Expression and regulation of osteopontin in type 1 diabetes

Gong, Qiaoke; Chipitsyna, Galina; Gray, Chancellor F.; Anandanadesan, Rathai; Arafat, Hwyda A.

doi:10.4161/isl.1.1.8629

Cited by 12 publications

(21 citation statements)

References 38 publications

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“…Osteopontin serves diverse roles including binding to calcium-based biominerals, such as calcium-phosphate, that is important to inhibition and regulation of bone mineralization [46]. Several physiological roles have also been identified for iOPN including cytoskeleton rearrangement, modulation of immune responses, and as an adaptor or scaffolding protein [42, 45, 47]. Similar to previous reports, we found that iOPN is highly expressed in human pancreatic islets and beta-cells [48].…”

Section: Discussionsupporting

confidence: 86%

“…A wide range of inflammatory cytokines and growth factors have been shown to regulate expression of iOPN including LPS, NO, IL-1β, IFN-γ, and TNF-α [42, 43, 45, 47]. Hyperglycemic conditions and the incretin hormone glucose-dependent insulinotropic polypeptide (GIP) also increase OPN mRNA and protein content in pancreatic islets [48].…”

Section: Discussionmentioning

confidence: 99%

“…Hyperglycemic conditions and the incretin hormone glucose-dependent insulinotropic polypeptide (GIP) also increase OPN mRNA and protein content in pancreatic islets [48]. Furthermore, it has been well documented that low level inflammation associated with the early stages of T2D leads to upregulation of OPN mRNA and iOPN protein expression in pancreatic islets [42, 44, 47, 53]. Elevation of iOPN serves a protective role in pancreatic islets where it acts as a negative feedback regulator of induced NO synthase (iNOS) and as a promoter of a protective Th2 immune response [42, 44, 47, 54].…”

Section: Discussionmentioning

confidence: 99%

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Osteopontin activates the diabetes-associated potassium channel TALK-1 in pancreatic β-cells

et al. 2017

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Glucose-stimulated insulin secretion (GSIS) relies on β-cell Ca2+ influx, which is modulated by the two-pore-domain K+ (K2P) channel, TALK-1. A gain-of-function polymorphism in KCNK16, the gene encoding TALK-1, increases risk for developing type-2 diabetes. While TALK-1 serves an important role in modulating GSIS, the regulatory mechanism(s) that control β-cell TALK-1 channels are unknown. Therefore, we employed a membrane-specific yeast two-hybrid (MYTH) assay to identify TALK-1-interacting proteins in human islets, which will assist in determining signaling modalities that modulate TALK-1 function. Twenty-one proteins from a human islet cDNA library interacted with TALK-1. Some of these interactions increased TALK-1 activity, including intracellular osteopontin (iOPN). Intracellular OPN is highly expressed in β-cells and is upregulated under pre-diabetic conditions to help maintain normal β-cell function; however, the functional role of iOPN in β-cells is poorly understood. We found that iOPN colocalized with TALK-1 in pancreatic sections and coimmunoprecipitated with human islet TALK-1 channels. As human β-cells express two K+ channel-forming variants of TALK-1, regulation of these TALK-1 variants by iOPN was assessed. At physiological voltages iOPN activated TALK-1 transcript variant 3 channels but not TALK-1 transcript variant 2 channels. Activation of TALK-1 channels by iOPN also hyperpolarized resting membrane potential (Vm) in HEK293 cells and in primary mouse β-cells. Intracellular OPN was also knocked down in β-cells to test its effect on β-cell TALK-1 channel activity. Reducing β-cell iOPN significantly decreased TALK-1 K+ currents and increased glucose-stimulated Ca2+ influx. Importantly, iOPN did not affect the function of other K2P channels or alter Ca2+ influx into TALK-1 deficient β-cells. These results reveal the first protein interactions with the TALK-1 channel and found that an interaction with iOPN increased β-cell TALK-1 K+ currents. The TALK-1/iOPN complex caused Vm hyperpolarization and reduced β-cell glucose-stimulated Ca2+ influx, which is predicted to inhibit GSIS.

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Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Osteopontin activates the diabetes-associated potassium channel TALK-1 in pancreatic β-cells

et al. 2017

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“…Concerning roles of diabetes mellitus on BBB permeability and changes in gene expression, the previous papers showed increased BBB permeability in diabetes mellitus. [41][42][43] In addition, other papers indicate that CD36 expression is increased in murine models of diabetes mellitus, 79 that high levels of osteopontin expression is seen in diabetic animals, 80,81 and that high plasma glucose increases the expression of MMP-13 in vessels. 82 Thus, it is likely that hyperglycemia as well as hypertension and cerebral ischemia induces BBB damage followed by the increased expression of these molecules (Fig.…”

Section: Overall Summary and Discussionmentioning

confidence: 99%

Blood‐brain barrier damage in vascular dementia

et al. 2015

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New findings on flow or drainage pathways of brain interstitial fluid and cerebrospinal fluid have been made. The interstitial fluid flow has an effect on the passage of blood-borne substances in the brain parenchyma, especially in areas near blood-brain barrier (BBB)-free regions. Actually, blood-borne substances can be transferred in areas with intact BBB function, such as the hippocampus, the corpus callosum, periventricular areas, and medial portions of the amygdala, presumably through leaky vessels in the subfornical organs or the choroid plexus. Increasing evidence indicates that dysfunction of the BBB function may play a significant role in the pathogenesis of vascular dementia. Accordingly, we have examined which insults seen in patients suffering from vascular dementia have an effect on the BBB using experimental animal models exhibiting some phenotypes of vascular dementia. The BBB in the hippocampus was clearly deteriorated in Mongolian gerbils exposed to acute ischemia followed by reperfusion and also in stroke-prone spontaneously hypertensive rats (SHRSP) showing hypertension. The BBB in the corpus callosum was clearly deteriorated in Wistar rats with permanent ligation of the bilateral common carotid arteries showing chronic hypoperfusion. The BBB in the hippocampus and the olfactory bulb was mildly deteriorated in aged senescence accelerated prone mice (SAMP8) showing cognitive dysfunction. The BBB in the hippocampus was mildly deteriorated in aged animals with hydrocephalus. Mild endothelial damage was seen in hyperglycemic db/db mice. In addition, mRNA expression of osteopontin, matrix metalloproteinase-13 (MMP-13), and CD36 was increased in vessels showing BBB damage in hypertensive SHRSP. As osteopontin, MMP-13 and CD36 are known to be related to brain injury and amyloid β accumulation or clearance, BBB damage followed by increased gene expression of these molecules not only contributes to the pathogenesis of vascular dementia, but also bridges the gap between vascular dementia and Alzheimer's disease.

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“…It is believed that extracellular and intracellular OPN serves different biological roles [3]. In rodents, all major islet cells including the beta cells express OPN [4, 5]. The role of OPN in islets is not fully established but OPN seems to prevent apoptosis and stimulate proliferation of islets and insulin producing cells, suggesting an overall islet protective role [4, 6, 7].…”

Section: Introductionmentioning

confidence: 99%

Osteopontin Affects Insulin Vesicle Localization and Ca2+ Homeostasis in Pancreatic Beta Cells from Female Mice

et al. 2017

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Type 2 diabetic patients suffer from insulin resistance and reduced insulin secretion. Osteopontin (OPN), a versatile protein expressed in several tissues throughout the body including the islets of Langerhans, has previously been implicated in the development of insulin resistance. Here we have investigated the role of OPN in insulin secretion using an OPN knock out mouse model (OPN-/-). Ultra-structural analyzes of islets from OPN-/- and WT mice indicated weaker cell-cell connections between the islet cells in the OPN-/- mouse compared to WT. Analysis of the insulin granule distribution in the beta cells showed that although OPN-/- and WT beta cells have the same number of insulin granules OPN-/- beta cells have significantly fewer docked granules. Both OPN-/- and WT islets displayed synchronized Ca2+ oscillations indicative of an intact beta cell communication. OPN-/- islets displayed higher intracellular Ca2+ concentrations when stimulated with 16.7 mM glucose than WT islets and the initial dip upon elevated glucose concentrations (which is associated with Ca2+ uptake into ER) was significantly lower in these islets. Glucose-induced insulin secretion was similar in OPN-/- and WT islets. Likewise, non-fasted blood glucose levels were the same in both groups. In summary, deletion of OPN results in several minor beta-cell defects that can be compensated for in a healthy system.

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Expression and regulation of osteopontin in type 1 diabetes

Cited by 12 publications

References 38 publications

Osteopontin activates the diabetes-associated potassium channel TALK-1 in pancreatic β-cells

Osteopontin activates the diabetes-associated potassium channel TALK-1 in pancreatic β-cells

Blood‐brain barrier damage in vascular dementia

Osteopontin Affects Insulin Vesicle Localization and Ca2+ Homeostasis in Pancreatic Beta Cells from Female Mice

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