Protein Kinase-C Beta Activation Contributes to Impaired Endothelial Insulin Signaling in Humans With Diabetes Mellitus

Tabit, Corey E.; Shenouda, Sherene M.; Holbrook, Monika; Frame, Alissa A.; Kluge, Matthew A.; Duess, Mai‐Ann; Kim, Brian H; Levit, Aaron; Held, Aaron; Rosenzweig, James L.; Ruderman, Neil B.; Vita, Joseph A.; Hamburg, Naomi M.

doi:10.1016/s0735-1097(12)62134-2

Cited by 28 publications

(40 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The targets of PKC activation, which inhibits insulin's activation of p-Akt and p-eNOS in the endothelial cells, appear to be very different from those in other cells. Recently, a group showed that PKC␤2 expression is increased and inversely correlated with flow-mediated dilation in endothelial cells from patients with type II diabetes (29). They also observed that treatment with LY379196, a PKC␤2 inhibitor, improves insulin-induced p-eNOS in diabetic endothelial cells (29).…”

Section: Discussionmentioning

confidence: 99%

“…Recently, a group showed that PKC␤2 expression is increased and inversely correlated with flow-mediated dilation in endothelial cells from patients with type II diabetes (29). They also observed that treatment with LY379196, a PKC␤2 inhibitor, improves insulin-induced p-eNOS in diabetic endothelial cells (29). Multiple sites on IR and IRS1 have been identified as targets of PKC phosphorylation (7,30,31).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Serine Phosphorylation Sites on IRS2 Activated by Angiotensin II and Protein Kinase C To Induce Selective Insulin Resistance in Endothelial Cells

Park

Rask‐Madsen

et al. 2013

Molecular and Cellular Biology

View full text Add to dashboard Cite

Protein kinase C (PKC) activation, induced by hyperglycemia and angiotensin II (AngII), inhibited insulin-induced phosphorylation of Akt/endothelial nitric oxide (eNOS) by decreasing tyrosine phosphorylation of IRS2 (p-Tyr-IRS2) in endothelial cells. PKC activation by phorbol ester (phorbol myristate acetate [PMA]) reduced insulin-induced p-Tyr-IRS2 by 46% ± 13% and, similarly, phosphorylation of Akt/eNOS. Site-specific mutational analysis showed that PMA increased serine phosphorylation at three sites on IRS2 (positions 303, 343, and 675), which affected insulin-induced tyrosine phosphorylation of IRS2 at positions 653, 671, and 911 (p-Tyr-IRS2) and p-Akt/eNOS. Specific PKCβ2 activation decreased p-Tyr-IRS2 and increased the phosphorylation of two serines (Ser303 and Ser675) on IRS2 that were confirmed in cells overexpressing single point mutants of IRS2 (S303A or S675A) containing a PKCβ2-dominant negative or selective PKCβ inhibitor. AngII induced phosphorylation only on Ser303 of IRS2 and inhibited insulin-induced p-Tyr911 of IRS2 and p-Akt/eNOS, which were blocked by an antagonist of AngII receptor I, losartan, or overexpression of single mutant S303A of IRS2. Increases in p-Ser303 and p-Ser675 and decreases in p-Tyr911 of IRS2 were observed in vessels of insulin-resistant Zucker fatty rats versus lean rats. Thus, AngII or PKCβ activation can phosphorylate Ser303 and Ser675 in IRS2 to inhibit insulin-induced p-Tyr911 and its anti-atherogenic actions (p-Akt/eNOS) in endothelial cells.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Serine Phosphorylation Sites on IRS2 Activated by Angiotensin II and Protein Kinase C To Induce Selective Insulin Resistance in Endothelial Cells

Park

Rask‐Madsen

et al. 2013

Molecular and Cellular Biology

View full text Add to dashboard Cite

show abstract

“…In agreement, insulin uptake and insulin-mediated eNOS activation were impaired in all mutant ECs. Similarly, altered eNOS activation and low insulin action have recently been demonstrated in the endothelium of patients with diabetes mellitus [36]. Thus, impaired insulin delivery to ECs may lead to defective NOS and eNOS activation in PKR1 ec-/-aortas, consequently impairing endothelium-dependent relaxation.…”

Section: Prokineticin In Cardiovascular Regulationmentioning

confidence: 92%

Obesity Peptide: Prokineticin

Nebigil¹

2017

Adiposity - Omics and Molecular Understanding

View full text Add to dashboard Cite

Obesity confers an increased risk for cardiovascular renal diseases, diabetes mellitus, nonalcoholic steatohepatitis, musculoskeletal disorders, and cancers. Prokineticin-2 is a peptide hormone, which exists as both a circulating hormone system and a local paracrine-signaling mechanism within various tissues including the brain, kidney, and adipose. It acts on the G-protein-coupled receptors (GPCRs) PKR1 and PKR2. The role of prokineticin-2 in the central nervous system is the control of food intake. Its anorexigenic effect is at least partly through the hypothalamic melanocortin system. Prokineticin-2 also prevents adipose tissue expansion by limiting preadipocyte proliferation and differentiation capacity. Prokineticin-2 signaling is important for insulin capillary passages. It also regulates heart and kidney development and function. Here, we discuss a new obesity peptide prokineticin signaling in central regulation of food intake, adipocyte tissue development, and cardiovascular function. Prokineticin may play a key role in the association between obesity and cardiovascular diseases. We also outline the potential of prokineticin receptor-1 as target for the treatment of obesity and cardiovascular diseases.

show abstract

“…Nitrotyrosine levels were higher in diabetic patients indicating endothelial oxidative stress, and protein kinase C-β expression was higher in those patients and was associated with lower flow-mediated dilation (r=-0.541, p=0.02) [91]. In T. gondii, calcium-dependent protein kinases (serine/threonine kinases) are key mediators of signaling [92], and a protein kinase C receptor 1 was identified in tachyzoites [93].…”

Section: Disturbances Of Innate Immunity In Patients With Diabetes Immentioning

confidence: 99%

“…Experimental studies indicated that disruption of endothelial insulin signaling through the activity of protein kinase C-β and NFκB reduces NO availability, and Tabit et al [91] observed 1.7-fold higher basal eNOS phosphorylation at serine 1177 in patients with diabetes (p=0.007). Nitrotyrosine levels were higher in diabetic patients indicating endothelial oxidative stress, and protein kinase C-β expression was higher in those patients and was associated with lower flow-mediated dilation (r=-0.541, p=0.02) [91].…”

Section: Disturbances Of Innate Immunity In Patients With Diabetes Immentioning

confidence: 99%

T. gondii Infection Acquired during Pregnancy and/or after Birth may be Responsible for Development of both Type 1 and 2 Diabetes Mellitus

Pr¹,

ota²

2013

J Diabetes Metab

View full text Add to dashboard Cite

Recently, it was suggested that maternal T and potentially B cells transferred during pregnancy and/or the breast milk feeding and their encounter with the antigen in mesenteric lymph nodes might play a role in development of type 1 diabetes mellitus (T1DM). T. gondii infection during gestation and/or after birth may be responsible for development of both T1DM and T2DM in children, adolescents and adults because: a) maternal microchimerism in peripheral blood was demonstrated to be significantly higher in patients with T1DM compared to unaffected siblings and healthy subjects, b) transmission of T. gondii as a Trojan horse in various types of eukaryotic cells, including T and B lymphocytes, c) swallowing by the fetus of amniotic fluid containing infected leukocytes and other cells, d) elimination of T. gondii in the breast milk during lactation, e) involvement of mesenteric lymph nodes after oral infection with the parasite, and f) damage of the myenteric neurons during infection with the parasite in both the animals with streptozotocin-induced diabetes and diabetic patients. Moreover, a significantly lower occurrence of antibodies against T. gondii found in the sera of patients with T1DM compared with their first-degree family members or healthy controls may be due to their T and/or B cell exhaustion perspective caused by chronic infection with the parasite. This suggestion may be supported by the finding that latent toxoplasmosis was associated with markedly reduced lymphocyte B-cell counts responsible for production of antibodies, markedly lower serum IgG, IgM, and IgA levels, and a significant suppression of IL-2. On the other hand, patients with T2DM had increased anti-T. gondii antibodies significantly more frequently than respective controls. Impaired vascular endothelial function characteristic for the patients with diabetes mellitus may be at least in part due to the preferential T. gondii infection of endothelial cells. Vitamin D and minocycline exerted beneficial effects on development and clinical course of diabetes mellitus probably because of their immunomodulatory and antitoxoplasmatic activities. These data strongly suggest that the parasite play an important role in development of both types of diabetes mellitus.

show abstract

Protein Kinase-C Beta Activation Contributes to Impaired Endothelial Insulin Signaling in Humans With Diabetes Mellitus

Cited by 28 publications

References 0 publications

Serine Phosphorylation Sites on IRS2 Activated by Angiotensin II and Protein Kinase C To Induce Selective Insulin Resistance in Endothelial Cells

Serine Phosphorylation Sites on IRS2 Activated by Angiotensin II and Protein Kinase C To Induce Selective Insulin Resistance in Endothelial Cells

Obesity Peptide: Prokineticin

T. gondii Infection Acquired during Pregnancy and/or after Birth may be Responsible for Development of both Type 1 and 2 Diabetes Mellitus

Contact Info

Product

Resources

About