Islet Structure Research Articles

Glycemic disorders in acute pancreatitis: significance of microstructural changes of pancreatic parenchyma

Objective. To study the character and peculiarities of pathohistological changes of pancreatic tissues on the autopsy material, including its endocrine apparatus in acute necrotic pancreatitis and to determine connection between established changes and occurrence of glycemia.
 Materials and methods. Pathohistological investigation of 48 preparation of pancreatic gland was performed on the autopsy material in 11 dead patients with an acute necrotic pancreatitis, using method of the light microscopy.
 Results. There was established the presence of microstructural disorder of pancreatic acinar apparatus with various degree of spread and depth of the organ parenchyma necrosis, as well as parapancreatic cellular tissue. With beginning of the false pancreatic cysts formation there was demonstrated occurrence of the connective tissue elements, as well as focal and diffuse sclerosing, while the structure of islets of Langerhans remained unchanged.
 Conclusion. The signs of hyperglycemia in the disease course may be do not connected with destruction of the organ endocrine apparatus.

The protective roles of allicin on type 1 diabetes mellitus through AMPK/mTOR mediated autophagy pathway.

Background: Type 1 diabetes mellitus (T1DM) is one of the most common endocrine and metabolic diseases in children. Pancreatic β cells are thought to be critical cells involved in the progression of T1DM, and their injury would directly lead to impaired insulin secretion. Purpose: To investigate the protective effects of allicin on pancreatic β cell injury and elucidate the underlying mechanism. Methods: The streptozotocin (STZ)-induced mouse T1DM model in vivo and STZ-induced pancreatic β cell Min6 model in vitro were used to explore the effects of allicin on T1DM. The experiments include fasting blood glucose test, oral glucose tolerance detection, HE staining, immunohistochemistry, immunofluorescence, TUNEL staining, western blot, real-time quantitative PCR (RT-qPCR), and flow cytometry. Results: Allicin could significantly decrease blood glucose level, improve islet structure and insulin expression, and inhibit apoptosis to reduce STZ-induced pancreatic β cell injury and loss through activating AMPK/mTOR mediated autophagy pathway. Conclusion: Allicin treatment significantly reduced STZ-induced T1DM progression, suggesting that allicin may be a potential therapy option for T1DM patients.

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

Methods to induce islet β-cells from induced pluripotent stem cells or embryonic stem cells have been established. However, islet β-cells are susceptible to apoptosis under hypoxic conditions, so the technique used to transplant β-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 β-cells, vascular endothelial cells, and mesenchymal stem cells for 1 day. The islet β-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 β-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 β-cells, vascular endothelial cells, and mesenchymal stem cells were able to form islet tissue. There were two main findings. First, the islet β-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.

Onopordum acanthium L. extract attenuates pancreatic β-Cells and cardiac inflammation in streptozocin-induced diabetic rats.

Methanolic extract from Onopordum acanthium L. leaves (MEOAL) has been discovered to treat diabetic complications. The objective of this study is to evaluate the ameliorative role of MEOAL on pancreatic islet injury and myocardial inflammation in diabetic rats. Forty male Wister albino rats were allocated into five groups of eight rats each. Group A was the negative control group. Single intraperitoneal injection of streptozocin (50mg/kg) were used for the four experimental groups. Group B served as the positive control group. The rats in Groups C, D, and E received glibenclamide (5mg/kg), MEOAL (200, and 400 mg/kg) respectively, for eight weeks. Group C served as the standard drug group. High performance liquid chromatography (HPLC) and 2,2-diphenyl-1-picryl-hydrazyl-hydrate (DPPH) assays for antioxidant activity were conducted in MEOAL. In silico study, calculation of molecular binding energy (DG), and inhibition constant (pKi) of bioactive constituents in MEOAL were performed. Administration of MEOAL significantly increases insulin content in β-cells with a marked enhancement of pancreatic islet structure, resulting in a significant reduction of blood glucose level and body weight loss. MEOAL treatment suppressed the increase of inflammatory cell score in myocardial tissue with an elevation of M2 -like macrophage. The phytochemical studies recorded the presence of six polyphenols, including catechin, kaempferol, syringic acid, p-coumaric acid, epicatechin and gallic acid in MEOAL. Moreover, the antioxidant activity of the extract was greater than that of standard ascorbic acid. The docking studies of the ligands Catechin, kaempferol and epicatechin with proteins showed high affinities with various targets related in β-Cells and cardiac inflammation. The attenuation of pancreatic β-Cells damage and cardiac inflammation by MEOAL could be attributed to the presence of Catechin, kaempferol and epicatechin which have high affinities with the receptors namely pancreatic alpha-amylase, glucokinase, COX-2, and COX-1.

Reduced volume of diabetic pancreatic islets in rodents detected by synchrotron X-ray phase-contrast microtomography and deep learning network

The pancreatic islet is a highly structured micro-organ that produces insulin in response to rising blood glucose. Here we develop a label-free and automatic imaging approach to visualize the islets in situ in diabetic rodents by the synchrotron radiation X-ray phase-contrast microtomography (SRμCT) at the ID17 station of the European Synchrotron Radiation Facility. The large-size images (3.2mm×15.97mm) were acquired in the pancreas in STZ-treated mice and diabetic GK rats. Each pancreas was dissected by 3000 reconstructed images. The image datasets were further analysed by a self-developed deep learning method, AA-Net. All islets in the pancreas were segmented and visualized by the three-dimension (3D) reconstruction. After quantifying the volumes of the islets, we found that the number of larger islets (=>1500 μm3) was reduced by 2-fold (wt 1004±94 vs GK 419±122, P<0.001) in chronically developed diabetic GK rat, while in STZ-treated diabetic mouse the large islets were decreased by half (189±33 vs 90±29, P<0.001) compared to the untreated mice. Our study provides a label-free tool for detecting and quantifying pancreatic islets in situ. It implies the possibility of monitoring the state of pancreatic islets in vivo diabetes without labelling.

Combination therapy with human amniotic epithelial cells and hyaluronic acid promotes immune balance recovery in type 1 diabetic rats through local engraftment.

Stem cell engraftment is currently a promising approach for type 1 diabetes mellitus (T1DM) treatment. In our previous study, engraftment of a combination of human amniotic epithelial cells (hAECs) and hyaluronic acid (HA) showed potent anti-diabetic effect in streptozotocin (STZ)-induced T1DM mice via tail vein injection. Here, we adopted a different route of stem cell delivery, that is via pancreatic subcapsular transplantation. This combined local engraftment of hAECs and HA in STZ-induced T1DM rats showed potent anti-diabetic activity, leading to stronger hypoglycaemia, more intact islet structure and increased number of insulin-positive cells compared with those with hAECs or insulin treatments. Engraftment of hAECs alone increased the proportion of Th1 and T-reg cells and decreased the proportion of Th2 and Th17 cells to protect islet β cells in STZ-induced T1DM rats, whereas the combined engraftment of hAECs and HA showed more potent regulatory capacity, considerably decreased the level of TNF-α and IL-17 and increased the level of TGF-β1 compared with those by other treatments. The potent synergistic effect of HA contributed to the recovery of immune balance in the diabetic rat model, thereby suggesting a new strategy for effective treatment of T1DM.

Deep Sea Water Inhibited Pancreatic β-Cell Apoptosis and Regulated Glucose Homeostasis by Affecting Lipid Metabolism in Db/Db Mice

Deep sea water (DSW) is a natural resource rich in minerals, which participates in biological processes such as energy metabolism, regulates serum glucose and lipids levels, and has a certain protective effect on endocrine and metabolism-related diseases. Studies have shown that the improvement of glucose tolerance in diabetic mice by DSW may be associated with the protective effect on the structure and function of pancreatic islets, and the specific mechanism is still unclear. Other studies have shown that long-term exposure to high concentrations of fatty acids can lead to apoptosis and dysfunction of pancreatic β-cell, increasing the risk of type 2 diabetes mellitus (T2DM). Down-regulation of plasma fatty acid levels may reduce pancreatic β-cell dysfunction, thereby improving glucose homeostasis. Understanding the specific mechanism of DSW regulating blood glucose is of great significance for its clinical application. In the present study we used db/db mice as a T2DM model and treated mice with deep ocean mineral concentration (DOMC, a commercial product of DSW) for 4 and 12 weeks. Basic information, serum biochemical indicators, and pathological tissues were gathered for exploration. The db/db mice treated with 4 weeks' DOMC (db/db+DOMC) showed decreased plasma cholesterol and triglyceride levels. Tests implied that in adipose tissues, the db/db+DOMC group's lipolysis process was inhibited, and the β-fatty acid oxidation process was promoted. Besides, DOMC reduced lipogenesis and encouraged β-oxidation in the liver, as a result, improved fatty liver in db/db mice. Further measurements showed DOMC improved glucose homeostasis slightly in db/db animals after a 12-week treatment by preventing pancreatic β-cell apoptosis. DOMC inhibited pancreatic β-cell apoptosis and regulated glucose homeostasis in db/db mice by lowering the lipid levels via regulation of fatty acid β-oxidation, lipolysis, and lipogenesis processes.

Effects of adipokine chemerin on the improvement of islet function in diabetic mice by aerobic exercise and its mechanisms

Objective: To investigate the effects of adipokines chemerin on the improvement of islet function caused by exercise in mice with diabetes, and the possible mechanism of glucagon-like peptide 1 (GLP-1). Methods: Male ICR mice were randomly divided into a control group fed with normal diet (Con, n=6) and a diabetic modeling group fed with 60% kcal high-fat diet (n=44). After 6 weeks, the diabetic modeling group was once given a fasting intraperitoneal injection of streptozotocin (100 mg/kg). The successfully modeled mice were divided into diabetes group (DM), diabetes plus exercise group (EDM), and diabetes plus exercise and exogenous chemerin group (EDMC), 6 in each group. Mice in exercise groups participated in a six-week modest intensity treadmill running exercise with a gradually increased load. Mice in the EDMC group were intraperitoneally injected with exogenous chemerin (8 μg/kg) from the 4th week of the exercise period, six days per week, and one time per day. And the other groups were untreated. Adipose chemerin knockout mice were constructed. Then they and the control mice were divided into 6 groups (n=4): Normal diet control group (Con-ND), Normal diet chemerin knockout heterozygote mice group (Chemerin(+/-)-ND), Normal diet chemerin knockout homozygotes mice group(Chemerin(-/-)-ND), High-fat diet control group (Con-HFD), High-fat diet chemerin knockout heterozygote mice group (Chemerin(+/-)-HFD), High-fat diet chemerin knockout homozygotes mice group (Chemerin(-/-)-HFD). They were fed with normal or high-fat diet for 11 weeks and oral glucose tolerance test (OGTT) was conducted. After the mice of each group were executed under anesthesia, the samples such as pancreas and colon were collected. Fasting blood glucose (FBG) and fasting insulin (FINS) levels in mice were measured, and the insulin resistance index (HOMA-IR) was calculated. HE staining was used to observe the structure of islets. ELISA was used to detect the GLP-1 level in serum. The mRNA levels of proglucagon (GCG) and chemerin in the colon were measured by real-time PCR. And the protein levels of GCG and chemerin in the colon were detected by Western blot. Results: Compared with the DM group, the vacuolar degeneration and shrinkage of islet cells in the EDM group were reduced, the islet structure was improved, while the levels of FINS, HOMA-IR and FBG were decreased significantly (P＜0.05 or P＜0.01). The colon and serum chemerin levels were decreased significantly(P＜0.05), while the colonic GCG mRNA and protein levels were increased significantly (P＜0.05 or P＜0.01). Compared with the EDM group, the islet cells in the EDMC group were shrunken, with unclear borders. The structure of the islets was damaged, and the levels of FINS, HOMA-IR and FBG were increased significantly (P＜0.01), while the mRNA and protein levels of GCG were decreased significantly (P＜0.05 or P＜0.01). Compared with the Con-HFD group, the blood glucose at 30, 90 and 120 min after oral glucose in the chemerin (-/-)-HFD group was significantly lower (P＜0.01), and the area under the blood glucose time curve was significantly lower (P＜0.01). The islets had clear structure, regular shape and well-defined boundaries, while the serum GLP-1 and colonic GCG protein levels were increased significantly(P＜0.05). Conclusion: Aerobic exercise improves the structure and function of pancreatic islets by reducing the level of chemerin in diabetes mice, which is related to the negative regulation of chemerin on GLP-1 level.

Functional and metabolic alterations of gut microbiota in children with new-onset type 1 diabetes

Gut dysbiosis has been linked to type 1 diabetes (T1D); however, microbial capacity in T1D remains unclear. Here, we integratively profiled gut microbial functional and metabolic alterations in children with new-onset T1D in independent cohorts and investigated the underlying mechanisms. In T1D, the microbiota was characterized by decreased butyrate production and bile acid metabolism and increased lipopolysaccharide biosynthesis at the species, gene, and metabolite levels. The combination of 18 bacterial species and fecal metabolites provided excellently discriminatory power for T1D. Gut microbiota from children with T1D induced elevated fasting glucose levels and declined insulin sensitivity in antibiotic-treated mice. In streptozotocin-induced T1D mice, butyrate and lipopolysaccharide exerted protective and destructive effects on islet structure and function, respectively. Lipopolysaccharide aggravated the pancreatic inflammatory response, while butyrate activated Insulin1 and Insulin2 gene expression. Our study revealed perturbed microbial functional and metabolic traits in T1D, providing potential avenues for microbiome-based prevention and intervention for T1D.

Histomorphological and carbohydrate histochemical study of the pancreas in native ducks (Anas Platyrhynchos)

In the current study, the histomorphological and histochemical characteristics of the pancreas in native ducks are examined with a particular emphasis on the structure of pancreatic acini and Langerhans islets (LI). Five adult male native ducks (Anas Platyrhynchos) are examined from the local market of Mosul. All samples are processed routinely for histological and histochemical analyses. Hematoxylin & Eosin, PAS-AB (pH 2.5), Toluidine blue, and Masson's Trichrome stains are used. The morphological examination reveals that male ducks’ pancreas is made up of three major lobes (dorsal, ventral, and third lobes). The pancreas is a small, semi-wide structure with a pale to white pinkish tone located between the duodenum branches. The findings show that the pancreas is enveloped in a thin layer of loose connective tissue capsule and mesothelial; septa extend from the capsule into parenchyma dividing it into many lobules. The study concludes that the pancreatic lobules are composed of a large area of exocrine acini and a small amount of LI, with an exocrine component consisting of round or oval acini with zymogen granules. The endocrine component is represented by three distinct LI types and lacks defined boundaries. Alpha islets are formed of alpha cells (ACs) and a few delta cells (DCs); beta islets are composed of peripherally located beta cells (BCs) and a few (DCs); and mixed islets are composed of alpha, beta, and delta cells. The present study sheds light on the morphological, histological, and histochemical characteristics of the indigenous duck pancreas. However, future research should focus on the pancreas of other bird species as well.

Acrylamide and Potential Risk of Diabetes Mellitus: Effects on Human Population, Glucose Metabolism and Beta-Cell Toxicity.

Diabetes mellitus is a frequent endocrine disorder characterized by hyperglycemia. Acrylamide (AA) is food contaminant formed during the high-temperature processing of food rich in carbohydrates and low in proteins. Recent human epidemiological studies have shown a potential association between AA exposure and the prevalence of diabetes in the general population. In male rats, AA treatment promoted pancreatic islet remodeling, which was determined by alpha-cell expansion and beta-cell reduction, while in female rats AA caused hyperglycemia and histopathological changes in pancreatic islets. In vitro and in vivo rodent model systems have revealed that AA induces oxidative stress in beta cells and that AA impairs glucose metabolism and the insulin signaling pathway. Animal studies have shown that diabetic rodents are more sensitive to acrylamide and that AA aggravates the diabetic state. In this review, we provide an overview of human epidemiological studies that examined the relation between AA exposure and glucose disorders. In addition, the effects of AA treatment on pancreatic islet structure, beta-cell function and glucose metabolism in animal models are comprehensively analyzed with an emphasis on sex-related responses. Furthermore, oxidative stress as a putative mechanism of AA-induced toxicity in beta cells is explored. Finally, we discuss the effects of AA on diabetics in a rodent model system.

Antioxidative, Antidiabetic, and Hypolipidemic Properties of Probiotic-Enriched Fermented Camel Milk Combined with Salvia officinalis Leaves Hydroalcoholic Extract in Streptozotocin-Induced Diabetes in Rats.

Antioxidative, antidiabetic, and hypolipidemic properties of probiotic-enriched fermented camel milk (FCM) combined with Salvia officinalis L. leaves hydroalcoholic extract (SOHE) in streptozotocin-induced diabetes in rats were investigated. Phytochemicals analysis and antioxidant capacity indicated that S. officinalis contained high phenolics with super antioxidant activity. Subsequently, HPLC analysis demonstrated 13 phenolic acids and 14 flavonoids in considerable amounts with ferulic acid and resveratrol as predominant, respectively. The antidiabetic and hypolipidemic properties of FCM and SOHE were examined in a designed animal model consisting of seven treated groups for four weeks. There was a negative group (G1); the positive group (G2) received a single dose (50 mg kg−1) of streptozotocin (STZ) by intraperitoneal injection (i.p.); in G3, diabetic rats (DRs) orally received 5 mL FCM kg−1 daily; in G4, DRs orally received 50 mg GAE SOHE kg−1 daily; in G5, DRs orally received 5 mL FCM contains 25 mg GAE SOHE kg−1 daily; in G6, DRs orally received 5 mL FCM contains 50 mg GAE SOHE kg−1 daily; in G7, DRs orally received 50 mg metformin kg−1 daily. Combining FCM with SOHE at 25 or 50 mg kg−1 exhibited a synergistic effect in significantly lowering random blood glucose (RBG), fasting blood glucose (FBG), and improved weight gain recovery %. The hypolipidemic effect of FCM + 50 mg GAE SOHE kg−1 was significantly higher than using FCM or SOHE individually, and attenuation in triglycerides (TG), total cholesterol (CHO), and high- and low-density lipoproteins (HDL and LDL), and very-low-density lipoproteins (VLDL) was remarked. Combining FCM with SOHE at 25 or 50 mg kg−1 ameliorated liver and kidney functions better than individual uses of FCM, SOHE, or metformin. Interestingly, FCM with 50 mg SOHE kg−1 presented significant improvement in the activity of antioxidant enzymes, reduced glutathione (GSH), catalase (CAT), superoxide dismutase (SOD), and a substantial reduction in malonaldehyde (MDA) levels with 53.75%, 89.93%, 63.06%, and 58.69% when compared to the STZ group (G2), respectively. Histopathologically, administrating FCM + 25, 50 mg SOHE kg−1 or 50 mg kg−1 metformin showed a normal histological structure of both islets of Langerhans cells and acini. In conclusion, combining FCM with SOHE presented synergistic and therapeutical efficacy. It could be beneficial and profitable for controlling diabetes mellitus complications and protecting against oxidative stress.

Combination Therapy of Alpha-Lipoic Acid, Gliclazide and Ramipril Protects Against Development of Diabetic Cardiomyopathy via Inhibition of TGF-β/Smad Pathway.

Background: Diabetic cardiomyopathy (DCM) is a major long-term complication of diabetes mellitus, accounting for over 20% of annual mortality rate of diabetic patients globally. Although several existing anti-diabetic drugs have improved glycemic status in diabetic patients, prevalence of DCM is still high. This study investigates cardiac effect of alpha-lipoic acid (ALA) supplementation of anti-diabetic therapy in experimental DCM. Methods: Following 12 h of overnight fasting, 44 male Sprague Dawley rats were randomly assigned to two groups of healthy control (n = 7) and diabetic (n = 37) groups, and fasting blood glucose was measured. Type 2 diabetes mellitus (T2DM) was induced in diabetic group by intraperitoneal (i.p.) administration of nicotinamide (110 mg/kg) and streptozotocin (55 mg/kg). After confirmation of T2DM on day 3, diabetic rats received monotherapies with ALA (60 mg/kg; n = 7), gliclazide (15 mg/kg; n = 7), ramipril (10 mg/kg; n = 7) or combination of the three drugs (n = 7) for 6 weeks while untreated diabetic rats received distilled water and were used as diabetic control (n = 9). Rats were then sacrificed, and blood, pancreas and heart tissues were harvested for analyses using standard methods. Results: T2DM induction caused pancreatic islet destruction, hyperglycemia, weight loss, high relative heart weight, and development of DCM, which was characterized by myocardial degeneration and vacuolation, cardiac fibrosis, elevated cardiac damage markers (plasma and cardiac creatine kinase-myocardial band, brain natriuretic peptide and cardiac troponin I). Triple combination therapy of ALA, gliclazide and ramipril preserved islet structure, maintained body weight and blood glucose level, and prevented DCM development compared to diabetic control (p < 0.001). In addition, the combination therapy markedly reduced plasma levels of inflammatory markers (IL-1β, IL-6 and TNF-α), plasma and cardiac tissue malondialdehyde, triglycerides and total cholesterol while significantly increasing cardiac glutathione and superoxide dismutase activity and high-density lipoprotein-cholesterol compared to diabetic control (p < 0.001). Mechanistically, induction of T2DM upregulated cardiac expression of TGF-β1, phosphorylated Smad2 and Smad3 proteins, which were downregulated following triple combination therapy (p < 0.001). Conclusion: Triple combination therapy of ALA, gliclazide and ramipril prevented DCM development by inhibiting TGF-β1/Smad pathway. Our findings can be extrapolated to the human heart, which would provide effective additional pharmacological therapy against DCM in T2DM patients.

Effects of a prolonged diet regimen on autophagic function in rat islets with aging

The prevalence of type 2 diabetes increases with age-associated increased susceptibility of islet β-cells and altered dietary patterns, in part because of insufficient compensation of β-cell functional mass in the face of increasing insulin resistance. However, the underlying mechanisms have not been fully elucidated. In the present study, we investigated the effects of a long-term calorie-restricted (CR) or high-fat (HF) diet compared to a normal ad libitum diet on β-cell structure-function relationships and autophagy in the islets of 3- and 24-month-old Fischer 344 rats. Aging and the HF diet decreased the β-cell-to-islet area ratio, disorganized the islet structure, and increased the expression of senescence markers. Aging and the long-term HF diet also decreased autophagy-related proteins, which suggests compromised autophagic function. These findings were further corroborated by increased p62 accumulation and polyubiquitin aggregates observed with aging and the HF diet intervention; these are cardinal markers of attenuated autophagic function. It is important to note that the 24-month-old rats maintained on the CR diet closely mimicked the 3-month-old rats, which indicates that a long-term CR diet can delay islet aging and prevent the decline in the autophagic function of islets during the aging process. Taken together, our results indicate an autophagy-dependent mechanism responsible for islet function in older people or those with altered dietary patterns and lay the foundations for future research leading to novel therapeutic strategies for treating diabetes.

Ac3IV, a V1a and V1b receptor selective vasopressin analogue, protects against hydrocortisone-induced changes in pancreatic islet cell lineage

The Avpr1a (V1a) and Avpr1b (V1b) receptor selective, vasopressin (AVP) analogue, Ac3IV has been shown to improve metabolism and pancreatic islet structure in diabetes and insulin resistance. The present study further investigates these actions by assessing the ability of Ac3IV to protect against pancreatic islet architectural disturbances induced by hydrocortisone (HC) treatment in transgenic Ins1Cre/+;Rosa26-eYFP mice, that possess beta-cell lineage tracing capabilities. HC intervention increased (p < 0.001) energy intake but reduced (p < 0.01) body weight gain, with no impact of Ac3IV. All HC mice had reduced (p < 0.05) circulating glucose, but plasma insulin and glucagon concentrations remained unchanged. However, HC mice presented with increased (p < 0.001) pancreatic insulin content, which was further augmented by Ac3IV. In addition, Ac3IV treatment countered HC-induced increases in islet-, beta- and alpha-cell areas (p < 0.01), as well as promoting islet number towards control levels. This was accompanied by reduced (p < 0.05) beta-cell growth, but enhanced (p < 0.001) alpha-cell proliferation. There were no changes in islet cell apoptotic rates in any of the groups of HC mice, but co-expression of CK19 with insulin in pancreatic ductal cells was reduced by Ac3IV. Assessment of beta-cell lineage revealed that Ac3IV partially protected against HC-mediated de-differentiation of mature beta-cells, whilst also decreasing (p < 0.01) beta- to alpha-cell transdifferentiation. Our data indicate that sustained activation of V1a and V1b receptors exerts positive islet cell transition effects to help retain beta-cell identity in HC mice.

Histopatologi Organ Pankreas Tikus DM tipe 2 yang diberi Ekstrak Etanol Daun Gedi Merah (Abelmoscus manihot L. Medik)

Gedi Merah leaf (Abelmoschus manihot L.Medik) is a tropical plant used by the community as a traditional medicine to reduce cholesterol, hypertension, and antidiabetic levels. Diabetes mellitus is a disorder of carbohydrate, protein, and fat metabolism due to a lack of the hormone insulin so that glucose in the blood increases which is characterized by changes in the histopathological structure of the pancreatic islets of Langerhans. The purpose of this study was to see the histopathological description of the pancreas in male white rats (Rattus norvegicus) Wistar strain model of type II diabetes mellitus by administering ethanol extract of red gedi leaves (Abelmoschus manihot L.Medik). Modeling of diabetes mellitus in experimental animals was carried out by administering a high-fat diet and intraperitoneal induction of streptozotocin 30 mg/kg. After modeling, male rats were grouped into 6 treatment groups, namely a normal control group, a positive control group, a negative control group, and a group that was given the ethanol extract of red gedi leaves at a dose of 75 mg/kg BW, 150 mg/kg BW 300 mg/kg BW. The results of the histopathological examination of the pancreas and the number of endocrine cells showed that the ethanolic extract of red gedi leaves (Abelmoschus manihot L.Medik) was effective in repairing pancreatic cells and regenerating endocrine cells in the islets of langerhans.

Neu-P11 - a novel melatonin receptor agonist, could improve the features of type-2 diabetes mellitus in rats.

Melatonin (Mel) and its receptors are promising for glycaemic control in patients with type 2 diabetes mellitus (T2DM) and its complications, but there is significant heterogeneity among studies. This study aims to investigate the effects of Mel receptor agonist Neu-P11 on glucose metabolism, immunity, and islet function in T2DM rats. In this study, SD rats were treated with a high-fat diet and streptozotocin (STZ) to establish a T2DM model. The glucose oxidase method was used to measure blood glucose levels. Glucose and insulin tolerance tests were used to assess glucose metabolism. Haematoxylin-eosin staining was used to observe pancreatic tissue injury. The apoptosis of isletβ cells was analysed by TUNEL and insulin staining. Reactive oxygen species (ROS) levels and immune cell expression were analysed by flow cytometry. IF was used to analyse the activation of microglia. The immunoglobulins: IgA, IgG, IgM, tumour necrosis factorα (TNF-α), interleukins IL-10 and IL-1β, interferonγ (IFN-γ), C-peptide, and insulin levels were determined by ELISA. The expression of CD11b, CD86, cleaved caspase 3, p21, and P16 proteins were analysed by western blot. The results showed that the blood glucose level increased, insulin resistance occurred, spleen coefficient and ROS levels increased, humoral immunity in peripheral blood decreased, and inflammation increased in the model group compared to the control group. After Mel and Neu-P11 treatment, the blood glucose level decreased significantly, insulin sensitivity improved, spleen coefficient and ROS levels decreased, humoral immunity in peripheral blood was enhanced, and inflammation improved in T2DM rats. Brain functional analysis of T2DM rats showed that microglia cells were activated, TNF-α and IL-β levels were increased, and IL-10 levels were decreased. Mel and Neu-P11 treatment reversed these indexes. Functional analysis of islets in T2DM rats showed that islet structure inflammation was impaired, isletβ cells were apoptotic, p21 and p16 protein expressions were increased, and blood C-peptide and insulin were decreased. Mel and Neu-P11 treatment restored the function of pancreatic b cells and improved the damage of pancreatic tissue. Melatonin and its receptor Neu-P11 can reduce the blood glucose level, enhance humoral and cellular immunity, inhibit microglia activation and inflammation, and repair isletβ cell function, and this improve the characterization of T2DM-related diseases.

Single-Cell Transcriptomics Links Loss of Human Pancreatic β-Cell Identity to ER Stress.

The maintenance of pancreatic islet architecture is crucial for proper β-cell function. We previously reported that disruption of human islet integrity could result in altered β-cell identity. Here we combine β-cell lineage tracing and single-cell transcriptomics to investigate the mechanisms underlying this process in primary human islet cells. Using drug-induced ER stress and cytoskeleton modification models, we demonstrate that altering the islet structure triggers an unfolding protein response that causes the downregulation of β-cell maturity genes. Collectively, our findings illustrate the close relationship between endoplasmic reticulum homeostasis and β-cell phenotype, and strengthen the concept of altered β-cell identity as a mechanism underlying the loss of functional β-cell mass.

Anti-diabetic effects of Protaetia brevitarsis in pancreatic islets and a murine diabetic model.

In this study, the antidiabetic efficacy of Protaetia brevitarsis in alloxan-treated pancreatic islets and db/db mice was investigated. P. brevitarsis was tested for alloxan-mediated cytotoxicity and nitric oxide production in mice pancreatic islets. The anti-diabetic effect of P. brevitarsis was also evaluated in db/db mice after 4 weeks of administration. Biochemical analysis, oral glucose tolerance test (OGTT), and pancreatic histological analysis were performed. P. brevitarsis displayed hypoglycemic activity in alloxan-treated mice pancreatic islets. Our results showed that P. brevitarsis protects pancreatic islets from cytotoxicity. Moreover, daily oral supplementation with P. brevitarsis for 4 weeks reduced plasma glucose levels without affecting body weight and food intake, elevated glucose tolerance in OGTT, improved blood lipid parameters, inhibited fat accumulation, and restored islet structure of db/db mice. The present study provided evidence for the anti‑diabetic effect of P. brevitarsis in alloxan-treated pancreatic islets and db/db mice. These results suggest that P. brevitarsis may be used as an adjunctive anti-diabetic agent or as a functional food.

Electroacupuncture at "Zusanli"(ST36) ameliorates tau hyperphosphorylation in pancreas and hippocampus of diabetic rats

To observe the effect of electroacupuncture (EA) at "Zusanli"(ST36) on the phosphorylated tau levels in pancreas and hippocampus of type 2 diabetes mellitus (T2DM) rats，so as to explore the underlying mechanism of EA in diabetic demention rats. Forty-eight male Sprague-Dawley rats were randomly divided into control, model and EA groups, with 16 rats in each group. The T2DM model was established by 6 weeks of high-fat, high-sugar diet as well as intrape-ritoneal injection of streptozocin (STZ) solution (35 mg/kg). After that, EA (2 Hz, 0.1 mA) was applied to unilateral "Zusanli"(ST36) for 30 min, once a day, 6 times a week for 4 weeks. The survival rate was recorded every week, and the fasting blood glucose (FBG) was detected on the 1st, 6th and 11th week. The level of serum insulin (INS) was measured by using ELISA. The morphological structure of pancreas islet was observed by H.E. staining. The expressions of phosphorylated tau at the sites of Ser 396 (pS396) and Thr 231 (pT231), total tau (Tau5), phosphorylated glycogen synthase kinase-3β (pGSK-3β) and total glycogen synthase kinase-3β (GSK-3β) in pancreas and hippocampus were detected by Western blot. The expression and distribution of pS396 and pT231 in pancreas and hippocampus were assayed with immunohistochemistry. Compared with the control group, the survival rate presented a significant decline, the contents of FBG and INS were obviously higher(P<0.01), and the structure of the pancreas islet appeared shrunken, obscure and disordered in the model group. Furthermore, the levels of pS396, pT231 in pancreas and hippocampus were obviously higher in the model group(P<0.01)，while the level of pGSK-3β in pancreas and hippocampus was significantly lower in the model group(P<0.01). In comparison with the model group, the survival rate of EA group was higher. Following 4 weeks' interventions, the enhanced levels of tau phosphorylation and GSK-3β activity in pancreas and hippocampus were partly reversed in the EA group compared to the model group(P<0.05，P<0.01). EA at ST36 can reduce the level of tau phosphorylation via regulating the activity of GSK-3β in the pancreas and hippocampus of T2DM rats, which may be related with the effect of EA on the brain function in T2DM rats.