To explore the possible new mechanism of acupuncture in the treatment of diabetes mellitus type 2 (T2DM) based on the islet inflammatory response. Islet macrophages, pancreatic adipose cells and islet β cells all participate in the pathogenesis of T2DM, and the three could form a network interaction. Acupuncture could regulate the functional phenotype of islet macrophages, improve the ectopic deposition of pancreatic adipose and repair the function of islet β cells, and play a unique advantage of overall regulation. It is suggested that acupuncture can be a potential treatment strategy for T2DM.
Acupuncture Therapy ; Diabetes Mellitus, Type 2/therapy* ; Humans ; Insulin-Secreting Cells/pathology* ; Islets of Langerhans/pathology* ; Macrophages

OBJECTIVETo study the effects of early high fat diet on sugar metaboliam, insulin sensibility and pancreatic β cellularity in young rats.

METHODSSixty male weaned young rats were randomly fed with high fat diet (high fat group) and normal diet (control group). The body weight, viscus fattiness and fasting plasma glucose (FPG) were measured after 3, 6 and 9 weeks. Serum insulin level was measured with radioimmunoassay. The ultrastructure of pancreas was observed under an electricmicroscope.

RESULTSThe high fat group had significantly higher body weight and visceral fat weight than the control group after 3 weeks. There were no significant differences in the FPG level between the two groups at all time points. The levels of fasting insulin and HOMAIR in the high fat group were significantly higher than those in the control group after 3, 6 and 9 weeks (P<0.01). Dilation of rough endoplasmic reticulum and mild swelling of mitochondria of islet β-cells were observed in the high fat group after 6 weeks.

CONCLUSIONSEarly high fat diet may induce a reduction in insulin sensitivity and produce insulin resistance in young rats. Endoplasmic reticulum expansion in β-cells may be an early sign of β-cell damage due to obesity.

Animals ; Blood Glucose ; analysis ; Dietary Fats ; adverse effects ; Insulin ; Insulin Resistance ; Insulin-Secreting Cells ; pathology ; ultrastructure ; Intra-Abdominal Fat ; pathology ; Male ; Rats ; Rats, Sprague-Dawley

Insulin granule trafficking is a key step in the secretion of glucose-stimulated insulin from pancreatic β-cells. The main feature of type 2 diabetes (T2D) is the failure of pancreatic β-cells to secrete sufficient amounts of insulin to maintain normal blood glucose levels. In this work, we developed and applied tomography based on scanning transmission electron microscopy (STEM) to image intact insulin granules in the β-cells of mouse pancreatic islets. Using three-dimensional (3D) reconstruction, we found decreases in both the number and the grey level of insulin granules in db/db mouse pancreatic β-cells. Moreover, insulin granules were closer to the plasma membrane in diabetic β-cells than in control cells. Thus, 3D ultra-structural tomography may provide new insights into the pathology of insulin secretion in T2D.
Animals ; Diabetes Mellitus, Type 2 ; pathology ; Electron Microscope Tomography ; Insulin ; metabolism ; Insulin-Secreting Cells ; metabolism ; pathology ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Obese ; Secretory Vesicles ; metabolism ; pathology

Diabetes mellitus is a complex metabolic disorder characterized by chronic hyperglycemia due to absolute or relative lack of insulin. Though great efforts have been made to investigate the pathogenesis of diabetes, the underlying mechanism behind the development of diabetes and its complications remains unexplored. Cumulative evidence has linked mitochondrial modification to the pathogenesis of diabetes and its complications and they are also observed in various tissues affected by diabetes. Proteomics is an attractive tool for the study of diabetes since it allows researchers to compare normal and diabetic samples by identifying and quantifying the differentially expressed proteins in tissues, cells or organelles. Great progress has already been made in mitochondrial proteomics to elucidate the role of mitochondria in the pathogenesis of diabetes and its complications. Further studies on the changes of mitochondrial protein specifically post-translational modifications during the diabetic state using proteomic tools, would provide more information to better understand diabetes.
Adipose Tissue ; metabolism ; Diabetes Complications ; Diabetes Mellitus ; metabolism ; pathology ; Humans ; Insulin ; metabolism ; Insulin-Secreting Cells ; cytology ; metabolism ; Liver ; metabolism ; Mitochondria ; metabolism ; Muscle, Skeletal ; metabolism ; Proteome ; metabolism ; Proteomics

β-cell failure coupled with insulin resistance plays a key role in the development of type 2 diabetes mellitus (T2DM). Changed adipokines in circulating level form a remarkable link between obesity and both β-cell failure and insulin resistance. Some adipokines have beneficial effects,whereas others have detrimental properties. The overall contribution of adipokines to β-cell failure mainly depends on the interactions among adipokines. This article reviews the role of individual adipokines such as leptin,adiponectin,and resistin in the function,proliferation,death,and failure of β-cells. Future studies focusing on the combined effects of adipokines on β-cells failure may provide new insights in the treatment of T2DM.
Adipokines ; metabolism ; Adiponectin ; metabolism ; Diabetes Mellitus, Type 2 ; physiopathology ; Humans ; Insulin Resistance ; Insulin-Secreting Cells ; pathology ; Leptin ; metabolism ; Obesity ; Resistin ; metabolism

The loss of or decreased functional pancreatic β-cell is a major cause of type 1 and type 2 diabetes. Previous studies have shown that adult β-cells can maintain their ability for a low level of turnover through replication and neogenesis. Thus, a strategy to prevent and treat diabetes would be to enhance the ability of β-cells to increase the mass of functional β-cells. Consequently, much effort has been devoted to identify factors that can effectively induce β-cell expansion. This review focuses on recent reports on small molecules and protein factors that have been shown to promote β-cell expansion.
Cell Communication ; genetics ; Cell Differentiation ; genetics ; Cell Proliferation ; Diabetes Mellitus, Type 1 ; genetics ; pathology ; Diabetes Mellitus, Type 2 ; genetics ; pathology ; Humans ; Insulin-Secreting Cells ; chemistry ; metabolism ; pathology

Thioredoxin-interacting protein (TXNIP), also known as vitamin D3-up-regulated protein (VDUP1), is an endogenous inhibitor of thioredoxin (Trx), which regulates the cellular reduction-oxidation (redox) state. TXNIP regulates cellular survival, apoptosis and inflammation induced by glucotoxicity, heat shock and mechanical pressure. The above functions of TXNIP are regulated by carbohydrate response element binding protein (ChREBP) and AMP-dependent protein kinase (AMPK). In recent years, numerous studies showed that TXNIP is involved in diabetes and diabetic complications. On the one hand, TXNIP functions in diabetes by increasing insulin resistance and hepatic gluconeogenesis. TXNIP expression is induced by high glucose, which is implicated in pancreatic beta cell glucotoxicity and endothelial cells dysfunction. TXNIP may contribute to the development and progression of diabetes and its vascular complications. TXNIP may be a new target for diabetes and its vascular complications therapy.
Apoptosis ; Carrier Proteins ; metabolism ; Diabetes Complications ; drug therapy ; metabolism ; Diabetes Mellitus ; drug therapy ; metabolism ; Endothelial Cells ; pathology ; Humans ; Inflammation ; Insulin Resistance ; Insulin-Secreting Cells ; pathology ; Vascular Diseases ; drug therapy ; metabolism

Although bulk endocytosis has been found in a number of neuronal and endocrine cells, the molecular mechanism and physiological function of bulk endocytosis remain elusive. In pancreatic beta cells, we have observed bulk-like endocytosis evoked both by flash photolysis and trains of depolarization. Bulk-like endocytosis is a clathrin-independent process that is facilitated by enhanced extracellular Ca(2+) entry and suppressed by the inhibition of dynamin function. Moreover, defects in bulk-like endocytosis are accompanied by hyperinsulinemia in primary beta cells dissociated from diabetic KKAy mice, which suggests that bulk-like endocytosis plays an important role in maintaining the exo-endocytosis balance and beta cell secretory capability.
Animals ; Calcium ; metabolism ; Cytoplasmic Granules ; metabolism ; Diabetes Mellitus ; metabolism ; pathology ; Disease Models, Animal ; Dynamins ; metabolism ; Electric Capacitance ; Endocytosis ; physiology ; Insulin ; metabolism ; Insulin-Secreting Cells ; metabolism ; pathology ; Male ; Mice ; Mice, Inbred C57BL ; Patch-Clamp Techniques ; Photolysis ; Primary Cell Culture

Type 1 diabetes mellitus is caused by the autoimmune destruction of beta cells within the islets. In recent years, innate immunity has been proposed to play a key role in this process. High-mobility group box 1 (HMGB1), an inflammatory trigger in a number of autoimmune diseases, activates proinflammatory responses following its release from necrotic cells. Our aim was to determine the significance of HMGB1 in the natural history of diabetes in non-obese diabetic (NOD) mice. We observed that the rate of HMGB1 expression in the cytoplasm of islets was much greater in diabetic mice compared with non-diabetic mice. The majority of cells positively stained for toll-like receptor 4 (TLR4) were beta cells; few alpha cells were stained for TLR4. Thus, we examined the effects of anti-TLR4 antibodies on HMGB1 cell surface binding, which confirmed that HMGB1 interacts with TLR4 in isolated islets. Expression changes in HMGB1 and TLR4 were detected throughout the course of diabetes. Our findings indicate that TLR4 is the main receptor on beta cells and that HMGB1 may signal via TLR4 to selectively damage beta cells rather than alpha cells during the development of type 1 diabetes mellitus.
Animals ; Diabetes Mellitus, Type 1/immunology/*metabolism/pathology ; Female ; Gene Expression Regulation ; Glucagon-Secreting Cells/immunology/metabolism/pathology ; HMGB1 Protein/*genetics/metabolism ; Humans ; Immunity, Innate ; Insulin-Secreting Cells/immunology/metabolism/*pathology ; Macrophages/immunology/pathology ; Mice ; Mice, Inbred C57BL ; Mice, Inbred NOD ; Necrosis ; Protein Binding ; Signal Transduction ; Toll-Like Receptor 4/*antagonists & inhibitors/genetics/immunology

OBJECTIVE: To investigate the effect of complete Freund's adjuvant (CFA) on islet beta cell apoptosis in preventing diabetes in non-obese diabetic (NOD) mice, and the influence on apoptotic related-gene expression. METHODS: Four-week-old female NOD mice were randomly divided into Group CFA (n=5) and Group saline (NS) control (n=5). Mice in Group CFA were injected in the hind footpad with 50 microL CFA and mice in Group NS with 50 microL NS. Blood sugar was monitored and diabetes was diagnosed if blood sugar was higher than 11.1 mmol/L for 2 continuous days in the NOD mice. The mice were sacrificed when diagnosed as diabetes or at 30 weeks of age. Pancreatic sections were made for: evaluation of insulitis severity with HE staining; counting of apoptotic beta cells with the terminal deoxynucleotidyl transferase mediated deoxyuridine triphosphate nick end labeling (TUNEL) method, and ABC immunohistochemical double labeling; counting of Fas, FasL and Bcl-x positive cells respectively with ABC immunohistochemical method. RESULTS: By 30 weeks of age, none of the 5 CFA-treated mice, compared with 3 of the 5 control mice, had developed diabetes. The insulitis score was lower (1.820+/-0.962 vs. 3.020+/-1.040, P<0.05), the rates of apoptotic beta cells, Fas positive cells and FasL positive cells were lower [(10.2+/-2.8)% vs. (15.9+/-6.5)%, (54.9+/-14.5)% vs. (75.7+/-12.9)%, (20.3+/-10.4)% vs. (27.9+/-12.0)%, P<0.05), and the Bcl-x positive cell rate was higher [(74.9+/-10.7)% vs. (66.0+/-18.3)%, P<0.05] in the CFA-treated group than those in the NS-treated group respectively. CONCLUSION CFA may inhibit beta cell apoptosis in NOD mice by regulating Fas, FasL and Bcl-x expression on cells within islets.
Animals ; Apoptosis ; drug effects ; Diabetes Mellitus, Type 1 ; pathology ; Fas Ligand Protein ; metabolism ; Female ; Freund's Adjuvant ; pharmacology ; Insulin-Secreting Cells ; drug effects ; pathology ; Mice ; Mice, Inbred NOD ; bcl-X Protein ; metabolism ; fas Receptor ; metabolism