Pancreatic Β-cell Regeneration Research Articles

Harnessing androgen receptor: Revolutionizing diabetes treatment in men with selective androgen receptor modulators

Diabetes is a chronic metabolic disorder. Among different types, type 2 diabetes mellitus (T2DM) is the most prevalent accounting for 90 % to 95 % of all reported cases. T2DM is more prevalent in men compared to women. According to several literature reports, men with low testosterone levels and/or decreased androgen receptor (AR) expression are prone to T2DM. Consistently, androgen therapy was effective in treating T2DM in several preclinical and clinical studies. Activation of AR has been shown to induce the gene expression of NGN3 and NEUROD1 which helps in pancreatic β-cell differentiation, regeneration, and proliferation. AR activation can also increase the gene expression of glucose transporter (GLUT4) in the hepatocytes, skeletal muscle fibers, and adipocytes. An increase in GLUT4 expression could augment the activity of insulin and could help to reduce the insulin dose. However, testosterone therapy even for the short term was found to produce significant adverse effects. The rate-limiting being the increase in the hematocrit value. Hence, to minimize or avoid the serious adverse effects associated with androgen therapy, selective androgen receptor modulators (SARMs) could be employed to harness the goodness of the AR. A preliminary study based on the network analysis of the genes associated with T2DM has also pointed towards the importance of AR in T2DM.

Harnessing androgen receptor: Revolutionizing diabetes treatment in men with selective androgen receptor modulators

Diabetes is a chronic metabolic disorder. Among different types, type 2 diabetes mellitus (T2DM) is the most prevalent accounting for 90 % to 95 % of all reported cases. T2DM is more prevalent in men compared to women. According to several literature reports, men with low testosterone levels and/or decreased androgen receptor (AR) expression are prone to T2DM. Consistently, androgen therapy was effective in treating T2DM in several preclinical and clinical studies. Activation of AR has been shown to induce the gene expression of NGN3 and NEUROD1 which helps in pancreatic β-cell differentiation, regeneration, and proliferation. AR activation can also increase the gene expression of glucose transporter (GLUT4) in the hepatocytes, skeletal muscle fibers, and adipocytes. An increase in GLUT4 expression could augment the activity of insulin and could help to reduce the insulin dose. However, testosterone therapy even for the short term was found to produce significant adverse effects. The rate-limiting being the increase in the hematocrit value. Hence, to minimize or avoid the serious adverse effects associated with androgen therapy, selective androgen receptor modulators (SARMs) could be employed to harness the goodness of the AR. A preliminary study based on the network analysis of the genes associated with T2DM has also pointed towards the importance of AR in T2DM.

Ginseng extract improves pancreatic islet injury and promotes β-cell regeneration in T2DM mice.

Panax ginseng C. A. Mey. (Araliaceae; Ginseng Radix et Rhizoma), a traditional plant commonly utilized in Eastern Asia, has demonstrated efficacy in treating neuro-damaging diseases and diabetes mellitus. However, its precise roles and mechanism in alleviating type 2 diabetes mellitus (T2DM) need further study. The objective of this study is to explore the pharmacological effects of ginseng extract and elucidate its potential mechanisms in protecting islets and promoting β-cell regeneration. The T2DM mouse model was induced through streptozotocin combined with a high-fat diet. Two batches of mice were sacrificed on the 7th and 28th days following ginseng extract administration. Body weight, fasting blood glucose levels, and glucose tolerance were detected. Morphological changes in the pancreatic islets were examined via H & E staining. Levels of serum insulin, glucagon, GLP-1, and inflammatory factors were measured using ELISA. The ability of ginseng extract to promote pancreatic islet β-cell regeneration was evaluated through insulin & PCNA double immunofluorescence staining. Furthermore, the mechanism behind β-cells regeneration was explored through insulin & glucagon double immunofluorescence staining, accompanied by immunohistochemical staining and western blot analyses. The present research revealed that ginseng extract alleviates symptoms of T2DM in mice, including decreased blood glucose levels and improved glucose tolerance. Serum levels of insulin, GLP-1, and IL-10 increased following the administration of ginseng extract, while levels of glucagon, TNF-α, and IL-1β decreased. Ginseng extract preserved normal islet morphology, increased nascent β-cell population, and inhibited inflammatory infiltration within the islets, moreover, it decreased α-cell proportion while increasing β-cell proportion. Mechanistically, ginseng extract might inhibit ARX and MAFB expressions, increase MAFA level to aid in α-cell to β-cell transformation, and activate AKT-FOXM1/cyclin D2 to enhance β-cell proliferation. Our study suggests that ginseng extract may be a promising therapy in treating T2DM, especially in those with islet injury.

Rosa canina extract relieves methylation alterations of pancreatic genes in STZ-induced diabetic rats : Gene methylation in diabetic rats treated with an extract.

Diabetes is a chronic metabolic disease that affects many parts of the body. Considering diabetes as a beta cells' defect and loss, the focus is on finding mechanisms and compounds involved in stimulating the function and regeneration of pancreatic β-cells. DNA methylation as an epigenetic mechanism plays a pivotal role in the β-cells' function and development. Considering the regenerative and anti-diabetic effects of Rosa canina extract, this study aimed to assess the methylation levels of Pdx-1, Pax-4, and Ins-1 genes in diabetic rats treated with Rosa Canina extract. Streptozotocin-induced diabetic rats were used to evaluate the frequency of Pdx-1, Pax-4, and Ins-1 gene methylation. Treatment groups were exposed to Rosa canina as spray-dried and decoction extracts. Following blood glucose measurement, pancreatic DNA was extracted and bisulfited. Genes' methylation was measured using MSP-PCR and qRT-PCR techniques. Oral administration of Rosa canina extracts significantly reduced blood sugar levels in diabetic rats compared to the control group. The methylation levels of the Pdx-1, Pax-4, and Ins-1 genes promoter in streptozotocin-induced diabetic rats increased compared to the control rats while, the treatment of diabetic rats with Rosa canina extracts, spray-dried samples especially, led to a decreased methylation in these genes. The results of this study showed that Rosa canina extract as a spray-dried sample could be effective in treating diabetes by regulating the methylation of genes including Pdx-1, Pax-4, and Ins-1 involved in the activity and regeneration of pancreatic islet cells.

Aged garlic extract preserves beta-cell functioning via modulation of nuclear factor kappa-B (NF-κB)/Toll-like receptor (TLR)-4 and sarco endoplasmic reticulum calcium ATPase (SERCA)/Ca2+ in diabetes mellitus

BackgroundPeripheral insulin resistance and compromised insulin secretion from pancreatic β-cells are significant factors and pathogenic hallmarks of diabetes mellitus (DM). NF-κβ/TLR-4 and SERCA/Ca2+ pathways have been identified as potential pathways regulating insulin synthesis by preserving pancreatic β-cell functioning. The current study aimed to evaluate the therapeutic effect of aged garlic extract (AGE) against DM in a streptozotocin (STZ)-induced rat model with particular emphasis on pancreatic β-cell functioning.MethodsAGE was characterized by gas chromatography-mass spectrometry (GC-MS), Fourier-transform infrared spectroscopy (FTIR), and scanning electron microscopy (SEM) to evaluate its physio-chemical characteristics followed by in-vitro anti-diabetic and antioxidant potential. This was followed by the induction of DM in laboratory animals for investigating the therapeutic action of AGE by evaluating the role of NF-κβ/TLR-4 and the SERCA/Ca2+ pathway. The parameters assessed in the present experimental setup encompassed antioxidant parameters, metabolic indicators, insulin concentration, intracellular calcium levels, apoptotic markers (CCK-8 and Caspase Glo-8), and protein expression (P-62 and APACHE-II).ResultsAGE characterization by SEM, GC-MS, and X-ray diffraction (XRD) revealed the presence of phenylalanine, alliin, S-allylmercaptocysteine (SAMC), tryptophan, 1-methyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid as major bioactive constituents of AGE. Metabolic studies, including intraperitoneal glucose tolerance test (IPGTT), revealed significantly lower blood glucose levels in the AGE group compared to the disease control group. In contrast, the intraperitoneal insulin tolerance test (ITT) exhibited no significant difference in insulin sensitivity between the AGE supplementation group and the DM control group. Interestingly, AGE was found to have no significant effect on fasting glucose and serum insulin levels. In contrast, AGE supplementation was found to cause significant hypoglycaemia in postprandial blood glucose and insulin levels. Importantly, AGE causes restoration of intracellular Ca2+ levels by modulation of SERCA/Ca2 functioning and inhibition NF-κB/TLR-4 pathway. AGE was found to interact with and inhibit the DR-5/ caspase-8/3 apoptotic complex. Furthermore, microscopic studies revealed degeneration and apoptotic changes in pancreatic β-cells of the DM control group, while supplementation of AGE resulted in inhibition of apoptotic pathway and regeneration of pancreatic β-cells.ConclusionThe current study suggests that AGE enhance glucose homeostasis by exerting their effects on pancreatic β-cells, without ameliorating peripheral sensitivity. Moreover, AGEs promote an increase in β-cell mass by mitigating the apoptosis of pancreatic β-cells. These findings suggest that AGE could aid in developing a viable alternative therapy for diabetes mellitus (DM).

Gut Microbiota-Tryptophan Metabolism-GLP-1 Axis Participates in β-Cell Regeneration Induced by Dapagliflozin.

Sodium-glucose co-transporter 2 (SGLT2) inhibitor, an efficacious anti-diabetic agent, which has cardiovascular and renal benefits, can promote pancreatic β-cell regeneration in type 2 diabetic mice. However, the underlying mechanism remains unclear. In this study, we aimed to use multi-omics to identify the mediators involved in β-cell regeneration induced by dapagliflozin. We showed that dapagliflozin lowered blood glucose level, upregulated plasma insulin level, and increased islet area in db/db mice. Dapagliflozin reshaped gut microbiota, and modulated microbiotic and plasmatic metabolites related to tryptophan metabolism, especially L-tryptophan, in the diabetic mice. Notably, L-tryptophan upregulated the mRNA level of GLP-1 production-related genes (Gcg and Pcsk1) expression and promoted GLP-1 secretion in cultured mouse intestinal L-cells, and it increased supernatant insulin level in primary human islets, which was eliminated by GPR142 antagonist. Transplantation of fecal microbiota from dapagliflozin-treated mice, supplementation of L-tryptophan or treatment with dapagliflozin upregulated L-tryptophan, GLP-1, and insulin or C-peptide level, and promoted β-cell regeneration in db/db mice. Addition of exendin 9-39, a GLP-1 receptor (GLP-1R) antagonist, or pancreatic Glp1r knockout diminished these beneficial effects. In summary, treatment with dapagliflozin in type 2 diabetic mice promotes β-cell regeneration by upregulating GLP-1 production, which is mediated via gut microbiota and tryptophan metabolism.

A Novel Variant Of Regenerating Iα Gene (REG) In Type II Diabetics Among Pakistani Targeted Population

Objective: Regeneration of pancreatic β-cells, is an essential step towards diabetes management. The regenerating (REG) Iα gene is secreted from damaged β-cell for the synthesis of β-cell. This study aimed to identify REG Iα gene polymorphisms and their association with Type II diabetes (T2DM). Methods: Patients (110) with T2DM and age-related controls were selected from PNS Shifa Hospital, Karachi. DNA was extracted PCR was performed and amplified products were sequenced to identify polymorphisms. For six exons of the REG 1a gene, 6 sets of primers were designed. The selected (51) samples were amplified and sequenced for 306 (51x6) times. Odds ratios were calculated through logistic regression analysis. The correlation was used to find an association between REG Iα and diseases. p< 0.05 was considered significant. Results: Blood samples were drawn from 90 finalized patients, including 70 diabetics and 20 controls with an M: F ratio of 12:8. Twenty patients opted to withdraw. The REG Iα and disease duration in type II diabetics showed a negative correlation (r= -0.355, p=0.005). The single nucleotide polymorphisms (SNPs) of eight sites were detected: g.-385T>C, g.-243T>G, g.-145G>A, g.+142A, g.+209G>T, g.+226A>G, g.+2199G>A, g.+2360A>G. The novel SNP g.-145G>A was found in all patients (controls, T2DM). Among all SNPs, only g.+209G>T showed a positive association (OR= 2.4, p=0.01) with T2DM. Whereas, g.-243T>G showed a positive association (OR=8.06, p=0.0003) with smoking. Conclusion: A novel variant g.-145G>A REG Iα gene was found among all participants. The SNPs g.+209G>T had a significant positive association with T2DM and SNP g.-243T>G showed an increased risk of the disease among smokers. Keywords: REG Iα gene, Type II diabetes, β-cells regeneration, Polymorphisms.

Comparative assessment of physicochemical properties of plant active molecules having antidiabetic potential

Diabetes mellitus is one of the most prevalent diseases found in all parts of the world. It is a complex heterogeneous group of metabolic disorders including hyperglycemia and is associated with imbalances in carbohydrate, protein, and lipid metabolism. The management of diabetes mellitus is considered a global problem. In current allopathic therapy, oral hypoglycaemic agents and insulin are used to control diabetic conditions. Traditional herbal drugs with multiple phytoconstituents and properties have been used as medicines for the treatment of a wide range of diabetes. Herbal medicines have been intrinsically safe, due to their natural occurrence, efficacy, and fewer side effects. The active molecules present in different phytoconstituents of herbal medicines act by different mechanisms to reduce the amount of glucose level in the blood. The functional efficiency of these active molecules largely depends on their physicochemical properties. In the present study, the physicochemical properties of important plant active molecules are analyzed and assessed which have antidiabetic potential and are particularly involved in regeneration of pancreatic β-cells.

Indigenous Antidiabetic Medicinal Plants Used in Nigeria: A Review

Diabetes mellitus is among the most prevalent endocrine disease that causes morbidity and mortality in Nigeria. Traditional medical system has been used for the both prevention and treatment of diabetes mellitus since ages. This paper reviewed the use of 35 Nigerian plants with putative anti-diabetic properties with the help of published literature. As per the International Union for Conservation of Nature (IUCN), status of these species include Sterculia tragacantha, Newbouldia laevis, Solanum anomalum, Ficus exasperate, Raffia palm (Raphia hookeri) Azadirachta indica, Syzygium cumini, Terminalia catapp, Solanum macrocarpon, Petersianthus macrocarpus, Xylopia aethiopica, Costus aferker-gawl, Spondias mombin, Eucalyptus globulus Parkia biglobosa, Persea americana, Anacardium occidentale, Vernonia amygdalina as least concern. While the status of Hunteria umbellate and Vitex doniana are reported as threatened and Dacryodes edulis and Dennettia tripetala as vulnerable species. However, the status of Annona muricata, Chrysophyllum albidum, Citrus paradisi Macfad, Aloe vera (Aloe barbadensis) are not evaluated. The following species like Phyllanthus amarus, Phyllanthus niruri and Telfairia occidentalis are data deficient. Most of the species belonging to common families like Solanaceae, Anacardiaceae, Euphorbiaceae, Annonaceae and Rutaceae. This review offers relevant information and recent scientific findings on the plants used to treat and manage diabetes in Nigeria. The cellular mechanisms through which these natural agents exert their protective and therapeutic effects on diabetes mellitus may include antioxidative stress, restricting the breakdown of glycogen, pancreatic β-cell regeneration, gluconeogenesis, anti-inflammatory and intracellular signals transduction pathways. This study concludes that indigenous medicinal herbs utilized in Nigeria have the potential to treat diabetes mellitus in Nigeria. Further studies are needed to discover potential drugs from these indigenous plants.

The effect of Kawa Daun (Coffea canephora) decoction on blood glucose levels and pancreatic β-cells regeneration in rats with diabetes

Giving coffee leaves Kawa Daun (Coffea canephora), which contains flavonoids and chlorophyll, which are antioxidants, is one of the therapies that may be used to treat diabetes mellitus, which is expected to affect 783 million people worldwide by 2045. This study, therefore, aims to demonstrate Kawa Daun decoction’s potency in lowering blood glucose levels and restoring pancreatic β-cells in rats with diabetes mellitus. Wistar rats (2-3 months, 200 g, n = 28) were used in this true experimental study, which applied a pre-post-control group design. Regular feeding + no intervention was for the group (K-); Kawa Daun was not provided to (K+) DM (alloxan) rats + regular feeding; (P1) DM rats (alloxan) received 3.6 ml/200 g BW/day of Kawa Daun decoction along with regular feeding; Kawa Daun decoction 7.2 ml/200 g body weight/day in addition to regular feeding was given to (P2) DM rats (alloxan). For 14 days, the intervention was given orally. A spectrophotometer was utilized to detect blood glucose levels, and histological analysis using H&E staining was employed to determine the state of the pancreatic β-cells. In comparison to the (K+) group, the intervention group significantly decreased blood glucose levels (p = 0.001), according to the findings. The P2 group's reduction in blood sugar levels (∆ = 139.33 mg/dl 38.45) was more significant than that of the P1 group (∆ = 109.17 mg/dl 35.32). Compared to the (K+) (27.1% damage) group, the intervention group's pancreatic β-cells revealed improvement according to the histopathological examination results. The group's (P2 = 14.9%) damage area was less than the group's (P1 = 22.4%). This study emphasizes how administering Kawa Daun decoction can improve blood glucose levels and reconstruct the pancreatic β-cells damage and its protection. Finally, this kind of leaf could be a substitute compound for diabetic herbal therapy.

Regeneration of Pancreatic β-Cells for Diabetes Therapeutics by Natural DYRK1A Inhibitors.

The pathogenesis of diabetes mellitus is characterized by insulin resistance and islet β-cell dysfunction. Up to now, the focus of diabetes treatment has been to control blood glucose to prevent diabetic complications. There is an urgent need to develop a therapeutic approach to restore the mass and function of β-cells. Although exogenous islet cell transplantation has been used to help patients control blood glucose, it is costly and has very narrow application scenario. So far, small molecules have been reported to stimulate β-cell proliferation and expand β-cell mass, increasing insulin secretion. Dual-specificity tyrosine-regulated kinase 1A (DYRK1A) inhibitors can induce human β-cell proliferation in vitro and in vivo, and show great potential in the field of diabetes therapeutics. From this perspective, we elaborated on the mechanism by which DYRK1A inhibitors regulate the proliferation of pancreatic β-cells, and summarized several effective natural DYRK1A inhibitors, hoping to provide clues for subsequent structural optimization and drug development in the future.

Therapeutic Strategies Targeting Pancreatic Islet β-Cell Proliferation, Regeneration, and Replacement.

Diabetes results from insufficient insulin production by pancreatic islet β-cells or a loss of β-cells themselves. Restoration of regulated insulin production is a predominant goal of translational diabetes research. Here, we provide a brief overview of recent advances in the fields of β-cell proliferation, regeneration, and replacement. The discovery of therapeutic targets and associated small molecules has been enabled by improved understanding of β-cell development and cell cycle regulation, as well as advanced high-throughput screening methodologies. Important findings in β-cell transdifferentiation, neogenesis, and stem cell differentiation have nucleated multiple promising therapeutic strategies. In particular, clinical trials are underway using in vitro-generated β-like cells from human pluripotent stem cells. Significant challenges remain for each of these strategies, but continued support for efforts in these research areas will be critical for the generation of distinct diabetes therapies.

Arid1a loss potentiates pancreatic β-cell regeneration through activation of EGF signaling.

The dynamic regulation of β-cell abundance is poorly understood. Since chromatin remodeling plays critical roles in liver regeneration, these mechanisms could be generally important for regeneration in other tissues. Here, we show that the ARID1A mammalian SWI/SNF complex subunit is a critical regulator of β-cell regeneration. Arid1a is highly expressed in quiescent β-cells but is physiologically suppressed when β-cells proliferate during pregnancy or after pancreas resection. Whole-body Arid1a knockout mice are protected against streptozotocin-induced diabetes. Cell-type and temporally specific genetic dissection show that β-cell-specific Arid1a deletion can potentiate β-cell regeneration in multiple contexts. Transcriptomic and epigenomic profiling of mutant islets reveal increased neuregulin-ERBB-NR4A signaling. Chemical inhibition of ERBB or NR4A1 blocks increased regeneration associated with Arid1a loss. Mammalian SWI/SNF (mSWI/SNF) complex activity is a barrier to β-cell regeneration in physiologic and disease states.

The progress of pluripotent stem cell-derived pancreatic β-cells regeneration for diabetic therapy.

Diabetes is a complex metabolic disorder of carbohydrate metabolism, characterized by high blood glucose levels either due to an absolute deficiency of insulin secretion or an ineffective response of cells to insulin, a hormone synthetized by β-cells in the pancreas. Despite the current substantial progress of new drugs and strategies to prevent and treat diabetes, we do not understand precisely the exact cause of the failure and impairment of β-cells. Therefore, there is an urgent need to find new methods to restore β-cells. In recent years, pluripotent stem cells (PSCs) such as embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSC) can serve as an ideal alternative source for the pancreatic β-cells. In this review, we systematically summarize the current progress and protocols of generating pancreatic β-cells from human PSCs. Meanwhile, we also discuss some challenges and future perspectives of human PSCs treatments for diabetes.

The Effect of Klika Ongkea Extract (Mezzetia parviflora Becc.) on Pancreatic β-Cells Regeneration by Streptozotocin-Induced in Wistar Rats

This study aimed to determine the effect of Klika ongkea (Mezzetia parviflora Becc.) extract on the regeneration of pancreatic β-cells on Wistar rats that were induced using streptozotocin. Streptozotocin (STZ) with a 40 mg/kg BW dose was used in this study. Eighty adult male Wistar rats were used for this study. The animals were divided into four groups, Group I, as a healthy controls; Group II as an STZ-induced, Group III, STZ-induced and treated with galvus (Vildagliptin) 0.9 mg/200 g BW; Group IV, STZ-induced and treated with Klika ongkea 100 mg/kg BW. This study was conducted for 28 days. Four animals each group on the 1st, 7th, 14th, 21st and 28th days were observed to analyze the number of pancreatic β-cells. On the last day, pancreases were isolated and stained with hematoxylin & eosin (H&E) to analyze the regeneration of pancreatic β-cells. The data analysis was performed using an Independent-Sample T-Test to compare the number of pancreatic β-cells. The results showed that the administration of Klika ongkea extracts affected the pancreatic β-cells regeneration. These findings suggest that Klika ongkea has an effect on the regeneration of pancreatic β-cells in streptozotocin-induced rats.

Inhibition of CXXC5 function reverses obesity-related metabolic diseases.

BackgroundMetabolic diseases, including type 2 diabetes, have long been considered incurable, chronic conditions resulting from a variety of pathological conditions in obese patients. Growing evidence suggests the Wnt/β‐catenin pathway is a major pathway in adipose tissue remodelling, pancreatic β‐cell regeneration and energy expenditure through regulation of key metabolic target genes in various tissues. CXXC5‐type zinc finger protein 5 (CXXC5) is identified negative feedback regulator of the Wnt/β‐catenin pathway that functions via Dishevelled (Dvl) binding.MethodsExpression level of CXXC5 was characterised in clinical samples and diabetes‐induced mice model. Diabetes‐induced mice model was established by using high‐fat diet (HFD). HFD‐fed mice treated with KY19334, a small molecule inhibiting CXXC5‐Dvl protein–protein interaction (PPI), was used to assess the role of CXXC5 in metabolic diseases.ResultsHere, we show that CXXC5 is overexpressed with suppression of Wnt/β‐catenin signalling in visceral adipose tissues of patients with obesity‐related diabetes. Meanwhile, Cxxc5−/− mice fed an HFD exhibited resistance to metabolic dysregulation. KY19334 restores the lowered Wnt/β‐catenin signalling and reverses metabolic abnormalities as observed in HFD‐fed Cxxc5−/− mice. Administration of KY19334 on HFD‐fed mice had a long‐lasting glucose‐controlling effect through remodelling of adipocytes and regeneration of pancreatic β‐cells.ConclusionOverall, the inhibition of CXXC5 function by small molecule‐mediated interference of Dvl binding is a potential therapeutic strategy for the treatment of obesity‐related diabetes.

Gymnemic Acid Ameliorates Pancreatic β-Cell Dysfunction by Modulating Pdx1 Expression: A Possible Strategy for β-Cell Regeneration.

Endogenous pancreatic β-cell regeneration is a promising therapeutic approach for enhancing β-cell function and neogenesis in diabetes. Various findings have reported that regeneration might occur via stimulating β-cell proliferation, neogenesis, or conversion from other pancreatic cells to β-like cells. Although the current scenario illustrates numerous therapeutic strategies and approaches that concern endogenous β-cell regeneration, all of them have not been successful to a greater extent because of cost effectiveness, availability of suitable donors and rejection in case of transplantation, or lack of scientific evidence for many phytochemicals derived from plants that have been employed in traditional medicine. Therefore, the present study aims to investigate the effect of gymnemic acid (GA) on β-cell regeneration in streptozotocin-induced type 1 diabetic rats and high glucose exposed RIN5-F cells. The study involves histopathological and immunohistochemical analysis to examine the islet's architecture. Quantitative polymerase chain reaction (qPCR) and/or immunoblot were employed to quantify the β-cell regeneration markers and cell cycle proliferative markers. The immunoexpression of E-cadherin, β-catenin, and phosphoinositide 3-kinases/protein kinase B were significantly increased in GA-treated diabetic rats. On the other hand, treatment with GA upregulated the pancreatic regenerative transcription factor viz. pancreatic duodenal homeobox 1, Neurogenin 3, MafA, NeuroD1, and β-cells proliferative markers such as CDK4, and Cyclin D1, with a simultaneous downregulation of the forkhead box O, glycogen synthase kinase-3, and p21cip1 in diabetic treated rats. Adding to this, we noticed increased nuclear localization of Pdx1 in GA treated high glucose exposed RIN5-F cells. Our results suggested that GA acts as a potential therapeutic candidate for endogenous β-cell regeneration in treating type 1 diabetes.

Calorie restriction potentiates the therapeutic potential of GABA in managing type 2 diabetes in a mouse model

Dysfunctional adipocytes/β-cells advance type 2 diabetes (T2D). Calorie restriction (CR) improves insulin sensitivity and fasting blood glucose (FBG) levels, while γ-aminobutyric acid (GABA) exerts regenerative effects. The impact of therapies was assessed by a high-fat diet (HFD) + streptozotocin (STZ) induced T2D mouse model. The mice were fed a CR diet (30% reduction of HFD) and treated with GABA (2.5 mg/kg i.p) for 5 weeks. Standard protocols were used to assess metabolic parameters. The mRNA expression was monitored by SYBR Green-qPCR in the targeted tissues. Oxygen consumption rate in the mitochondrial complexes was evaluated by oxytherm clark-type oxygen electrode. Pancreatic β-cell regeneration and apoptosis were analysed by immunohistochemistry. CR + GABA combination therapy showed improved metabolic parameters compared to the monotherapies. We have observed improved transcript levels of G6Pase, PEPCK, Glycogen Phosphorylase, GLUT2 and GCK in liver; ACC and ATGL in adipose tissue. Also increased SIRT-1, PGC-1α and TFAM expression; up-regulated mitochondrial complexes I-III activities were observed. We have seen increased BrdU/Insulin and PDX1/Ngn3/Insulin co-positive cells in CR + GABA treated group with a reduction in apoptotic marker (TUNEL/Insulin co-positive cells). Our results indicate that CR in combination with GABA ameliorates T2D in HFD + STZ treated mice by GABA induced β-cell regeneration, and CR mediated insulin sensitivity.

White saffron (Curcuma mangga Val.) attenuates diabetes and improves pancreatic β-cell regeneration in streptozotocin-induced diabetic rats

Diabetes is a chronic disease caused by an imbalance of insulin release to the bloodstream in response to excessive glucose influx, which causes hyperglycemia. White saffron (Curcuma mangga Val.), an Indonesian aromatic spice, contains essential phytochemicals and has a number of potential health benefits. Here, we examined the effects of oral administration of white saffron powder (WSP): 1.5 and 4.5 g (WSP 1.5 and WSP 4.5) in streptozotocin (STZ)-induced diabetic rats. WSP was administered orally on a daily basis for one month and its antidiabetic, anti-inflammatory, and antioxidative effects were investigated by measuring the concentrations of blood glucose, insulin, interleukin 6 (IL-6), tumor necrosis factor-α (TNF-α), interleukin 8 (IL-8), malondialdehyde (MDA), and superoxide dismutase (SOD) activity. In response to high WSP intervention (WSP 4.5), treated rats showed increased insulin level and SOD activity and reduced blood glucose, IL-6, IL-8, TNF-α, and MDA levels, which were closely related to the positive control (PC) group. In addition, Hematoxylin and Eosin (H&E) staining of the pancreatic tissues showed that WSP 4.5-treated rats had significant improvement in β-cell regeneration, which taken together reflected the antidiabetic potential of Curcuma mangga Val.

An Immunohistochemical Evaluation of Glut 2 in Islets of Langerhans Treated with Gymnema Sylvestre and Metformin in Streptozotocin-induced Animals

Diabetes mellitus is a generally known metabolic disorder affecting individuals, not only the elderly population, but all age groups. Among the etiologies of diabetes, reduction of glucose transporter GLUT-2 is accompanied by a loss in glucose-mediated insulin secretion, causing diabetes. To treat diabetes, the present scenario is the demand for time to use herbal drugs with minimal detrimental effects. Considering the benefits of Gymnema sylvestre, an anti-diabetic herbal drug, our current study is designed to expose the plausible relationship between the anti-diabetic activity and GLUT-2 expression, and the efficacy is evaluated in a streptozotocin-induced diabetic model.
 Materials and Methods: Wistar albino adult rats (n=36) weighing about 140–160 g. Each group consisted of 6 animals and was divided into six groups based on the high fat diet (42 days), the streptozotocin-induced diabetic model (5 days) and treated for 22 days using ethanolic extract of Gymnema sylvestre at low (200mg) and high dosage (400mg) and metformin (25mg). During the experimental period, blood glucose levels and the animal weight were carefully monitored. 
 Results: Decreased body weight, pancreatic weight, and increased blood glucose were observed in Group III along with a reduced level of GLUT-2 expression, indicating the manifestation of diabetes. In diabetic rats, however, these abnormalities are significantly restored after treatment with Gymnema sylvestre, albeit at a higher dosage.The Gymnema sylvestre displays the antidiabetic activity through the regeneration of pancreatic β-cells, maintaining GLUT-2 expression in diabetic induced animal model and Our histological study of pancreatic tissue also confirms the regeneration of beta cells.