Β-cell Regeneration Research Articles

Research progress in molecular mechanism of acupuncture for diabetes mellitus

This paper discusses the mechanism of acupuncture for diabetes mellitus from the perspective of molecular biology, aiming to reveal the potential rules of restoring the balance in the body and fighting against diabetes mellitus (DM). By searching the basic research literature of acupuncture treatment for DM, it is found that the molecular biological mechanism of acupuncture treatment for DM is closely related to the regulation of insulin signaling pathway, the modulation of inflammatory response, the protection and regeneration of islet β-cells, fat metabolism and energy balance. It points out that there are few studies of acupuncture on the type 1 diabetes mellitus and the large-scale randomized controlled trials, as well as the studies on the upstream regulation mechanism, the specific cellular molecules and the interaction mechanism of various molecules. It needs to deepen the multi-level, multi-target and multi-dimensional exploration on the molecular biological mechanism of acupuncture for diabetes mellitus.

Antidiabetic Potential of Mangifera Indica: Insights from In Vitro and In Vivo Studies

Background: Diabetes mellitus is a chronic endocrine disorder characterized by elevated blood glucose levels. Owing to the adverse side effects of synthetic drugs, natural products attract research interest because of their fewer side effects and prominent efficacy. In the present study, we examined the antidiabetic effects of the seeds of Mangifera indica. Materials & Methods: Phytochemical analysis (quantitative and free radical scavenging activity), in vitro enzymatic assays, and in vivo antidiabetic studies were performed on the hydroalcoholic extract of M. indica. Additionally, an immunohistochemistry approach was utilized to illustrate the alteration of the cellular architecture in the pancreatic islets of extract-treated diabetic rats. Results: The hydroalcoholic extract exhibited good phenolic and flavonoid contents, prominent radical scavenging ability, and antidiabetic activity in an in vitro enzymatic assay. At a dose of 200 mg/kg body weight, the hydroalcoholic extract significantly decreased the blood glucose and HbA1c levels and substantially improved the serum marker levels (GLU, ALB, UREA, CREA, CHOL, TG, SGPT, SGOT, TP, HDL, and ALP). The immunohistological study revealed 40% regeneration of pancreatic β-cells upon extract treatment. Conclusion: The hydroalcoholic extract has prominent antidiabetic activity, as evidenced by both in vitro and in vivo studies, by modulating the cellular composition and regenerating the β-cells of the pancreatic islet.

In Vivo Differentiation of Endogenous Bone Marrow-Derived Cells into Insulin-Producing Cells Using Four Soluble Factors.

Four soluble factors-putrescine, glucosamine, nicotinamide, and signal transducer and activator of transcription 3 (STAT3) inhibitor BP-1-102-were shown to differentiate bone marrow mononucleated cells (BMNCs) into functional insulin-producing cells (IPCs) in vitro. Transplantation of these IPCs improved hyperglycemia in diabetic mice. However, the role of endogenous BMNC regeneration in this effect was unclear. This study aimed to evaluate the effect of these factors on in vivo BMNC differentiation into IPCs in diabetic mice. Mice were orally administered the factors for 5 days, twice at 2-week intervals, and monitored for 45-55 days. Glucose tolerance, glucose-stimulated insulin secretion, and pancreatic insulin content were measured. Chimeric mice harboring BMNCs from insulin promoter luciferase/green fluorescent protein (GFP) transgenic mice were used to track endogenous BMNC fate. These factors lowered blood glucose levels, improved glucose tolerance, and enhanced insulin secretion. Immunostaining confirmed IPCs in the pancreas, showing the potential of these factors to induce β-cell regeneration and improve diabetes treatment.

Examining the liver-pancreas crosstalk reveals a role for the molybdenum cofactor in β-cell regeneration.

Regeneration of insulin-producing β-cells is an alternative avenue to manage diabetes, and it is crucial to unravel this process in vivo during physiological responses to the lack of β-cells. Here, we aimed to characterize how hepatocytes can contribute to β-cell regeneration, either directly or indirectly via secreted proteins or metabolites, in a zebrafish model of β-cell loss. Using lineage tracing, we show that hepatocytes do not directly convert into β-cells even under extreme β-cell ablation conditions. A transcriptomic analysis of isolated hepatocytes after β-cell ablation displayed altered lipid- and glucose-related processes. Based on the transcriptomics, we performed a genetic screen that uncovers a potential role of the molybdenum cofactor (Moco) biosynthetic pathway in β-cell regeneration and glucose metabolism in zebrafish. Consistently, molybdenum cofactor synthesis 2 (Mocs2) haploinsufficiency in mice indicated dysregulated glucose metabolism and liver function. Together, our study sheds light on the liver-pancreas crosstalk and suggests that the molybdenum cofactor biosynthesis pathway should be further studied in relation to glucose metabolism and diabetes.

Oral drug delivery vehicle for insulin and curcumin based on egg albumin-dextran conjugate: In vitro and in vivo studies

The increasing desire for oral delivery vehicle systems encouraged the development of micro and nano encapsulation technologies to protect drugs against gastric and enzymatic degradation. This study aimed to develop egg albumin-dextran conjugate as a delivery vehicle for oral administration. For this purpose, insulin was selected as a macromolecule drug and curcumin as a natural lipophilic polyphenol, both show negative absorption kinetics in gastrointestinal tract. Egg albumin-dextran conjugate was prepared by Maillard reaction under mild conditions and subsequently be used to encapsulate insulin and curcumin, respectively. The encapsulation efficiency reached to 97 % and 95.5 % at 300 mg/ml of insulin and curcumin, respectively. The profile of in vitro drug release for the insulin and curcumin indicates that approximately 60 % of the drugs were partially retained by the conjugate in gastric pH environment while a more extensive release was observed under intestinal pH conditions. Application of oral administration of insulin conjugate (IC) and/or curcumin conjugate (CC) to streptozotocin (STZ) induced diabetic rats was investigated for 6 weeks and compared with trade insulin drug. Fifty-four albino rats were separated into nine equivalent groups. Control, insulin conjugate (IC), curcumin conjugate (CC), and IC + CC. The remaining groups injected with STZ and subsequently received vehicle, IC, CC, IC + CC, and trade insulin drug; respectively.Interestingly, insulin conjugate and/or curcumin conjugate significantly reduced hyperglycemia, hyperlipidemia, decreased fructosamine level, decreased HOMA-IR, increased insulin level, increased HOMA-β, increased antioxidant defense molecules, along with modulating morphological pancreatic degeneration caused by STZ. In conclusion, oral insulin-conjugate is more effective than the trade insulin drug. Also, curcumin-conjugate has a promising role as antidiabetic agent as it may contribute in β-cells regeneration. Further, the combination between them may have synergetic antidiabetic effect. But, more detailed studies should be done to investigate the possible mechanisms of their antidiabetic effect.

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.

Decoding and understanding molecular mechanisms: Cell signaling pathways, pancreatic β-cell regeneration, and stem cell niche engineering for diabetes

Stem cell bioengineering addresses regenerative medicine and cellular therapies by applying advanced techniques to stem-cell-derived systems. Despite their promise, stem cell applications are limited by incomplete knowledge. Stem cells and phytochemicals show potential in treating diabetes by halting β-cell degeneration and promoting endogenous islet regeneration. Current diabetes cell therapies include stem cells, mature pancreatic cells, endocrine progenitors, and β-cells, with researchers actively seeking new cell sources for clinically relevant β-cells. Stem cell-derived pancreatic cells are particularly promising for pancreatic islet regeneration. Diabetes mellitus results from cell loss or malfunction: Type 1 diabetes stems from autoimmune damage, whereas Type 2 diabetes is largely attributed to cell malfunction or insulin resistance. The only operative therapy, islet transplantation, necessitates lifelong immune suppression. Significant progress has been made in strategies for therapeutic adult β-cell regeneration. This review assesses studies on cellular signaling pathways linked to β-cell survival and proliferation, exploring regenerative medicine methodologies for pancreatic islet replacement or regeneration. While the “replacement” technique involves cell transplantation, the “regeneration” strategy preserves cell populations through replication. Moreover, artemether and gamma-aminobutyric acid induce pancreatic cells to adopt β-cell-like phenotypes, potentially aiding in the development of new β-cell-like cells for treating severe diabetes in rats. Understanding G-protein-coupled receptor activation pathways is crucial, as new treatment strategies for insulin-dependent diabetic mellitus may emerge from this knowledge.

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.

Unraveling Verapamil's Multidimensional Role in Diabetes Therapy: From β-Cell Regeneration to Cholecystokinin Induction in Zebrafish and MIN6 Cell-Line Models.

This study unveils verapamil's compelling cytoprotective and proliferative effects on pancreatic β-cells amidst diabetic stressors, spotlighting its unforeseen role in augmenting cholecystokinin (CCK) expression. Through rigorous investigations employing MIN6 β-cells and zebrafish models under type 1 and type 2 diabetic conditions, we demonstrate verapamil's capacity to significantly boost β-cell proliferation, enhance glucose-stimulated insulin secretion, and fortify cellular resilience. A pivotal revelation of our research is verapamil's induction of CCK, a peptide hormone known for its role in nutrient digestion and insulin secretion, which signifies a novel pathway through which verapamil exerts its therapeutic effects. Furthermore, our mechanistic insights reveal that verapamil orchestrates a broad spectrum of gene and protein expressions pivotal for β-cell survival and adaptation to immune-metabolic challenges. In vivo validation in a zebrafish larvae model confirms verapamil's efficacy in fostering β-cell recovery post-metronidazole infliction. Collectively, our findings advocate for verapamil's reevaluation as a multifaceted agent in diabetes therapy, highlighting its novel function in CCK upregulation alongside enhancing β-cell proliferation, glucose sensing, and oxidative respiration. This research enriches the therapeutic landscape, proposing verapamil not only as a cytoprotector but also as a promoter of β-cell regeneration, thereby offering fresh avenues for diabetes management strategies aimed at preserving and augmenting β-cell functionality.

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.

Protective Effect of Betulin on Streptozotocin-Nicotinamide-Induced Diabetes in Female Rats.

Type 2 diabetes is characterized by hyperglycemia and a relative loss of β-cell function. Our research investigated the antidiabetic potential of betulin, a pentacyclic triterpenoid found primarily in birch bark and, intriguingly, in a few marine organisms. Betulin has been shown to possess diverse biological activities, including antioxidant and antidiabetic activities; however, no studies have fully explored the effects of betulin on the pancreas and pancreatic islets. In this study, we investigated the effect of betulin on streptozotocin-nicotinamide (STZ)-induced diabetes in female Wistar rats. Betulin was prepared as an emulsion, and intragastric treatments were administered at doses of 20 and 50 mg/kg for 28 days. The effect of treatment was assessed by analyzing glucose parameters such as fasting blood glucose, hemoglobin A1C, and glucose tolerance; hepatic and renal biomarkers; lipid peroxidation; antioxidant enzymes; immunohistochemical analysis; and hematological indices. Administration of betulin improved the glycemic response and decreased α-amylase activity in diabetic rats, although insulin levels and homeostatic model assessment for insulin resistance (HOMA-IR) scores remained unchanged. Furthermore, betulin lowered the levels of hepatic biomarkers (aspartate aminotransferase, alanine aminotransferase, and alpha-amylase activities) and renal biomarkers (urea and creatine), in addition to improving glutathione levels and preventing the elevation of lipid peroxidation in diabetic animals. We also found that betulin promoted the regeneration of β-cells in a dose-dependent manner but did not have toxic effects on the pancreas. In conclusion, betulin at a dose of 50 mg/kg exerts a pronounced protective effect against cytolysis, diabetic nephropathy, and damage to the acinar pancreas and may be a potential treatment option for diabetes.

Anti-Diabetic Potentials ofLactobacillus Strains by Modulating Gut Microbiota Structure and β-Cells Regeneration in the Pancreatic Islets of Alloxan-Induced Diabetic Rats.

Diabetes mellitus, a most common endocrine disorder of glucose metabolism, has become a global epidemic and poses a serious public health threat with an increased socio-economic burden. Escalating incidence of diabetes is correlated with changes in lifestyle and food habits that cause gut microbiome dysbiosis and β-cells damage, which can be addressed with dietary interventions containing probiotics. Hence, the search for probiotics of human origin with anti-diabetic, anti-AGE, and anti-ACE potentials has gained renewed interest for the effective management of diabetes and its associated complications. The present study used an alloxan (AXN)-induced diabetic rat model to investigate the effects of potential probiotic Lacticaseibacillus casei MKU1, Lactiplantibacillus pentosus MKU3, and Lactiplantibacillus plantarum MKU7 administration individually on physiochemical parameters related to diabetic pathogenesis. Experimental animals were randomly allotted into six groups viz. NCG (control), DCG (AXN), DGM (metformin), DGP1 (MKU1), DGP2 (MKU3), and DGP3 (MKU7), and biochemical data like serum glucose, insulin, AngII, ACE, HbA1c, and TNF-α levels were measured until 90days. Our results suggest that oral administration with MKU1, MKU3, or MKU7 significantly improved serum insulin levels, glycemic control, glucose tolerance, and body weight. Additionally, β-cell mass was increased by preserving islet integrity in Lactobacillus-treated diabetic rats, whereas TNF-α (~40%), AngII (~30%), and ACE levels (~50%) were strongly inhibited and enhanced sIgA production (5.8 folds) abundantly. Furthermore, Lactobacillus administration positively influenced the gut microbiome with a significant increase in the abundance of Lactobacillus species and the beneficial Bacteroides uniformis and Bacteroides fragilis, while decreased the pathogenic Proteus vulgaris and Parabacteroides distasonis. Among the probiotic treatment groups, L. pentosus MKU3 performed greatly in almost all parameters, indicating its potential use for alleviating diabetes-associated complications.

Isomaltulose Enhances GLP-1 and PYY Secretion to a Mixed Meal in People With or Without Type 2 Diabetes as Compared to Saccharose.

Secretion of the gut hormones glucagon-like peptide (GLP-1) and peptide YY (PYY) are induced by nutrients reaching the lower small intestine which regulate insulin and glucagon release, inhibit appetite, and may improve β-cell regeneration. The aim is to test the effect of a slowly digested isomaltulose (ISO) compared to the rapidly digested saccharose (SAC) as a snack given 1h before a standardized mixed meal test (MMT) on GLP-1, PYY, glucose-dependent insulinotropic peptide (GIP), and metabolic responses in participants with or without type 2 diabetes (T2DM). Fifteenhealthy volunteers and 15 patients with T2DM consumed either 50g ISO or SAC 1h preload of MMT on nonconsecutive days. Clinical parameters and incretin hormones are measured throughout the whole course of MMT. Administration of 50g ISO as compared to SAC induced a significant increase in GLP-1, GIP, and PYY responses over 2h after intake of a typical lunch in healthy controls. Patients with T2DM showed reduced overall responses of GLP-1 and delayed insulin release compared to controls while ISO significantly enhanced the GIP and almost tripled the PYY response compared to SAC. A snack containing ISO markedly enhances the release of the metabolically advantageous gut hormones PYY and GLP-1 and enhances GIP release in response to a subsequent complex meal.

β-Cell Regeneration Is Driven byPancreatic Plasticity.

The pancreas has been considered a non-regenerative organ. β cells lost in diabetes are not replaced due to the inability of the pancreas to regenerate. However, ample evidence generated in the last few decades using murine models has demonstrated that the pancreas has a remarkable plasticity wherein differentiated cells can change cell fate toward a β-like cell phenotype. Although this process is observed after using rather artificial stimuli and the conversion efficiency is very limited, these findings have shed some light on novel pathways for β-cell regeneration. In this chapter, we will summarize the different cellular interconversion processes described to date, the experimental details and molecular regulation of such interconversions, and the genomic technologies that have allowed the identification of potential new ways to generate β cells.

Development, regeneration, and physiological expansion of functional β-cells: Cellular sources and regulators.

Pancreatic regeneration is a complex process observed in both normal and pathological conditions. The aim of this review is to provide a comprehensive understanding of the emergence of a functionally active population of insulin-secreting β-cells in the adult pancreas. The renewal of β-cells is governed by a multifaceted interaction between cellular sources of genetic and epigenetic factors. Understanding the development and heterogeneity of β-cell populations is crucial for functional β-cell regeneration. The functional mass of pancreatic β-cells increases in situations such as pregnancy and obesity. However, the specific markers of mature β-cell populations and postnatal pancreatic progenitors capable of increasing self-reproduction in these conditions remain to be elucidated. The capacity to regenerate the β-cell population through various pathways, including the proliferation of pre-existing β-cells, β-cell neogenesis, differentiation of β-cells from a population of progenitor cells, and transdifferentiation of non-β-cells into β-cells, reveals crucial molecular mechanisms for identifying cellular sources and inducers of functional cell renewal. This provides an opportunity to identify specific cellular sources and mechanisms of regeneration, which could have clinical applications in treating various pathologies, including in vitro cell-based technologies, and deepen our understanding of regeneration in different physiological conditions.

Restoring physiological parameters of the pancreas and kidney through treatment with a polymeric nano-formulation of C-peptide and lisofylline combination in diabetic nephropathy.

Diabetic nephropathy (DN) is a progressive kidney disorder that develops as a complication of diabetes due to long-term exposure to elevated blood glucose levels (BGLs). In this case, an intervention of therapeutic moieties is needed to target the specific elements involved in diabetes to prevent/delay the deterioration of kidney function. Therefore, the present study focused on designing and evaluating a potent nano-formulation of a combination of C-peptide (CPep) and the anti-diabetic drug lisofylline (LSF) to prevent streptozotocin (STZ)-induced DN. As a strategic intervention, an LSF-oleic acid prodrug (LSF-OA) was initially synthesized and further encapsulated in an in-house-synthesized cationic polymer [(mPEG-b-P(CB-{g-DMDP}-co-LA)); mPLM] to prepare polymeric nano-complexes of CPep via electrostatic interaction, possessing a size of 218.6 ± 14.4 nm and zeta potential of +5.2 mV together with stability for 30 days at 25 °C. mPLM-LSF-OA-CPep nanoparticles demonstrated hemocompatibility with RBCs and exhibited potent anti-oxidant activity by reducing nitrite levels, inducing the release of anti-oxidant GSH and protecting metabolically stressed rat kidneys and murine insulinoma cells from apoptosis. In vivo pharmacokinetics depicted an increase in t½ and mean residence time in rats, which further improved the BGL and renal conditions and reduced plasma IL-6 and TNF-α levels in the STZ-induced DN animal model when treated with mPLM-LSF-OA-CPep compared to free LSF and CPep. Moreover, an increase in the plasma insulin level and detection of proliferative marker cells in pancreatic islets suggested the regeneration of β-cells in diabetic animals.

Evaluation of antidiabetic and antioxidant activity of methanolic extract of Limonia acidissima leaves in alloxan-induced diabetic wister albino rats: a randomized controlled experimental study

Objectives: The present study was carried out to find graded-doses antidiabetic and antioxidant activities of methanolic extract of Limonia acidissima (MELA) leaves in rats. Materials and Methods: Male Wistar rats were randomly divided into 6 groups (n=8): Normal control, Diabetic control (Alloxan-induced), and test groups where varying doses of MELA (100mg/kg, 200mg/kg, and 400mg/kg) or Metformin (100mg/kg) administered post-alloxan induction. Random blood sugar (RBS) levels were estimated at specific intervals over a 28-day period. Moreover, antioxidant markers (malondialdehyde, superoxide dismutase, and reduced glutathione) were assessed on day 28. Histopathological examination of pancreatic tissue was conducted. Results: Overall, mean RBS levels decreased at all intervals. There was a significant decrease in median malondialdehyde, an increase in median superoxide dismutase, and reduced glutathione levels (all p-values<0.0001). The change in RBS (p-values<0.0001) and antioxidants (p-value>0.05) levels was greater in Group VI than in Group V. On histopathology, Groups VI and V demonstrated regeneration of necrotic β-cells in the islets, and this was more pronounced than Group IV. Conclusion: Results of our study suggested that MELA possesses dose-dependent significant antidiabetic and antioxidant activity.

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.