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

Type 2 diabetes is characterized by hyperglycemia and a relative loss of ß-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 ß-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.

Metabolomics analysis of islet regeneration in partial pancreatectomy mice reveals increased levels of long-chain fatty acids and activated cAMP signaling pathway.

Islet regeneration is a complex process involving multiple metabolic adaptions, but the specific characterization of the islet metabolome in relation to cell proliferation has not been established. This study aimed to investigate the metabolomic changes of regenerative islets from partial pancreatectomy (Ppx) mice and speculate underlying mechanisms. Islet samples were collected from C57/BL6 mice undergoing 70-80% Ppx or sham surgery, followed by analyses of glucose homeostasis, islet morphology, and untargeted metabolomics profiles using liquid chromatography-tandem mass spectrometry (LC-MS/MS). There is no difference in blood glucose and body weight between sham and Ppx mice. After surgery, the Ppx mice showed impaired glucose tolerance, increased Ki67 positive beta cells, and elevated beta-cell mass. LC-MS/MS analysis identified fourteen differentially changed metabolites in islets of Ppx mice, including long-chain fatty acids (e.g., docosahexaenoic acid) and amino acid derivatives (e.g., creatine). Pathway analysis based on the KEGG database revealed five significantly enriched signaling pathways including cAMP signaling pathway. Further immunostaining assay on pancreatic tissue sections showed the levels of p-CREB, a transcription factor downstream of cAMP, elevated in islets from Ppx mice. In conclusion, our results demonstrate that islet regeneration involves metabolic alterations in long-chain fatty acids and amino acid derivatives, as well as the activation of the cAMP signaling pathway.

Single-cell resolution analysis of the human pancreatic ductal progenitor cell niche.

We have described multipotent progenitor-like cells within the major pancreatic ducts (MPDs) of the human pancreas. They express PDX1, its surrogate surface marker P2RY1, and the bone morphogenetic protein (BMP) receptor 1A (BMPR1A)/activin-like kinase 3 (ALK3), but not carbonic anhydrase II (CAII). Here we report the single-cell RNA sequencing (scRNA-seq) of ALK3bright+-sorted ductal cells, a fraction that harbors BMP-responsive progenitor-like cells. Our analysis unveiled the existence of multiple subpopulations along two major axes, one that encompasses a gradient of ductal cell differentiation stages, and another featuring cells with transitional phenotypes toward acinar tissue. A third potential ducto-endocrine axis is revealed upon integration of the ALK3bright+ dataset with a single-cell whole-pancreas transcriptome. When transplanted into immunodeficient mice, P2RY1+/ALK3bright+ populations (enriched in PDX1+/ALK3+/CAII- cells) differentiate into all pancreatic lineages, including functional ß-cells. This process is accelerated when hosts are treated systemically with an ALK3 agonist. We found PDX1+/ALK3+/CAII- progenitor-like cells in the MPDs of types 1 and 2 diabetes donors, regardless of the duration of the disease. Our findings open the door to the pharmacological activation of progenitor cells in situ.

The Values and Perspectives of Organoids in the Field of Metabolic Syndrome.

Metabolic syndrome (MetS) has become a global health problem, and the prevalence of obesity at all stages of life makes MetS research increasingly important and urgent. However, as a comprehensive and complex disease, MetS has lacked more appropriate research models. The advent of organoids provides an opportunity to address this issue. However, it should be noted that organoids are still in their infancy. The main drawbacks are a lack of maturity, complexity, and the inability to standardize large-scale production. Could organoids therefore be a better choice for studying MetS than other models? How can these limitations be overcome? Here, we summarize the available data to present current progress on pancreatic and hepatobiliary organoids and to answer these open questions. Organoids are of human origin and contain a variety of human cell types necessary to mimic the disease characteristics of MetS in their development. Taken together with the discovery of hepatobiliary progenitors in situ, the dedifferentiation of beta cells in diabetes, and studies on hepatic macrophages, we suggest that promoting endogenous regeneration has the potential to prevent the development of end-stage liver and pancreatic lesions caused by MetS and outline the direction of future research in this field.

Human Multipotent Stromal Cell Secreted Effectors Accelerate Islet Regeneration.

Human multipotent stromal cells (hMSC) can induce islet regeneration after transplantation via the secretion of proteins that establish an islet regenerative niche. However, the identity of hMSC-secreted signals and the mechanisms by which pancreatic islet regeneration is induced remain unknown. Recently, mammalian pancreatic α-cells have been shown to possess considerable plasticity, and differentiate into ß-like cells after near complete ß-cell loss or overexpression of key transcriptional regulators. These studies have generated new excitement that islet regeneration during diabetes may be possible if we can identify clinically applicable stimuli to modulate these key regulatory pathways. Herein, we demonstrate that intrapancreatic-injection of concentrated hMSC-conditioned media (CM) stimulated islet regeneration without requiring cell transfer. hMSC CM-injection significantly reduced hyperglycemia, increased circulating serum insulin concentration, and improved glucose tolerance in streptozotocin-treated mice. The rate and extent of endogenous ß-cell mass recovery was dependent on total protein dose administered and was further augmented by the activation of Wnt-signaling using GSK3-inhibition during CM generation. Intrapancreatic hMSC CM-injection immediately set in motion a cascade of regenerative events that included the emergence of proliferating insulin+ clusters adjacent to ducts, NKX6.1 expression in glucagon+ cells at days 1-4 suggesting the acquisition of ß-cell phenotype by α-cells, and accelerated ß-cell maturation with increased MAFA-expression for >1 month postinjection. Discovery and validation of islet regenerative hMSC-secreted protein may lead to the development of cell-free regenerative therapies able to tip the balance in favor of ß-cell regeneration versus destruction during diabetes. Stem Cells 2019;37:516-528.

Glucagon receptor antagonism increases mouse pancreatic δ-cell mass through cell proliferation and duct-derived neogenesis.

Pancreatic δ-cells, which produce somatostatin, play an indispensable role in glucose homeostasis by inhibiting glucagon and insulin secretion in a paracrine manner. Recent studies have shown that δ-cells are couple with ß-cells to suppress α-cell activity. Under certain circumstances, δ-cells could also be trans-differentiated into insulin-producing ß-cells. Thus, pancreatic islet may benefit from δ-cell hyperplasia. However, an effective way to increase δ-cell mass has been rarely reported. Here, we found that REMD 2.59, a human monoclonal antibody and competitive antagonist of the glucagon receptor, massively boosted δ-cell number and increased plasma somatostatin level in both normoglycemic and type 1 diabetic (T1D) mice. The increased δ-cells were due to both δ-cell proliferation and derivation of duct lining cells. Notably, the enlarged δ-cell mass could reduce ß-cell burdens by inducing FoxO1 nuclear translocation in normoglycemic mice. Moreover, some somatostatin-positive cells were co-localized with C-peptide in T1D mice, suggesting that δ-cells might be a source of the newborn ß-cells. Collectively, these observations suggest that treatment with the glucagon receptor monoclonal antibody can increase pancreatic δ-cell mass by promoting self-replication and inducing duct-derived neogenesis both in normoglycemia and diabetic mice.

Hope vs hype: where are we in type 1 diabetes?

Much progress has been made in type 1 diabetes research. Biological replacement of islet function has been achieved with pancreas transplantation and with islet transplantation. In the future, human embryonic stem cells and/or induced pluripotent stem cells may offer a potentially unlimited source of cells for islet replacement. Another potential strategy is to induce robust beta cell replication so that regeneration of islets can be achieved. Immune interventions are being studied with the hope of arresting the type 1 diabetes disease process to either prevent the disease or help preserve beta cell function. Mechanical replacement of islet cell function involves the use of glucose sensor-controlled insulin infusion systems. As all of these avenues are pursued, headlines often overstate the case, thus hyping any given advance, which provides enormous hope for patients and families seeking a cure for type 1 diabetes. Often, however, it is an animal study or a pilot trial that is being described. The reality is that translation to successful trials in human beings may not be readily achievable. This article discusses both the hype and the hopes in type 1 diabetes research.

Intravenous Infusion of Human Adipose Tissue-Derived Mesenchymal Stem Cells to Treat Type 1 Diabetic Mellitus in Mice: An Evaluation of Grafted Cell Doses.

Mesenchymal stem cell (MSC) transplantation is a novel treatment for diabetes mellitus, especially type 1 diabetes. Many recent publications have demonstrated the efficacy of MSC transplantation on reducing blood glucose and increasing insulin production in both preclinical and clinical trials. However, the investigation of grafted cell doses has been lacking. Therefore, this study aimed to evaluate the different doses of MSCs on treatment of type 1 diabetes in mouse models. MSCs were isolated and expanded from human adipose tissue. Streptozotocin (STZ)-induced diabetic mice were divided into two groups that were intravenously transfused with two different doses of human MSCs: 106 or 2.106 cells/mouse. After transplantation, both grafted and placebo mice were monitored weekly for their blood glucose levels, glucose and insulin tolerance, pancreatic structural changes, and insulin production for 56 days after transplantation. The results showed that the higher dose of MSCs (2.106 cells/mouse) remarkably reduced death rate. The death rates were 50%, 66%, and 0% in placebo group, low-dose (1.106 MSCs) group, and high-dose (2.106 MSCs) group, respectively, after 56 days of treatment. Moreover, blood glucose levels were lower for the high-dose group compared to other groups. Glucose and insulin tolerance, as well as insulin production, were significantly improved in mice transplanted with 2.106 cells. The histochemical analyses also support these results. Thus, a higher (e.g., 2.106) dose of MSCs may be an effective dose for treatment of type 1 diabetes mellitus.

Expanded Hematopoietic Progenitor Cells Reselected for High Aldehyde Dehydrogenase Activity Demonstrate Islet Regenerative Functions.

Human umbilical cord blood (UCB) hematopoietic progenitor cells (HPC) purified for high aldehyde dehydrogenase activity (ALDH(hi) ) stimulate islet regeneration after transplantation into mice with streptozotocin-induced ß cell deletion. However, ALDH(hi) cells represent a rare progenitor subset and widespread use of UCB ALDH(hi) cells to stimulate islet regeneration will require progenitor cell expansion without loss of islet regenerative functions. Here we demonstrate that prospectively purified UCB ALDH(hi) cells expand efficiently under serum-free, xeno-free conditions with minimal growth factor supplementation. Consistent with the concept that ALDH-activity is decreased as progenitor cells differentiate, kinetic analyses over 9 days revealed the frequency of ALDH(hi) cells diminished as culture time progressed such that total ALDH(hi) cell number was maximal (increased 3-fold) at day 6. Subsequently, day 6 expanded cells (bulk cells) were sorted after culture to reselect differentiated progeny with low ALDH-activity (ALDH(lo) subset) from less differentiated progeny with high ALDH-activity (ALDH(hi) subset). The ALDH(hi) subset retained primitive cell surface marker coexpression (32.0% ± 7.0% CD34(+) /CD38(-) cells, 37.0% ± 6.9% CD34(+) /CD133(+) cells), and demonstrated increased hematopoietic colony forming cell function compared with the ALDH(lo) subset. Notably, bulk cells or ALDH(lo) cells did not possess the functional capacity to lower hyperglycemia after transplantation into streptozotocin-treated NOD/SCID mice. However, transplantation of the repurified ALDH(hi) subset significantly reduced hyperglycemia, improved glucose tolerance, and increased islet-associated cell proliferation and capillary formation. Thus, expansion and delivery of reselected UCB cells that retain high ALDH-activity after short-term culture represents an improved strategy for the development of cellular therapies to enhance islet regeneration in situ.

Transplantation of mesenchymal stem cells improves type 1 diabetes mellitus.

Bone-marrow-derived stem cells can regenerate pancreatic tissue in a model of type 1 diabetes mellitus. Mesenchymal stem cells (MSCs) form the main part of bone marrow. We show that the intrapancreatic transplantation of MSCs elevates serum insulin and C-peptide, while decreasing blood glucose. MSCs engrafted into the damaged rat pancreas become distributed into the blood vessels, acini, ducts, and islets. Renascent islets, islet-like clusters, and a small number of MSCs expressing insulin protein have been observed in the pancreas of diabetic rats. Intrapancreatic transplantation of MSCs triggers a series of molecular and cellular events, including differentiation towards the pancreas directly and the provision of a niche to start endogenous pancreatic regeneration, which ameliorates hypoinsulinemia and hyperglycemia caused by streptozotocin. These data establish the many roles of MSCs in the restoration of the function of an injured organ.

Genetic lineage tracing identifies adaptive mechanisms of pancreatic islet ß cells in various mouse models of diabetes with distinct age of initiation.

During the pathogenesis of type 1 diabetes (T1D) and type 2 diabetes (T2D), pancreatic islets, especially the ß cells, face significant challenges. These insulin-producing cells adopt a regeneration strategy to compensate for the shortage of insulin, but the exact mechanism needs to be defined. High-fat diet (HFD) and streptozotocin (STZ) treatment are well-established models to study islet damage in T2D and T1D respectively. Therefore, we applied these two diabetic mouse models, triggered at different ages, to pursue the cell fate transition of islet ß cells. Cre-LoxP systems were used to generate islet cell type-specific (α, ß, or δ) green fluorescent protein (GFP)-labeled mice for genetic lineage tracing, thereinto ß-cell GFP-labeled mice were tamoxifen induced. Single-cell RNA sequencing (scRNA-seq) was used to investigate the evolutionary trajectories and molecular mechanisms of the GFP-labeled ß cells in STZ-treated mice. STZ-induced diabetes caused extensive dedifferentiation of ß cells and some of which transdifferentiated into a or δ cells in both youth- and adulthood-initiated mice while this phenomenon was barely observed in HFD models. ß cells in HFD mice were expanded via self-replication rather than via transdifferentiation from α or δ cells, in contrast, α or δ cells were induced to transdifferentiate into ß cells in STZ-treated mice (both youth- and adulthood-initiated). In addition to the re-dedifferentiation of ß cells, it is also highly likely that these "α or δ" cells transdifferentiated from pre-existing ß cells could also re-trans-differentiate into insulin-producing ß cells and be beneficial to islet recovery. The analysis of ScRNA-seq revealed that several pathways including mitochondrial function, chromatin modification, and remodeling are crucial in the dynamic transition of ß cells. Our findings shed light on how islet ß cells overcome the deficit of insulin and the molecular mechanism of islet recovery in T1D and T2D pathogenesis.

Garlic Extract Promotes Pancreatic Islet Neogenesis Through α-to-ß-Cell Transdifferentiation and Normalizes Glucose Homeostasis in Diabetic Rats.

SCOPE: Garlic extract (GE) has been shown to ameliorate hyperglycemia in diabetic rats (DRs) by increasing insulin production. However, the mechanism through which it exerts its effects remains unclear. Here, it investigates the molecular process and the origin of regenerating ß-cell in rats with streptozotocin (STZ)-induced diabetes in response to GE. METHODS AND RESULTS: In this study, quantitative RT-PCR (qRT-PCR), western blotting, and immunohistochemical analysis are carried out after pancreas isolation. These findings show that 1 week of GE treatment increases the expression of the endocrine progenitor cell markers Neurogenin3 (Neurog3), pancreatic and duodenal homeobox 1 (Pdx1), neurogenic differentiation factor 1 (Neurod1), paired box proteins (Pax)4, V-maf musculoaponeurotic fibrosarcoma oncogene homolog B (Mafb), and NK homeobox factors (Nkx)6-1 in STZ-induced DRs. Continuation with GE treatment for 8 weeks causes the expression of the mature ß-cell markers insulin(Ins)2, urocortin3 (Ucn3), and glucose transporter 2 (Glut2) to peak. Comprehensive examination of the islet through immunohistochemical analysis reveals the presence of a heterogeneous cell population including INS+/GLUT2- and INS+/GLUT2+ ß-cell subpopulations with few bihormonal INS+/GCG+ cells after 4 weeks. By week 8, islet architecture is reestablished, and glucose-stimulated insulin secretion was restored through the upregulation of Ucn3. CONCLUSION: GE induces ß-cell neogenesis in DRs and restores islet architecture. The newly formed mature ß-like cells could have originated through the differentiation of endocrine progenitor cells as well as α- to ß-cell transdifferentiation.

Tricultured Cell Sheets Develop into Functional Pancreatic Islet Tissue with a Vascular Network.

Methods to induce islet ß-cells from induced pluripotent stem cells or embryonic stem cells have been established. However, islet ß-cells are susceptible to apoptosis under hypoxic conditions, so the technique used to transplant ß-cells must maintain the viability of cells in vivo. This study describes the development of a tricultured cell sheet, which was made by coculturing islet ß-cells, vascular endothelial cells, and mesenchymal stem cells for 1 day. The islet ß-cells in the tricultured cell sheet self-organized into islet-like structures surrounded by a dense vascular network in vitro. Triple-layered tricultured cell sheets engrafted well after transplantation in vivo and developed into insulin-secreting tissue with abundant blood vessels and a high density of islet ß-cells. We anticipate that the tricultured cell sheet could be used as an in vitro pseudo-islet model for pharmaceutical testing and may have potential for development into transplantable grafts for use in regenerative medicine. Impact statement This research assessed whether tricultured cell sheets containing islet ß-cells, vascular endothelial cells, and mesenchymal stem cells were able to form islet tissue. There were two main findings. First, the islet ß-cells in the tricultured cell sheet self-organized into islet structures surrounded by a dense vascular network in vitro. Second, triple-layered tricultured sheets engrafted well onto rat muscle and developed into insulin-secreting tissue with an abundance of blood vessels. The tricultured cell sheet could be used as a pseudo-islet model for pharmaceutical testing and may have potential for development into a transplantable graft for application in the clinical setting.

In Vitro Human Fetal Pancreatic Islets to Redefine Pancreatic Research.

BACKGROUND: In vitro studies with human fetal islets of different gestational ages (GA) would be a great tool to generate information on the developmental process of the islets as this would help to recontextualize diabetes research and clinical practice. Pancreatic islets from human cadavers and other animal species are extensively researched to explore their suitability for islet transplantation procedure, one of the upcoming treatment strategies for insulin-dependent diabetes mellitus. Although human fetal islets are also considered for islet transplantation, ethical issues and limited knowledge constraints their use. The fetal islets could be explored to address the information lacunae on the maturity process of pancreatic islets and the endocrine-exocrine signaling mechanisms. AIM: This study aimed to assess the feasibility of isolating viable islets and study the cytoarchitecture of the fetal pancreas of GA 22-29 weeks, not reported otherwise. METHODOLOGY: Pancreas obtained from the aborted fetuses of GA 22-29 weeks were subjected to collagenase digestion and were further cultured to determine the viability in vitro. Parameters assessed were expression of markers for endocrine cell lineages and insulin release to glucose challenge. RESULTS: Islets were viable in vitro and islets were shown to maintain cues for post-digestion re-aggregation and expansion in culture. The immunofluorescent staining showed islets of varying sizes, homogenous cell clusters aggregating to form heterogenous cell clusters, otherwise not reported for this GA. On stimulation with different concentrations of glucose (2.8 and 28 mM), the fetal islets in the culture exhibited insulin release, and this response confirmed their viability in vitro. CONCLUSION: Our findings showed that viable islets could be isolated and cultured in vitro for further in-depth studies to explore their proliferative potential as well as for the identification of pancreatic progenitors, a good strategy to take forward.

Bariatric Surgery: Targeting pancreatic ß cells to treat type II diabetes.

Pancreatic ß-cell function impairment and insulin resistance are central to the development of obesity-related type 2 diabetes mellitus (T2DM). Bariatric surgery (BS) is a practical treatment approach to treat morbid obesity and achieve lasting T2DM remission. Traditionally, sustained postoperative glycemic control was considered a direct result of decreased nutrient intake and weight loss. However, mounting evidence in recent years implicated a weight-independent mechanism that involves pancreatic islet reconstruction and improved ß-cell function. In this article, we summarize the role of ß-cell in the pathogenesis of T2DM, review recent research progress focusing on the impact of Roux-en-Y gastric bypass (RYGB) and vertical sleeve gastrectomy (VSG) on pancreatic ß-cell pathophysiology, and finally discuss therapeutics that have the potential to assist in the treatment effect of surgery and prevent T2D relapse.

Dynamic scRNA-seq of live human pancreatic slices reveals functional endocrine cell neogenesis through an intermediate ducto-acinar stage.

Human pancreatic plasticity is implied from multiple single-cell RNA sequencing (scRNA-seq) studies. However, these have been invariably based on static datasets from which fate trajectories can only be inferred using pseudotemporal estimations. Furthermore, the analysis of isolated islets has resulted in a drastic underrepresentation of other cell types, hindering our ability to interrogate exocrine-endocrine interactions. The long-term culture of human pancreatic slices (HPSs) has presented the field with an opportunity to dynamically track tissue plasticity at the single-cell level. Combining datasets from same-donor HPSs at different time points, with or without a known regenerative stimulus (BMP signaling), led to integrated single-cell datasets storing true temporal or treatment-dependent information. This integration revealed population shifts consistent with ductal progenitor activation, blurring of ductal/acinar boundaries, formation of ducto-acinar-endocrine differentiation axes, and detection of transitional insulin-producing cells. This study provides the first longitudinal scRNA-seq analysis of whole human pancreatic tissue, confirming its plasticity in a dynamic fashion.

Emerging diabetes therapies: Bringing back the ß-cells.

BACKGROUND: Stem cell therapies are finally coming of age as a viable alternative to pancreatic islet transplantation for the treatment of insulin-dependent diabetes. Several clinical trials using human embryonic stem cell (hESC)-derived ß-like cells are currently underway, with encouraging preliminary results. Remaining challenges notwithstanding, these strategies are widely expected to reduce our reliance on human isolated islets for transplantation procedures, making cell therapies available to millions of diabetic patients. At the same time, advances in our understanding of pancreatic cell plasticity and the molecular mechanisms behind ß-cell replication and regeneration have spawned a multitude of translational efforts aimed at inducing ß-cell replenishment in situ through pharmacological means, thus circumventing the need for transplantation. SCOPE OF REVIEW: We discuss here the current state of the art in hESC transplantation, as well as the parallel quest to discover agents capable of either preserving the residual mass of ß-cells or inducing their proliferation, transdifferentiation or differentiation from progenitor cells. MAJOR CONCLUSIONS: Stem cell-based replacement therapies in the mold of islet transplantation are already around the corner, but a permanent cure for type 1 diabetes will likely require the endogenous regeneration of ß-cells aided by interventions to restore the immune balance. The promise of current research avenues and a strong pipeline of clinical trials designed to tackle these challenges bode well for the realization of this goal.

Andrographolide promotes pancreatic duct cells differentiation into insulin-producing cells by targeting PDX-1.

Regeneration of ß-cells by differentiation of pancreatic progenitor cells has the potential to fundamentally solve the problems of the loss of ß-cell function and mass during disease progression in both type 1 or 2 diabetes. Therefore, discovery of novel differentiation inducers to promote islet regeneration is of great significance. Pancreatic and duodenal homeobox1 (PDX-1) is a key transcription factor that promotes the development and maturation of pancreatic ß-cells. To screen potential novel small molecules for enhancing differentiation of PNAC-1 cells, a human pancreatic ductal cell lines into insulin-producing cells (IPCs), we developed a high-throughput screening method through fusing the PDX-1 promoter region with a luciferase reporter gene. We screened and identified that andrographolide named C1037 stimulates PDX-1 expression in both mRNA and protein level and significantly promotes PANC-1 cells differentiation into IPCs as compared with that of control cells. The therapeutic effect of C037 in Streptozotocin induced diabetic mouse model through differentiation of pancreatic ductal cells into insulin positive islets was also observed. Our study provides a novel method to screen compounds regulating the differentiation of pancreatic progenitor cells having the potential of enhancing islet regeneration for diabetes therapy.

Elevated ß-cell stress levels promote severe diabetes development in mice with MODY4.

Maturity-onset diabetes of the young (MODY) is a group of monogenetic forms of diabetes mellitus caused by mutations in genes regulating ß-cell development and function. MODY represents a heterogeneous group of non-insulin-dependent diabetes arising in childhood or adult life. Interestingly, clinical heterogeneity in MODY patients like variable disease onset and severity is observed even among individual family members sharing the same mutation, an issue that is not well understood. As high blood glucose levels are a well-known factor promoting ß-cell stress and ultimately leading to cell death, we asked whether additional ß-cell stress might account for the occurrence of disease heterogeneity in mice carrying a MODY4 mutation. In order to challenge ß-cells, we established a MODY4 animal model based on Pdx1 (pancreatic and duodenal homeobox 1) haploinsufficiency, which allows conditional modulation of cell stress by genetic inhibition of the stress-responsive IKK/NF-κB signalling pathway. While Pdx1+/- mice were found glucose intolerant without progressing to diabetes, additional challenge of ß-cell function by IKK/NF-κB inhibition promoted rapid diabetes development showing hyperglycaemia, hypoinsulinemia and loss of ß-cell mass. Disease pathogenesis was characterized by deregulation of genes controlling ß-cell homeostasis and function. Importantly, restoration of normal IKK/NF-κB signalling reverted the diabetic phenotype including normalization of glycaemia and ß-cell mass. Our findings implicate that the avoidance of additional ß-cell stress can delay a detrimental disease progression in MODY4 diabetes. Remarkably, an already present diabetic phenotype can be reversed when ß-cell stress is normalized.

Veiled Potential of Secretagogin in Diabetes: Correlation or Coincidence?

Secretagogin (SCGN) is a calcium sensor protein enriched in neuroendocrine cells in general and pancreatic ß-cells in particular. SCGN regulates insulin secretion through several Ca2+-dependent interactions. Recent studies implicate SCGN in the ß-cell physiology and extracellular insulin function, making it an intriguing candidate in diabetes research. Here, we propose a conjoining theme of diversified SCGN function in diabetes pathology. In our opinion, SCGN is an attractive therapeutic candidate ascribed by its role in ß-cell maintenance and neuronal functions and in the efficacy of insulin. To scrutinize the therapeutic prospects of SCGN, we abridge putative diabetes-related properties of SCGN and put forth strategies to determine the precise role of SCGN in the pathogenesis/preclusion of diabetes.