Islet-Sparing Effects of Protein Tyrosine Phosphatase-1b Deficiency Delays Onset of Diabetes in IRS2 Knockout Mice

Howard Hughes Medical Institute, Joslin Diabetes Center, and Division of Endocrinology, Children's Hospital, Harvard Medical School, Boston, Massachusetts 02215, USA.
Diabetes (Impact Factor: 8.1). 02/2004; 53(1):61-6. DOI: 10.2337/diabetes.53.1.61
Source: PubMed


Protein tyrosine phosphatase-1b (Ptp1b) inhibits insulin and leptin signaling by dephosphorylating specific tyrosine residues in their activated receptor complexes. Insulin signals are mediated by tyrosine phosphorylation of the insulin receptor and its downstream targets, such as Irs1 and Irs2. Irs2 plays an especially important role in glucose homeostasis because it mediates some peripheral actions of insulin and promotes pancreatic beta-cell function. To determine whether the deletion of Ptp1b compensates for the absence of Irs2, we analyzed mice deficient in both Ptp1b and Irs2. Pancreatic beta-cell area decreased in Ptp1b(-/-) mice, consistent with decreased insulin requirements owing to increased peripheral insulin sensitivity. By contrast, peripheral insulin sensitivity and beta-cell area increased in Irs2(-/-)::Ptp1b(-/-) mice, which improved glucose tolerance in Irs2(-/-)::Ptp1b(-/-) mice and delayed diabetes until 3 months of age. However, beta-cell function eventually failed to compensate for absence of Irs2. Our studies demonstrate a novel role for Ptp1b in regulating beta-cell homeostasis and indicate that Ptp1b deficiency can partially compensate for lack of Irs2.

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    • "PTP1B plays a major role in several physiological functions including energy balance and the regulation of glucose homeostasis [26]–[28], hence it is a potential target for the treatment of Diabetes. On this regard, much effort has been done in order to describe the role of PTP1B in peripheral tissues [11]–[14], [29], but information about its role in endocrine pancreas is limited [15], [16]. To our knowledge, this is the first study showing that PTP1B modulates β-cell mass in a cell autonomous manner through the regulation of key signalling pathways involved in β cell proliferation and apoptosis. "
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    ABSTRACT: Protein tyrosine phosphatase 1B (PTP1B) is a negative regulator of the insulin signalling pathway. It has been demonstrated that PTP1B deletion protects against the development of obesity and Type 2 Diabetes, mainly through its action on peripheral tissues. However, little attention has been paid to the role of PTP1B in β-cells. Therefore, our aim was to study the role of PTP1B in pancreatic β-cells. Silencing of PTP1B expression in a pancreatic β-cell line (MIN6 cells) reveals the significance of this endoplasmic reticulum bound phosphatase in the regulation of cell proliferation and apoptosis. Furthermore, the ablation of PTP1B is able to regulate key proteins involved in the proliferation and/or apoptosis pathways, such as STAT3, AKT, ERK1/2 and p53 in isolated islets from PTP1B knockout (PTP1B (-)/(-)) mice. Morphometric analysis of pancreatic islets from PTP1B (-)/(-) mice showed a higher β-cell area, concomitantly with higher β-cell proliferation and a lower β-cell apoptosis when compared to islets from their respective wild type (WT) littermates. At a functional level, isolated islets from 8 weeks old PTP1B (-)/(-) mice exhibit enhanced glucose-stimulated insulin secretion. Moreover, PTP1B (-)/(-) mice were able to partially reverse streptozotocin-induced β-cell loss. Together, our data highlight for the first time the involvement of PTP1B in β-cell physiology, reinforcing the potential of this phosphatase as a therapeutical target for the treatment of β-cell failure, a central aspect in the pathogenesis of Type 2 Diabetes.
    PLoS ONE 02/2014; 9(2):e90344. DOI:10.1371/journal.pone.0090344 · 3.23 Impact Factor
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    • "As it has been reported that PTP1B deficiency improves beta-cell function in IRS2 −/− diabetic mice (Kushner et al. 2004), we performed histological analysis of the endocrine pancreas in wild-type and PTP1B −/− mice at 3 and 16 months. As expected for an insulin resistant state, pancreatic sections from 16-month old, obese wild-type mice showed enlarged islets with a 2.5-fold increase in islet area. "
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    ABSTRACT: Protein tyrosine phosphatase 1B (PTP1B) is a negative regulator of insulin signaling and a therapeutic target for type 2 diabetes (T2DM). In this study, we have evaluated the role of PTP1B in the development of aging-associated obesity, inflammation, and peripheral insulin resistance by assessing metabolic parameters at 3 and 16 months in PTP1B(-/-) mice maintained on mixed genetic background (C57Bl/6J × 129Sv/J). Whereas fat mass and adipocyte size were increased in wild-type control mice at 16 months, these parameters did not change with aging in PTP1B(-/-) mice. Increased levels of pro-inflammatory cytokines, crown-like structures, and hypoxia-inducible factor (HIF)-1α were observed only in adipose tissue from 16-month-old wild-type mice. Similarly, islet hyperplasia and hyperinsulinemia were observed in wild-type mice with aging-associated obesity, but not in PTP1B(-/-) animals. Leanness in 16-month-old PTP1B(-/-) mice was associated with increased energy expenditure. Whole-body insulin sensitivity decreased in 16-month-old control mice; however, studies with the hyperinsulinemic-euglycemic clamp revealed that PTP1B deficiency prevented this obesity-related decreased peripheral insulin sensitivity. At a molecular level, PTP1B expression and enzymatic activity were up-regulated in liver and muscle of 16-month-old wild-type mice as were the activation of stress kinases and the expression of p53. Conversely, insulin receptor-mediated Akt/Foxo1 signaling was attenuated in these aged control mice. Collectively, these data implicate PTP1B in the development of inflammation and insulin resistance associated with obesity during aging and suggest that inhibition of this phosphatase by therapeutic strategies might protect against age-dependent T2DM.
    Aging cell 12/2011; 11(2):284-96. DOI:10.1111/j.1474-9726.2011.00786.x · 6.34 Impact Factor
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    • "Vol. XX, No. X, XXXX ISLETS OF LANGERHANS DEGENERATION IN RODENT MODELS OF TYPE 2 DIABETES 11 Mouse model hIAPP +/+ (mouse insulin promoter driven) β-cell insulin receptor –/– GLUT2 –/– Glucokinase (GK) +/– PDX –/– (targeted to β cell) PDX +/– and GLUT4 +/– IRS2 –/– Target protein function in β cell Human islet amylin polypeptide Insulin receptor High-Km glucose transporter High-Km hexokinase, glucose sensor Transcription factor; involved in pancreatic development GLUT4 expressed in muscle cells Insulin receptor substrate (growth and survival; part of insulin signaling) Glucose Hyper Hyper Hyper Mild hyper Hyper Mild hyper Hyper Insulin Mildly reduced Normal Low Normal Low Raised Low Downstream β-cell protein expression changes Reduced insulin Reduced insulin (large effect), GLUT and GK (lesser effects) Reduced insulin, IAPP and GLUT2 expression.Increased expression of glucagon Reduced insulin and PDX1 β-Cell functional abnormalities Decreased prolifera tion and increased apoptosis leading to a reduction in β-cell mass Loss of acute phase insulin secretion Reduced GSIS Reduced GSIS Reduced GSIS Reduced GSIS; greater GSIS than PDX +/– mice Increased GSIS Islet pathology Hyaline replacement of islet area Eventual reduction in β-cell mass None None None reported Eventual islet hyperplasia Islet atrophy and reduced β-cell mass Notes Hyperphagia, glycosuria, neonatal death Homozygous knockout fatal soon after birth with severe hyperglycemia and insulinopenia Diabetes develops with age; normoglycemic until ~17 weeks IGT is more severe than β-cell-specific PDX –/– GLUT4+/+; Insulin resistance Insulin resistance, leptin resistance References Andrikopoulos, et al. (2000), Butler et al. (2004) Kulkarni et al. (1999), Otani et al. (2004) Guillam et al. (1997), Bady et al. (2006) Terauchi et al. (1995), Remedi et al. (2005) Ahlgren et al. (1998) Brissova et al. (2004) Withers et al. (1998), Kubota et al. (2004), Kushner et al. (2004) "
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    ABSTRACT: Type 2 diabetes mellitus (TTDM) is characterized by progressive loss of glucose control through multifactorial mechanisms. The search for an understanding of TTDM has relied on animal models since the realization of the importance of the pancreas in controlling plasma glucose concentration. Rodent models of TTDM are developed to express hyperglycemia and not islet degeneration per se. Degeneration of the islets of Langerhans with beta-cell loss is secondary to insulin resistance and is regarded as the more important lesion. Despite this, differences between models are seen in the development and progression of islet degeneration. Assessing the differences between the models is important to appreciate the various aspects of TTDM and understand their advantages as well as their deficiencies. Relevant animal models of TTDM provide opportunities to investigate important physiological and cell biological processes that may ultimately lead to development of targeted therapies. This article reviews the importance, advantages, and limitations of rodent models of TTDM in relation to the histopathological changes that characterize islet degeneration. Pathophysiological mechanisms that contribute to islet degeneration are also discussed and are placed into the context of changes in islet histological appearances.
    Toxicologic Pathology 06/2008; 36(4):529-51. DOI:10.1177/0192623308318209 · 2.14 Impact Factor
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