Mannogalactoglucan from mushrooms protects pancreatic islets via restoring UPR and promotes insulin secretion in TIDM mice

Type 1 diabetes mellitus(T1DM) lacks insulin secretion due to autoimmune deficiency of pancreaticβ-cells.Protecting pancreatic islets and enhancing insulin secretion has been therapeutic approaches.Mannogalactoglucan is the main type of polysaccharide from natural mushroom,which has potential medicinal prospects.Nevertheless,the antidiabetic property of mannogalactoglucan in T1DM has not been fully elucidated.In this study,we obtained the neutral fraction of alkali-soluble Armillaria mellea polysaccharide(AAMP-N) with the structure of mannogalactoglucan from the fruiting body of A.mellea and investigated the potential therapeutic value of AAMP-N in T1DM.We demonstrated that AAMP-N lowered blood glucose and improved diabetes symptoms in T1DM mice.AAMP-N activated unfolded protein response(UPR) signaling pathway to maintain ER protein folding homeostasis and promote insulin secretion in vivo.Besides that,AAMP-N promoted insulin synthesis via upregulating the expression of transcription factors,increased Ca^(2+) signals to stimulate intracellular insulin secretory vesicle transport via activating calcium/calmodulin-dependent kinase Ⅱ(CamkⅡ) and cAMP/PKA signals,and enhanced insulin secretory vesicle fusion with the plasma membrane via vesicle-associated membrane protein 2(VAMP2).Collectively,these studies demonstrated that the therapeutic potential of AAMP-N on pancreatic islets function,indicating that mannogalactoglucan could be natural nutraceutical used for the treatment of T1DM.

Regenerative medicine of pancreatic islets

The pancreas became one of the first objects of regenerative medicine,since other possibilities of dealing with the pancreatic endocrine insufficiency were clearly exhausted.The number of people living with diabetes mellitus is currently approaching half a billion,hence the crucial relevance of new methods to stimulate regeneration of the insulin-secretingβ-cells of the islets of Langerhans.Natural restrictions on the islet regeneration are very tight;nevertheless,the islets are capable of physiological regeneration viaβ-cell self-replication,direct differentiation of multipotent progenitor cells and spontaneousα-toβ-orδ-toβ-cell conversion(trans-differentiation).The existing preclinical models ofβ-cell dysfunction or ablation(induced surgically,chemically or genetically)have significantly expanded our understanding of reparative regeneration of the islets and possible ways of its stimulation.The ultimate goal,sufficient level of functional activity ofβ-cells or their substitutes can be achieved by two prospective broad strategies:β-cell replacement andβ-cell regeneration.The“regeneration”strategy aims to maintain a preserved population ofβ-cells through in situ exposure to biologically active substances that improveβ-cell survival,replication and insulin secretion,or to evoke the intrinsic adaptive mechanisms triggering the spontaneous non-β-toβ-cell conversion.The“replacement”strategy implies transplantation ofβ-cells(as non-disintegrated pancreatic material or isolated donor islets)orβ-like cells obtained ex vivo from progenitors or mature somatic cells(for example,hepatocytes orα-cells)under the action of small-molecule inducers or by genetic modification.We believe that the huge volume of experimental and clinical studies will finally allow a safe and effective solution to a seemingly simple goal-restoration of the functionally activeβ-cells,the innermost hope of millions of people globally.

Survival of encapsulated islets: More than a membrane story

At present, proven clinical treatments but no cures are available for diabetes, a global epidemic with a huge economic burden. Transplantation of islets ofLangerhans by their infusion into vascularized organs is an experimental clinical protocol, the first approach to attain cure. However, it is associated with lifelong use of immunosuppressants. To overcome the need for immunosuppression, islets are encapsulated and separated from the host immune system by a permselective membrane. The lead material for this application is alginate which was tested in many animal models and a few clinical trials. This review discusses all aspects related to the function of transplanted encapsulated islets such as the basic requirements from a permselective membrane(e.g., allowable hydrodynamic radii, implications of the thickness of the membrane and relative electrical charge). Another aspect involves adequate oxygen supply, which is essential for survival/performance of transplanted islets, especially when using large retrievable macrocapsules implanted in poorly oxygenated sites like the subcutis. Notably, islets can survive under low oxygen tension and are physiologically active at > 40 Torr. Surprisingly, when densely crowded, islets are fully functional under hyperoxic pressure of up to 500 Torr(> 300% of atmospheric oxygen tension). The review also addresses an additional category of requirements for optimal performance of transplanted islets, named auxiliary technologies. These include control of inflammation, apoptosis, angiogenesis, and the intra-capsular environment. The review highlights that curing diabetes with a functional bio-artificial pancreas requires optimizing all of these aspects, and that significant advances have already been made in many of them.

Glucose-stimulated insulin secretion in isolated pancreatic islets: Multiphysics FEM model calculations compared to results of perifusion experiments with human islets

Because insulin released by the β-cells of pancreatic islets is the main regulator of glucose levels, the quantitative modeling of their glucose-stimulated insulin secretion is of obvious interest not only to improve our understanding of the processes involved, but also to allow better assessment of β -cell function in diabetic patients or islet transplant recipients as well as the development of improved artificial or bioartificial pancreas devices. We have recently developed a general, local concentrations-based multiphysics computational model of insulin secretion in avascular pancreatic islets that can be used to calculate insulin secretion for arbitrary geometries of cultured, perifused, transplanted, or encapsulated islets in response to various glucose profiles. Here, experimental results obtained from two different dynamic glucose-stimulated insulin release (GSIR) perifusion studies performed by us following standard procedures are compared to those calculated by the model. Such perifusion studies allow the quantitative assessment of insulin release kinetics under fully controllable experimental conditions of varying external concentrations of glucose, oxygen, or other compounds of interest, and can provide an informative assessment of islet quality and function. The time-profile of the insulin secretion calculated by the model was in good agree- ment with the experimental results obtained with isolated human islets. Detailed spatial distributions of glucose, oxygen, and insulin were calculated and are presented to provide a quantitative visualization of various important aspects of the insulin secretion dynamics in perifused islets.

Study of the immunoisolating effects of barium-alginate microencapsu lation on rat islets allograft survival

Objective: To evaluate the immunoisola ti ng effects of barium-alginate microencapsulation on islets allograft survival. Methods: The nonmicroencapsulated and microencapsulated islets w ere transplanted under the kidney capsule or intraperitoneally into Wistar rat w ith STZ-induced diabetes. The blood glucose and insulin secretion of grafts wer e observed. Graft function was tested by oral glucose tolerance test (OGTT). Results: ①Five diabetic rats became normoglycemic for 48 to 72 h after microencapsulated islets transplantation. The survival of transplanted i slets was on an average of 6 W. ②The normalization of the glycemia and insulin in the transplanted rats was associated with normal glucose and insulin profiles in response to OGTT. Conclusion: Microencapsulation with barium -alginate membrane can prolong islet survival and protect islets against allore jection.

Bone marrow increases human islets insulin positive cells in co-culture: quantification with flow cytometry

We have previously demonstrated that allogeneic human bone marrow (BM) supports human islet function and longevity in vitro. We hypothesize that BM supporting human islets may include to increase β-cell in cultured islets. In this study, we developed a method to quantify insulin-producing β cells from cultured islets by using immunofluorescent staining and flow cytometry analysis to explore this possibility. The results show that human islets cocultured with BM for 39 days contained a significantly higher number of insulin-positive β cells (42.3% ± 4.5%) compared to the islet-only cultures (1.15% ± 0.78%), and increased insulin release levels evaluated by ELISA is consistent with increased β cells in same culture condition. Human islet culture with BM significantly increase β-cells while islet only culture lost β-cells in same culture period supports the possibility of BM increasing β-cells in cultured islets.

Study on Delaunay Triangulation with the Islets Constraints

Aiming at Delaunay triangulation with islets constrains in terrain simulation. A general Delaunay triangulation algorithm for constrained data set with islets is proposed. The algorithm firstly constructs Constrained Delaunay Triangulation with constraint polygons which are inner boundary of islets, then according to topological relations within edge, surface, arc segment, applies bidirectional search to find the triangle in islet, lastly it carries on certain corresponding processing to complete the Delaunay triangulation algorithm with islets. The analyses show the algorithm simple, fast speed. The algorithm can be used in 3-D terrain vision.

On Damped Wave Diffusion of Oxygen in Pancreatic Islets: Parabolic and Hyperbolic Models

Damped wave diffusion effects during oxygen transport in islets of Langerhans is studied. Simultaneous reaction and diffusion models were developed. The asymptotic limits of first and zeroth order in Michaelis and Menten kinetics was used in the study. Parabolic Fick diffusion and hyperbolic damped wave diffusion were studied separately. Method of relativistic transformation was used in order to obtain the solution for the hyperbolic model. Model solutions was used to obtain mass inertial times. Convective boundary condition was used. Sharma number (mass) may be used in evaluating the importance of the damped wave diffusion process in relation to other processes such as convection, Fick steady diffusion in the given application. Four regimes can be identified in the solution of hyperbolic damped wave diffusion model. These are;1) Zero Transfer Inertial Regime, 0 0≤τ≤τinertia;2) Rising Regime during times greater than inertial regime and less than at the wave front, Xp > τ, 3) at Wave front , τ = Xp;4) Falling Regime in open Interval, of times greater than at the wave front, τ > Xp. Method of superposition of steady state concentration and transient concentration used in both solutions of parabolic and hyperbolic models. Expression for steady state concentration developed. Closed form analytic model solutions developed in asymptotic limits of Michaelis and Menten kinetic at zeroth order and first order. Expression for Penetration Length Derived-Hypoxia Explained. Expression for Inertial Lag Time Derived. Solution was obtained by the method of separation of variables for transient for parabolic model and by the method of relativistic transformation for hyperbolic models. The concentration profile was expressed as a sum of steadty state and transient parts.

Characterization of Islets from Chronic Calcific Pancreatitis Patients of Tropical Region with Distinct Phenotype

Background and Objective: Islet autotransplantation is performed to preserve endocrine function in patients undergoing pancreatic resections for painful chronic pancreatitis. We characterized islets isolated from chronic pancreatitis patients (CP) of tropical region. Patients and Methods: Pancreatic tissues were obtained from CP patients with and without diabetes undergoing pancreatic resections (n = 35) and brain-dead multi organ donors (n = 6;considered as controls). Islets isolated were assessed for yield, purity, viability and in vitro islet function (Glucose stimulated insulin release, GSIR) as per standard protocols. Results: Islets from CP patients without diabetes were similar to controls in yield (control 4120 - 6100 IE/g, CP 3550 - 5660 IE/g), purity (control 78% ± 12%, CP 70% ± 8.2%) and viability (control 85% ± 8%, CP 81% ± 10%) and islets from CP patients with diabetes showed decreases in yield (3002 - 2300 IE/g), purity (61% ± 16%) and viability (62% ± 21%). Islets measuring 50 - 200 μ were similar in abundance in controls (94.74% ± 3.2%) and CP patients with and without diabetes, 86.31% ± 4.9%, 91.03% ± 3.8%. GSIR of islets from CP patients and controls were similar at 5.5 mM glucose (2.8 - 3.1 μU/ml). However, GSIR at 16.5 mM glucose was decreased in CP patients (control 18.5 ± 0.6, CP without diabetes 11.8 ± 0.3, CP with diabetes 4.3 ± 0.3 μU/ml). Conclusion: Our results demonstrate suitability of islets isolated from CP patients of tropical region for autotransplantation.

Apoptosis and oxidative injury of donor islets during isolation and purification

Objective To observe the changes of islet cell apoptosis and oxidation - antioxidation before transplantation,and to explore pathways of islet protection. Methods Fifteen human pancreases were perfused with Hanks solution containing collagenase,then digested and isolated.

Bone marrow cells produce nerve growth factor and promote angiogenesis around transplanted islets

AIM:To clarify the mechanism by which bone marrow cells promote angiogenesis around transplanted islets.METHODS: Streptozotocin induced diabetic BALB/ c mice were transplanted syngeneically under the kidney capsule with the following: (1) 200 islets (islet group: n=12), (2) 1-5×106 bone marrow cells (bone marrow group: n=11), (3) 200 islets and 1-5×106 bone marrow cells (islet + bone marrow group: n= 13), or (4) no cells (sham group:n=5). All mice were evaluated for blood glucose, serum insulin, serum nervegrowth factor (NGF) and glucose tolerance (GTT) up to postoperative day (POD) 14. Histological assessment for insulin, von Willebrand factor (vWF) and NGF was performed at POD 3, 7 and 14.RESULTS: Blood glucose level was lowest and serum insulin was highest in the islet + bone marrow group. Serum NGF increased in islet, bone marrow, and islet + bone marrow groups after transplantation, and there was a significant difference (P=0.0496, ANOVA) between the bone marrow and sham groups. The number of vessels within the graft area was signif icantly increased in both the bone marrow and islet + bone marrow groups at POD 14 as compared to the islet alone group (21.2 ± 3.6 in bone marrow, P=0.01, vs islet group, 22.6 ± 1.9 in islet + bone marrow, P = 0.0003, vs islet group, 5.3 ± 1.6 in islet-alone transplants). NGF was more strongly expressed in bone marrow cells compared with islets. CONCLUSION: Bone marrow cells produce NGF and promote angiogenesis. Islet co-transplantation with bone marrow is associated with improvement of islet graft function.

Prevention of central cell damage to isolated islets of Langerhans in hamsters by low temperature preconditioning

BACKGROUND: The efficacy of clinical islet transplanta- tion has been demonstrated with autografts, and although islet allografts have established insulin independence in a small number of IDDM patients, the treatment is con- founded by the necessity of central cell damage immuno- suppression, the lack of donor tissue, and recurring islet immunogenicity. These limitations underscore a need to develop therapies to serve the large population of diabetic patients. This study was designed to document central cell damage to isolated islets of Langerhans in hamsters and its prevention. METHODS: Islets were cultured at 37 °C for 7-14 days after isolation, and then at 26 °C for 2,4 and 7 days before addi- tional culture at 37 °C for an additional 7 days. Central cell damage in the isolated islets was monitored by video-mi- croscopy and analyzed quantitatively by a computer-assis- ted image analysis system. The analysis included daily measurement of the diameter and the area of the isolated is- lets and the area of the central cell damage that developed in those islets over time during culture. Histological exami- nation and TdT-mediated dUTP-biotin nick end labeling (TUNEL) assay were used to characterize cell damage and to monitor islet function. RESULTS; Microscopic analysis showed that during the 7 to 14 days of culture at 37 °C, central cell damage appeared in the larger islets with diameters greater than 200 μm, which included both necrotic and apoptotic cell death. Low temperature (26 °C) culture prevented central cell damage of isolated islets. The 7-day culture procedure at 26 °C could inhibit most of the central cell ( excluding diameters greater than 300 μm) damage when the islets were re- warmed to 37 °C. CONCLUSIONS: Our results indicate that central cell da- mage to isolated islets of Langerhans correlates with the size of the islets. Low temperature (26 °C) culture can preventcentral cell damage to the isolated islets, and is capable to successfully precondition these islets for 37 °C culture. These novel findings may help to understand the patho- physiology of early loss of islet tissue after transplantation, and may provide a new strategy to improve graft function in the clinical setting of islet transplantation.

Effects of Glucagon-Like Peptide 1 on PDX-1, PAX-6 and NKx2.2 Gene Expressions in Isolated Pancreatic Islets

Objective： To observe the effect of glucagon-like peptide 1 （GLP-1） on the gene expressions of transcription factors （PDX-1, PAX-6 and NKx2.2 ） in freshly isolated rat pancreatic islets and investigate the associated physiological and therapeutic implication of GLP-1. Methods： The isolated rat islets were incubated with 10 nmol/L GLP-1 for 1, 3 and 5 days, respectively. Total cellular RNA was extracted and the expressions of PDX-1, PAX-6 and NKx2.2 gene were detected by semiquantity RT-PCR. Results： Compared with the control group, the PDX-1, PAX-6 and NKx2.2 gene expressions were significantly increased after co-cultured with GLP-1 for 1 day （P 〈 0.05）. The effect was shown in a time-dependent manner. All three gene expressions reached the peak on the 5th day. Conclusion： GLP-1 can improve the function of pancreatic islet by regulating the gene expressions of transcription factors in β cells.

ATP Synthase β-subunit Abnormality in Pancreas Islets of Rats with Polycystic Ovary Syndrome and Type 2 Diabetes Mellitus

This study investigated the abnormal expression of ATP synthase β-subunit（ATPsyn-β） in pancreas islets of rat model of polycystic ovary syndrome（PCOS） with type 2 diabetes mellitus（T2DM）,and the secretion function changes after up-regulation of ATP5 b.Sixty female SD rats were divided into three groups randomly and equally.The rat model of PCOS with T2 DM was established by free access to the high-carbohydrate/high-fat diet,subcutaneous injections of DHEA,and a single injection of streptozotocin.The pancreas was removed for the detection of the ATPsyn-β expression by immunohistochemical staining,Western blotting and reverse transcription-PCR（RT-PCR）.The pancreas islets of the rats were cultured,isolated with collagenase Ⅴ and purified by gradient centrifugation,and the insulin secretion after treatment with different glucose concentrations was tested.Lentivirus ATP5 b was successfully constructed with the vector of GV208 and transfected into the pancreas islets for the over-expression of ATPsyn-β.The insulin secretion and intracellular ATP content were determined after transfection of the PCOS-T2 DM pancreas islets with Lenti-ATP5 b.The results showed that the expression of ATPsyn-β protein and m RNA was significantly decreased in the pancreas of PCOS-T2 DM rats.The ATP content in the pancreas islets was greatly increased and the insulin secretion was improved after the up-regulation of ATPsyn-β in the pancreas islets transfected with lenti-ATP5 b.These results indicated that for PCOS,the ATPsyn-β might be one of the key factors for the attack of T2 DM.

Expression profiling of putative type 2 diabetes susceptibility genes in human islets and in rat beta cell lines

Over 50 single nucleotide polymorphisms (SNPs) have been identified by genome wide association studies (GWAS) to be associated with susceptibility to type 2 diabetes (T2D);however the causal gene in most cases is not known. In this study we sought to identify which may be the most likely causal genes at five T2D GWAS loci by measuring their expression in control and T2D islets, as well as observing their regulation by glucose. We measured the expression of ten genes at five loci (CDKN2A/2B, CDC123/CAMK-1D, HHEX/IDE, TSPAN8/LGR5, and DGKB/TMEM 195), in control and human pancreatic islets by real-time PCR. We then measured the expression of these genes in the rodent pancreatic beta cell line INS-1 exposed to 5.6 mmol/l, 11 mmol/l and 28 mmol/l glucose for 48 hours. We found differential expression of the longest isoform of CDKN2B specifically between control and T2D human islets, whereas the shortest isoform of this gene had no expression in islets. Tmem195 was the only gene to show differential expression in response to increasing glycemia in INS-1 cells under the conditions described. Our study is an example of how the differential expression of genes in loci spanning more than one gene can aid identification of the more likely causal gene.

Effects of mature Sertoli cells on allogeneic islets cocultured in vitro

Objective： To set up a method for isolation and culture of mature Sertoli cells and to estimate their effects on allogeneic islets cocultured in vitro. Methods： Adult SD rat testicular Sertoli cells were prepared successfully by three-step enzyme digestion. Then they were cocultured respectively with allogeneic islets and activated Wistar rat splenocytes. 24-hour cumulative insulin release and glucose-stimulated insulin secretion test were performed to detect islet function between pure islets culture group and coculture group. Splenocyte proliferation activity was determined by MTT colorimetry assay to observe the inhibition effect of Sertoli cells in different densities. Result： Firstly, in pure islet culture group, the 24-hour cumulative insulin release was gradually decreased in 21-day culture time. Compared to day 3, this change was significant on day 7 （P 〈 0.05） and on day 10,14,21 （P 〈 0.01）. In contrast, in coculture group, compared to day 3, the 24-hour cumulative insulin release was increased significantly on day 7 （P 〈 0.01 ）, and then gradually decreased on day 10 and 14, but still higher than that of day 3. It was on day 21 that it began to decrease compared to day 3 （P 〈 0.05）. During the culture time in vitro, the 24-hour cumulative insulin release of islet coculture group was significantly higher than that of pure islets culture group （P 〈 0.01）. In the case of stimulation index（SI）, there was a similar tendency as insulin release in the two groups. Secondly, mature Sertoli cells（1×10^6/mL） pretreated by 15 grays irradiation could decrease proliferation activity of activated splenocytes compared to that of control group （P 〈 0.01 ）. This inhibition effect was dose-dependent. Conclusion： Mature Sertoli cells can improve the function and prolong the survival of islet cells cultured in vitro. They can also provide an immune protection to islet cells. The approach described above might be applicable to human islet transplantation as soon as if it is also valid in large animal models.

Oral nano-formulation improves pancreatic islets dysfunction via lymphatic transport for antidiabetic treatment

Type 2 diabetes mellitus(T2DM)therapy is facing the challenges of long-term medication and gradual destruction of pancreatic isletβ-cells.Therefore,it is timely to develop oral prolonged action formulations to improve compliance,while restoringβ-cells survival and function.Herein,we designed a simple nanoparticle with enhanced oral absorption and pancreas accumulation property,which combined apical sodiumdependent bile acid transporter-mediated intestinal uptake and lymphatic transportation.In this system,taurocholic acid(TCA)modified poly(lactic-co-glycolic acid)(PLGA)was employed to achieve pancreas location,hydroxychloroquine(HCQ)was loaded to execute therapeutic efficacy,and 1,2-dilauroyl-sn-glycero-3-phosphocholine(DLPC)was introduced as stabilizer together with synergist(PLGA-TCA/DLPC/HCQ).In vitro and in vivo results have proven that PLGA-TCA/DLPC/HCQ reversed the pancreatic islets damage and dysfunction,thus impeding hyperglycemia progression and restoring systemic glucose homeostasis via only once administration every day.In terms of mechanism PLGA-TCA/DLPC/HCQ ameliorated oxidative stress,remodeled the inflammatory pancreas microenvironment,and activated PI3K/AKT signaling pathway without obvious toxicity.This strategy not only provides an oral delivery platform for increasing absorption and pancreas targetability but also opens a new avenue for thorough T2DM treatment.

A novel bioartificial pancreas fabricated via islets microencapsulation in anti-adhesive core-shell microgels and macroencapsulation in a hydrogel scaffold prevascularized in vivo

Islets transplantation is a promising treatment for type 1 diabetes mellitus. However, severe host immune rejection and poor oxygen/nutrients supply due to the lack of surrounding capillary network often lead to transplantation failure. Herein, a novel bioartificial pancreas is constructed via islets microencapsulation in core-shell microgels and macroencapsulation in a hydrogel scaffold prevascularized in vivo. Specifically, a hydrogel scaffold containing methacrylated gelatin (GelMA), methacrylated heparin (HepMA) and vascular endothelial growth factor (VEGF) is fabricated, which can delivery VEGF in a sustained style and thus induce subcutaneous angiogenesis. In addition, islets-laden core-shell microgels using methacrylated hyaluronic acid (HAMA) as microgel core and poly(ethylene glycol) diacrylate (PEGDA)/carboxybetaine methacrylate (CBMA) as shell layer are prepared, which provide a favorable microenvironment for islets and simultaneously the inhibition of host immune rejection via anti-adhesion of proteins and immunocytes. As a result of the synergistic effect between anti-adhesive core-shell microgels and prevascularized hydrogel scaffold, the bioartificial pancreas can reverse the blood glucose levels of diabetic mice from hyperglycemia to normoglycemia for at least 90 days. We believe this bioartificial pancreas and relevant fabrication method provide a new strategy to treat type 1 diabetes, and also has broad potential applications in other cell therapies.

Epinephrine also acts on beta cells and insulin secretion

In a recent review examining neurotransmitter modulation of insulin secretion,the significant impact of epinephrine was not addressed.Its primary action involves inhibiting insulin release via alpha-adrenergic receptors,thereby reducing the response to insulin secretion stimulators,through the activation of K+channels and resulting in membrane hyperpolarization in beta cells.

Dietary Green Tea Extract and Antioxidants Improve Insulin Secretory Functions of Pancreatic β-Cells in Mild and Severe Experimental Rodent Model of Chronic Pancreatitis

Chronic pancreatitis (CP) is a progressive inflammatory disorder of the pancreas. It is predominantly idiopathic (with an unknown cause) in India and mostly due to alcohol in the West. Diabetes that occur secondary to chronic pancreatitis (T3c Diabetes) is often brittle, and is difficult to attain normoglycemia with conventional treatment requiring multiple doses of insulin. Mild and severe model of CP was induced in mice by repeated intraperitoneal injections of cerulein and L-arginine respectively with an intent to study islet dysfunction and develop therapeutic strategy in animal models of CP. Dietary intervention of epigallocatechin-3-gallate (EGCG) was tested in both the models of CP for its beneficial effects on insulin secretory functions. Pancreata collected upon euthanasia were used to study alterations in the morphology of pancreatic parenchyma and inflammation by staining with H&E and fibrotic changes by Masson’s trichrome and picrosirius staining. Insulin secretory functions of islets were evaluated to test the efficacy of the dietary intervention on β-cell functions. Intraperitoneal glucose tolerance test was performed to monitor the glucose homeostasis before and after the dietary intervention. Both the models resulted in CP with dispersed acini, inflammation and fibrosis. The loss of acini and extent of fibrosis was more in L-arginine model. 2-fold improvement in glucose-stimulated insulin secretory functions of islets was observed with 0.5% EGCG dietary intervention in cerulein model of CP and 1.6-fold in L-arginine model of CP. A further improvement in insulin secretion by 3.2-fold was observed with additional dietary supplements like N-acetyl cysteine, curcumin in combination with EGCG. Our results thus demonstrate and highlight the therapeutic potential of dietary green tea (EGCG) supplementation in reversing islet dysfunction and improving glucose homeostasis in experimental chronic pancreatitis in mice.