Approaches to Type 1 Diabetes Prevention by Intervention in Cytokine Immunoregulatory Circuits

Type 1 (insulin-dependent) diabetes mellitus, like other organ specific autoimmune diseases, results from a disorder of immunoregulation. T cells specific for pancreatic islet ß cell constituents (autoantigens) exist normally but are restrained by regulatory mechanisms (self-tolerant state). When regulation fails, ß cell-specific autoreactive T cells become activated and expand clonally. Current evidence indicates that islet ß cell-specific autoreactive T cells belong to a T helper 1 (Th1) subset, and these Th1 cells and their characteristic cytokine products, IFNγ and IL-2, are believed to cause islet inflammation (insulitis) and ß cell destruction. Immune-mediated destruction of ß cells precedes hyperglycemia and clinical symptoms by many years because these become apparent only when most of the insulin-secreting ß cells have been destroyed. Therefore, several approaches are being tested or are under consideration for clinical trials to prevent or arrest complete autoimmune destruction of islet ß cells and insulin-dependent diabetes. Approaches that attempt to correct underlying immunoregulatory defects in autoimmune diabetes include interventions aimed at i) deleting ß cell autoreactive Th1 cells and cytokines (IFNγ and IL-2) and/or ii) increasing regulatory Th2 cells and/or Th3 cells and their cytokine products (IL-4, IL-10 and TGFßI)

Combination Therapy With Glucagon-Like Peptide-1 and Gastrin Restores Normoglycemia in Diabetic NOD Mice

OBJECTIVE—Glucagon-like peptide-1 (GLP-1) and gastrin promote pancreatic β-cell function, survival, and growth. Here, we investigated whether GLP-1 and gastrin can restore the β-cell mass and reverse hyperglycemia in NOD mice with autoimmune diabetes

Combined experimental and theoretical study on the blast response of arching masonry walls

This paper studies the nonlinear dynamic response of arching masonry walls to blast load. The methodology combines laboratory blast testing and nonlinear dynamic modeling of arching one-way masonry walls and their response to blast load. The paper aims at enhancing the understanding of the dynamic and nonlinear physical response of the structural system. The experimental phase focuses on a one-way arching masonry wall tested in a blast simulator. The test is designed to explore global and local measures of the response of such walls. New experimental data that contributes to the understanding of the blast response and for validating theoretical and numerical models is presented. The theoretical phase develops a nonlinear, dynamic, continuous beam-type model that considers the deformability of the mortar joints and the masonry units. The model combines inertial effects with geometrical and material nonlinearities and uses the finite element method for the numerical solution. The model is examined and evaluated against the experimental benchmark, and then it is used to explore the impact of the boundary conditions and the blast intensity on the dynamic response. The combined investigation highlights, explores, and quantifies the unique aspects of the complex dynamic response of such walls to blast loading

Activation of GPR119 Stimulates Human β-Cell Replication and Neogenesis in Humanized Mice with Functional Human Islets

Using humanized mice with functional human islets, we investigated whether activating GPR119 by PSN632408, a small molecular agonist, can stimulate human β-cell regeneration in vivo. Human islets were transplanted under the left kidney capsule of immunodeficient mice with streptozotocin- (STZ-) induced diabetes. The recipient mice were treated with PSN632408 or vehicle and BrdU daily. Human islet graft function in the mice was evaluated by nonfasting glucose levels, oral glucose tolerance, and removal of the grafts. Immunostaining for insulin, glucagon, and BrdU or Ki67 was performed in islet grafts to evaluate α- and β-cell replication. Insulin and CK19 immunostaining was performed to evaluate β-cell neogenesis. Four weeks after human islet transplantation, 71% of PSN632408-treated mice achieved normoglycaemia compared with 24% of vehicle-treated mice. Also, oral glucose tolerance was significantly improved in the PSN632408-treated mice. PSN632408 treatment significantly increased both human α- and β-cell areas in islet grafts and stimulated α- and β-cell replication. In addition, β-cell neogenesis was induced from pancreatic duct cells in the islet grafts. Our results demonstrated that activation of GPR119 increases β-cell mass by stimulating human β-cell replication and neogenesis. Therefore, GPR119 activators may qualify as therapeutic agents to increase human β-cell mass in patients with diabetes

(A) Confocal images represent insulin (red) immunostained pancreas sections from diabetic mice treated with vehicle, PSN632408, sitagliptin, or PSN632408 plus sitagliptin.

<p><b>(B)</b> Quantification of β-cell mass in the pancreases of non-diabetic control mice and diabetic mice with restored normoglycemia after 7 weeks of treatment with PSN632408, sitagliptin, or PSN632408 and sitagliptin combination (3 to 4 mice per group). β-Cell mass was significantly higher in mice treated with PSN632408 and sitagliptin combination than in mice treated with PSN632408 alone or sitagliptin alone (P<0.05).</p

(A) OGTT in non-diabetic control mice and diabetic mice treated with vehicle, and those that achieved normoglycemia after 7 weeks treatment with PSN632408, sitagliptin, or PSN632408 and sitagliptin combination (n = 5 mice per group).

<p>Blood glucose levels in mice treated with PSN632408 and sitagliptin combination were significantly lower than in mice treated with PSN632408 alone at 45 minutes and at 90 minutes (p<0.01) and in mice treated with sitagliptin alone at 90 minutes (p<0.01). <b>(B)</b> Blood glucose AUC_0–120 in mice treated with PSN632408, sitagliptin, or PSN632408 and sitagliptin combination was significantly lower than in mice treated with vehicle (P<0.01).</p

(A) Immunostaining of insulin (red), BrdU (yellow), and DAPI (blue) in pancreas sections from BrdU treated non-diabetic control mice and diabetic mice with restored normoglycemia after 7 weeks of treatment with PSN632408, sitagliptin, or PSN632408 combined with sitagliptin.

<p>White arrows indicate insulin/BrdU/DAPI co-positive cells. <b>(B)</b> The percentage of insulin/BrdU co-positive cells among total insulin positive cells was significantly higher in mice treated with PSN632408 and sitagliptin combination than in mice treated with PSN632408 alone (p<0.01, n = 4 to 6 mice per group).</p