Pancreatic Beta Cell Regeneration Research Articles

The Potency of Senggani (Melastoma malabathricum L) Leaves in Repair of Pancreatic Beta Cells for Diabetes Mellitus Patients: A Narrative Review

Diabetes mellitus is often caused by damage to pancreatic beta cells which play a role in secreting insulin in the body. Damage to pancreatic beta cells causes the body to lack insulin. Dipeptidyl peptidase-4 (DPP-4) is a peptidase enzyme complex located on the surface of the cell membrane. Inhibition of the DPP4 enzyme will increase blood GLP-1 levels and induce regeneration of pancreatic beta cells. Senggani leaf (Melastoma malabathricum) boiled water is believed by the people of the Ciamis area to be used as a diabetes medicine. There have been many studies and reviews related to Senggani (Melastoma malabathricum) and its potential. This review focuses on the discussion of Senggani as an antidiabetic by analyzing the reduction in glucose levels and the repair ability of pancreatic beta cells. The results of the literature study that show that senggani leaves have the ability to reduce blood glucose levels and repair activity of pancreatic beta cells through the DPP-4 enzyme inhibition mechanism supported by molecular docking simulation data. There are 12 active compounds that have a binding site similarity above 50% with the comparison compound vildagliptin. Rutin is the best active compound which has a 100% similarity of the binding site. Based on in vivo research and toxicity analysis on the admetsar database, senggani leaf extract and active compounds of senggani leaves have low toxicity, making it safe to be used as antidiabetic herbal preparations.

WATER EXTRACT OF CAESALPINIA PULCHERRIMA FLOWERS INCREASES GLUCOSE UPTAKE IN INSULIN RESISTANT ADIPOCYTES IN A DOSEDEPENDENT MANNER

Caesalpinia pulcherrima (CP) flower extract has been shown to have antidiabetic effects on pancreatic beta cell regeneration and improved skeletal muscle glucose utilisation. However, little is known about its effect on adipocytes, particularly insulin resistant adipocytes. This study investigated the possibility of improving glucose uptake in adipocytes obtained from chickens which are naturally insulin resistant via direct effects of water extract of Caesalpinia pulcherrima flowers. The extract was prepared by boiling air dried CP flowers in a water based modified Krebs Ringer Bicarbonate buffer for 5mins and sterilizing the filtrate via vacuum filtration. A glucose load of 18mM and 10% ITS was added to the extract. In the absence of adipocytes, the glucose concentration of the CP extract remained unchanged (p=0.5087). Insulin resistance in the chicken adipocytes was confirmed by delayed and limited glucose uptake (maximum 2.9% + 1.62% in 60mins). This was reversed via the addition of the water extract of the CP flowers as concentrations as low as 2.8mg/ml doubled glucose uptake and concentrations as low as 5.6mg/ml increased the rate of glucose uptake to that of insulin sensitive cells. These results suggest that water extract of CP flowers directly modulate glucose uptake into insulin resistant cells at concentrations as low as 2.8mg/ml following a 5mins decoction preparation.

GABA from medical nutrition to pancreatic beta-cell regeneration

GABA from medical nutrition to pancreatic beta-cell regeneration

Preliminary Nutrient Determination and Regeneration of Pancreatic Islet Cells by Extracts of Spondias mombin Leaves in Streptozotocin-Induced Diabetic Rats

Background: There is a growing trend towards the use of medicinal plant that can prevent degeneration of pancreatic cells and regenerate islet cells in diabetes treatment Objectives: The possible effects of the extracts of Spondias mombin leaves on the regeneration of pancreatic beta cells in streptozotocin (STZ)-induced diabetic rats were determined in this study. Methods: Twenty-five male Wistar rats were randomly divided into 5 groups (A-E) including normal and diabetic rats. Aqueous and ethanol extracts of S. mombin were administered orally to diabetic rats in groups D and E for 12 weeks. Blood samples were collected for serum insulin and C-peptide assays. The pancreases were also collected for histopathological examination. Additionally, mineral and vitamin contents of the leaves were determined using standard procedures. Results: The highest vitamin content was vitamin C in the leaves, while the highest mineral content was calcium. Treatment with extracts of Spondias mombin attenuated the STZ-induced hypoinsulinemia, which was evident from the increased serum insulin and c-peptide levels in the extract treated groups. Histopathological examination of the pancreas revealed an increase in the number and size of the pancreatic beta cells in the extracts treated groups in comparison to the shrunken and diminished islet cells observed in the untreated animals. Conclusion: Extracts of S. mombin leaves are capable of regenerating pancreatic β-cells which were destroyed by streptozotocin induction.

Key Developmental Regulators Suggest Multiple Origins of Pancreatic Beta Cell Regeneration.

Extensive efforts have been done to try to restore the lost β cell mass for the cure of diabetes. Animal models have been established to provide evidences of cellular origins and contextual regulators of β cell regeneration. Here, we used a zebrafish β cell ablation and regeneration model to investigate β cell neogenesis in the first few days after a near-total β cell loss. Regeneration of β cells first occurred within 7 h post-treatment. Developmental regulators such as neurod, pdx1, mnx1, and nkx2.2a were active in the regenerating β cells, while at the same time suggesting different subpopulations of regenerative cellular origins. Using Cre/loxP-based lineage tracing, we showed that intrapancreatic ductal cells resisted to give rise to regenerating β cells. Given that transdifferentiation of α cell and δ cell can regenerate β cell, here we have provided further molecular evidence highly suggesting that the regenerating β cells originate from multiple cellular origins.

The effect of exosomes derived from mesenchymal stem cells in the treatment of induced type 1 diabetes mellitus in rats.

The aim of the current study was to evaluate the therapeutic and regenerative effects of MSCs derived exosomes in the treatment of type 1 DM and to compare its effects with MSCs themselves. The experiment was done on forty albino rats grouped as follows, group (1): Ten healthy rats, group (2): Ten induced type 1 DM rats, group (3): Ten induced type 1 DM rats received exosomes intraperitoneally, and group (4): Ten induced type 1 DM rats received MSCs intraperitoneally. Serum glucose and plasma insulin levels were assessed weekly. QRT-PCR was done to assess regeneration of pancreatic beta cells by measuring insulin, Pdx1, Smad2, Smad3 and TGFβ genes. Additionally, histopathological and immune-histochemical examinations were done to confirm pancreatic tissue regeneration. Regarding the assessed genes (insulin, Pdx1, Smad2, Smad3 and Tgfβ) gene expression in MSCs treated group showed significant increase compared to diabetic group (p value < 0.001) and gene expression in exosomes treated group was increased significantly compared to diabetic and MSCs treated groups (p value < 0.001). Histopathological and immune-histochemical examination revealed regeneration of pancreatic islets in both treated groups. MSCs Derived exosomes showed superior therapeutic and regenerative results than MSCs themselves.

GABA from Medical Nutrition to Pancreatic Beta-Cell Regeneration

GABA from Medical Nutrition to Pancreatic Beta-Cell Regeneration

Assessment of the Annona muricata Leaf Ethanol Extract Effect on The Diameter of Pancreatic Islets in Alloxan-Induced Mice

Diabetes mellitus is one of a non-communicable disease whose prevalence continues to increase from year to year in both developed and developing countries. In Indonesia, it is estimated that 12 million people aged ≥15 years old had diabetes mellitus in 2013. Treatment of diabetes mellitus by using plant extract has been reported to have good results. One of the plants that have antidiabetic effects is Annona muricata. Annona muricata leaf extract was found to increase pancreatic beta-cell regeneration. This study aimed to determine the effect of Soursop Leaf Ethanol Extract (SLEE) on the diameter of pancreatic islets in alloxan-induced mice. This study used a true experimental design with posttest-only control group design. The samples used were 30 male Swiss Webster mice with 12-14 weeks of age and 20-30 grams of body weight. Samples were then randomly divided into 5 groups, induced with alloxan and treated for 14 days. The group consisted of: negative control, positive control that was treated with 0,65 mg/kg BW of glibenclamide, P1 that was treated with 150 mg/kg BW, P2 with 300 mg/kg BW and P3 with 600 mg/kg BW of SLEE. The diameter of pancreatic islets was measured by histopathological examination stained with Hematoxylin-Eosin (HE). Data were analyzed by one-way ANOVA test and followed by Bonferroni post hoc test. Bivariate analysis showed a significant difference between negative control group with P1 (p = 0.007) and P2 (p = 0.004) group. Therefore, soursop leaf ethanol extract given in a dose of 300 mg/kg BW was the most effective in increasing the diameter of pancreatic islets.

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.

Autologous Peripheral Blood Mononuclear Cells can lead to Pancreatic Beta Cell Regeneration

Autologous Peripheral Blood Mononuclear Cells can lead to Pancreatic Beta Cell Regeneration

Autologous Peripheral Blood Mononuclear Cells can Lead to Pancreatic Beta Cell Regeneration

Autologous Peripheral Blood Mononuclear Cells can Lead to Pancreatic Beta Cell Regeneration

Autologous Peripheral Blood Mononuclear Cells can Lead to Pancreatic Beta Cell Regeneration

Introduction: Type-1 diabetes (T1D) is a disease that leads to pancreatic beta cells death, resulting in complete insulin loss. T1D occurs as a result of autoimmunity which takes insulin producing β cells as a target and is considered as a metabolic disorder causing hyperglycemia resulting from a serious loss of endogenous insulin roduction. Using cadaveric islets as a replacement therapy was done to reverse diabetes. Many various progenitor cell types have been found in the peripheral blood mononuclear cell (PBMC) fraction denoting hose PBMCs may have the ability to differentiate into many mature functional cell types in certain microenvironments. It is settled that circulating peripheral blood mononuclear cells (PBMC) contain germinal cell population which can share in the regeneration of tissues in different organs. Materials and Methods: 2 groups of type I diabetes patients had been monitored in a private clinic, number 40 each group, with 35 females and 45 males. It lied between 8-25 years old with 4-7 years of diabetes onset. The first group was on insulin therapy and they received peripheral blood mononuclear cells concentrate directly in the dorsal pancreatic artery. The second group was only on insulin injection. Results: The results show a significant increase in c peptide levels after direct injection of peripheral blood mononuclear cells in the dorsal pancreatic artery with p-value less than 0.0001. Conclusion: The peripheral blood mononuclear cells can induce beta cell regeneration and increase beta cell mass which is detected by an increase in c peptide levels.

Antidiabetic Effects of the Ethanolic Root Extract of Uvaria chamae P. Beauv (Annonaceae) in Alloxan-Induced Diabetic Rats: A Potential Alternative Treatment for Diabetes Mellitus.

Diabetes mellitus has been a menace to mankind from time immemorial. However, a natural product such as U. chamae P. Beauv (Annonaceae) offers alternative treatment for diabetes mellitus. The study aimed at evaluating antidiabetic activity of the ethanolic root extract of U. chamae in alloxan-induced diabetic rats. Diabetes was induced in Sprague Dawley rats after overnight fast with 150 mg/kg alloxan intraperitoneally. After 72 h, those with plasma glucose levels >200 mg/dl were classified as diabetic. Five diabetic rats in each group were treated daily for 14 days orally with 100, 250, and 400 mg/kg of the extract, glibenclamide (71 µg/kg) and pioglitazone (429 µg/kg), respectively, while another group was untreated. Control received 0.5 ml of Acacia senegal. Effects of extract on glucose, other biochemical, and hematological parameters were evaluated. α-amylase and α-glucosidase inhibitory activities of extract and its fractions were also evaluated. Percentage inhibition and IC50 values were determined. Diabetic control was achieved on the 7th day of the study with 100, 250, and 400 mg/kg of the extract showing glucose reduction of 72.14%, 78.75%, and 87.71%, respectively. The HDL-cholesterol levels of diabetic rats treated with extracts were significantly increased. Extract and its fractions caused α-amylase and α-glucosidase inhibition. Histologically, pancreas of diabetic rats treated with extract showed regenerated islet cells which were not seen in rats treated with glibenclamide and pioglitazone. This study showed that U. chamae has antidiabetic activity which may be through α-amylase and α-glucosidase inhibition and regeneration of pancreatic beta cells. Also, it may reduce the risk of cardiovascular disease by increasing HDL-cholesterol levels.

Immune Modulation and Vascular Repair Sustain Pancreatic Beta Cell Regeneration To Reverse Late Stage Type 1 Diabetes

Abstract Type 1 diabetes (T1D) is a chronic inflammatory disease which manifests when the pancreatic β-cells are destroyed by cells of the immune system. We have previously shown that antigen-specific therapy with Ig-GAD2, an Ig chimera carrying glutamic acid decarboxylase 206–220 sequence (GAD2), induces regeneration of β-cells and reverses T1D when intervention is made at the pre-diabetic stage. However, Ig-GAD2 could not reverse T1D when the treatment is made at the onset of disease (diabetic stage). Surprisingly, endothelial precursor cells (EPCs), alongside Ig-GAD2, sustain reversal of the disease at the diabetic stage. This combination therapy proved effective in driving immune modulation and repair of the islet vasculature leading to formation of new endogenous β-cells that were able to thrive and restore long-lasting normoglycemia. We now have evidence that combination therapy leads to formation of healthy islets by inducing division of residual β-cells and differentiation of precursor cells. Furthermore, while the pancreas is cleared of immune infiltration during recovery from disease, both the lymph nodes and spleen displayed a significant reduction in Th17 cells and the disease did not rebound. These findings suggest that combination therapy is able to drive long lasting immune modulation and islet vascular repair which provides a micro-environment suitable for regeneration of β-cells at late stages of the disease. These circumstances are relevant to humans as intervention could be made at early as well as late stages after diagnosis.

Therapeutic Potential of Lentivirus-Mediated Glucagon-Like Peptide-1 Gene Therapy for Diabetes.

Postprandial glucose-induced insulin secretion from the islets of Langerhans is facilitated by glucagon-like peptide-1 (GLP-1)-a metabolic hormone with insulinotropic properties. Among the variety of effects it mediates, GLP-1 induces delta cell secretion of somatostatin, inhibits alpha cell release of glucagon, reduces gastric emptying, and slows food intake. These events collectively contribute to weight loss over time. During type 2 diabetes (T2DM), however, the incretin response to glucose is reduced and accompanied by a moderate reduction in GLP-1 secretion. To compensate for the reduced incretin effect, a human immunodeficiency virus-based lentiviral vector was generated to deliver DNA encoding human GLP-1 (LentiGLP-1), and the anti-diabetic efficacy of LentiGLP-1 was tested in a high-fat diet/streptozotocin-induced model of T2DM. Therapeutic administration of LentiGLP-1 reduced blood glucose levels in obese diabetic Sprague Dawley rats, along with improving insulin sensitivity and glucose tolerance. Normoglycemia was correlated with increased blood GLP-1 and pancreatic beta cell regeneration in LentiGLP-1-treated rats. Plasma triglyceride levels were also normalized after LentiGLP-1 injection. Collectively, these data suggest the clinical potential of GLP-1 gene transfer therapy for the treatment of T2DM.

Virgin Beta Cells Persist throughout Life at a Neogenic Niche within Pancreatic Islets

Postnatal maintenance or regeneration of pancreatic beta cells is considered to occur exclusively via the replication of existing beta cells, but clinically meaningful restoration of human beta cell mass by proliferation has never been achieved. We discovered a population of immature beta cells that is present throughout life and forms from non-beta precursors at a specialized micro-environment or "neogenic niche" at the islet periphery. These cells express insulin, but lack other key beta cell markers, and are transcriptionally immature, incapable of sensing glucose, and unable to support calcium influx. They constitute an intermediate stage in the transdifferentiation of alpha cells to cells that are functionally indistinguishable from conventional beta cells. We thus identified a lifelong source of new beta cells at a specialized site within healthy islets. By comparing co-existing immature and mature beta cells within healthy islets, we stand to learn how to mature insulin-expressing cells into functional beta cells.

Antidiabetic Activity of Aqueous Extract of Solanum nigrum Linn Berries in Alloxan Induced Diabetic Wistar Albino Rats.

Solanum nigrum Linn. is a common medicinal plant possessing a wide variety of pharmacological activity. Current treatment of diabetes mellitus has plenty of adverse effects necessitating the search of alternate drugs. Evaluation of antidiabetic effect of Aqueous Extract of Solanum Nigrum Linn Berries (AESNB) in alloxan induced diabetic Wistar rats. There were five groups (normal control, diabetic control, AESNB 200 mg/kg/day, ASENB 400 mg/kg/day and standard i.e., glimepride 0.1 mg/kg/day) with six animals in each group. Alloxan was used to induce diabetes in rats. The standard drug glimepride in the dose of 0.1 mg/kg/day and the test drug AESNB were given orally in the doses of 200 mg/kg/day and 400 mg/kg/day. The fasting blood glucose level was measured by glucometer on day 0, 1,7,14 and 21 after 12 hour. On 21st day after the blood glucose measurement all the animals were sacrificed and their pancreas were analysed histopathologically. The results were analysed statistically by using one-way ANOVA. Aqueous extract of Solanum nigrum Linn berries in the dose of 200 mg/kg/day produced significant blood glucose reduction (p<0.01) from day 7 and 400 mg/kg/day produced highly significant reduction in blood glucose from day 7 (p<0.001). The standard drug glimepride reduced the blood glucose as equal to normal on day 21 (p<0.001). Histopathological examination showed the regeneration of pancreatic beta cells in AESNB group. Aqueous extract of Solanum nigrum Linn berries possess antidiabetic activity.

Oxidative Stress in Pancreatic Beta Cell Regeneration

Pancreatic β cell neogenesis and proliferation during the neonatal period are critical for the generation of sufficient pancreatic β cell mass/reserve and have a profound impact on long-term protection against type 2 diabetes (T2D). Oxidative stress plays an important role in β cell neogenesis, proliferation, and survival under both physiological and pathophysiological conditions. Pancreatic β cells are extremely susceptible to oxidative stress due to a high endogenous production of reactive oxygen species (ROS) and a low expression of antioxidative enzymes. In this review, we summarize studies describing the critical roles and the mechanisms of how oxidative stress impacts β cell neogenesis and proliferation. In addition, the effects of antioxidant supplements on reduction of oxidative stress and increase of β cell proliferation are discussed. Exploring the roles and the potential therapeutic effects of antioxidants in the process of β cell regeneration would provide novel perspectives to preserve and/or expand pancreatic β cell mass for the treatment of T2D.

Hypoxic Preconditioning Improves the Therapeutic Potential of Aging Bone Marrow Mesenchymal Stem Cells in Streptozotocin-Induced Type-1 Diabetic Mice.

Insulin replacement is the current therapeutic option for type-1 diabetes. However, exogenous insulin cannot precisely represent the normal pattern of insulin secretion. Another therapeutic strategy is transplantation of pancreatic islets, but this is limited by immune rejection, intrinsic complications, and lack of donor availability. Stem cell therapy that results in the regeneration of insulin-producing cells represents an attractive choice. However, with advancing age, stem cells also undergo senescence, which leads to changes in the function of various cellular processes that result in a decrease in the regeneration potential of these aging stem cells. In this study, the effect of young and aging mesenchymal stem cells (MSCs) on the regeneration of pancreatic beta cells in streptozotocin (STZ)-induced type-1 diabetic mice was observed after hypoxic preconditioning. Hypoxia was chemically induced by 2, 4-dinitrophenol (DNP). Plasma insulin and glucose levels were measured at various time intervals, and pancreatic sections were analyzed histochemically. The effect of DNP was also analyzed on apoptosis of MSCs by flow cytometry and on gene expression of certain growth factors by quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR). We observed that hypoxic preconditioning caused changes in the gene expression levels of growth factors in both young and aging MSCs. Young MSCs showed significant regeneration potential compared with the aging cells in vivo. However, hypoxic preconditioning was able to improve the regeneration potential of aging MSCs. It is concluded from the present study that the regeneration potential of aging MSCs into pancreatic β-cells can be enhanced by hypoxic preconditioning, which causes changes in the gene expression of certain growth factors.

Parathyroid Hormone-Related Peptide (1-36) Enhances Beta Cell Regeneration and Increases Beta Cell Mass in a Mouse Model of Partial Pancreatectomy.

Aims/HypothesisFinding ways to stimulate the regeneration of endogenous pancreatic beta cells is an important goal in the treatment of diabetes. Parathyroid hormone-related protein (PTHrP), the full-length (1–139) and amino-terminal (1–36) peptides, enhance beta cell function, proliferation, and survival. Therefore, we hypothesize that PTHrP(1–36) has the potential to regenerate endogenous beta cells.MethodsThe partial pancreatectomy (PPx) mouse model of beta cell injury was used to test this hypothesis. Male Balb/c mice underwent either sham-operation or PPx, and were subsequently injected with PTHrP(1–36) (160μg/kg) or vehicle (veh), for 7, 30, or 90 days. The four groups of mice, sham-veh, sham-PTHrP, PPx-veh, and PPx-PTHrP were assessed for PTHrP and receptor expression, and glucose and beta cell homeostasis.ResultsPTHrP-receptor, but not the ligand, was significantly up-regulated in islets from mice that underwent PPx compared to sham-operated mice. This suggests that exogenous PTHrP could further enhance beta cell regeneration after PPx. PTHrP did not significantly affect body weight, blood glucose, plasma insulin, or insulin sensitivity, in either sham or PPx mice. Glucose tolerance improved in the PPx-PTHrP versus PPx-veh mice only in the early stages of treatment. As hypothesized, there was a significant increase in beta cell proliferation in PPx-PTHrP mice at days 7 and 30; however, this was normalized by day 90, compared to PPx-veh mice. Enhanced beta cell proliferation translated to a marked increase in beta cell mass at day 90, in PPx-PTHrP versus PPx-veh mice.ConclusionsPTHrP(1–36) significantly enhances beta cell regeneration through increased beta cell proliferation and beta cell mass after PPx. Future studies will determine the potential of PTHrP to enhance functional beta cell mass in the setting of diabetes.