Lessons on autoimmune diabetes from animal models

2006 ◽  
Vol 110 (6) ◽  
pp. 627-639 ◽  
Author(s):  
Yang Yang ◽  
Pere Santamaria
Keyword(s):  
Animal Models ◽  
Autoimmune Diabetes ◽  
Type I Diabetes ◽  
Vascular Complications ◽  
Diabetic Mouse ◽  
Suboptimal Control ◽  
Type I ◽  
Genetic Elements ◽  
Glucose Levels ◽  
Islet Inflammation

T1DM (Type I diabetes mellitus) results from selective destruction of the insulin-producing β-cells of the pancreas by the immune system, and is characterized by hyperglycaemia and vascular complications arising from suboptimal control of blood glucose levels. The discovery of animal models of T1DM in the late 1970s and early 1980s, particularly the NOD (non-obese diabetic) mouse and the BB (BioBreeding) diabetes-prone rat, had a fundamental impact on our ability to understand the genetics, aetiology and pathogenesis of this disease. NOD and BB diabetes-prone rats spontaneously develop a form of diabetes that closely resembles the human counterpart. Early studies of these animals quickly led to the realization that T1DM is caused by autoreactive T-lymphocytes and revealed that the development of T1DM is controlled by numerous polymorphic genetic elements that are scattered throughout the genome. The development of transgenic and gene-targeting technologies during the 1980s allowed the generation of models of T1DM of reduced genetic and pathogenic complexity, and a more detailed understanding of the immunogenetics of T1DM. In this review, we summarize the contribution of studies in animal models of T1DM to our current understanding of four fundamental aspects of T1DM: (i) the nature of genetic elements affording T1DM susceptibility or resistance; (ii) the mechanisms underlying the development and recruitment of pathogenic autoreactive T-cells; (iii) the identity of islet antigens that contribute to the initiation and/or progression of islet inflammation and β-cell destruction; and (iv) the design of avenues for therapeutic intervention that are rooted in the knowledge gained from studies of animal models. Development of new animal models will ensure continued progress in these four areas.

Vildagliptin/pioglitazone combination improved the overall glycemic control in type I diabetic rats

2018 ◽  
Vol 96 (8) ◽  
pp. 710-718 ◽  
Author(s):  
Amir Mohamed Abdelhamid ◽  
Rania Ramadan Abdelaziz ◽  
Hatem Abdelrahman Ali Salem
Keyword(s):  
Glycemic Control ◽  
Type I Diabetes ◽  
Serum Insulin ◽  
Immunohistochemical Analysis ◽  
Diabetic Rats ◽  
Suboptimal Control ◽  
Type I ◽  
Β Cells ◽  
Treatment Regimens ◽  
Glucose Levels

Type I diabetes (TID) is generally assumed to be caused by an immune associated, if not directly immune-mediated, destruction of pancreatic β-cells. In patients with long-term diabetes, the pancreas lacks insulin-producing cells and the residual β-cells are unable to regenerate. Patients with TID are subjected to a lifelong insulin therapy which shows risks of hypoglycemia, suboptimal control and ketosis. In this study, we investigated the potential role of vildagliptin (Vilda) alone or in combination with pioglitazone (Pio), as treatment regimens for TID using streptozotocin (STZ)-induced TID model in rats. Daily oral administration of Vilda (5 mg/kg) alone or in combination with Pio (20 mg/kg) for 7 weeks significantly reduced blood glucose levels and HbA1c. It increased serum insulin levels and decreased serum glucagon. It also showed a strong antioxidant activity. Immunohistochemical analysis showed a marked improvement in β-cells in treated groups when compared with the diabetic group, which appeared in the normal cellular and architecture restoration of β-cells in the islets of Langerhans. Vilda alone or in combination with Pio has the ability to improve the overall glycemic control in type I diabetic rats and may be considered a hopeful and effective remedy for TID.

Antidiabetic effect of Psychotria malayana Jack in induced type 1 diabetic rat

MEDISAINS ◽  
2020 ◽  
Vol 18 (1) ◽  
pp. 19
Author(s):  
Fairuz Fairuz ◽  
Hasna Dewi ◽  
Humaryanto Humaryanto
Keyword(s):  
Blood Glucose ◽  
Side Effects ◽  
Type I Diabetes ◽  
Langerhans Cell ◽  
Diabetic Rat ◽  
Type I ◽  
Antidiabetic Effect ◽  
Glucose Levels ◽  
Blood Glucose Levels

Background: Therapies for hyperglycemic treatment, including insulin and oral diabetes medications, have been confirmed to cause several side effects. Thus, finding new drugs with fewer side effects is of high importance. Salung leaf herb (Psychotria malayana Jack) reported used in traditional societies as a treatment for diabetes. However, the scientific proof of this plant for diabetes treatment is still lacking.Objective: To evaluate the antidiabetic effect of the P. malayana jack in induced type 1 diabetic rats by assessing blood glucose level and pancreatic cells in white rats.Methods: Alloxan used to induce type I diabetes. Rats randomly divided into six groups. A Group P1 received 250 mg/kg BW; group P2 received 500 mg/kg BW, group P3 received 1000 mg/kg BW. While group 4 basal received no treatment, group 5 received distilled water as a negative control, and group 6 received glibenclamide as a positive control. Medications are given for six days. Glucose levels were measured, and observation of pancreatic Langerhans cell damages.Results:  A decrease in blood glucose levels observed in all treatment groups. The most significant reduction (49.76%; 1000 mg/kg BW) occurred in the P3 group. Morphological features of pancreatic Langerhans cell damage were slightly high in the P1 group.Conclusion: P. malayana Jack can consider having an antidiabetic effect in a type 1 diabetic rat by reducing blood glucose levels.

Type I Diabetes Mellitus

2019 ◽  
Author(s):  
Joseph I. Wolfsdorf ◽  
Katharine Garvey
Keyword(s):  
Diabetes Mellitus ◽  
Type 1 Diabetes ◽  
Glycemic Control ◽  
Type 1 Diabetes Mellitus ◽  
Diabetic Ketoacidosis ◽  
Autoimmune Diabetes ◽  
Type I ◽  
Insulin Deficiency ◽  
Glucose Levels

Type 1 diabetes mellitus is characterized by severe insulin deficiency, making patients dependent on exogenous insulin replacement for survival. These patients can experience life-threatening events when their glucose levels are significantly abnormal. Type 1 diabetes accounts for 5 to 10% of all diabetes cases, with type 2 accounting for most of the remainder. This review details the pathophysiology, stabilization and assessment, diagnosis and treatment, disposition and outcomes of patients with Type 1 diabetes mellitus. Figures show the opposing actions of insulin and glucagon on substrate flow and plasma levels; plasma glucose, insulin and C-peptide levels throughout the day; the structure of human proinsulin; current view of the pathogenesis of Type 1 autoimmune diabetes mellitus; pathways that lead from insulin deficiency to the major clinical manifestations of Type 1 diabetes mellitus; relationship between hemoglobin A1c values at the end of a 3-month period and calculated average glucose levels during the 3-month period; different combinations of various insulin preparations used to establish glycemic control; and basal-bolus and insulin pump regimens. Tables list the etiologic classification of Type 1 diabetes mellitus, typical laboratory findings and monitoring in diabetic ketoacidosis, criteria for the diagnosis of Type 1 diabetes, clinical goals of Type 1 diabetes treatment, and insulin preparations. This review contains 10 figures, 9 tables, and 40 references. Keywords: Type 1 diabetes mellitus, optimal glycemic control, hypoglycemia, hyperglycemia, polyuria, polydipsia, polyphagia, HbA1c, medical nutrition therapy, Diabetic Ketoacidosis

scholarly journals Integration of Islet/Beta-Cell Transplants with Host Tissue Using Biomaterial Platforms

Endocrinology ◽  
2020 ◽  
Vol 161 (11) ◽  
Author(s):  
Daniel W Clough ◽  
Jessica L King ◽  
Feiran Li ◽  
Lonnie D Shea
Keyword(s):  
Stem Cell ◽  
Immune Responses ◽  
Cell Function ◽  
Type I Diabetes ◽  
Glucose Sensing ◽  
Trophic Factors ◽  
Design Parameters ◽  
Type I ◽  
Β Cells ◽  
Glucose Levels

Abstract Cell-based therapies are emerging for type I diabetes mellitus (T1D), an autoimmune disease characterized by the destruction of insulin-producing pancreatic β-cells, as a means to provide long-term restoration of glycemic control. Biomaterial scaffolds provide an opportunity to enhance the manufacturing and transplantation of islets or stem cell–derived β-cells. In contrast to encapsulation strategies that prevent host contact with the graft, recent approaches aim to integrate the transplant with the host to facilitate glucose sensing and insulin distribution, while also needing to modulate the immune response. Scaffolds can provide a supportive niche for cells either during the manufacturing process or following transplantation at extrahepatic sites. Scaffolds are being functionalized to deliver oxygen, angiogenic, anti-inflammatory, or trophic factors, and may facilitate cotransplantation of cells that can enhance engraftment or modulate immune responses. This local engineering of the transplant environment can complement systemic approaches for maximizing β-cell function or modulating immune responses leading to rejection. This review discusses the various scaffold platforms and design parameters that have been identified for the manufacture of human pluripotent stem cell–derived β-cells, and the transplantation of islets/β-cells to maintain normal blood glucose levels.

DISTINCTIVE FEATURES OF PROCOAGULANT RESPONSE OF MONOCYTES FROM DIABETIC PATIENTS

1987 ◽  
Author(s):  
B JUDE ◽  
A WATEL ◽  
D FONTAINE ◽  
P FONTAINE ◽  
A COSSON
Keyword(s):  
Type I Diabetes ◽  
Vascular Complications ◽  
Coagulation Factor ◽  
Factor Vii ◽  
Diabetic Patients ◽  
Type I ◽  
Factor X ◽  
Female Ratio ◽  
Male Female Ratio

Hypercoagulability is one of the possible factors reported in genesis or aggravation of vascular complications in diabetes mellitus. We therefore examined procoagulant activity (PCA) of disrupted monocytes frcm 26 patients with Type I diabetes and 6 with Type II, versus 32 control subjects (male/ female ratio = 1 in each group).Diabetes monocytes exhibited a slight but detectable PCA before any incubation or in vitro stimulation, whereas control monocytes did not. Data obtained with coagulation factor deficient plasmas or phospholipase C indicated that PCA was tissue factor (TF) alone in 22 cases and TF associated with a significant amount of factor VII/VIIa activity in 10 cases.Incubation in serum free medium led to significant raise of PCA in diabetes cells when stimulated with endotoxin or not, and in control cells only after stimulation. Furthermore, PCA appeared earlier in diabetes monocytes than in control ones, (4 hours, versus 20 hours). PCA frcm control cells was FT-like. PCA frcm diabetes cells was FT-like when no VII/VIIa activity was present on non-stimulated cells, and prothrombinase-like when VII/VIIa activity was early associated with the cells. In the latter case, trace amounts of factor X activity were also detectable. Whether factor VII and factor X activities were of plasmatic origin and associated to the cells, or synthesized in vitro by the cells remains unclear. The characteristics of PCA were net correlated with clinical features (age, diabetic complications) nor with the type of diabetes.Our data suggest that in diabetes patients, monocytes exhibit an increased PCA, possibly corresponding to a baseline stimulation, or at least a higher responsiveness to undergoing stimuli in vitro.

scholarly journals SENP3 regulates high glucose-induced endothelial dysfunction via ROS dependent signaling

2020 ◽  
Vol 17 (6) ◽  
pp. 147916412097089
Author(s):  
Fuheng Chen ◽  
Dongdong Ma ◽  
Aizhong Li
Keyword(s):  
Endothelial Dysfunction ◽  
High Glucose ◽  
Type I Diabetes ◽  
Free Radical Scavenger ◽  
Radical Scavenger ◽  
Type I ◽  
Dependent Manner ◽  
Glucose Levels ◽  
And Migration

Background: The current study aimed to explore the role of SENP3 in endothelial cell dysfunction in a high-glucose setting. Methods: The gene and protein expressions of SENP3 in high-glucose cultured HAECs were examined using quantitative PCR and western blotting. The effects of SENP3 on HAEC viability, apoptosis, migration, and endothelial–monocyte adhesion were evaluated in vitro by knockdown. Moreover, a mouse streptozotocin-induced type I diabetes model was established for SENP3 expression assessment. In addition, the effects of SENP3 on ROS-related signaling pathways were investigated in high-glucose cultured HAECs. Results: Significantly increased levels of SENP3 mRNA and protein were found in high-glucose cultured HAECs in a time-dependent manner. SENP3 knockdown reversed high glucose-induced HAEC viability, apoptosis, and migration reduction. SENP3 knockdown attenuated the high glucose-induced intercellular adhesion of THP-1 monocytic cells and HAECs via downregulation of ICAM-1 and VCAM-1 expression. Increased levels of SENP3, ICAM-1, and VCAM-1 expression were observed in the aorta tissue of mice with type I diabetes. Downregulation of SENP3 expression was observed in HAECs cultured with high glucose levels using the free radical scavenger N-acetyl-L-cysteine or NOX4 siRNA. Conclusions: SENP3 was involved in high glucose-induced endothelial dysfunction, and ROS-dependent signaling served as the mechanism.

scholarly journals T Helper 2 (Th2) T Cells Induce Acute Pancreatitis and Diabetes in Immune-compromised Nonobese Diabetic (NOD) Mice

1997 ◽  
Vol 186 (2) ◽  
pp. 299-306 ◽  
Author(s):  
Syamasundar V. Pakala ◽  
Michael O. Kurrer ◽  
Jonathan D. Katz
Keyword(s):  
T Cells ◽  
Islet Cell ◽  
Autoimmune Diabetes ◽  
Type I Diabetes ◽  
Nod Mice ◽  
Type I ◽  
T Helper ◽  
T Helper 1 ◽  
Th1 Cell ◽  
Nonobese Diabetic

Autoimmune diabetes is caused by the CD4+, T helper 1 (Th1) cell-mediated apoptosis of insulin-producing β cells. We have previously shown that Th2 T cells bearing the same T cell receptor (TCR) as the diabetogenic Th1 T cells invade islets in neonatal nonobese diabetic (NOD) mice but fail to cause disease. Moreover, when mixed in excess and cotransferred with Th1 T cells, Th2 T cells could not protect NOD neonates from Th1-mediated diabetes. We have now found, to our great surprise, the same Th2 T cells that produced a harmless insulitis in neonatal NOD mice produced intense and generalized pancreatitis and insulitis associated with islet cell necrosis, abscess formation, and subsequent diabetes when transferred into immunocompromised NOD.scid mice. These lesions resembled allergic inflamation and contained a large eosinophilic infiltrate. Moreover, the Th2-mediated destruction of islet cells was mediated by local interleukin-10 (IL-10) production but not by IL-4. These findings indicate that under certain conditions Th2 T cells may not produce a benign or protective insulitis but rather acute pathology and disease. Additionally, these results lead us to question the feasibility of Th2-based therapy in type I diabetes, especially in immunosuppressed recipients of islet cell transplants.

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