Pancreatic Islets Of Langerhans Research Articles

Advances in Stem Cell and Regenerative Therapies in Autoimmune and Metabolic Diseases: Implications for Healthy Longevity

Type 1 diabetes (T1D) is an important autoimmune disease characterized by the destruction of insulin-secreting β-cells in pancreatic islets of Langerhans resulting in hyperglycemia. More than 1.3 people in United States are suffering from T1D, and current treatments have failed to offer a lasting cure. T1D management requires lifelong daily injections of exogenous insulin to control blood sugar levels and secondary complications of this progressive disease, unless receiving pancreas or islet transplant with its associated risks from immunosuppression. Peptide therapy aims to alter the response of cells by inducing or reducing cellular responses appropriate to the type of peptides used. The aim of this study was to investigate the protective effect on autoimmunity of Mito Organelle (MO) Peptides on the function and survival of peptides on pancreatic β-cells in non-obese diabetes (NOD) mice model. MO peptide product (Biopep Inc) is a mixture of organ-specific cellular extracts that were extracted from organ specific cells, homogenized, filtered, and sterilized. MO Peptides administered twice-weekly (IM) over 17-week period in NOD mice model were able to prevent the progression of autoimmune-mediated β–cell destruction and the onset of hyperglycemia (blood glucose >300 mg dL) as compared to the saline treated control mice. These studies will help understand the mechanisms of immunological protection in T1D and may serve as a model for other autoimmune disorders with peptides.

Illuminating the complete ß-cell mass of the human pancreas- signifying a new view on the islets of Langerhans

Pancreatic islets of Langerhans play a pivotal role in regulating blood glucose homeostasis, but critical information regarding their mass, distribution and composition is lacking within a whole organ context. Here, we apply a 3D imaging pipeline to generate a complete account of the insulin-producing islets throughout the human pancreas at a microscopic resolution and within a maintained spatial 3D context. These data show that human islets are far more heterogenous than previously accounted for with regards to their size distribution and cellular make up. By deep tissue 3D imaging, this in-depth study demonstrates that 50% of the human insulin-expressing islets are virtually devoid of glucagon-producing α-cells, an observation with significant implications for both experimental and clinical research.

Extracellular metallothionein as a therapeutic target in the early progression of type 1 diabetes.

Type 1 diabetes (T1D) is characterized by lymphocyte infiltration into the pancreatic islets of Langerhans, leading to the destruction of insulin-producing beta cells and uncontrolled hyperglycemia. In the nonobese diabetic (NOD) murine model of T1D, the onset of this infiltration starts several weeks before glucose dysregulation and overt diabetes. Recruitment of immune cells to the islets is mediated by several chemotactic cytokines, including CXCL10, while other cytokines, including SDF-1α, can confer protective effects. Global gene expression studies of the pancreas from prediabetic NOD mice and single-cell sequence analysis of human islets from prediabetic, autoantibody-positive patients showed an increased expression of metallothionein (MT), a small molecular weight, cysteine-rich metal-binding stress response protein. We have shown that beta cells can release MT into the extracellular environment, which can subsequently enhance the chemotactic response of Th1 cells to CXCL10 and interfere with the chemotactic response of Th2 cells to SDF-1α. These effects can be blocked in vitro with a monoclonal anti-MT antibody, clone UC1MT. When administered to NOD mice before the onset of diabetes, UC1MT significantly reduces the development of T1D. Manipulation of extracellular MT may be an important approach to preserving beta cell function and preventing the development of T1D.

Motor properties of Myosin 5c are modulated by tropomyosin isoforms and inhibited by pentabromopseudilin.

Myosin 5c (Myo5c) is a motor protein that is produced in epithelial and glandular tissues, where it plays an important role in secretory processes. Myo5c is composed of two heavy chains, each containing a generic motor domain, an elongated neck domain consisting of a single α-helix with six IQ motifs, each of which binds to a calmodulin (CaM) or a myosin light chain from the EF-hand protein family, a coiled-coil dimer-forming region and a carboxyl-terminal globular tail domain. Although Myo5c is a low duty cycle motor, when two or more Myo5c-heavy meromyosin (HMM) molecules are linked together, they move processively along actin filaments. We describe the purification and functional characterization of human Myo5c-HMM co-produced either with CaM alone or with CaM and the essential and regulatory light chains Myl6 and Myl12b. We describe the extent to which cofilaments of actin and Tpm1.6, Tpm1.8 or Tpm3.1 alter the maximum actin-activated ATPase and motile activity of the recombinant Myo5c constructs. The small allosteric effector pentabromopseudilin (PBP), which is predicted to bind in a groove close to the actin and nucleotide binding site with a calculated ΔG of -18.44kcal/mol, inhibits the motor function of Myo5c with a half-maximal concentration of 280nM. Using immunohistochemical staining, we determined the distribution and exact localization of Myo5c in endothelial and endocrine cells from rat and human tissue. Particular high levels of Myo5c were observed in insulin-producing β-cells located within the pancreatic islets of Langerhans.

Evaluating maternal toxicity induced by aqueous extract of Bambusa vulgaris shoot through biochemical, hematological, and histopathological assessment in pregnant Wistar rats

Exposure to teratogenic agents during pregnancy can lead to fetal abnormalities. Establishing histological, hematological, and biochemical parameters is pivotal to enhancing the evaluation of the effect of any substance on embryo-fetal development. The present study investigated the maternal toxicity of aqueous extract of Bambusa vulgaris Schrad. ex J.C. Wendl shoots in pregnant Wistar rats. The pregnant rats were then allocated into four groups (n=6): a control group (without treatment) and three test groups (treated with the extract 250, 500, and 1000 mg/Kg, respectively). The treatment was initiated on gestational day (GD) 6 and continued until the 15th day. On GD 20, all the rats were anesthetized and subjected to laparotomy. Blood samples were collected from the pregnant rats for hematological and biochemical analyses, while various organs were isolated for histopathological studies. The study demonstrates dose-dependent toxicity of the extract, with significant variations (P<0.001) observed in ALP and AST levels at the 1000 mg/kg dose, suggesting hepatic impairment in maternal subjects. Moreover, significant variations in total leukocyte and lymphocyte counts suggested pronounced inflammation or multi-organ dysfunction at this dose. Histopathological examination also revealed various indicators of multi-organ failure, including transmural mixed inflammation in the gall bladder, disruption of cardiac myofibre arrangement, tubular cell damage in the kidneys, cellular alterations in the liver, shrinking of pancreatic Langerhans islets, and lymphoid depletion in the spleen at 1000 mg/kg dose. These findings underscore the potential maternal toxicity associated with Bambusa vulgaris shoots, highlighting its potential risk for consumption during pregnancy and emphasizing the need for further research and caution regarding its use during this critical period.

Ectopic pancreatic adenocarcinoma in Meckel’s diverticulum: a case report

BackgroundMalignant neoplasms arising from Meckel’s diverticulum are rare and an adenocarcinoma in Meckel’s diverticulum originating from ectopic pancreatic tissue is even rarer. Herein, we report a patient with an ectopic pancreatic adenocarcinoma in Meckel’s diverticulum who was successfully treated with surgery and chemotherapy.Case presentationA woman in her sixties presented to another hospital with abdominal pain. Plain computed tomography suggested an abdominal tumor and she was referred to our hospital. Enhanced computed tomography revealed a 23-mm low-density tumor in the abdominal cavity. Surgery was performed with a tentative diagnosis of a mesenteric tumor, such as a gastrointestinal stromal tumor, schwannoma, or lymphoma. First, we inspected the peritoneal cavity with a laparoscope. This revealed numerous nodules in the small bowel mesentery, suggesting peritoneal dissemination. A 20-mm-diameter white tumor was found in the small intestine and diagnosed as a small intestinal cancer. The small intestine was partially resected laparoscopically through a small skin incision. The patient’s postoperative course was uneventful, and she was discharged on postoperative day 9. Pathological examination revealed well-differentiated adenocarcinoma in the small intestine. The tumor had developed from a sac-like portion protruding toward the serosal side and had a glandular structure lined with flattened atypical cells. Neither pancreatic acinar cells nor islets of Langerhans were evident, suggesting a Heinrich type 3 ectopic pancreas. The final diagnosis was an adenocarcinoma originating from an ectopic pancreas in Meckel’s diverticulum. After a smooth recovery, the patient commenced chemotherapy for pancreatic cancer.ConclusionsWe present a very rare case of ectopic pancreatic carcinoma in Meckel’s diverticulum.

On Chip Sorting of Stem Cell-Derived β Cell Clusters Using Traveling Surface Acoustic Waves.

There is a critical need for sorting complex materials, such as pancreatic islets of Langerhans, exocrine acinar tissues, and embryoid bodies. These materials are cell clusters, which have highly heterogeneous physical properties (such as size, shape, morphology, and deformability). Selecting such materials on the basis of specific properties can improve clinical outcomes and help advance biomedical research. In this work, we focused on sorting one such complex material, human stem cell-derived β cell clusters (SC-β cell clusters), by size. For this purpose, we developed a microfluidic device in which an image detection system was coupled to an actuation mechanism based on traveling surface acoustic waves (TSAWs). SC-β cell clusters of varying size (∼100-500 μm in diameter) were passed through the sorting device. Inside the device, the size of each cluster was estimated from their bright-field images. After size identification, larger clusters, relative to the cutoff size for separation, were selectively actuated using TSAW pulses. As a result of this selective actuation, smaller and larger clusters exited the device from different outlets. At the current sample dilutions, the experimental sorting efficiency ranged between 78% and 90% for a separation cutoff size of 250 μm, yielding sorting throughputs of up to 0.2 SC-β cell clusters/s using our proof-of-concept design. The biocompatibility of this sorting technique was also established, as no difference in SC-β cell cluster viability due to TSAW pulse usage was found. We conclude the proof-of-concept sorting work by discussing a few ways to optimize sorting of SC-β cell clusters for potentially higher sorting efficiency and throughput. This sorting technique can potentially help in achieving a better distribution of islets for clinical islet transplantation (a potential cure for type 1 diabetes). Additionally, the use of this technique for sorting islets can help in characterizing islet biophysical properties by size and selecting suitable islets for improved islet cryopreservation.

The Effects Of Simvastatin On Islets Of Langerhans In The Pancreas Of Rats: A Histological And Biochemical Study

Objective: This study explored the effect of simvastatin on the histomorphology of islets of Langerhans, glucose and insulin levels in rats. Study Design: The study was a one-year laboratory-based experimental control trial. Place and duration of study: It was conducted at Army Medical College Rawalpindi, in collaboration with the National Institute of Health Islamabad and Armed Force Institute of Pathology Rawalpindi. Methods: A one-year, laboratory-based, two-group experimental control trial was conducted. Thirty rats were assigned to each group: a control group receiving saline injections, and a simvastatin group receiving a simvastatin 60 mg/kg/day. Histological analysis of pancreatic islets, and measurements of blood glucose and insulin levels were performed. Statistical analysis was conducted using independent sample t-tests, with significance set at p &lt; 0.005. Results: While simvastatin treatment did not affect the number of islets of Langerhans, The area of pancreatic islets of Langerhans was significantly higher in the simvastatin treatment group compared to control (52,664±38,871 μm2 vs 24,643±16,256 μm2, p=0.001). Serum insulin levels were also significantly elevated with simvastatin treatment (21.49±7.03 μIU/ml) compared to control (16.72±5.38 μIU/ml) (p=0.005). There were no significant differences in weekly fasting blood glucose levels at 4 or 12 weeks between groups (p&gt;0.05). These findings suggest potential modulation of pancreatic islet function by simvastatin without affecting glycemic control in this model. Conclusions: These findings demonstrate that simvastatin treatment significantly impacts the morphology and function of pancreatic islets in rats, increasing insulin secretion without affecting blood glucose levels. Further research is necessary to elucidate the underlying mechanisms and clinical implications of these observations. Keywords: Simvastatin, islets of Langerhans, Sprague-Dawley rats, insulin, glucose, pancreas.

Molecular determinants and intracellular targets of taurine signalling in pancreatic islet β-cells.

Despite its abundance in pancreatic islets of Langerhans and proven antihyperglycemic effects, the impact of the essential amino acid, taurine, on islet β-cell biology has not yet received due consideration, which prompted the current studies exploring the molecular selectivity of taurine import into β-cells and its acute and chronic intracellular interactions. The molecular aspects of taurine transport were probed by exposing the clonal pancreatic BRIN BD11 β-cells and primary mouse and human islets to a range of the homologs of the amino acid (assayed at 2-20 mM), using the hormone release and imaging of intracellular signals as surrogate read-outs. Known secretagogues were employed to profile the interaction of taurine with acute and chronic intracellular signals. Taurine transporter TauT was expressed in the islet β-cells, with the transport of taurine and homologs having a weak sulfonate specificity but significant sensitivity to the molecular weight of the transporter. Taurine, hypotaurine, homotaurine, and β-alanine enhanced insulin secretion in a glucose-dependent manner, an action potentiated by cytosolic Ca2+ and cAMP. Acute and chronic β-cell insulinotropic effects of taurine were highly sensitive to co-agonism with GLP-1, forskolin, tolbutamide, and membrane depolarization, with an unanticipated indifference to the activation of PKC and CCK8 receptors. Pre-culturing with GLP-1 or KATP channel inhibitors sensitized or, respectively, desensitized β-cells to the acute taurine stimulus. Together, these data demonstrate the pathways whereby taurine exhibits a range of beneficial effects on insulin secretion and β-cell function, consistent with the antidiabetic potential of its dietary low-dose supplementation.

The Effect of Arumanis Mango Rind (Mangifera indica L) Extract as Antidiabetic in Rats Model

Arumanis  mango (Mangifera indica L) rind is one of the organic wastes containing flavonoid compounds. The objectives of this study were to find out the effect of arumanis mango rind extract on alloxan-induced blood glucose reduction in rats, to find out the most effective dose for reducing the levels of blood glucose in diabetic rats, and to find out the histopathology of the pancreas in diabetic rats.We used experimental method. In this study, 24 rats were divided into six groups consisting of I negative control, II positive control, III, IV, V different doses of 100 mg/kg BW, 200 mg/kg BW, 400 mg/kg BW and VI comparison group ( glibenclamide ). Groups II to VI were administered alloxan at 150 mg/kg BW for 3 days, and then the extract was administered to each group for 14 days, except group II. The levels of blood glucose were measured using a glucometer via the capillary of rat’s tail,  before and after induction and after administration of extract to all groups. The results are analyzed by the one-way ANOVA it showed significantly different results (p&lt; 0.05 ). The extract of arumanis mango rind in all doses, had an effect on decreasing the level of blood glucose in diabetic rats effectively in dose of 400 mg/kg BW ( group V ) and histopathology desricptive results showed that arumanis mango rind extract could reduce damage to the pancreatic islet of Langerhans with histopathology of the exocrine glands and endocrine glands at group V was better than at group III and IV.

Insulin's Function in Health and Disease

Insulin is a polypeptide hormone that is primarily released by cells in the pancreatic islets of Langerhans. The hormone may work in tandem with glucagon to control blood sugar levels; glucagon has catabolic properties while insulin has anabolic ones. Insulin controls blood glucose levels and causes the liver, muscles, and adipose tissue to store glucose, which causes total weight gain. Insulin plays a crucial role in the initiation and development of many chronic diseases because it modulates a variety of physiological processes. Other techniques are based on the exogenous infusion of glucose or insulin, or both, either under steady-state (the insulin suppression test) or under dynamic conditions (the insulin tolerance test, intravenous glucose-tolerance test with minimal model analysis, and constant infusion of glucose with model analysis). Homeostatic model assessment uses fasting plasma glucose and insulin concentrations to derive indices of insulin sensitivity and secretion from a mathematical model.

Kisspeptin upregulates β-cell serotonin production during pregnancy.

During pregnancy the maternal pancreatic islets of Langerhans undergo adaptive changes to compensate for gestational insulin resistance. The lactogenic hormones are well established to play a key role in regulating the islet adaptation to pregnancy, and one of the mechanisms through which they act is through upregulating β-cell serotonin production. During pregnancy islet serotonin levels are significantly elevated, where it is released from the β-cells to drive the adaptive response through paracrine and autocrine effects. We have previously shown that placental kisspeptin (KP) also plays a role in promoting the elevated insulin secretion and β-cell proliferation observed during pregnancy, although the precise mechanisms involved are unclear. In the present study we investigated the effects of KP on expression of pro-proliferative genes and serotonin biosynthesis within rodent islets. Whilst KP had limited effect on pro-proliferative gene expression at the time points tested, KP did significantly stimulate expression of the serotonin biosynthesis enzyme Tph-1. Furthermore, the islets of pregnant β-cell-specific GPR54 knockdown mice were found to contain significantly fewer serotonin-positive β-cells when compared to pregnant controls. Our previous studies suggested that reduced placental kisspeptin production, with consequent impaired kisspeptin-dependent β-cell compensation, may be a factor in the development of GDM in humans. These current data suggest that, similar to the lactogenic hormones, KP may also contribute to serotonin biosynthesis and subsequent islet signalling during pregnancy. Furthermore, upregulation of serotonin biosynthesis may represent a common mechanism through which multiple signals might influence the islet adaptation to pregnancy.

Heterotopia of salivary gland tissue in the pancreas

Heterotopia of the salivary gland occurs mainly in the head and neck region of the human body, rarely in regions such as the rectum, but has never been demonstrated in the pancreas. Within a screening effort of pancreatic samples for detecting ΔNp63 expression, we discovered two pancreatic samples from a 35-year-old male showing salivary gland heterotopia. Immunohistochemical stainings were done for markers of healthy and neoplastic salivary glands and showed expression of calponin, CD142 and KRT14 but not of S100p, GFAP or CD117. A PAS-staining and Alcian Blue staining showed the presence of acid mucins. These staining patterns were consistent with non-neoplastic submandibular gland tissue comprised of abundant seromucous glands, basal cells and myoepithelial cells, all features typically absent in the pancreas. Also, no pancreatic islets of Langerhans were detected. We show for the first time that salivary gland heterotopia can occur at the location of the pancreas.

A flexible implant for acute intrapancreatic electrophysiology.

Microelectrode arrays (MEAs) have proven to be a powerful tool to study electrophysiological processes over the last decades with most technology developed for investigation of the heart or brain. Other targets in the field of bioelectronic medicine are the peripheral nervous system and its innervation of various organs. Beyond the heart and nervous systems, the beta cells of the pancreatic islets of Langerhans generate action potentials during the production of insulin. In vitro experiments have demonstrated that their activity is a biomarker for blood glucose levels, suggesting that recording their activity in vivo could support patients suffering from diabetes mellitus with long-term automated read-out of blood glucose concentrations. Here, we present a flexible polymer-based implant having 64 low impedance microelectrodes designed to be implanted to a depth of 10 mm into the pancreas. As a first step, the implant will be used in acute experiments in pigs to explore the electrophysiological processes of the pancreas in vivo. Beyond use in the pancreas, our flexible implant and simple implantation method may also be used in other organs such as the brain.

Hypoxic secretome mesenchymal stem cells inhibiting interleukin-6 expression prevent oxidative stress in type 1 diabetes mellitus.

Aim Type 1 diabetes mellitus (T1DM) is an autoimmune disease characterized by the chronic inflammation of the pancreatic islets of Langerhans. Hyperglycaemia leads to suppressed antioxidant enzyme and increased inflammation in the pancreatic cell, resulting in pancreatic cell death. Hypoxic secretome mesenchymal stem cells (HS-MSCs) are soluble molecules secreted by MSCS that have the antiinflammation ability by secreting various cytokines including IL-10 and TGF-β which potent as a promising therapeutic modality for T1DM. This study aims to investigate the role of HS-MSCs in regulating superoxide dismutase (SOD) and caspase-3 gene expression in T1DM model. Methods Twenty male Wistar rats (6 to 8 weeks old) were randomly divided into four groups (sham, control, HS-MSCs 0.5 mL and HS-MSCs 1 mL intraperitoneal treatment group). Streptozotocin (STZ) 60mg/kgBB was conducted once on day 1, HS-MSCs 0.5mL (T1) and HS-MSCs 1 mL (T2) were administrated intraperitoneally on day 7, 14, and 21 after STZ administration. The rats were sacrificed on day 28; the gene expression of SOD and IL-6 was analysed by qRT-PCR. Results This study showed that the ratio of SOD significantly increased in HS-MSCs treatment associated with suppression of IL-6 gene expression. Conclusion HS-MSCs administration suppresses oxidative stress and inflammation by up regulating SOD and inhibiting IL-6 to control T1DM.

Uji In Vivo Elaeocarpus sphaericus Schum terhadap Kadar Gula Darah dan Struktur Jaringan Testis, Pankreas, dan Ginjal

Genitri plant (Elaeocarpus sphaericus Schum) has a complex chemical compound that has the potential to lower blood sugar levels. The purpose of this study was to analyze in vivo blood sugar levels and changes in tissue structure of the pancreas, testes seminiferous tubules, and sucrose-induced kidneys. The study used an experimental approach, 24 male Mus musculus mice were grouped into 4 treatment groups. Negative control (P0), positive control giving sucrose at a dose of 1.125 mg/g (P1); Sucrose induction treatment was at a dose of 1.125 mg/g and Gintri seed simplicia was at a dose of 1.300 mg/g (P2). Experimental animals before being induced by sucrose were fasted for 2 hours. Sucrose induction was carried out for 5 days, the experimental animals were given food and drink ad libitum. Checking blood sugar levels every 4 hours through the tail vein. Blood sugar levels of experimental animals P2 and P3 were 126 mg/ each followed by administration of a solution of genitri seeds and fruit for 36 days, every 6 days data was collected on blood sugar levels. On the 37th day, dislocation, surgery and organ harvesting of the testes, pancreas and kidneys were carried out, and preparation of HE staining tissue was made. Data analysis using One Way Anova. The results showed that sucrose induction reduced the diameter of the islets of Langerhans, increased the diameter of the seminiferous tubules of the testes, and reduced the diameter of the glomerulus of the kidney. Giving genitri seeds and fruit lowers blood sugar levels, affects the tissue structure of the pancreas, testes, and glomerulus. The F value of the diameter of the pancreatic islets of Langerhans 16,662; testicular seminiferous tubule diameter 13,433; Glomerular diameter 28,958.

Pancreatic beta-cell specific BAG3 knockout results in chronic hyperinsulinemia inducing insulin resistance

BackgroundInsulin, secreted from pancreatic islets of Langerhans, is of critical importance in regulating glucose homeostasis. Defective insulin secretion and/or the inability of tissues to respond to insulin results in insulin resistance and to several metabolic and organ alterations. We have previously demonstrated that BAG3 regulates insulin secretion. Herein we explored the consequences of beta-cells specific BAG3 deficiency in an animal model. MethodsWe generated a beta-cells specific BAG3 knockout mouse model. Glucose and insulin tolerance tests, proteomics, metabolomics, and immunohistochemical analysis were used to investigate the role of BAG3 in regulating insulin secretion and the effects of chronic exposure to excessive insulin release in vivo. ResultsBeta-cells specific BAG3 knockout results in primary hyperinsulinism due to excessive insulin exocytosis finally leading to insulin resistance. We demonstrate that resistance is mainly muscle-dependent while the liver remains insulin sensitive. The chronically altered metabolic condition leads in time to histopathological alterations in different organs. We observe elevated glycogen and lipid accumulation in the liver reminiscent of non-alcoholic fatty liver disease as well as mesangial matrix expansion and thickening of the glomerular basement membrane, resembling the histology of chronic kidney disease. ConclusionAltogether, this study shows that BAG3 plays a role in insulin secretion and provides a model for the study of hyperinsulinemia and insulin resistance.

Building Fucoidan/Agarose-Based Hydrogels as a Platform for the Development of Therapeutic Approaches against Diabetes.

Current management for diabetes has stimulated the development of versatile 3D-based hydrogels as in vitro platforms for insulin release and as support for the encapsulation of pancreatic cells and islets of Langerhans. This work aimed to create agarose/fucoidan hydrogels to encapsulate pancreatic cells as a potential biomaterial for diabetes therapeutics. The hydrogels were produced by combining fucoidan (Fu) and agarose (Aga), marine polysaccharides derived from the cell wall of brown and red seaweeds, respectively, and a thermal gelation process. The agarose/fucoidan (AgaFu) blended hydrogels were obtained by dissolving Aga in 3 or 5 wt % Fu aqueous solutions to obtain different proportions (4:10; 5:10, and 7:10 wt). The rheological tests on hydrogels revealed a non-Newtonian and viscoelastic behavior, while the characterization confirmed the presence of the two polymers in the structure of the hydrogels. In addition, the mechanical behavior showed that increasing Aga concentrations resulted in hydrogels with higher Young's modulus. Further, the ability of the developed materials to sustain the viability of human pancreatic cells was assessed by encapsulation of the 1.1B4HP cell line for up to 7 days. The biological assessment of the hydrogels revealed that cultured pancreatic beta cells tended to self-organize and form pseudo-islets during the period studied.

Molecular Insights into the Self-Assembly of a Full-Length hIAPP Trimer: β-Protofibril Formed by β-Hairpin Lateral or Longitudinal Association.

The fibrillar protein deposits of the human islet amyloid polypeptide (hIAPP) in the pancreatic islet of Langerhans are pathological hallmark of type II diabetes. Extensive experimental studies have revealed that the oligomeric formations of the hIAPP are more toxic than the mature fibrils. Exploring the oligomeric conformations in the early aggregation state is valuable for effective therapeutics. In this work, using the all-atom explicit-solvent replica exchange molecular dynamic (REMD) simulations, we investigated the structural features and the assembly mechanisms of the full-length hIAPP trimer in solution. The hIAPP trimer adopted more β-sheets than a-helix conformations, and three types of ordered conformations including open β-barrel, single-layer, and double-layer U-shaped β-sheet structures with five β-strands were captured in our simulations. A representative single-layer β-sheet conformation with a CCS value of 1400 Å2 in our simulations matches exactly the experimentally ESI-IMS-MS-derived hIAPP trimer sample. These five β-strand conformations formed via the β-hairpin lateral and longitudinal association, respectively, showing two β-protofibril formation models. To the best of our knowledge, it is the first time to reveal two routes to β-sheet formation in the hIAPP trimers on the atomic level. The contact probabilities between pairs of the β-stranded residue show that the hydrophobic interactions between the residues F15 ∼ V17 and A25 ∼ L27 are responsible for the inter- and intra-peptide β-hairpin formations. All of these results indicate that the β-sheet formation is the first step in the conformational changes toward pathological aggregation and provides evidence of the β-sheet assembly mechanism into hIAPP aggregation.

Emerging Anti-Diabetic Drugs for Beta-Cell Protection in Type 1 Diabetes.

Type 1 diabetes (T1D) is a chronic autoimmune disorder that damages beta cells in the pancreatic islets of Langerhans and results in hyperglycemia due to the loss of insulin. Exogenous insulin therapy can save lives but does not halt disease progression. Thus, an effective therapy may require beta-cell restoration and suppression of the autoimmune response. However, currently, there are no treatment options available that can halt T1D. Within the National Clinical Trial (NCT) database, a vast majority of over 3000 trials to treat T1D are devoted to insulin therapy. This review focuses on non-insulin pharmacological therapies. Many investigational new drugs fall under the category of immunomodulators, such as the recently FDA-approved CD-3 monoclonal antibody teplizumab. Four intriguing candidate drugs fall outside the category of immunomodulators, which are the focus of this review. Specifically, we discuss several non-immunomodulators that may have more direct action on beta cells, such as verapamil (a voltage-dependent calcium channel blocker), gamma aminobutyric acid (GABA, a major neurotransmitter with effects on beta cells), tauroursodeoxycholic acid (TUDCA, an endoplasmic reticulum chaperone), and volagidemab (a glucagon receptor antagonist). These emerging anti-diabetic drugs are expected to provide promising results in both beta-cell restoration and in suppressing cytokine-derived inflammation.