Humans ; Diabetes Mellitus, Type 1 ; Hypoglycemia/chemically induced* ; Hypoglycemic Agents/adverse effects* ; China ; Blood Glucose ; Insulin

OBJECTIVETo get a better understanding of the mechanisms underlying type 1 diabetes mellitus, the differentially expressed pancreatic proteins from multiple low-dose streptozotocin (MLD-SIZ) mouse and normal mouse were analyzed and compared.

METHODS20 male rats were separated into 2 groups (n=10): model mice treated with MLD-STZ and normal mice,differences of pancreatic proteome among in the two groups of mice, were analyzed by two dimensional polyacryamide gel electrophoresis (2DE). Protein quantification was analyzed and the differentially expressed spots were identified using mass spectrometry and MASCOT database searching.

RESULTSCompared with control group, 23 proteins had changed significantly in the model group, 8 proteins expression were up-regulated, 15 proteins expressions down-regulated significantly. Using MALDI-TOF-MS, 15 proteins with significant change were identified by peptide fingerprinting map and the results were searched in MASCOT database. The function analyzed showed that proteins with change were associated with metabolic, anti-oxidant, structural, catalytic enzymes and chaperone, et al.

CONCLUSIONType 1 diabetes is probably exerted via multi-target and multi-path mechanism. The proteins with significant change are newly target for type 1 diabetes early diagnosis and treatment.

Animals ; Diabetes Mellitus, Experimental ; physiopathology ; Diabetes Mellitus, Type 1 ; chemically induced ; metabolism ; physiopathology ; Male ; Mice ; Pancreas ; metabolism ; Proteins ; metabolism ; Proteomics ; methods ; Streptozocin

The hippocampus is affected by various stimuli that include hyperglycemia, depression, and ischemia. Calcium-binding proteins (CaBPs) have protective roles in the response to such stimuli. However, little is known about the expression of CaBPs under diabetic conditions. This study was conducted to examine alterations in the physiological parameters with type 1 diabetes induced with streptozotocin (STZ) as well as time-dependent changes in the expression of two CaBPs changes of were being evaluated. Rats treated with STZ (70 mg/kg) had high blood glucose levels (>21.4 mmol/L) along with increased food intake and water consumption volumes compared to the sham controls. In contrast, body weight of the animals treated with STZ was significantly reduced compared to the sham group. CB-specific immunoreactivity was generally increased in the hippocampal CA1 region and granule cell layer of the dentate gyrus (DG) 2 weeks after STZ treatment, but decreased thereafter in these regions. In contrast, the number of PV-immunoreactive neurons and fibers was unchanged in the hippocampus and DG 2 weeks after STZ treatment. However, this number subsequently decreased over time. These results suggest that CB and PV expression is lowest 3 weeks after STZ administration, and these deficits lead to disturbances in calcium homeostasis.
Animals ; Calbindin 1/*genetics/metabolism ; Diabetes Mellitus, Experimental/*chemically induced ; Diabetes Mellitus, Type 1/*chemically induced ; *Gene Expression Regulation ; Hippocampus/*metabolism ; Male ; Parvalbumins/*genetics/metabolism ; Rats ; Rats, Wistar ; Streptozocin/administration & dosage

With the increasing use of immune checkpoint inhibitors (ICI) including anti-cytotoxic T lymphocyte associated antigen-4 (CTLA-4) and anti-programmed cell death-1 (PD-1) in cancers, ICI-induced type 1 diabetes has been reported throughout the world. In this review, we aim to summarize the characteristics of this disease and discuss the mechanism of it. As an immune-related adverse event, type 1 diabetes developed after the administration of anti-PD-1 or anti-PD-ligand 1 (PD-L1) in the combination with or without anti-CTLA-4. It usually presented with acute onset, and 62.1% of the reported cases had diabetic ketoacidosis. Only a third of them had positive autoantibodies associated with type 1 diabetes. Susceptible HLA genotypes might be associated. T-cell-stimulation by blocking of the interaction of PD-1 and PD-L1 in pancreatic β cells was the main mechanism involved in the pathology. Insulin was the only effective treatment of ICI-induced type 1 diabetes. In conclusions, ICI-induced type 1 diabetes is a potentially life-threating adverse event after the immunotherapy of cancers. Screening and early recognition is important. Further investigation of the mechanism may help to better understand the pathology of type 1 diabetes.
CTLA-4 Antigen ; Diabetes Mellitus, Type 1/chemically induced* ; Humans ; Immune Checkpoint Inhibitors ; Immunologic Factors/therapeutic use* ; Immunotherapy/adverse effects* ; Neoplasms/drug therapy*

The aim of this study is to investigate the therapeutic effect of RegIII-proinsulin-pBudCE4.1 plasmid on streptozotocin (STZ)-induced type 1 diabetes mellitus and its underlying mechanisms. The model of type 1 diabetes mellitus was established by intraperitoneal injections of STZ (40 mg kg(-1)) to Balb/c mice for five consecutive days. Then, ten type 1 diabetic mice were intramuscularly injected with 100 microg RegIII-proinsulin-pBudCE4.1 plasmid for 4 weeks (one time/week) and the blood glucose levels were monitored every week; whereas another ten diabetic mice served as negative control group were injected with pBudCE4.1 vector at the same dose. Normal control and model control mice were treated with normal saline at identical volume under the same way. Western blotting, MTT assay, ELISA, HE staining and Tunel assay were applied to explore the underlying mechanisms. Results showed that RegIII-proinsulin-pBudCE4.1 plasmid ameliorated the hyperglycemia symptoms in diabetic mouse remarkably. It induced an immunological tolerance state in type 1 diabetic mice by inhibiting the proliferation of splenic lymphocytes and recovering Th1/Th2 balance evidenced by MTT and ELISA analysis. Furthermore, it elevated insulin concentration in the serum of type 1 diabetic mice and promoted the regeneration of beta cells supported by the results of HE staining and Tunel assay. In conclusion, RegIII-proinsulin-pBudCE4.1 plasmid possesses powerful anti-diabetic ability, which may be involved in the inducing of immunological tolerance and enhancing beta cells recovery.
Animals ; Apoptosis ; Blood Glucose ; metabolism ; Cell Proliferation ; Diabetes Mellitus, Experimental ; metabolism ; pathology ; therapy ; Diabetes Mellitus, Type 1 ; chemically induced ; metabolism ; pathology ; therapy ; Genetic Therapy ; Hyperglycemia ; therapy ; Injections, Intramuscular ; Insulin ; blood ; Islets of Langerhans ; cytology ; Male ; Mice ; Mice, Inbred BALB C ; Plasmids ; Proinsulin ; genetics ; metabolism ; therapeutic use ; Proteins ; genetics ; metabolism ; therapeutic use ; Streptozocin ; T-Lymphocytes ; cytology ; Th1-Th2 Balance

OBJECTIVETo study the effect of Astragalus polysaccharide (APS) on pancreatic beta cell mass in type 1 diabetic mice.

METHODDiabetic mice induced by multiple low dose streptozotocin (MLD-STZ) were administered either APS (100, 200, 400 mg x kg(-1) body weight) or saline intraperitoneally daily, and sacrificed after 15 or 30 days of treatment. Streptavidin-peroxidase immunohistochemical method with counterstain was performed to determine the effect of APS on insulitis. Indirect double immunofluorescence for Insulin/Ki67 (counterstained by Hoechst33258) and Insulin/Cleaved caspase-3 was used to evaluate pancreatic cell (besides beta cell) proliferation, beta cell neogenesis, beta cell apoptosis and beta cell mass. Semi-quantitative RT-PCR was utilized to characterize pancreatic regenerating protein 1 mRNA levels, and ELISA method was performed to measure the levels of cytokine IFN-gamma and IL-4 secreted by splenocytes.

RESULTAttenuated insulitis, upregulated beta cell mass, increased number of neogenetic pancreas islets, decreased number of apoptosis beta cells and downregulation of Th1/Th2 cytokine ratio were significantly time-and dose-dependent on APS treatment, when compared to saline controls. However, no significant differences of the number of pancreatic proliferative cells or replicative cells and pancreatic regenerating protein 1 mRNA levels were demonstrated between APS (APS100, APS200 and APS400) and saline vehicle group on day 15 and 30 with APS treatment.

CONCLUSIONAPS can upregulate pancreatic beta cell mass in type 1 diabetic mice, strongly associated with improved autoimmunity.

Animals ; Apoptosis ; drug effects ; Astragalus membranaceus ; chemistry ; Carrier Proteins ; metabolism ; Diabetes Mellitus, Experimental ; chemically induced ; metabolism ; pathology ; Diabetes Mellitus, Type 1 ; chemically induced ; metabolism ; pathology ; Enzyme-Linked Immunosorbent Assay ; Insulin-Secreting Cells ; drug effects ; metabolism ; pathology ; Interferon-gamma ; metabolism ; Interleukin-4 ; metabolism ; Islets of Langerhans ; drug effects ; metabolism ; pathology ; Lithostathine ; biosynthesis ; genetics ; Male ; Mice ; Mice, Inbred C57BL ; Plants, Medicinal ; chemistry ; Polysaccharides ; isolation & purification ; pharmacology ; RNA, Messenger ; biosynthesis ; genetics ; Reverse Transcriptase Polymerase Chain Reaction ; Streptozocin ; Transcription Factors

OBJECTIVETo investigate the effects of icariin on cardiac functions and mitochondrial oxidative stress in streptozotocin (STZ)-induced diabetic rats.

METHODMale SD rats were randomly divided into normal control group, icariin control group, diabetic group, and diabetic groups administered with a low dose (30 mL x kg(-1) x d(-1), ig) or a high dose (120 mL x kg(-1) d(-1), ig) of icariin for 8 weeks. The body weight, blood glucose, cardiac functions, left ventricular weight, and myocardial collagen level were assayed. The cardiac mitochondrial reactive oxygen species (ROS) level, malondialdehyde (MDA) level, and superoxide dismutase (SOD) activity were measured.

RESULTTreatment with icariin reduced the losing of body weight in diabetic rats. Icariin markedly reduced the ratio of ventricular weight and body weight, increased the left ventricular develop pressure and +/- dp/dt(max), and decreased the left ventricular end diastolic pressure in diabetic rats. The myocardial collagen and the level of cardiac mitochondrial ROS in diabetic rats were all markedly reduced by icariin. Furthermore, high dose of icariin significantly decreased the mitochondrial MDA level and increased SOD activity in diabetic rat hearts.

CONCLUSIONTreatment with icariin for 8 weeks markedly improved the cardiac function, which may be related to reducing mitochondrial oxidative stress injuries in diabetic rats.

Animals ; Body Weight ; drug effects ; Collagen ; drug effects ; metabolism ; Diabetes Mellitus, Experimental ; chemically induced ; drug therapy ; metabolism ; pathology ; Diabetes Mellitus, Type 1 ; drug therapy ; metabolism ; pathology ; Diabetic Cardiomyopathies ; drug therapy ; metabolism ; pathology ; Drugs, Chinese Herbal ; administration & dosage ; Enteral Nutrition ; Flavonoids ; administration & dosage ; Heart Ventricles ; metabolism ; pathology ; Male ; Malondialdehyde ; metabolism ; Mitochondria, Heart ; drug effects ; metabolism ; pathology ; Organ Size ; Oxidative Stress ; drug effects ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species ; metabolism ; Streptozocin ; Superoxide Dismutase ; drug effects ; metabolism