Antihyperglycemic effect of extra virgin sacha inchi oil in type 2 diabetic rats: Mechanisms involved in pancreatic ß-cell function and apoptosis.

Background and aim: The purpose of the study was to investigate the anti-hyperglycemic effect of extra virgin sacha inchi oil (EVSIO) and its possible mechanisms and actions against pancreatic ß-cell death and dysfunction in type 2 diabetic (T2D) rats. Experimental procedure: T2D rats were induced with a high-fat diet and low-dose of streptozotocin. The rats were then treated for 5 weeks with EVSIO (0.5, 1, and 2 ml/kg), or pioglitazone. Biochemical and histopathological studies, oxidative and inflammatory markers, and expression of apoptotic-related proteins were then evaluated. Results: EVSIO treatment exhibited a dose-dependent reduction of fasting blood glucose, area under the curve of glucose, total cholesterol, and triglyceride levels in the diabetic rats, while improved pancreatic ß-function was demonstrated by increasing pancreatic and serum insulin levels. EVSIO treatment effectively lowered atrophic pancreatic islets and reduced the level of serum and pancreatic MDA in the diabetic rats. In addition to serum and pancreatic GPx activities in the diabetic rats, EVSIO also augmented serum SOD. Increased levels of NF-κB, TNF-α and IL-6 present in the diabetic rats were greatly reduced by EVSIO treatment. Furthermore, EVSIO revealed an anti-apoptotic effect on the diabetic rat pancreas by upregulating Bcl-2, and downregulating Bax and cleaved caspase-3 protein expression. Conclusion: The overall study results demonstrated the potential anti-hyperglycemic effect of EVSIO in the diabetic rats. The beneficial effects of EVSIO may be attributed to its ability to improve pancreatic ß-cell function and ameliorate ß-cell apoptosis by inhibiting oxidative stress and inflammatory cytokines.

Probiotic co-supplementation with absorbent smectite for pancreatic beta-cell function in type 2 diabetes: a secondary-data analysis of a randomized double-blind controlled trials.

Introduction: There is growing evidence from animal and clinical studies suggesting probiotics can positively affect type 2 diabetes (T2D). In a previous randomized clinical study, we found that administering a live multistrain probiotic and absorbent smectite once a day for eight weeks to patients with T2D could reduce chronic systemic inflammatory state, insulin resistance, waist circumference and improve the glycemic profile. However, there is a lack of evidence supporting the efficacy of probiotic co-supplementation with absorbent smectite on pancreatic ß-cell function in T2D. Aim: This secondary analysis aimed to assess the effectiveness of an alive multistrain probiotic co-supplementation with absorbent smectite vs placebo on ß-cell function in T2D patients. Material and methods: We performed a secondary analysis on a previously published randomized controlled trial (NCT04293731, NCT03614039) involving 46 patients with T2D. The main inclusion criteria were the presence of ß-cell dysfunction (%B<60%) and insulin therapy alone or combined with oral anti-diabetic drugs. The primary outcome was assessing ß-cell function as change C-peptide and %B. Results: We observed only a tendency for improving ß-cell function (44.22 ± 12.80 vs 55.69 ± 25.75; р=0.094). The effectiveness of the therapy probiotic-smectite group was confirmed by fasting glycemia decreased by 14% (p=0.019), HbA1c - 5% (p=0.007), HOMA-2 - 17% (p=0.003) and increase of insulin sensitivity by 23% (p=0.005). Analysis of the cytokine profile showed that statistical differences after treatment were in the concentration of both pro-inflammatory cytokines: IL-1ß (22.83 ± 9.04 vs 19.03 ± 5.57; p=0.045) and TNF-α (31.25 ± 11.32 vs 26.23 ± 10.13; p=0.041). Conclusion: Adding a live multistrain probiotic and absorbent smectite supplement slightly improved ß-cell function and reduced glycemic-related parameters in patients with T2D. This suggests that adjusting the gut microbiota could be a promising treatment for diabetes and warrants further investigation through more extensive studies.

A Review of Antidiabetic Medicinal Plants as a Novel Source of Phosphodiesterase Inhibitors: Future Perspective of New Challenges Against Diabetes Mellitus.

Intracellular glucose concentration plays a crucial role in initiating the molecular secretory process of pancreatic ß-cells through multiple messengers and signaling pathways. Cyclic nucleotides are key physiological regulators that modulate pathway interactions in ß -cells. An increase of cyclic nucleotides is controled by hydrolysed phosphodiesterases (PDEs), which degrades cyclic nucleotides into inactive metabolites. Despite the undeniable therapeutic potential of PDE inhibitors, they are associated with several side effects. The treatment strategy for diabetes based on PDE inhibitors has been proposed for a long time. Hence, the world of natural antidiabetic medicinal plants represents an ideal source of phosphodiesterase inhibitors as a new strategy for developing novel agents to treat diabetes mellitus. This review highlights medicinal plants traditionally used in the treatment of diabetes mellitus that have been proven to have inhibitory effects on PDE activity. The contents of this review were sourced from electronic databases, including Science Direct, PubMed, Springer Link, Web of Science, Scopus, Wiley Online, Scifinder and Google Scholar. These databases were consulted to collect information without any limitation date. After comprehensive literature screening, this paper identified 27 medicinal plants that have been reported to exhibit anti-phosphodiesterase activities. The selection of these plants was based on their traditional uses in the treatment of diabetes mellitus. The review emphasizes the antiphosphodiesterase properties of 31 bioactive components derived from these plant extracts. Many phenolic compounds have been identified as PDE inhibitors: Brazilin, mesozygin, artonin I, chalcomaracin, norartocarpetin, moracin L, moracin M, moracin C, curcumin, gallic acid, caffeic acid, rutin, quercitrin, quercetin, catechin, kaempferol, chlorogenic acid, and ellagic acid. Moreover, smome lignans have reported as PDE inhibitors: (+)-Medioresinol di-O-ß-d-glucopyranoside, (+)- Pinoresinol di-O-ß-d-glucopyranoside, (+)-Pinoresinol-4-O-ß-d-glucopyranosyl (1→6)-ß-dglucopyranoside, Liriodendrin, (+)-Pinoresinol 4'-O-ß-d-glucopyranoside, and forsythin. This review provides a promising starting point of medicinal plants, which could be further studied for the development of natural phosphodiesterase inhibitors to treat diabetes mellitus. Therefore, it is important to consider clinical studies for the identification of new targets for the treatment of diabetes.

The Possible Role of Β-Cell Senescence in the Development of Type 2 Diabetes Mellitus

This minireview discusses the very important biomedical problem of treating type 2 diabetes mellitus (T2D). T2D accounts for more than 90% of the total number of diagnosed cases of diabetes mellitus and can result from aging, inflammation, obesity and ß-cell senescence. The main symptom of both T2D and type 1 diabetes (T1D) is an increase in blood glucose concentration. While T1D is insulin-dependent and is associated with the destruction of pancreatic ß-cells, T2D does not require lifelong insulin administration. In this case, pancreatic ß-cells are not destroyed, but their functional activity is deregulated. In T2D, metabolic stress increases the number of senescent ß-cells while impairing glucose tolerance. The potential paracrine effects of senescent ß-cells highlight the importance of the ß-cell senescenceassociated secretory phenotype (SASP) in driving metabolic dysfunction. We believe that the main reason for the deregulation of the functional activity of pancreatic ß-cells in T2D is associated with their "aging" or senescence, which may be induced by various stressors. We propose the use of peroxiredoxin 6 as a new senolytic drug, and the role of ß-cell senescence in the development of T2D is discussed in this review.

HM-Chromanone Alleviates Hyperglycemia by Protecting Pancreatic Islet Cells in Streptozotocin-Induced Diabetic Mice.

We examined the effects of HM-chromanone (HMC) on alleviating hyperglycemia and protecting pancreatic ß-cells from streptozotocin (STZ)-induced damage in C57BL/6J mice. HMC was administered to STZ-induced diabetic mice at 10 or 30 mg/kg, for 14 days. Thereafter, changes in fasting blood glucose levels, insulin-secretion, histopathological examination of pancreas islet cell and apoptotic protein levels, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay were determined. The results revealed that HMC dose-dependently improved blood glucose concentrations and alleviated pancreatic islet cells damage. In diabetic mice, degeneration of the islet cells was observed wherein they appeared shrunken, with hyaline deterioration, nuclear dissolution, and condensation. However, morphology of the islet cell was restored, and nuclei were visibly rounded in the HMC (30 mg/kg)-administered diabetic mice. In addition, ß-cell numbers were markedly increased in HMC mice compared to STZ-induced diabetic mice, and the number of cells stained with glucagon was decreased. HMC markedly decreased the expression of proapoptotic proteins and increased antiapoptotic proteins, and the number of apoptotic cells detected by TUNEL was elevated. HMC decreased expression of interleukin (IL)-1ß, IL-6, and tumor necrosis factor-α in diabetic mice. Moreover, HMC increased antioxidant-enzymes activity, and decreased reactive oxygen species generation. In conclusion, the results demonstrate the potential of HMC to alleviate hyperglycemia by protecting the pancreatic ß-cells in diabetic mice.

Trans-differentiation of mouse mesenchymal stem cells into pancreatic ß-like cells by a traditional anti-diabetic medicinal herb Medicago sativa L.

Background and aim: Medicago sativa L. is a medicinal herb first cultivated in ancient Iran. Traditionally, it has been utilized for the treatment of several disorders. The plant has been in the human diet for at least 1500 years. Although the hypoglycaemic and anti-diabetic effects of the plant have been approved in traditional medicine, further investigations are needed to support the rational use of M. sativa by humans. This project aimed to evaluate the trans-differentiation potential of bone marrow mesenchymal stem cells (MSCs) to pancreatic ß-like cells (insulin-producing cells; IPCs) under the influence of M. sativa extract. Experimental procedure: Bone marrow MSCs isolated, characterized, and then treated by flower or leaf extract of M. sativa. Beta-cell characteristics of the differentiated cells were evaluated by several techniques, including specific staining, QPCR, immunofluorescence, and ELISA. Results: The results showed that the differentiated cells were able to express some specific pancreatic genes (PDX-1, insulin1, and insulin2) and proteins (insulin receptor beta, insulin, proinsulin, and C peptide). Furthermore, ELISA analysis indicated the ability of these cells in the production and secretion of insulin, after exposure to glucose. Conclusion: Overall, both the flower and leaf extract of M. sativa had the potential of differentiation induction of MSCs into IPCs with the characteristics of pancreatic ß-like cells. Therefore, M. sativa, as an herbal drug, may be beneficial for the treatment of diseases including diabetes.

Metformin and Gegen Qinlian Decoction boost islet α-cell proliferation of the STZ induced diabetic rats.

BACKGROUND: The traditional Chinese medicine Gegen Qinlian Decoction (GQD), as well as metformin, had been reported with anti-diabetic effects in clinical practice. OBJECTIVE: To verify whether these two medicines effectively ameliorate hyperglycemia caused by deficiency of islet ß-cell mass which occurs in both type 1 and type 2 diabetes. METHODS: SD rats were injected with a single dose of STZ (55 mg/kg) to induce ß-cell destruction. The rats were then divided into control, diabetes, GQD and metformin group. GQD and metformin groups were administered with GQD extract or metformin for 6 weeks. The islet α-cell or ß-cell mass changes were tested by immunohistochemical and immunofluorescent staining. The potential targets and mechanisms of GQD and metformin on cell proliferation were tested using in silico network pharmacology. Real-time PCR was performed to test the expression of islet cells related genes and targets related genes. RESULTS: Both GQD and metformin did not significantly reduce the FBG level caused by ß-cell mass reduction, but alleviated liver and pancreas histopathology. Both GQD and metformin did not change the insulin positive cell mass but increased α-cell proliferation of the diabetic rats. Gene expression analysis showed that GQD and metformin significantly increased the targets gene cyclin-dependent kinase 4 (Cdk4) and insulin receptor substrate (Irs1) level. CONCLUSION: This research indicates that GQD and metformin significantly increased the α-cell proliferation of ß-cell deficiency induced diabetic rats by restoring Cdk4 and Irs1 gene expression.

In vitro differentiation of human pancreatic duct-derived PANC-1 cells into ß-cell phenotype using Tinospora cordifolia.

Type 1 diabetes mellitus is an autoimmune disorder leading to loss of beta cells. There is a dire need to inhibit apoptosis and induce regeneration of new beta cells. There are plants in the Indian medicine system having the potential for rejuvenation. In the present study, we have attempted to evaluate the capacity of aqueous extract of Tinospora cordifolia to regenerate beta cells from PANC-1 ductal cells. After differentiation, the characterization of ß-cell phenotype was carried out using dithizone and Gomori's staining and further confirmed by mRNA expression study of insulin, Pdx-1, and carbonic anhydrase-9. Insulin production was estimated with ELISA. Aqueous extract of Tinospora cordifolia at 15 µg/ml concentration can effectively induce differentiation of PANC-1 cells into beta cells. The morphological observations showed brownish-colored dithizone and purple-colored Gomori's staining. The ß-cells demonstrated significant mRNA expression of insulin and Pdx-1 and downregulation of carbonic anhydrase-9. The functionality of beta cells was demonstrated by 1.5-fold increase in insulin secretion in response to high glucose. Tinospora cordifolia has potential to differentiate PANC-1 ductal cells into functional beta cells and can be a lead towards non-invasive treatment of type 1 diabetes mellitus.

Effects of Combined Garcinia kola and Kigelia africana on Insulin and Paraoxonase 1 (PON1) Levels in Type 2 Diabetic Rats.

BACKGROUND: Individual extracts of Garcinia kola and Kigelia africana have been shown to have therapeutic effects against a variety of variables linked to the development of diabetes mellitus. However, there is still a lack of information about the combined effects of these extracts on Insulin and Paraoxonase 1 (PON-1) in Streptozotocin-Nicotinamide-induced type-2 diabetic Wistar rats. METHODS: Forty-two young male rats (180-200g) were randomly divided into six groups (n = 7/group). Diabetes was intraperitoneally induced with 110 mg/kg of nicotinamide constituted in distilled water and fifteen minutes later with 65 mg/kg of streptozocin freshly prepared in 0.1M citrate buffer (pH of 4.5) and treated for six weeks as follows: the control rats received either 0.9% normal saline (NS) or 250 mg/kg extract by gavage. The remaining animals were diabetes induced and subsequently treated with either NS, graded doses of the extract (250 mg/kg and 500 mg/kg), or 5 mg/kg Glibenclamide + 100mg/kg Metformin. Gas chromatography-mass spectrometry (GCMS) of the combined extracts was also analyzed to identify the bioactive compounds present in it. Insulin, PON-1 levels, lipid profiles, and atherogenic index were assessed. RESULTS: Our findings show that Insulin and PON-1 levels in the plasma of diabetic rats treated with the combined extracts were significantly increased when compared to the control rats. Moreover, the GCMS of the extract shows the presence of both monounsaturated (oleic acid) and polyunsaturated (linoleic acid) fatty acids. CONCLUSION: The current findings suggest that the extract may help improve glucose homeostasis and prevent atherosclerosis through the established mechanism of the identified bioactive compounds.

Aloperine protects beta-cells against streptozocin-induced injury to attenuate diabetes by targeting NOS1.

Type 1 diabetes (T1D) is a metabolic dysfunction characterized by the selective destruction of islet ß-cells, with oxidative stress playing an essential role in the manifestation of this disease state. Aloperine (ALO) represents the main active alkaloid extracted from the traditional Chinese herbal Sophora alopecuroides L. and features outstanding antioxidative properties. In this study, T1D was induced by a single high dose streptozotocin (STZ, 150 mg/kg, intraperitoneal) in mice. Diabetic animals were intragastrically administered ALO at a dose of 50 mg/kg/day. Notably, treatment of ALO (50 mg/kg/day) for seven consecutive days could observably reverse the onset of diabetes induced by STZ accompanied by weight gain, lower blood glucose levels, and relief of ß-cells damage. Our in vitro study further demonstrated that ALO protected ß-cells from STZ/hydrogen peroxide-induced oxidative damage as manifested by increased expression of MnSOD and CAT. Furthermore, a network pharmacology study revealed that NOS1 represented the main target of ALO. Mechanistic studies subsequently showed that treatment of ALO increased the expression of NOS1, whereas NOS2 was decreased. Moreover, a docking study carried out suggested that ALO could fit into the binding pocket of human NOS1 and molecular dynamics simulation further validated this docking event. Collectively, the administration of ALO prior to diabetes could be a viable approach to the prevention of ß-cell injury. This study may offer a novel potential herbal medicine against T1D and may further help improve the understanding of the underlying molecular mechanisms of ALO-mediated protection against oxidative stress.

Bitter melon fruit extract enhances intracellular ATP production and insulin secretion from rat pancreatic ß-cells.

Bitter melon (Momordica charantia L.) has been shown to have various health-promoting activities, including antidiabetic and hypoglycaemic effects. Improvement in insulin sensitivity and increase in glucose utilisation in peripheral tissues have been reported, but the effect on insulin secretion from pancreatic ß-cells remains unclear. In this study, we investigated the effect of bitter melon fruit on insulin secretion from ß-cells and the underlying mechanism. The green fruit of bitter melon was freeze-dried and extracted with methanol. The bitter melon fruit extract (BMFE) was fractionated using ethyl acetate (fraction A), n-butanol (fraction B) and water (fraction C). Insulin secretory capacity from INS-1 rat insulinoma cell line and rat pancreatic islets, as well as glucose tolerance in rats by oral glucose tolerance test (OGTT), was measured using BMFE and fractions. ATP production in ß-cells was also examined. BMFE augmented insulin secretion from INS-1 cells in a dose-dependent manner. The significant augmentation of insulin secretion was independent of the glucose dose. Fraction A (i.e. hydrophobic fraction), but not fractions B and C, augmented insulin secretion significantly at the same level as that by BMFE. This finding was also observed in pancreatic islets. In OGTT, BMFE and fraction A decreased blood glucose levels and increased serum insulin levels after glucose loading. The decrease in blood glucose levels was also observed in streptozotocin-induced diabetic rats. In addition, BMFE and fraction A increased the ATP content in ß-cells. We concluded that hydrophobic components of BMFE increase ATP production and augment insulin secretion from ß-cells, consequently decreasing blood glucose levels.

The Coffee Diterpene, Kahweol, Ameliorates Pancreatic ß-Cell Function in Streptozotocin (STZ)-Treated Rat INS-1 Cells through NF-kB and p-AKT/Bcl-2 Pathways.

Kahweol is a diterpene molecule found in coffee that exhibits a wide range of biological activity, including anti-inflammatory and anticancer properties. However, the impact of kahweol on pancreatic ß-cells is not known. Herein, by using clonal rat INS-1 (832/13) cells, we performed several functional experiments including; cell viability, apoptosis analysis, insulin secretion and glucose uptake measurements, reactive oxygen species (ROS) production, as well as western blotting analysis to investigate the potential role of kahweol pre-treatment on damage induced by streptozotocin (STZ) treatment. INS-1 cells pre-incubated with different concentrations of kahweol (2.5 and 5 µM) for 24 h, then exposed to STZ (3 mmol/L) for 3 h reversed the STZ-induced effect on cell viability, apoptosis, insulin content, and secretion in addition to glucose uptake and ROS production. Furthermore, Western blot analysis showed that kahweol downregulated STZ-induced nuclear factor kappa B (NF-κB), and the antioxidant proteins, Heme Oxygenase-1 (HMOX-1), and Inhibitor of DNA binding and cell differentiation (Id) proteins (ID1, ID3) while upregulated protein expression of insulin (INS), p-AKT and B-cell lymphoma 2 (BCL-2). In conclusion, our study suggested that kahweol has anti-diabetic properties on pancreatic ß-cells by suppressing STZ induced apoptosis, increasing insulin secretion and glucose uptake. Targeting NF-κB, p-AKT, and BCL-2 in addition to antioxidant proteins ID1, ID3, and HMOX-1 are possible implicated mechanisms.

Management of Type 2 Diabetes: Current Strategies, Unfocussed Aspects, Challenges, and Alternatives.

Type 2 diabetes mellitus (T2DM) accounts for >90% of the cases of diabetes in adults. Resistance to insulin action is the major cause that leads to chronic hyperglycemia in diabetic patients. T2DM is the consequence of activation of multiple pathways and factors involved in insulin resistance and ß-cell dysfunction. Also, the etiology of T2DM involves the complex interplay between genetics and environmental factors. This interplay can be governed efficiently by lifestyle modifications to achieve better management of diabetes. The present review aims at discussing the major factors involved in the development of T2DM that remain unfocussed during the anti-diabetic therapy. The review also focuses on lifestyle modifications that are warranted for the successful management of T2DM. In addition, it attempts to explain flaws in current strategies to combat diabetes. The employability of phytoconstituents as multitargeting molecules and their potential use as effective therapeutic adjuvants to first line hypoglycemic agents to prevent side effects caused by the synthetic drugs are also discussed.

YY1 deficiency in ß-cells leads to mitochondrial dysfunction and diabetes in mice.

BACKGROUND: The transcription factor YY1 is an important regulator for metabolic homeostasis. Activating mutations in YY1 lead to tumorigenesis of pancreatic ß-cells, however, the physiological functions of YY1 in ß-cells are still unknown. Here, we investigated the effects of YY1 ablation on insulin secretion and glucose metabolism. METHODS: We established two models of ß-cell-specific YY1 knockout mice. The glucose metabolic phenotypes, ß-cell mass and ß-cell functions were analyzed in the mouse models. Transmission electron microscopy was used to detect the ultrastructure of ß-cells. The flow cytometry analysis, measurement of OCR and ROS were performed to investigate the mitochondrial function. Histological analysis, quantitative PCR and ChIP were performed to analyze the target genes of YY1 in ß-cells. RESULTS: Our results showed that loss of YY1 resulted in reduction of insulin production, ß-cell mass and glucose tolerance in mice. Ablation of YY1 led to defective ATP production and mitochondrial ROS accumulation in pancreatic ß-cells. The inactivation of YY1 impaired the activity of mitochondrial oxidative phosphorylation, induced mitochondrial dysfunction and diabetes in mouse models. CONCLUSION: Our findings demonstrate that the transcriptional activity of YY1 is essential for the maintenance of mitochondrial functions and insulin secretion in ß-cells.

Coloured Rice Phenolic Extracts Increase Expression of Genes Associated with Insulin Secretion in Rat Pancreatic Insulinoma ß-cells.

Glucose-induced oxidative stress is associated with the overproduction of reactive oxygen species (ROS), which may dysregulate the expression of genes controlling insulin secretion leading to ß-cell dysfunction, a hallmark of type 2 diabetes mellitus (T2DM). This study investigated the impact of coloured rice phenolic extracts (CRPEs) on the expression of key genes associated with ß-cell function in pancreatic ß-cells (INS-1E). These genes included glucose transporter 2 (Glut2), silent mating type information regulation 2 homolog 1 (Sirt1), mitochondrial transcription factor A (Tfam), pancreatic/duodenal homeobox protein 1 (Pdx-1) and insulin 1 (Ins1). INS-1E cells were cultured in high glucose (25 mM) to induce glucotoxic stress conditions (HGSC) and in normal glucose conditions (NGC-11.1 mM) to represent normal ß-cell function. Cells were treated with CRPEs derived from two coloured rice cultivars, Purple and Yunlu29-red varieties at concentrations ranged from 50 to 250 µg/mL. CRPEs upregulated the expression of Glut2, Sirt1 and Pdx-1 significantly at 250 µg/mL under HGSC. CRPEs from both cultivars also upregulated Glut2, Sirt1, Tfam, Pdx-1 and Ins1 markedly at 250 µg/mL under NGC with Yunlu29 having the greatest effect. These data suggest that CRPEs may reduce ß-cell dysfunction in T2DM by upregulating the expression of genes involved in insulin secretion pathways.

Ficus carica leaves extract inhibited pancreatic ß-cell apoptosis by inhibiting AMPK/JNK/caspase-3 signaling pathway and antioxidation.

The aim of this study was to explore the inhibitory effects of Ficus carica leaves (FCL) extract on AMPK/JNK/caspase3 signaling pathway and antioxidation in pancreatic ß-cells. H&E staining, insulin immunohistochemistry, and TUNEL methods were used to investigate the effects of FCL on pancreatic histopathology in type 1 diabetic mice. The expression levels of caspase-3, AMPK, and JNK protein in the pancreatic tissue and MIN6 cells [induced by palmitic acid (PA) and hydrogen peroxide] were determined. Flow cytometry was used to detect the effects of FCL on apoptosis and ROS production of MIN6 cells. FCL (2 g/kg, continuous gavage for 6 weeks) significantly improved the pancreatic tissue injury in type 1 diabetic mice and reduced the expression levels of apoptosis-related proteins such as FasL, caspase8, Bax/Bcl-2, Cyt-C, caspase-3, p-AMPK, and p-JNK. FCL inhibited cell apoptosis induced by PA and the protein expression levels of caspase-3, p-AMPK, and p-JNK. The AMPK agonist AICAR could reverse the protective effects of FCL on MIN6 cells. The AMPK inhibitor compound C had a similar effect on MIN6 cells as that of FCL. FCL could inhibit cell apoptosis induced by hydrogen peroxide and reduced the production of ROS. In conclusion, FCL could inhibit pancreatic ß-cell apoptosis by inhibiting the AMPK/JNK/caspase-3 signaling pathway and by antioxidation properties.

Ameliorative effect of Myristica fragrans (nutmeg) extract on oxidative status and histology of pancreas in alloxan induced diabetic rats.

BACKGROUND: Many traditional treatments have been recommended in the alternative system of medicine for the treatment of diabetes mellitus. The aim of this study was to assess oxidative stress and histological changes in the pancreas of alloxan-induced diabetic rats following Myristica fragrans seed (nutmeg) extract treatment. MATERIALS AND METHODS: Forty-eight male Wistar rats weighing 200-250 g were randomly divided into six groups of 8 rats each - group I, non-diabetic rats; group II, diabetic rats; groups III, IV and V, diabetic rats given orally nutmeg extract at levels of 50, 100 and 200 mg/kg, respectively; and group VI, diabetic rats given orally metformin (100 mg/kg). The experiment lasted for 28 days. RESULTS: Data showed that nutmeg extract (100 and 200 mg/kg) significantly decreased the blood glucose levels and increased the levels of serum insulin in diabetic rats. Administration of nutmeg extract to diabetic rats reduced oxidative stress and improved the antioxidant activities in pancreatic tissue. Histopathologic results of treated groups revealed marked improvement in the morphology of the pancreas compared with the control diabetic group. In addition, number of pancreatic islets and per cent of ß-cells increased significantly in these groups in comparison with diabetic untreated group. CONCLUSIONS: These results suggest that nutmeg extract has potent antidiabetic and ß-cell protection activities in alloxan induced diabetic rats, possibly via its antioxidant properties.

Immunosuppressive effects of protein derivatives from Mucuna pruriens on a streptozotocin-induced type 1 diabetes murine model.

Type 1 diabetes is an autoimmune disease induced by abnormal insulin secretions from ß-cells in pancreas. The present study aimed to investigate the immunosuppressive effects from protein derivatives of Mucuna pruriens on a murine model of Type 1 diabetes. Hydrolyzate and five peptide fractions with different molecular weight were administered orally by 14 days, followed T1D murine model was built by intraperitoneal injection of streptozotocin over 5 days. The mice weight, blood glucose levels, anti-insulin, and anti-pancreatic islet ß-cells antibodies, pro-inflammatory cytokines as tumor necrosis factor alpha and interleukin-6 were determined in four times (0, 15, 30, and 45 day). Mice were sacrificed and pancreatic tissues samples were obtained and staining with hematoxylin and eosin to determine the degree of damage. The study demonstrated immunosuppressive activity in four of the six treatment groups: (a) T1D PPH, (b) T1D F 5-10 kDa, (c) T1D F 3-5 kDa, and (d) T1D F 1-3 kDa. PRACTICAL APPLICATIONS: Due to the high content of native protein in seeds of Mucuna pruriens, studies have reported potential in the elaboration of hydrolysates and peptides with biological activity. These protein derivatives could help in the treatment of immunological disorders that are observed in several chronic non-communicable disease and inflammatory diseases, such as T1D. Activated macrophages and lymphoplasmacytic infiltrate plays a crucial role in the initiation and maintenance of T1D; therefore, several studies has focused to reduce the effector functions of this cells for diminishing the clinical manifestations in inmmunocompromised patients. Thus, this study indicates the potential application of hydrolyzate and peptide fractions of M. pruriens in functional foods and dietary supplements could be developed for the treatment of inflammatory and chronic non-communicable diseases.

Hibiscus sabdariffa renews pancreatic ß-cells in experimental type 1 diabetic model rats.

This study evaluated the antidiabetic potentials of flavonoid-rich aqueous fraction of methanolic extract of Hibiscus sabdariffa calyx (HSCE) on the pancreatic ß-cells of experimental type I diabetic model rats. Type 1 diabetes mellitus was induced in Wistar rats by a single intraperitoneal injection of 80mg/kg b/w streptozotocin (STZ) dissolved in 0.1M citrate buffer (pH 6.3). The rats were divided into five groups (n=12) including normal control group, test group I, diabetic negative control, test group II, and diabetic positive control. The test groups received 1.75g/kg b/w of HSCE by gavage for 15 days. Animals were sacrificed; the splenic portion of their pancreas and serum were evaluated for histopathological and biochemical parameters respectively. The regenerative effects of the extract on STZ-diabetes ß-cells damage was evident from the results of the histopathological analysis and the biochemical parameters evaluated in the serum. Reduced levels of glutathione, catalase and superoxide dismutase in the serum of diabetic rats were significantly improved in the H. sabdariffa-treated rats (P<0.05). Histological examination of pancreatic islet sections revealed degenerative and necrotic changes (D) in the pancreatic islet of Langerhans, ß-cell degranulation, pyknotic ß-cell nuclei, decreased islet cellular density, and severe vacuolation (V) in the islet of STZ-diabetic negative control group. The morphology of the pancreas of HSCE-treated diabetic rats (test group II) revealed remarkable improvements in the islet of Langerhans. Stereological studies also revealed that HSCE-treatment remarkably improved volume of the pancreatic islets and the numerical density of ß-cell (number of ß-cells per unit area of islet) depleted by STZ diabetes. The study concluded that possible antidiabetic mechanism of Hibiscus sabdariffa in STZ diabetes is through induction of ß-cell regeneration and its strong antioxidant potential.

A whole organism small molecule screen identifies novel regulators of pancreatic endocrine development.

An early step in pancreas development is marked by the expression of the transcription factor Pdx1 within the pancreatic endoderm, where it is required for the specification of all endocrine cell types. Subsequently, Pdx1 expression becomes restricted to the ß-cell lineage, where it plays a central role in ß-cell function. This pivotal role of Pdx1 at various stages of pancreas development makes it an attractive target to enhance pancreatic ß-cell differentiation and increase ß-cell function. In this study, we used a newly generated zebrafish reporter to screen over 8000 small molecules for modulators of pdx1 expression. We found four hit compounds and validated their efficacy at different stages of pancreas development. Notably, valproic acid treatment increased pancreatic endoderm formation, while inhibition of TGFß signaling led to α-cell to ß-cell transdifferentiation. HC toxin, another HDAC inhibitor, enhances ß-cell function in primary mouse and human islets. Thus, using a whole organism screening strategy, this study identified new pdx1 expression modulators that can be used to influence different steps in pancreas and ß-cell development.