inhibition of ferroptosis.

Approximately 30% of diabetic patients develop diabetic nephropathy, a representative microvascular complication. Although the etiological mechanism has not yet been fully elucidated, renal tubular damage by hyperglycemia-induced expression of transforming growth factor-β (TGF-β) is known to be involved. Recently, a new type of cell death by iron metabolism called ferroptosis was reported to be involved in kidney damage in animal models of diabetic nephropathy, which could be induced by TGF-β. Bone morphogenetic protein-7 (BMP7) is a well-known antagonist of TGF-β inhibiting TGF-β-induced fibrosis in many organs. Further, BMP7 has been reported to play a role in the regeneration of pancreatic beta cells in diabetic animal models. We used protein transduction domain (PTD)-fused BMP7 in micelles (mPTD-BMP7) for long-lasting in vivo effects and effective in vitro transduction and secretion. mPTD-BMP7 successfully accelerated the regeneration of diabetic pancreas and impeded progression to diabetic nephropathy. With the administration of mPTD-BMP7, clinical parameters and representative markers of pancreatic damage were alleviated in a mouse model of streptozotocin-induced diabetes. It not only inhibited the downstream genes of TGF-β but also attenuated ferroptosis in the kidney of the diabetic mouse and TGF-β-stimulated rat kidney tubular cells. BMP7 impedes the progression of diabetic nephropathy by inhibiting the canonical TGF-β pathway, attenuating ferroptosis, and helping regenerate diabetic pancreas.

Effect of Momordica charantia on Insulin Immune-Reactive Pancreatic Beta Cells and Blood Glucose Levels in Streptozotocin-Induced Diabetic Rats.

The present study was conducted to determine the antidiabetic effect of Momordica charantia (MC) on pancreatic islets of Langerhans in streptozotocin (STZ)-induced diabetic male Wistar rats in relation to the distribution of insulin immuno-positive beta cells. MC was fed to rats at 2, 5, and 10% of the standard diet for 12 wk. After sacrification, the pancreatic tissues were obtained for histopathological and immunohistochemical observations. In addition, monitoring of fasting blood glucose was applied each month during experimental period. The results revealed that the oral doses of MC at 5% and 10% of the daily diet increased the percentage of insulin-positive pancreatic beta cells as well as the size and number of pancreatic islets. Moreover, significant (p≤0.0001) dose and time-depended reduction in fasting blood glucose levels were observed. In conclusion, these results suggest that MC induces antidiabetic effects via regeneration of insulin-positive pancreatic beta cells and increase the number of insulin secretory granules hence, blood glucose reduction.

Effect of Momordica charantia on Insulin Immune-reactive Pancreatic Beta Cells and Blood Glucose Levels in Streptozotocin-induced Diabetic Rats

The present study was conducted to determine the antidiabetic effect of Momordica charantia on pancreatic islets of Langerhans in streptozotocin-induced diabetic male Wistar rats in relation to the distribution of insulin immuno-positive beta cells. Momordica charantia was fed to rats at 2 %, 5 % and 10 % of the standard diet for 12 w. After sacrifice, the pancreatic tissues were obtained for histopathological and immunohistochemical observations. In addition, monitoring of fasting blood glucose was applied each month during experimental period. The results revealed that the oral doses of Momordica charantia at 5 % and 10 % of the daily diet increased the percentage of insulin-positive pancreatic beta cells as well as the size and number of pancreatic islets. Moreover, significant (p≤0.01) dose and time-dependent reduction in fasting blood glucose levels were observed. In conclusion, these results suggest that Momordica charantia induces antidiabetic effects via regeneration of insulin-positive pancreatic beta cells and increase the number of insulin secretory granules; hence, blood glucose reduction.

Antidiabetic Potential of Silver/Chitosan/Ascorbic Acid Nanocomposites

Background: Diabetes mellitus is the most common health problem in the world. Silver nanoparticles (AgNPs) exposed great intrinsic anti-inflammatory, antibacterial, antiviral, and antifungal activities. Chitosan is an oligosaccharide biopolymer with a great ability to lower hyperglycemia, and ascorbic acid is a water-soluble vitamin with strong antioxidant activity. Objective: The present study aimed to estimate AgNPs/chitosan/ascorbic acid nanocomposite (Ag-NCs) anti-diabetic properties in streptozotocin-induced diabetic rats. Method: Eighteen male Wistar albino rats were divided into three main groups (6 rats/group); control, diabetic, and Ag-NCs groups. Control group: after a single dose of citrate buffer at PH 4.5 (0.1 mol/L, i.p), the rats orally received 1 ml distilled water daily for four weeks. The diabetic model was induced by a single dose of streptozotocin (60 mg/kg, i.p) for type 1 diabetes and the rats orally received 1 ml distilled water daily for four weeks. The diabetic group was treated orally with Ag-NCs (0.25 mg/Kg body weight) daily for four weeks. Results: AgNPs/chitosan/ascorbic acid nanocomposite group showed a reduction in the concentrations of glucose, NO, MDA, LDL, and the activities of AST, ALT, ALP, and GGT. At the same time, it caused a general increase in insulin, albumin, TB, TC, TG, HDL, CAT, SOD, and GSH levels. The histopathological investigation illustrated regeneration of damaged pancreatic beta cells and a clear improvement in the hepatic architecture. Conclusion: The suggested mechanism of action for Ag-NCs in decreasing diabetic complications in the liver involved two pathways; the hypoglycemic activity and the antioxidant role of AgNPs, chitosan, and ascorbic acid.

Re – print- An Adjunct Treatment Reverses Chronic Insulin-dependent (Type 1) Diabetes in a Teenager

Globally, more than 30 million people suffer from diabetes mellitus type 1 (T1DM) characterized by pancreas producing little or no insulin hormone to facilitate glucose entering cells for energy production. T1DM patients tend to suffer a higher overall rate of atherosclerosis, cancer, and end-stage renal failure. No drug or surgical therapy seems to halt its annual upward trend amongst children and young adults. Consequently, a significant number of sufferers turn to complementary or alternative therapies for help to arrest this chronic endocrine condition. This paper discusses how a well-designed evidence-based dietary and nutritional therapy with some lifestyle modifications might offer a solution for this highly complex autoimmune disorder. The treatment outcome demonstrated a partial regeneration of pancreatic islet beta cells with substantial improvement for all relevant serum and urine markers tested.

Influence of Dipeptidyl Peptidase-4 (DPP4) on Mesenchymal Stem-Cell (MSC) Biology: Implications for Regenerative Medicine - Review.

Dipeptidyl peptidase IV (DPP4) is a ubiquitous protease that can be found in membrane-anchored or soluble form. Incretins are one of the main DPP4 substrates. These hormones regulate glucose levels, by stimulating insulin secretion and decreasing glucagon production. Because DPP4 levels are high in diabetes, DPP4 inhibitor (DPP4i) drugs derived from gliptin are widespread used as hypoglycemic agents for its treatment. However, as DPP4 recognizes other substrates such as chemokines, growth factors and neuropeptides, pleiotropic effects have been observed in patients treated with DPP4i. Several of these substrates are part of the stem-cell niche. Thus, they may affect different physiological aspects of mesenchymal stem-cells (MSC). They include viability, differentiation, mobilization and immune response. MSC are involved in tissue homeostasis and regeneration under both physiological and pathological conditions. Therefore, such cells and their secretomes have a high clinical potential in regenerative medicine. In this context, DPP4 activity may modulate different aspects of MSC regenerative capacity. Therefore, the aim of this review is to analyze the effect of different DPP4 substrates on MSC. Likewise, how the regulation of DPP4 activity by DPP4i can be applied in regenerative medicine. That includes treatment of cardiovascular and bone pathologies, cutaneous ulcers, organ transplantation and pancreatic beta-cell regeneration, among others. Thus, DPP4i has an important clinical potential as a complement to therapeutic strategies in regenerative medicine. They involve enhancing the differentiation, immunomodulation and mobilization capacity of MSC for regenerative purposes.

Ultrasound-Targeted Microbubble Destruction Mediates Gene Transfection for Beta-Cell Regeneration and Glucose Regulation.

Ultrasound-targeted microbubble destruction (UTMD) mediates gene transfection with high biosafety and thus has been promising toward treatment of type 1 diabetes. However, the potential application of UTMD in type 2 diabetes (T2D) is still limited, due to the lack of systematic design and dynamic monitoring. Herein, an efficient gene delivery system is constructed by plasmid deoxyribonucleic acid (DNA) encoding glucagon-like peptide 1 (GLP-1) in ultrasound-induced microbubbles, toward treatment of T2D in macaque. The as designed UTMD afforded enhancement of cell membrane penetration and GLP-1 expression in macaque, which is characterized by ultrasound-guided biopsy to monitor the dynamic process of islet cells for 6months. Also, improvement of pancreatic beta cell regeneration, and regulation of plasma glucose in macaque with T2D is achieved. The approach would serve as promising alternatives for the treatment of T2D.

Antidiabetic effect of fucoxanthin extracted from Sargassum angustifolium on streptozotocin-nicotinamide-induced type 2 diabetic mice.

This work aimed to study the antidiabetic effect of encapsulated fucoxanthin with porous starch (PS) in streptozotocin and nicotinamide‐induced type 2 diabetic mice. Fucoxanthin was extracted and purified from Sargassum angustifolium and encapsulated in porous starch (PS). Diabetic mice groups were gavaged daily with fucoxanthin (400 mg/kg), either free or encapsulated into PS, and metformin (50 mg/kg) for three weeks. The results exhibited that the fucoxanthin and fucoxanthin‐loaded PS markedly prevented the weight gain in treated groups (p < .05). Moreover, both free and encapsulated fucoxanthin could decrease the fasting blood glucose and increase the plasma insulin level similar to metformin (p < .05). In addition, total cholesterol, triglyceride, and low‐density lipoprotein were lower in the treated groups. These results confirm antiobesity effect of fucoxanthin by regulating lipid profile parameters. Moreover, the histopathology evaluation of pancreatic tissue in diabetic mice exhibited that oral administration of metformin and fucoxanthin caused regeneration of pancreatic beta cells. This study revealed the healthy effect of seaweed pigment as a suitable bioactive compound which can be used in functional foods for natural diabetes therapy.

Evaluation of Antidiabetic Activity of Rosmarinus officinalis var. prostratus Growing in Syria in Alloxan Diabetic Rats

Background: The genus of Rosmarinus officinalis (Rosemary) is found in many parts of the world. Traditionally, Rosemary has been used in traditional medicine due to its therapeutic virtues and its ability to treat some diseases. Rosmarinus officinalis var. prostrates grows in the Al Kalamoon region of Syria but only a limited amount of scientific research on the medicinal uses of this plant has been done. This study focused on the medicinally active substances found in ethanolic extract of the leaves and flowers of this plant and their antidiabetic effect in alloxan-induced diabetic rats. First, an acute toxicity study was carried out to detect the optimal dose of the Rosmarinus officinalis var. prostrates extract. Then, the effect of the optimal dose of 300mg/kg was measured over 36 days. Method: During the study, diabetic rats were treated with different doses of extract (100, 200, 300, 400, 500, and 600 mg/kg). The percentage of fasting blood glucose (FBG) was measured immediately after administration of the extract and at 2h, 4h and 8h after administration. The dose of 300mg/kg was then used in the second part of the study, which involved four groups of rats: a healthy group, a diabetic group without treatment (the control group), a diabetic group treated with 300mg/kg of extract, and a diabetic group treated by metformin (50mg/kg). The treatment continued for 36 days. Results: The results showed that the extract was rich with flavonoids, phenols and tannins. Levels of FBG and DPP-4 were significantly lower in the extract-treated group in comparison with the control group; however, the level of insulin was significantly elevated in the extract-treated group compared to the control group. This effect may be caused by two factors. First, the antioxidant effects of flavonoids which protect pancreatic beta cells from damage caused by alloxan, supports regeneration of pancreatic beta cells, and therefore insulin production. Second, the inhibition of DPP-4 activity, which in turn leads to increased secretion of insulin. Conclusion: The ethanolic extract of Rosmarinus officinalis var. prostrates has an antidiabetic effect.