Physical exercise enhances protein kinase C δ activity and insulin receptor tyrosine phosphorylation in diabetes-prone psammomys obesus

Heled, Yuval; Shapiro, Y; Shani, Yoav; Moran, D.; Langzam, Leah; Braiman, Liora; Sampson, Sanford R.; Meyerovitch, Joseph

doi:10.1016/s0026-0495(03)00154-9

Cited by 22 publications

(19 citation statements)

References 18 publications

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“…Insulin not only stimulates PKCd but also regulates its expression and protein levels (Horovitz-Fried et al 2006a,b, 2008, Horovitz-Fried & Sampson 2007. In addition, studies in intact animals have shown that elevated PKCd activity is involved in the effect of exercise to prevent the development of diabetes in diabetes-prone animals (Heled et al 2002(Heled et al , 2003. These findings present an apparent paradox.…”

Section: Discussionmentioning

confidence: 99%

The regulatory domain of protein kinase C delta positively regulates insulin receptor signaling

Jacob

Horovitz-Fried

Aga-Mizrachi

et al. 2009

Journal of Molecular Endocrinology

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Protein kinase C delta (PKCd) is induced by insulin to rapidly associate with insulin receptor (IR) and upregulates insulin signaling. We utilized specific JM and CT receptor domains and chimeras of PKCa and PKCd regulatory and catalytic domains to elucidate which components of PKCd are responsible for positive regulatory effects of PKCd on IR signaling. Studies were performed on L6 and L8 skeletal muscle myoblasts and myotubes. PKCd was preferentially bound to the JM domain of IR, and insulin stimulation increased this binding. Both PKCd/a and PKCa/d chimeras (regulatory/catalytic) were bound preferentially to the JM but not to the CT domain of IR. Although IR-PKCd binding was higher in cells expressing either the PKCd/a or PKCa/d chimera than in control cells, upregulation of IR signaling was observed only in PKCd/a cells. Thus, in response to insulin increases in tyrosine phosphorylation of IR and insulin receptor substrate-1, downstream signaling to protein kinase B and glycogen synthase kinase 3 (GSK3) and glucose uptake were greater in cells overexpressing PKCd/a and the PKCd/d domains than in cells expressing the PKCa/d domains. Basal binding of Src to PKCd was higher in both PKCd/a-and PKCa/d-expressing cells compared to control. Binding of Src to IR was decreased in PKCa/d cells but remained elevated in the PKCd/a cells in response to insulin. Finally, insulin increased Src activity in PKCd/a-expressing cells but decreased it in PKCa/d-expressing cells. Thus, the regulatory domain of PKCd via interaction with Src appears to determine the role of PKCd as a positive regulator of IR signaling in skeletal muscle.

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Section: Discussionmentioning

confidence: 99%

The regulatory domain of protein kinase C delta positively regulates insulin receptor signaling

Jacob

Horovitz-Fried

Aga-Mizrachi

et al. 2009

Journal of Molecular Endocrinology

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“…Like in humans, physical activity prevented the development of diabetes in DP P. obesus fed the HE diet (21,22). This could result from improved insulin signaling in skeletal muscle and liver, augmenting skeletal muscle glucose uptake and inhibiting hepatic phosphoenolpyruvate carboxykinase activity, a rate-limiting enzyme in hepatic gluconeogenesis that was resistant to hyperinsulinemia in P. obesus (8).…”

Section: Dietary and Genetic Effects On Insulin Sensitivitymentioning

confidence: 99%

Psammomys Obesus, a Model for Environment-Gene Interactions in Type 2 Diabetes

et al. 2005

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Type 2 diabetes is characterized by insulin resistance and progressive ␤-cell failure. Deficient insulin secretion, with increased proportions of insulin precursor molecules, is a common feature of type 2 diabetes; this could result from inappropriate ␤-cell function and/or reduced ␤-cell mass. Most studies using tissues from diabetic patients are retrospective, providing only limited information on the relative contribution of ␤-cell dysfunction versus decreased ␤-cell mass to the "␤-cell failure" of type 2 diabetes. The gerbil Psammomys obesus is a good model to address questions related to the role of insulin resistance and ␤-cell failure in nutritionally induced diabetes. Upon a change from its natural low-calorie diet to the calorie-rich laboratory food, P. obesus develops moderate obesity associated with postprandial hyperglycemia. Continued dietary load, superimposed on its innate insulin resistance, results in depletion of pancreatic insulin stores, with increased proportions of insulin precursor molecules in the pancreas and the blood. Inadequate response of the preproinsulin gene to the increased insulin needs is an important cause of diabetes progression. Changes in ␤-cell mass do not correlate with pancreatic insulin stores and are unlikely to play a role in disease initiation and progression. The major culprit is the inappropriate insulin production with depletion of insulin stores as a consequence. Similar mechanisms could operate during the evolution of type 2 diabetes in humans. Diabetes 54 (Suppl. 2):S137-S144, 2005 NUTRITION-INDUCED DIABETES IN PSAMMOMYS OBESUSPsammomys obesus is a diurnal gerbil that lives in North African and Eastern Mediterranean semi-desert regions. The Israeli P. obesus colony was established at the Hebrew University ϳ30 years ago from animals collected from the arid shores of the Dead Sea. In its native habitat, feeding mainly on the low-calorie Atriplex halimus plant, P. obesus is neither obese nor hyperglycemic. However, in captivity, when fed ad libitum calorie-rich rodent food, it exhibits a tendency to develop moderate obesity and postprandial hyperglycemia (1,2). The observation that not all animals develop hyperglycemia on the calorie-rich diet enabled the selection of two outbred lines of P. obesus by assorted breeding: a diabetes-prone (DP) line, in which Ͼ70% of the animals develop postprandial hyperglycemia within 4 -7 days of calorie-rich diet, and a diabetesresistant (DR) line, in which 60 -70% of the animals are normoglycemic despite the calorie-rich diet (3,4).Once postprandial hyperglycemia develops (nonfasted blood glucose Ͼ8.3 mmol/l), progression of diabetes is very rapid, reaching the end-stage of the disease, characterized by severe hypoinsulinemia, hyperlipidemia, and ketosis, within 4 -6 weeks of initiating the calorie-rich diet ( Fig. 1) (5,6). Although islet destruction is clearly demonstrated at this terminal stage, no signs of autoimmunity are evident at any time (6,7). Hyperglycemia in P. obesus is reversible, except for the hypoinsulinemic end...

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“…These data suggest that overexpression of PKCε may be causally related to the development of insulin resistance in these animals, possibly by increasing the degradation of IRs. Studies have also been performed on this animal model of nutritionally induced type 2 diabetes mellitus, in which physical exercise can prevent the progression of the disease [145]. It was reported that 4 weeks of physical exercise improved insulin-signaling responses in these animals and that this was associated with an increase in association of PKCδ with IR.…”

Section: Additional Studies On Animal Modelsmentioning

confidence: 99%

Specific protein kinase C isoforms as transducers and modulators of insulin signaling

Sampson

Cooper

2006

Molecular Genetics and Metabolism

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Recent studies implicate specific PKC isoforms in the insulin-signaling cascade. Insulin activates PKCsα, βII, δ and ζ in several cell types. In addition, as will be documented in this review, certain members of the PKC family may also be activated and act upstream of PI3 and MAP kinases. Each of these isoforms has been shown one way or another either to mimic or to modify insulin-stimulated effects in one or all of the insulin-responsive tissues. Moreover, each of the isoforms has been shown to be activated by insulin stimulation or conditions important for effective insulin stimulation. Studies attempting to demonstrate a definitive role for any of the isoforms have been performed on different cells, ranging from appropriate model systems for skeletal muscle, liver and fat, such as primary cultures, and cell lines and even in vivo studies, including transgenic mice with selective deletion of specific PKC isoforms. In addition, studies have been done on certain expression systems such as CHO or HEK293 cells, which are far removed from the tissues themselves and serve mainly as vessels for potential protein-protein interactions. Thus, a clear picture for many of the isoforms remains elusive in spite of over two decades of intensive research. The recent intrusion of transgenic and precise molecular biology technologies into the research armamentarium has opened a wide range of additional possibilities for direct involvement of individual isoforms in the insulin signaling cascade. As we hope to discuss within the context of this review, whereas many of the long soughtafter answers to specific questions are not yet clear, major advances have been made in our understanding of precise roles for individual PKC isoforms in mediation of insulin effects. In this review, in which we shall focus our attention on isoforms in the conventional and novel categories, a clear case will be made to show that these isoforms are not only expressed but are importantly involved in regulation of insulin metabolic effects.

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Physical exercise enhances protein kinase C δ activity and insulin receptor tyrosine phosphorylation in diabetes-prone psammomys obesus

Cited by 22 publications

References 18 publications

The regulatory domain of protein kinase C delta positively regulates insulin receptor signaling

The regulatory domain of protein kinase C delta positively regulates insulin receptor signaling

Psammomys Obesus, a Model for Environment-Gene Interactions in Type 2 Diabetes

Specific protein kinase C isoforms as transducers and modulators of insulin signaling

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