Diabetic Pancreas Research Articles

Immunohistochemical detection of enteroviruses in pancreatic tissues of patients with type 1 diabetes using a polyclonal antibody against 2A protease of Coxsackievirus.

ABSTRACTAims/IntroductionThe need for antiserum for immunohistochemical (IHC) detection of enterovirus (EV) in formaldehyde‐fixed and paraffin‐embedded samples is increasing. The gold standard monoclonal antibody (clone 5D8/1) against EV‐envelope protein (VP1) was proven to cross‐react with other proteins. Another candidate marker of EV proteins is 2A protease (2Apro), which is encoded by the EV gene and translated by the host cells during EV replication, and participates processing proproteins to viral capsid proteins.Materials and MethodsWe raised polyclonal antiserum by immunizing a rabbit with an 18‐mer peptide of Coxsackievirus B1 (CVB1)‐2Apro, and examined the specificity and sensitivity for EV on formaldehyde‐fixed and paraffin‐embedded tissue samples.ResultsEnzyme‐linked immunosorbent assay study showed a high titer of antibody for 18‐mer peptide of CVB1‐2Apro, cross‐reacting with CVB3‐2Apro peptide. IHC showed that antiserum against 2Apro reacted with CVB1‐infected and VP1‐positive Vero cells. Confocal laser scanning microscopy showed that antigen stained by the 2Apro antibody located in the same cell with VP1 stained by 5D8/1. IHC using 2Apro antiserum showed dense staining in the islets of EV‐associated fulminant type 1 diabetes pancreas and that located in the same cell stained positive for VP1 (5D8/1). Specificity of 2Apro antiserum by IHC staining was confirmed by negative 2Apro in 14 VP1‐negative non‐diabetes control pancreases.ConclusionsOur study provides a new polyclonal antiserum against CVB1‐2Apro, which might be useful for IHC of EV‐infected human tissues stored as archive of formaldehyde‐fixed and paraffin‐embedded tissue samples.

Vitamin D decreases pancreatic iron overload in type 2 diabetes through the NF-κB-DMT1 pathway

Emerging evidence has deemed vitamin D as a potential candidate for the intervention of type 2 diabetes (T2D). Herein, we explored the underlying mechanisms of T2D prevention by vitamin D, concentrating on pancreatic iron deposition reported recently. Zucker diabetic fatty (ZDF) rats were treated by vitamin D, with age-matched Zucker lean rats as control. As expected, vitamin D treatment for ZDF rats normalized islet morphology and β-cell function. Moreover, vitamin D alleviated iron accumulation and apoptosis in pancreatic cells of ZDF rats, accompanied by lowered divalent metal transporter 1 (DMT1) expression. Consistently, similar results were observed in high glucose-stimulated INS-1 cells treated with or without vitamin D. Nuclear factor-κB (NF-κB), a transcription factor involving DMT1 regulation, was activated in pancreases of ZDF rats and INS-1 cells exposed to high glucose, but inactivated by vitamin D or BAY 11-7082, a NF-κB inhibitor. Futhermore, IL-1β functioning as NF-κB activator abolished the suppression of NF-κB activation, DMT1 induction and the attenuation of apoptosis as a consequence of vitamin D incubation. Our study showed that iron overload in pancreas may contribute to T2D pathogenesis and uncovered a potentially protective role for vitamin D on iron deposition of diabetic pancreas through NF-κB- DMT1 signaling.

Altered cellular localisation and expression, together with unconventional protein trafficking, of prion protein, PrPC, in type 1 diabetes.

Normal cellular prion protein (PrPC) is a conserved mammalian glycoprotein found on the outer plasma membrane leaflet through a glycophosphatidylinositol anchor. Although PrPC is expressed by a wide range of tissues throughout the body, the complete repertoire of its functions has not been fully determined. The misfolded pathogenic isoform PrPSc (the scrapie form of PrP) is a causative agent of neurodegenerative prion diseases. The aim of this study is to evaluate PrPC localisation, expression and trafficking in pancreases from organ donors with and without type 1 diabetes and to infer PrPC function through studies on interacting protein partners. In order to evaluate localisation and trafficking of PrPC in the human pancreas, 12 non-diabetic, 12 type 1 diabetic and 12 autoantibody-positive organ donor tissue samples were analysed using immunofluorescence analysis. Furthermore, total RNA was isolated from 29 non-diabetic, 29 type 1 diabetic and 24 autoantibody-positive donors to estimate PrPC expression in the human pancreas. Additionally, we performed PrPC-specific immunoblot analysis on total pancreatic protein from non-diabetic and type 1 diabetic organ donors to test whether changes in PrPC mRNA levels leads to a concomitant increase in PrPC protein levels in human pancreases. In non-diabetic and type 1 diabetic pancreases (the latter displaying both insulin-positive [INS(+)] and -negative [INS(-)] islets), we found PrPC in islets co-registering with beta cells in all INS(+) islets and, strikingly, unexpected activation of PrPC in alpha cells within diabetic INS(-) islets. We found PrPC localised to the plasma membrane and endoplasmic reticulum (ER) but not the Golgi, defining two cellular pools and an unconventional protein trafficking mechanism bypassing the Golgi. We demonstrate PrPC co-registration with established protein partners, neural cell adhesion molecule 1 (NCAM1) and stress-inducible phosphoprotein 1 (STI1; encoded by STIP1) on the plasma membrane and ER, respectively, linking PrPC function with cyto-protection, signalling, differentiation and morphogenesis. We demonstrate that both PRNP (encoding PrPC) and STIP1 gene expression are dramatically altered in type 1 diabetic and autoantibody-positive pancreases. As the first study to address PrPC expression in non-diabetic and type 1 diabetic human pancreas, we provide new insights for PrPC in the pathogenesis of type 1 diabetes. We evaluated the cell-type specific expression of PrPC in the human pancreas and discovered possible connections with potential interacting proteins that we speculate might address mechanisms relevant to the role of PrPC in the human pancreas.

Physiology in Perspective: Insulin—100 Years of Physiological Discovery

Physiology in Perspective: Insulin—100 Years of Physiological Discovery

Endocrine Pancreas Development and Dysfunction Through the Lens of Single-Cell RNA-Sequencing.

A chronic inability to maintain blood glucose homeostasis leads to diabetes, which can damage multiple organs. The pancreatic islets regulate blood glucose levels through the coordinated action of islet cell-secreted hormones, with the insulin released by β-cells playing a crucial role in this process. Diabetes is caused by insufficient insulin secretion due to β-cell loss, or a pancreatic dysfunction. The restoration of a functional β-cell mass might, therefore, offer a cure. To this end, major efforts are underway to generate human β-cells de novo, in vitro, or in vivo. The efficient generation of functional β-cells requires a comprehensive knowledge of pancreas development, including the mechanisms driving cell fate decisions or endocrine cell maturation. Rapid progress in single-cell RNA sequencing (scRNA-Seq) technologies has brought a new dimension to pancreas development research. These methods can capture the transcriptomes of thousands of individual cells, including rare cell types, subtypes, and transient states. With such massive datasets, it is possible to infer the developmental trajectories of cell transitions and gene regulatory pathways. Here, we summarize recent advances in our understanding of endocrine pancreas development and function from scRNA-Seq studies on developing and adult pancreas and human endocrine differentiation models. We also discuss recent scRNA-Seq findings for the pathological pancreas in diabetes, and their implications for better treatment.

Antidiabetic and antihyperlipidemic activities of a novel polyherbal formulation in streptozotocin - nicotinamide induced diabetic wistar rats

Objective: To investigate the antidiabetic and antihyperlipidemic activities of polyherbal formulation (PHF) containing seven plants namely Cassia auriculata, Cassia fistula, Syzygium cumini, Cyperus rotundus, Saussurea lappa, Terminalia arjuna and Salacia reticulate in streptozotocin (STZ) - nicotinamide (NC) induced diabetic rats by administering oral doses (200 and 400 mg/kg body weight).
 Materials and Methods: Animals were divided into diabetic and nondiabetic groups. Rats were fed with normal laboratory diet and induced with a single intraperitoneal injection of 60mg/kg of STZ, and thereafter 120 mg/kg NC was injected after 15min. Diabetic rats were treated with formulation (200 and 400 mg/kg) and glibenclamide 5 mg/kg. Blood glucose levels were measured using blood glucose test strips with ACCU CHEK glucometer. Glycosylated haemoglobin, total haemoglobin, lipid profiles, lipoproteins, hepatic marker enzymes activity were determined in normal and STZ- NC induced diabetic rats after oral administration of the PHF for 28 days. Histopathological changes in normal and diabetic rat pancreas organs were also observed after PHF treatment.The statistical analysis of results was carried out using one-way analysis (ANOVA) followed by post hoc multiple comparison tests.
 Results: Treatment of diabetic rats with PHF (200 and 400 mg/kg) and glibenclamide (5 mg/kg) indicate significant decreased blood glucose level and significant improvement in body weight. PHF treated rats showed significant (P < 0.01) decrease in the level of HbA1C, TC, TG, LDL, VLDL, AST, ALT and ALP while a significant increment in the level of Hb, HDL cholesterol was observed. Furthermore, the PHF treated rats has a favourable effect on the histopathological changes of the pancreas in STZ-NC induced diabetes.
 Conclusion: These findings suggested the antihyperglycemic and antihyperlipidemic properties of the PHF and thus help in preventing future complications of diabetes.

ULTRASTRUCTURAL ANALYSIS OF DECELLULARIZED DIABETIC AND NON-DIABETIC CANINE PANCREAS FOR THE PRODUCTION OF BIOLOGICAL SCAFFOLDS

<h3>Background</h3> The canine species plays a significant role in the history of research related to Diabetes Mellitus, since it was in this species that the disease was first experimentally induced. The decellularization of organs and tissues is a recent technology for the creation of biomaterials. However, the production of scaffolds is already established and is a promising source to new tissues and organs in Regenerative Medicine. The aim of this study was to evaluate the ultrastructure of the decellularized canine pancreas extracellular matrix obtained from different protocols aiming to describe best protocol to preserve the extracellular matrix. <h3>Methods</h3> Pancreas was collected from diabetic and non-diabetic dogs, and samples were subsequently sectioned in ± 1 cm. Decellularization protocol was performed using 4% Sodium Deoxycholate (SDC) or 0.5% Sodium Dodecyl Sulfate (SDS) ionic detergents or 1% Triton X-100 non-ionic detergent under immersion and agitation during four days at room temperature. A final wash step was carried out in distilled water 3 times 30 minutes in orbital agitation. Histological techniques and Scanning Electron Microscopy analysis were carried out to evaluate physical structure, architectural and tissue ultrastructure, respectively. <h3>Results</h3> The surface of the native and decellularized diabetic and non-diabetic canine pancreas matrices were evaluated by Scanning Electron Microscopy to analyze the efficiency of the decellularization process in each protocols. Thethree decellularization protocols were efficient to remove the cells from the tissue. However, 4% SDC ionic detergent showed higher efficiency of cell removal and preservation of collagen fibers in the extracellular matrix. <h3>Conclusion</h3> The decellularized canine pancreas using 4% SDC ionic detergent presented better preservation of extracellular matrix fibers, when compared with the other protocols with 0.5% SDS or 1% Triton X-100, being this one recommended for production of pancreas scaffolds in Veterinary Medicine.

Evaluation of pancreatic regeneration activity of Tephrosia purpurea leaves in rats with streptozotocin-induced diabetes

Background and aimFlavonoid rich plant Tephrosia purpurea (T. purpurea), commonly known as Sarpunkha has been used in traditional systems of medicine to treat diabetes mellitus. However, its effectiveness in promoting regeneration of pancreas in diabetes has not been investigated. Therefore, the present study was undertaken to evaluate pancreatic β-cells regeneration, antioxidant and antihyperlipidemic potentials of T. purpurea leaves extract, its fractions and main constituent Rutin in diabetic rats. Experimental procedureThe leaves extract and its fractions were first screened for acute and sub-chronic antidiabetic activity in a dose range of 250–500 mg/kg orally. Further, fractions with potent antidiabetic activity were screened for pancreatic β-cells regeneration activity using histopathological studies and morphometric analysis, which was followed by estimation of biochemical parameters. Results and conclusionThe most significant antidiabetic, pancreatic regeneration and antihyperlipidemic activity was exhibited by n-butanol soluble fraction of ethanol extract at the dose level of 500 mg/kg. Histopathology revealed that treatment with this fraction improved the β-cell granulation of islets and prevented the β-cells damage which was further confirmed by morphometric analysis. Thus, the present study validated the traditional use of T. purpurea plant in the treatment of diabetes, which might be attributed to pancreatic β-cells regeneration potential of its active constituent Rutin. Taxonomy (classification by EVISE)Traditional Medicine; Metabolic Disorder; Experimental Design; Cell Regeneration and Histopathology.

Grape seed proanthocyanidin extract suppresses oxidative stress in the rat pancreas of type-1 diabetes

Aim This study aimed to elucidate the effects of grape seed proanthocyanidin extract (GSPE) on oxidative stress (OS), antioxidant enzymes, free radicals and cytokines in the pancreas of T1DM rats. Methods Two-month-old Wistar rats were assigned to the control (CON), CON + GSPE (CON + PA), diabetics (STZ, 60 mg/kg b.w.), diabetes + GSPE (STZ + PA), diabetes + insulin (STZ + INS, 3 U/day) and diabetics + GSPE and INS (STZ + INS + PA) groups. GSPE (75 mg/kg b.w.) was administered daily either alone or with INS for 8 weeks. Results Glutathione was lowest in diabetics while it increased in the STZ + INS + PA (p < .001) group, similar to catalase activity (p < .05). Hydrogen peroxide, superoxide and lipid peroxidation increased with iNOS, TNF-α and IL-1β in the diabetic pancreases, while GSPE decreased (p < .001). Further, reduced β-cells/islet number was improved in diabetics (p < .001) with treatment. Conclusion This study suggests that GSPE with INS is effective in minimising OS and pancreatic degeneration in T1DM rats.

Exocrine Pancreatic Enzymes Are a Serological Biomarker for Type 1 Diabetes Staging and Pancreas Size.

Exocrine pancreas abnormalities are increasingly recognized as features of type 1 diabetes. We previously reported reduced serum trypsinogen levels and in a separate study, smaller pancreata at and before disease onset. We hypothesized that three pancreas enzymes (amylase, lipase, and trypsinogen) might serve as serological biomarkers of pancreas volume and risk for type 1 diabetes. Amylase, lipase, and trypsinogen were measured from two independent cohorts, together comprising 800 serum samples from single-autoantibody-positive (1AAb+) and multiple-AAb+ (≥2AAb+) subjects, individuals with recent-onset or established type 1 diabetes, their AAb-negative (AAb-) first-degree relatives, and AAb- control subjects. Lipase and trypsinogen were significantly reduced in ≥2AAb+, recent-onset, and established type 1 diabetes subjects versus control subjects and 1AAb+, while amylase was reduced only in established type 1 diabetes. Logistic regression models demonstrated trypsinogen plus lipase (area under the receiver operating characteristic curve [AUROC] = 81.4%) performed equivalently to all three enzymes (AUROC = 81.4%) in categorizing ≥2AAb+ versus 1AAb+ subjects. For cohort 2 (n = 246), linear regression demonstrated lipase and trypsinogen levels could individually and collectively serve as indicators of BMI-normalized relative pancreas volume (RPVBMI, P < 0.001), previously measured by MRI. Serum lipase and trypsinogen levels together provide the most sensitive serological biomarker of RPVBMI and may improve disease staging in pretype 1 diabetes.

The Role of Isoflavones in Type 2 Diabetes Prevention and Treatment-A Narrative Review.

Given the growing number of type 2 diabetic individuals and the substantial social and financial costs associated with diabetes management, every effort should be made to improve its prevention and treatment methods. There is an ongoing search for natural dietary compounds that could be used for this purpose. This narrative review focuses on the therapeutic potential of isoflavones in diabetes prevention and treatment. This review summarizes (i) the molecular mechanisms of isoflavones action that are critical to their anti-diabetic properties; (ii) preclinical (in vitro and in vivo) studies evaluating the influence of isoflavones on the function of key organs involved in the pathogenesis of diabetes; and (iii) epidemiological studies and clinical trials that assessed the effectiveness of isoflavones in the prevention and treatment of type 2 diabetes in humans. Apart from discussing the effects of isoflavones on the function of organs “classically” associated with the pathogenesis of diabetes (pancreas, liver, muscles, and adipose tissue), the impact of these compounds on other organs that contribute to the glucose homeostasis (gastrointestinal tract, kidneys, and brain) is also reviewed.

Image-Based Machine Learning Algorithms for Disease Characterization in the Human Type 1 Diabetes Pancreas

Emerging data suggest that type 1 diabetes affects not only the β-cell-containing islets of Langerhans, but also the surrounding exocrine compartment. Using digital pathology, machine learning algorithms were applied to high-resolution, whole-slide images of human pancreata to determine whether the tissue composition in individuals with or at risk for type 1 diabetes differs from those without diabetes. Transplant-grade pancreata from organ donors were evaluated from 16 nondiabetic autoantibody-negative controls, 8 nondiabetic autoantibody-positive subjects with increased type 1 diabetes risk, and 19 persons with type 1 diabetes (0 to 12 years' duration). HALO image analysis algorithms were implemented to compare architecture of the main pancreatic duct as well as cell size, density, and area of acinar, endocrine, ductal, and other nonendocrine, nonexocrine tissues. Type 1 diabetes was found to affect exocrine area, acinar cell density, and size, whereas the type of difference correlated with the presence or absence of insulin-positive cells remaining in the pancreas. These changes were not observed before disease onset, as indicated by modeling cross-sectional data from pancreata of autoantibody-positive subjects and those diagnosed with type 1 diabetes. These data provide novel insights into anatomic differences in type 1 diabetes pancreata and demonstrate that machine learning can be adapted for the evaluation of disease processes from cross-sectional data sets.

Quantitative Magnetic Resonance Imaging of the Pancreas of Individuals With Diabetes.

Magnetic resonance imaging (MRI) has the potential to improve our understanding of diabetes and improve both diagnosis and monitoring of the disease. Although the spatial resolution of MRI is insufficient to directly image the endocrine pancreas in people, the increasing awareness that the exocrine pancreas is also involved in diabetes pathogenesis has spurred new MRI applications. These techniques build upon studies of exocrine pancreatic diseases, for which MRI has already developed into a routine clinical tool for diagnosis and monitoring of pancreatic cancer and pancreatitis. By adjusting the imaging contrast and carefully controlling image acquisition and processing, MRI can quantify a variety of tissue pathologies. This review introduces a number of quantitative MRI techniques that have been applied to study the diabetic pancreas, summarizes progress in validating and standardizing each technique, and discusses the need for image analyses that account for spatial heterogeneity in the pancreas.

Ishige okamurae reduces blood glucose levels in high-fat diet mice and improves glucose metabolism in the skeletal muscle and pancreas

Brown alga (Ishige okamurae; IO) dietary supplements have been reported to possess anti-diabetic properties. However, the effects of IO supplements have not been evaluated on glucose metabolism in the pancreas and skeletal muscle. C57BL/6 N male mice (age, 7 weeks) were arranged in five groups: a chow diet with 0.9% saline (NFD/saline group), high-fat diet (HFD) with 0.9% saline (HFD/saline group). high-fat diet with 25 mg/kg IO extract (HFD/25/IOE). high-fat diet with 50 mg/kg IO extract (HFD/50/IOE), and high-fat diet with 75 mg/kg IO extract (HFD/75/IOE). After 4 weeks, the plasma, pancreas, and skeletal muscle samples were collected for biochemical analyses. IOE significantly ameliorated glucose tolerance impairment and fasting and 2 h blood glucose level in HFD mice. IOE also stimulated the protein expressions of the glucose transporters (GLUTs) including GLUT2 and GLUT4 and those of their related transcription factors in the pancreases and skeletal muscles of HFD mice, enhanced glucose metabolism, and regulated blood glucose level. Our results suggest Ishige okamurae extract may reduce blood glucose levels by improving glucose metabolism in the pancreas and skeletal muscle in HFD-induced diabetes.

EP4 signalling is essential for controlling islet inflammation by causing a shift in macrophage polarization in obesity/type 2 diabetes.

Activation of the prostaglandin E2 receptor EP4 alters polarization of adipose tissue macrophages towards the anti-inflammatory M2 phenotype to suppress chronic inflammation. However, the role of EP4 signalling in pancreatic macrophages that affect insulin secretion is unclear. We examined the role of EP4 signalling in islet inflammation in vitro and in vivo. Obese diabetic db/db mice were treated with an EP4-selective agonist or vehicle for 4 weeks. Islet morphology did not significantly differ and glucose-stimulated insulin secretion was increased, whereas the pancreatic M1/M2 ratio was decreased in the EP4 agonist-treated group compared to the vehicle group. Because EP4 activation in MIN6 cells did not affect insulin secretion, we used a MIN6/macrophage co-culture system to evaluate the role of EP4 signalling in islet inflammation and subsequent inhibition of insulin release. Co-culture with M1-polarized macrophages markedly suppressed insulin expression in MIN6 cells; however, modulation of M1 polarization by the EP4 agonist significantly reversed the negative impact of co-cultivation on insulin production. The enhanced expression levels of pro-inflammatory cytokines in co-cultured MIN6 cells were markedly inhibited by EP4 agonist treatment of M1 macrophages. Thus, EP4 activation may suppress islet inflammation and protect β-cell function by altering inflammatory macrophages in the diabetic pancreas.

State-of-the-Art Technology of Model Organisms for Current Human Medicine.

Since the 1980s, molecular biology has been used to investigate medical field mechanisms that still require the use of crude biological materials in order to achieve their necessary goals. Transcription factor-induced pluripotent stem cells are used in regenerative medicine to screen drugs and to support lost tissues. However, these cells insufficiently reconstruct whole organs and require various intact cells, such as damaged livers and diabetic pancreases. For efficient gene transfer in medical use, virally mediated gene transfers are used, although immunogenic issues are investigated. To obtain efficient detective and diagnostic power in intractable diseases, biological tools such as roundworms and zebrafish have been found to be useful for high-throughput screening (HST) and diagnosis. Taken together, this biological approach will help to fill the gaps between medical needs and novel innovations in the field of medicine.

Which stem cells will eventually translate to the clinics for treatment of diabetes?

Human embryonic stem (hES) cells have been around for more than two decades now. It was expected that hES/iPS (induced pluripotent stem) cells will quickly translate to the clinics to treat diabetic patients and to obtain gametes in vitro for infertile couples. However, there is no breakthrough yet in either of the fields although considerable progress has been made. Research efforts are ongoing to obtain an insight into the gene expression changes associated with directed differentiation of hES/iPS cells. Autologous bone marrow/cord blood mononuclear cells’ therapy has also failed to show any regenerative potential and only remains as a standard method of care for blood diseases. Only mesenchymal stem cells (MSCs) have shown promise in the clinics to alleviate diabetic symptoms. But MSCs are stromal cells with no regenerative properties; rather “paracrine providers”, pericytes/stromal cells, better known for their trophic, immuno-modulatory, and anti-inflammatory properties and thus best termed as mesenchymal stromal cells (MSCs). Autologus bone marrow cells enriched for hematopoietic stem cells have no potential to cross boundaries and transdifferentiate into other lineages including endodermal pancreatic cells. Endogenous, pluripotent, very small embryonic-like stem cells (VSELs) emerge as the most likely endogenous stem cell candidates to regenerate adult diabetic pancreas. Transplanted MSCs provide a healthy paracrine support required for endogenous/ resident VSELs to differentiate into acinar cells and islets in a diabetic pancreas to enable restoration of homeostasis. Our recently published study shows that VSELs exist and can be enriched from intact mouse pancreas as well as from the islets and increase in numbers in diabetic pancreas. Providing “regenerative pressure” by subjecting diabetic mice to partial pancreatectomy stimulated the VSELs to undergo differentiation into various cell types in an attempt to restore homeostasis. Double-blinded, placebo controlled clinical trials need to be undertaken to evaluate the efficacy of transplanting MSCs in diabetic patients with conviction since now underlying fine play of endogenous VSELs and niche providing MSCs has emerged.

Decreased pancreatic acinar cell number in type 1 diabetes.

Individuals with longstanding and recent-onset type 1 diabetes have a smaller pancreas. Since beta cells represent a very small portion of the pancreas, the loss of pancreas volume in diabetes is primarily due to the loss of pancreatic exocrine mass. However, the structural changes in the exocrine pancreas in diabetes are not well understood. To characterise the pancreatic endocrine and exocrine compartments in diabetes, we studied pancreases from adult donors with type 1 diabetes compared with similarly aged donors without diabetes. Islet cell mass, islet morphometry, exocrine mass, acinar cell size and number and pancreas fibrosis were assessed by immunohistochemical staining. To better understand possible mechanisms of altered pancreas size, we measured pancreas size in three mouse models of insulin deficiency. Pancreases from donors with type 1 diabetes were approximately 45% smaller than those from donors without diabetes (47.4 ± 2.6 vs 85.7 ± 3.7g), independent of diabetes duration or age of onset. Diabetic donor pancreases had decreased beta cell mass (0.061 ± 0.025 vs 0.94 ± 0.21g) and reduced total exocrine mass (42.0 ± 4.9 vs 96.1 ± 6.5g). Diabetic acinar cells were similar in size but fewer in number compared with those in pancreases from non-diabetic donors (63.7 ± 8.1 × 109 vs 121.6 ± 12.2 × 109 cells/pancreas), likely accounting for the difference in pancreas size. Within the type 1 diabetes exocrine tissue, there was a greater degree of fibrosis. The pancreases in three mouse models of insulin deficiency were similar in size to those in control mice. Pancreases from donors with type 1 diabetes are smaller than normal donor pancreases because exocrine cells are fewer in number rather than smaller in size; these changes occur early in the disease process. Our mouse data suggest that decreased pancreas size in type 1 diabetes is not directly caused by insulin deficiency, but the precise mechanism responsible remains unclear.

Repeatability and Reproducibility of Pancreas Volume Measurements Using MRI

Reduced pancreas volume, as measured by non-contrast magnetic resonance imaging (MRI), is observed in individuals with newly-diagnosed type 1 diabetes (T1D) and declines over the first year after diagnosis. In this study, we determined the repeatability and inter-reader reproducibility of pancreas volume measurements by MRI. Test-retest scans in individuals with or without T1D (n = 16) had an intraclass correlation coefficient (ICC) of 0.985 (95% CI 0.961 to 0.995) for pancreas volume. Independent pancreas outlines by two board-certified radiologists (n = 30) yielded an ICC of 0.945 (95% CI 0.889 to 0.973). The mean Dice coefficient, a measurement of the degree of overlap between pancreas regions of interest between the two readers, was 0.77. Prandial state did not influence pancreatic measurements, as stomach volume did not correlate with pancreas volume. These data demonstrate that MRI measurements of pancreas volume between two readers are repeatable and reproducible with ICCs that correspond to excellent clinical significance (ICC > 0.9), are not related to changes in stomach volume, and could be a useful tool for clinical investigation of diabetes and other pancreas pathologies.

Systematic Transcriptome and Regulatory Network Analyses Reveal the Hypoglycemic Mechanism of Dendrobium fimbriatum

Type 2 diabetes (T2D) is a long-term metabolic disorder disease characterized by high blood sugar and relative lack of insulin. Previous studies have demonstrated that Dendrobium has potent glucose-lowing effects and may serve as add-ons or alternatives to classic medications for T2D prevention and treatment, but the underlying molecular mechanisms were still unclear. We performed biochemical and transcriptional profiling (RNA sequencing [RNA-seq] and microRNA sequencing [miRNA-seq]) analyses on the pancreas and liver of Dendrobium fimbriatum extract (DFE)-fed diabetic rats and control animals. Our sequencing and experimental data indicated that DFE significantly alleviated diabetes symptoms through inhibiting inflammation and preventing islet cell apoptosis in diabetic pancreas. Transcription factors in Stat/nuclear factor κB (NF-κB)/Irf families combined with miR-148a/375/9a served as key regulators in the inflammation and apoptosis pathways under DFE administration. Meanwhile, DFE improved the energy metabolism, lipid transport, and oxidoreductase activity in the liver, and thus decreased lipid accumulation and lipotoxicity-induced hepatocyte apoptosis. Our findings revealed that DFE may serve as a potential therapeutic agent to prevent T2D, and also showed the combination of transcriptome profiling and regulatory network analysis could act as an effective approach for investigating potential molecular mechanisms of traditional Chinese medicine on diseases.