TIMP-1 Transgenic Mice Recover From Diabetes Induced by Multiple Low-Dose Streptozotocin

Jiang, Hong; Zhu, Hanyu; Chen, Xiangmei; Peng, Youming; Wang, Jianzhong; Liu, Fuyou; Shi, Suozhu; Fu, Bo; Yang, Lu; Hong, Quan; Feng, Zhe; Hou, Kai; Sun, Xuefeng; Cai, Guangyan; Zhang, Xueguang

doi:10.2337/db06-0710

Cited by 35 publications

(19 citation statements)

References 47 publications

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“…These data suggest that the regenerating processes were enhanced in diabetic mice because of the presence of AG3340. In general agreement with our data, TIMP-1 has been shown to inhibit cytokine-induced apoptosis in multiple ␤ cell lines (43) and, in addition, TIMP-1 overexpression in mouse ␤ cells enhanced the replication of ␤ cells in TIMP-1 transgenic mice and contributed to the regeneration of ␤ cell mass in the STZ model of IDDM (44).…”

Section: Inhibition Of T Cell Mt1-mmp In Spontaneously Diabeticsupporting

confidence: 78%

Specific Inhibition of Autoimmune T Cell Transmigration Contributes to β Cell Functionality and Insulin Synthesis in Non-obese Diabetic (NOD) Mice

Savinov

Rozanov

Strongin

2007

Journal of Biological Chemistry

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Human diabetes mellitus (IDDM; type I diabetes) is a T cellmediated disease that is closely modeled in non-obese diabetic (NOD) mice. The pathogenesis of IDDM involves the transmigration of autoimmune T cells into the pancreatic islets and the subsequent destruction of insulin-producing ␤ cells. Therapeutic interventions leading to ␤ cell regeneration and the reversal of established IDDM are exceedingly limited. We report here that specific inhibition of T cell intra-islet transmigration by using a small molecule proteinase inhibitor restores ␤ cell functionality, increases insulin-producing ␤ cell mass, and alleviates the severity of IDDM in acutely diabetic NOD mice. As a result, acutely diabetic NOD mice do not require insulin injections for survival for a significant time period, thus providing a promising clue to effect IDDM reversal in humans. The extensive morphometric analyses and the measurements of both the C-peptide blood levels and the proinsulin mRNA levels in the islets support our conclusions. Diabetes transfer experiments suggest that the inhibitor specifically represses the T cell transmigration and homing processes as opposed to causing immunosuppression. Overall, our data provide a rationale for the pharmacological control of the T cell transmigration step in human IDDM.The pathogenesis of IDDM 2 involves the activation of autoimmune T killer cells. Activated autoimmune T cells transmigrate from the bloodstream through the pancreatic endothelium and into the islets of Langerhans, where they destroy insulin-producing ␤ cells. We suggested and then proved in our current work that the inhibition of T cell transmigration and homing would effectively control islet destruction and stimulate the functional recovery of the insulin-producing ␤ cells and the regeneration of the pancreatic islets.Mice of the NOD inbred strain develop a spontaneous disease closely resembling human IDDM and have been widely and successfully used as a model of IDDM (1-3). CD8ϩ T lymphocytes are involved in diabetogenesis in NOD mice; mice lacking CD8 ϩ T cells do not develop diabetes (4, 5). The cell surface CD44 levels are elevated in activated T cells (6). Via its interactions with endothelial hyaluronan, CD44 functions as a prominent adhesion receptor in autoimmune T cell adhesion on the endothelium and the subsequent transmigration events (7-11). Membrane type-1 matrix metalloproteinase (MT1-MMP) (12, 13) is the most important cell surface-associated proteinase that contributes to the shedding CD44 in the adherent autoimmune CD8 ϩ T cells (11,14). As demonstrated in our earlier cell-based tests (8, 9, 14), MT1-MMP cleavage releases the extracellular domain of CD44 from T cell surfaces and inactivates the CD44 cell receptor function. Similarly, the cleavage of CD44 by MT1-MMP plays a significant role in the regulation of tumor cell migration (15, 16). By means of this regulatory proteolysis, which our earlier data suggest (8, 9, 14), MT1-MMP appears to control the severity of the diabetic disease and mediates the transit...

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Section: Inhibition Of T Cell Mt1-mmp In Spontaneously Diabeticsupporting

confidence: 78%

Specific Inhibition of Autoimmune T Cell Transmigration Contributes to β Cell Functionality and Insulin Synthesis in Non-obese Diabetic (NOD) Mice

Savinov

Rozanov

Strongin

2007

Journal of Biological Chemistry

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“…Circulating TIMP-1 and TIMP-2 are increased in patients with metabolic syndrome and diabetes [81]. Overexpression of TIMP1 in pancreatic β-cells protects mice from streptozotocin-induced β-cell death and diabetes [84]. Likewise, genetic deletion of TIMP2 results in obesity and glucose intolerance in chow-fed mice that is further exacerbated in HF-fed mice [85].…”

Section: The Adipose Tissuementioning

confidence: 99%

The extracellular matrix and insulin resistance

Williams

Wasserman

2015

Trends in Endocrinology & Metabolism

184

212

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The extracellular matrix (ECM) is a highly dynamic compartment that undergoes remodeling as a result of injury and repair. Over the past decade, mounting evidence in humans and rodents suggest that ECM remodeling is associated with diet-induced insulin resistance in several metabolic tissues. Additionally, integrin receptors for the ECM have also been implicated in the regulation of insulin action. This review will address what is currently known about the ECM, integrins and insulin action in the muscle, liver and adipose tissue. Understanding how ECM remodeling and integrin signaling regulates insulin action may aid in the development of new therapeutic targets for the treatment of insulin resistance and type 2 diabetes.

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“…Hypothalamic TIMP-1 expression is regulated by an adipose-derived hormone, leptin, and the gene deletion of TIMP-1 causes increased food intake and obesity in female mice [62]. The overexpression of TIMP-1 in pancreatic β-cells protects mice from streptozotocin-induced β-cell death and diabetes [63]. While TIMP-1 mostly inhibits soluble MMPs alone, TIMP-2 can inhibit both soluble and MT-MMPs [51].…”

Section: Ecm Modifiers In the Adipose Tissuementioning

confidence: 99%

Adipose extracellular matrix remodelling in obesity and insulin resistance

Lin

Chun

2016

Biochemical Pharmacology

180

130

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The extracellular matrix (ECM) of adipose tissues undergoes constant remodelling to allow adipocytes and their precursor cells to change cell shape and function in adaptation to nutritional cues. Abnormal accumulation of ECM components and their modifiers in adipose tissues has been recently demonstrated to cause obesity-associated insulin resistance, a hallmark of type 2 diabetes. Integrins and other ECM receptors (e.g. CD44) that are expressed in adipose tissues have been shown to regulate insulin sensitivity. It is well understood that a hypoxic response is observed in adipose tissue expansion during obesity progression and that hypoxic response accelerates fibrosis and inflammation in white adipose tissues. The expansion of adipose tissues should require angiogenesis; however, the excess deposition of ECM limits the angiogenic response of white adipose tissues in obesity. While recent studies have focused on the metabolic consequences and the mechanisms of adipose tissue expansion and remodelling, little attention has been paid to the role played by the interaction between peri-adipocyte ECM and their cognate cell surface receptors. This review will address what is currently known about the roles played by adipose ECM, their modifiers, and ECM receptors in obesity and insulin resistance. Understanding how excess ECM deposition in the adipose tissue deteriorates insulin sensitivity would provide us hints to develop a new therapeutic strategy for the treatment of insulin resistance and type 2 diabetes.

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TIMP-1 Transgenic Mice Recover From Diabetes Induced by Multiple Low-Dose Streptozotocin

Cited by 35 publications

References 47 publications

Specific Inhibition of Autoimmune T Cell Transmigration Contributes to β Cell Functionality and Insulin Synthesis in Non-obese Diabetic (NOD) Mice

Specific Inhibition of Autoimmune T Cell Transmigration Contributes to β Cell Functionality and Insulin Synthesis in Non-obese Diabetic (NOD) Mice

The extracellular matrix and insulin resistance

Adipose extracellular matrix remodelling in obesity and insulin resistance

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